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Long J, Liang X, Ao Z, Tang X, Li C, Yan K, Yu X, Wan Y, Li Y, Li C, Zhou M. Stimulus-responsive drug delivery nanoplatforms for inflammatory bowel disease therapy. Acta Biomater 2024; 188:27-47. [PMID: 39265673 DOI: 10.1016/j.actbio.2024.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 08/26/2024] [Accepted: 09/06/2024] [Indexed: 09/14/2024]
Abstract
Inflammatory bowel disease (IBD) manifests as inflammation in the colon, rectum, and ileum, presenting a global health concern with increasing prevalence. Therefore, effective anti-inflammatory therapy stands as a promising strategy for the prevention and management of IBD. However, conventional nano drug delivery systems (NDDSs) for IBD face many challenges in targeting the intestine, such as physiological and pathological barriers, genetic variants, disease severity, and nutritional status, which often result in nonspecific tissue distribution and uncontrolled drug release. To address these limitations, stimulus-responsive NDDSs have received considerable attention in recent years due to their advantages in providing controlled release and enhanced targeting. This review provides an overview of the pathophysiological mechanisms underlying IBD and summarizes recent advancements in microenvironmental stimulus-responsive nanocarriers for IBD therapy. These carriers utilize physicochemical stimuli such as pH, reactive oxygen species, enzymes, and redox substances to deliver drugs for IBD treatment. Additionally, pivotal challenges in the future development and clinical translation of stimulus-responsive NDDSs are emphasized. By offering insights into the development and optimization of stimulus-responsive drug delivery nanoplatforms, this review aims to facilitate their application in treating IBD. STATEMENT OF SIGNIFICANCE: This review highlights recent advancements in stimulus-responsive nano drug delivery systems (NDDSs) for the treatment of inflammatory bowel disease (IBD). These innovative nanoplatforms respond to specific environmental triggers, such as pH reactive oxygen species, enzymes, and redox substances, to release drugs directly at the inflammation site. By summarizing the latest research, our work underscores the potential of these technologies to improve drug targeting and efficacy, offering new directions for IBD therapy. This review is significant as it provides a comprehensive overview for researchers and clinicians, facilitating the development of more effective treatments for IBD and other chronic inflammatory diseases.
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Affiliation(s)
- Jiang Long
- Department of Cardiology, Xuyong County People's Hospital, Luzhou, Sichuan 646000, China
| | - Xiaoya Liang
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Zuojin Ao
- Analysis and Testing Center, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Xiao Tang
- College of Integrated Chinese and Western Medicine, Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Chuang Li
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Kexin Yan
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Xin Yu
- Chinese Pharmacy Laboratory, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Ying Wan
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Yao Li
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China; Science and Technology Department, Southwest Medical University, Luzhou, Sichuan 646000, China.
| | - Chunhong Li
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China.
| | - Meiling Zhou
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China.
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Mondal S, Das M, Ghosh R, Singh M, Adhikari A, Darbar S, Kumar Das A, Bhattacharya SS, Pal D, Bhattacharyya D, Ahmed ASA, Mallick AK, Al-Rooqi MM, Moussa Z, Ahmed SA, Pal SK. Chitosan functionalized Mn 3O 4 nanoparticles counteracts ulcerative colitis in mice through modulation of cellular redox state. Commun Biol 2023; 6:647. [PMID: 37328528 PMCID: PMC10275949 DOI: 10.1038/s42003-023-05023-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 06/07/2023] [Indexed: 06/18/2023] Open
Abstract
Recent findings suggest a key role for reactive oxygen species (ROS) in the pathogenesis and progression of ulcerative colitis (UC). Several studies have also highlighted the efficacy of citrate functionalized Mn3O4 nanoparticles as redox medicine against a number of ROS-mediated disorders. Here we show that synthesized nanoparticles consisting of chitosan functionalized tri-manganese tetroxide (Mn3O4) can restore redox balance in a mouse model of UC induced by dextran sulfate sodium (DSS). Our in-vitro characterization of the developed nanoparticle confirms critical electronic transitions in the nanoparticle to be important for the redox buffering activity in the animal model. A careful administration of the developed nanoparticle not only reduces inflammatory markers in the animals, but also reduces the mortality rate from the induced disease. This study provides a proof of concept for the use of nanomaterial with synergistic anti-inflammatory and redox buffering capacity to prevent and treat ulcerative colitis.
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Affiliation(s)
- Susmita Mondal
- Department of Chemical, Biological Sciences, S. N. Bose National Centre for Basic Sciences, Block JD, Sector 3, Salt Lake, Kolkata, 700106, India
| | - Monojit Das
- Department of Zoology, Uluberia College, University of Calcutta, Uluberia, Howrah, 711315, India
- Department of Zoology, Vidyasagar University, Rangamati, Midnapore, 721102, India
| | - Ria Ghosh
- Department of Chemical, Biological Sciences, S. N. Bose National Centre for Basic Sciences, Block JD, Sector 3, Salt Lake, Kolkata, 700106, India
| | - Manali Singh
- Department of Biotechnology, Thapar Institute of Engineering and Technology, Bhadson Road, Patiala, Punjab, 147004, India
| | - Aniruddha Adhikari
- Department of Chemical, Biological Sciences, S. N. Bose National Centre for Basic Sciences, Block JD, Sector 3, Salt Lake, Kolkata, 700106, India
| | - Soumendra Darbar
- Research & Development Division, Dey's Medical Stores (Mfg.) Ltd, 62, Bondel Road, Ballygunge, Kolkata, 700019, India
| | - Anjan Kumar Das
- Department of Pathology, Cooch Behar Government Medical College & Hospital, Vivekananda Rd, Khagrabari, Cooch Behar, West Bengal, 736101, India
| | | | - Debasish Pal
- Department of Zoology, Uluberia College, University of Calcutta, Uluberia, Howrah, 711315, India
| | - Debasish Bhattacharyya
- Department of Gynecology & Obstetrics, Nil Ratan Sircar Medical College & Hospital, 138, AJC Bose Road, Sealdah, Raja Bazar, Kolkata, 700014, India
| | - Ahmed S A Ahmed
- Faculty of Medicine, Assiut University, 71516, Assiut, Egypt
| | - Asim Kumar Mallick
- Department of Pediatric Medicine, Nil Ratan Sirkar Medical College and Hospital, 38, Acharya Jagadish Chandra Bose Rd, Sealdah, Raja Bazar, Kolkata, West Bengal, 700014, India
| | - Munirah M Al-Rooqi
- Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, 21955, Makkah, Saudi Arabia
| | - Ziad Moussa
- Department of Chemistry, College of Science, United Arab Emirates University, P.O. Box 15551, Al Ain, United Arab Emirates
| | - Saleh A Ahmed
- Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, 21955, Makkah, Saudi Arabia.
- Department of Chemistry, Faculty of Science, Assiut University, 71516, Assiut, Egypt.
| | - Samir Kumar Pal
- Department of Chemical, Biological Sciences, S. N. Bose National Centre for Basic Sciences, Block JD, Sector 3, Salt Lake, Kolkata, 700106, India.
- Department of Zoology, Uluberia College, University of Calcutta, Uluberia, Howrah, 711315, India.
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Huang Z, Gong L, Jin Y, Stanton C, Ross RP, Zhao J, Yang B, Chen W. Different Effects of Different Lactobacillus acidophilus Strains on DSS-Induced Colitis. Int J Mol Sci 2022; 23:ijms232314841. [PMID: 36499169 PMCID: PMC9738729 DOI: 10.3390/ijms232314841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/22/2022] [Accepted: 11/24/2022] [Indexed: 12/05/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a worldwide chronic intestinal inflammatory immune-related disease. In this study, mice with dextran sulfate sodium (DSS)-induced colitis were used to evaluate the effect of Lactobacillus acidophilus on colitis. The results revealed that L. acidophilus CCFM137 and FAHWH11L56 show potential for relieving colitis symptoms, while L. acidophilus FGSYC48L79 did not show a protective effect. Moreover, L. acidophilus NCFM and FAHWH11L56 showed similar effects on various indicators of DSS-induced colitis, increasing the IL-10 and IL-17 in the colon, and modifying the CCL2/CCR2 axis and CCL3/CCR1 axis. For L. acidophilus CCFM137, its effects on colitis were different from the above two strains. Moreover, L. acidophilus FGSYC48L79 had negative effects on colitis by increasing the abundance of harmful bacteria in the gut microbiota and may promote the signaling of chemokines and their receptors. This may be related to its special genome compared to the other strains.
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Affiliation(s)
- Zheng Huang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Lei Gong
- Department of Gastroenterology, The Affiliated Wuxi Second People’s Hospital of Nanjing Medical University, Wuxi 214122, China
- Correspondence: (L.G.); (B.Y.); Tel.: +86-510-8591-2155 (B.Y.)
| | - Yan Jin
- Department of Gastroenterology, The Affiliated Wuxi Second People’s Hospital of Nanjing Medical University, Wuxi 214122, China
| | - Catherine Stanton
- International Joint Research Laboratory for Pharmabiotics & Antibiotic Resistance, Jiangnan University, Wuxi 214122, China
- APC Microbiome Ireland, University College Cork, T12 K8AF Cork, Ireland
- Teagasc Food Research Centre, Moorepark, Fermoy, P61 C996 Co. Cork, Ireland
| | - Reynolds Paul Ross
- International Joint Research Laboratory for Pharmabiotics & Antibiotic Resistance, Jiangnan University, Wuxi 214122, China
- APC Microbiome Ireland, University College Cork, T12 K8AF Cork, Ireland
| | - Jianxin Zhao
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
| | - Bo Yang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- International Joint Research Laboratory for Pharmabiotics & Antibiotic Resistance, Jiangnan University, Wuxi 214122, China
- Correspondence: (L.G.); (B.Y.); Tel.: +86-510-8591-2155 (B.Y.)
| | - Wei Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
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Zhao J, Yuan W, Wang S, Zhang H, Chen D, Niu X, Liu X, Liu L, Gao J. Comparative Pharmacokinetics and Tissue Distribution of M10 and Its Metabolite Myricetin in Normal and Dextran-Sodium-Sulfate-Induced Colitis Mice. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27238140. [PMID: 36500233 PMCID: PMC9740244 DOI: 10.3390/molecules27238140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/09/2022] [Accepted: 11/20/2022] [Indexed: 11/25/2022]
Abstract
M10, a novel myricetin derivative, is an anti-inflammatory agent designed for treatment of colitis. Here, we aim to investigate its pharmacokinetic behavior and tissue distribution in a mouse model with colitis. Pharmacokinetics and tissue distribution of M10 and its metabolite myricetin were compared in normal mice and in dextran-sodium-sulfate (DSS)-induced colitis mice. The role of fecal microbiota was also analyzed during metabolism of M10 in vitro. After oral administration, M10 was very low in the plasma of both normal and diseased mice. However, both M10 and myricetin were mainly distributed in the gastrointestinal tract, including the stomach, colon and small intestine, in physiological and pathological conditions. Significantly, M10 and myricetin were found in higher levels in gastrointestinal tracts with inflamed tissues than in normal tissues of mice. An in vitro assay revealed that 80% of M10 was metabolized to myricetin via fecal microbiota. After oral administration, M10 was not absorbed into circulation but mainly distributed in the inflamed submucosal tissues of colitic mice, where it was metabolized into myricetin to prevent colitis development.
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Affiliation(s)
- Jianchun Zhao
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
- Marine Biomedical Research Institute of Qingdao, Qingdao 266073, China
- Correspondence:
| | - Wenmin Yuan
- Marine Biomedical Research Institute of Qingdao, Qingdao 266073, China
| | - Shixiao Wang
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
| | - Hongwei Zhang
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
- Marine Biomedical Research Institute of Qingdao, Qingdao 266073, China
| | - Dan Chen
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
| | - Xiaochen Niu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
| | - Xiaochun Liu
- Marine Biomedical Research Institute of Qingdao, Qingdao 266073, China
| | - Li Liu
- Marine Biomedical Research Institute of Qingdao, Qingdao 266073, China
| | - Jiangming Gao
- Marine Biomedical Research Institute of Qingdao, Qingdao 266073, China
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Merana GR, Dwyer LR, Dhariwala MO, Weckel A, Gonzalez JR, Okoro JN, Cohen JN, Tamaki CM, Han J, Tasoff P, Palacios-Calderon Y, Ha CWY, Lynch SV, Segre JA, Kong HH, Kattah MG, Ma A, Scharschmidt TC. Intestinal inflammation alters the antigen-specific immune response to a skin commensal. Cell Rep 2022; 39:110891. [PMID: 35649365 PMCID: PMC9248974 DOI: 10.1016/j.celrep.2022.110891] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 04/08/2022] [Accepted: 05/05/2022] [Indexed: 12/13/2022] Open
Abstract
Resident microbes in skin and gut predominantly impact local immune cell function during homeostasis. However, colitis-associated neutrophilic skin disorders suggest possible breakdown of this compartmentalization with disease. Using a model wherein neonatal skin colonization by Staphylococcus epidermidis facilitates generation of commensal-specific tolerance and CD4+ regulatory T cells (Tregs), we ask whether this response is perturbed by gut inflammation. Chemically induced colitis is accompanied by intestinal expansion of S. epidermidis and reduces gut-draining lymph node (dLN) commensal-specific Tregs. It also results in reduced commensal-specific Tregs in skin and skin-dLNs and increased skin neutrophils. Increased CD4+ circulation between gut and skin dLN suggests that the altered cutaneous response is initiated in the colon, and resistance to colitis-induced effects in Cd4creIl1r1fl/fl mice implicate interleukin (IL)-1 in mediating the altered commensal-specific response. These findings provide mechanistic insight into observed connections between inflammatory skin and intestinal diseases.
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Affiliation(s)
- Geil R Merana
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Program, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Laura R Dwyer
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Program, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Miqdad O Dhariwala
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Antonin Weckel
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Jeanmarie R Gonzalez
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Program, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Joy N Okoro
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Jarish N Cohen
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Courtney M Tamaki
- Parnassus Flow Cytometry CoLab, University of California, San Francisco, San Francisco, 94143, USA
| | - Jungmin Han
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Preston Tasoff
- Benioff Center for Microbiome Medicine, Department of Medicine, University of California, San Francisco, CA 94143, USA
| | | | - Connie W Y Ha
- Benioff Center for Microbiome Medicine, Department of Medicine, University of California, San Francisco, CA 94143, USA
| | - Susan V Lynch
- Benioff Center for Microbiome Medicine, Department of Medicine, University of California, San Francisco, CA 94143, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Julia A Segre
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Heidi H Kong
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Michael G Kattah
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Averil Ma
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Tiffany C Scharschmidt
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA.
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Schaefer REM, Callahan RC, Atif SM, Orlicky DJ, Cartwright IM, Fontenot AP, Colgan SP, Onyiah JC. Disruption of monocyte-macrophage differentiation and trafficking by a heme analog during active inflammation. Mucosal Immunol 2022; 15:244-256. [PMID: 34916594 PMCID: PMC8881314 DOI: 10.1038/s41385-021-00474-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 09/23/2021] [Accepted: 11/23/2021] [Indexed: 02/04/2023]
Abstract
Heme metabolism is a key regulator of inflammatory responses. Cobalt protoporphyrin IX (CoPP) is a heme analog and mimic that potently activates the NRF2/heme oxygenase-1 (HO-1) pathway, especially in monocytes and macrophages. We investigated the influence of CoPP on inflammatory responses using a murine model of colitis. Surprisingly, conditional deletion of myeloid HO-1 did not impact the colonic inflammatory response or the protective influence of CoPP in the setting of dextran sodium sulfate-induced colitis. Rather, we reveal that CoPP elicits a contradictory shift in blood myeloid populations relative to the colon during active intestinal inflammation. Major population changes include markedly diminished trafficking of CCR2+Ly6Chi monocytes to the inflamed colon, despite significant mobilization of this population into circulation. This resulted in significantly diminished colonic expansion of monocyte-derived macrophages and inflammatory cytokine expression. These findings were linked with significant induction of systemic CCL2 leading to a disrupted CCL2 chemoattractant gradient toward the colon and concentration-dependent suppression of circulating monocyte CCR2 expression. Administration of CoPP also induced macrophage differentiation toward a MarcohiHmox1hi anti-inflammatory erythrophagocytic phenotype, contributing to an overall decreased inflammatory profile. Such findings redefine protective influences of heme metabolism during inflammation, and highlight previously unreported immunosuppressive mechanisms of endogenous CCL2 induction.
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Affiliation(s)
- Rachel E. M. Schaefer
- Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO,Department of Medicine, University of Colorado School of Medicine, Aurora, CO,Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO
| | - Rosemary C. Callahan
- Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO,Department of Medicine, University of Colorado School of Medicine, Aurora, CO,Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO
| | - Shaikh M. Atif
- Division of Allergy, Asthma and Clinical Immunology, University of Colorado School of Medicine, Aurora, CO
| | - David J. Orlicky
- Department of Pathology, University of Colorado School of Medicine, Aurora, CO
| | - Ian M. Cartwright
- Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO,Department of Medicine, University of Colorado School of Medicine, Aurora, CO,Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO
| | - Andrew P. Fontenot
- Division of Allergy, Asthma and Clinical Immunology, University of Colorado School of Medicine, Aurora, CO
| | - Sean P. Colgan
- Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO,Department of Medicine, University of Colorado School of Medicine, Aurora, CO,Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO
| | - Joseph C. Onyiah
- Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO,Department of Medicine, University of Colorado School of Medicine, Aurora, CO,Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, Corresponding author: Joseph C. Onyiah, M.D., University of Colorado School of Medicine, Rocky Mountain Regional VA Medical Center, 12700 East 19th Ave. MS B-146, Aurora, CO 80045,
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Revealing the Mechanism of Friedelin in the Treatment of Ulcerative Colitis Based on Network Pharmacology and Experimental Verification. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:4451779. [PMID: 34765000 PMCID: PMC8577922 DOI: 10.1155/2021/4451779] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 10/05/2021] [Indexed: 12/13/2022]
Abstract
Objectives Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colon, and its incidence is rising worldwide. This study was designed to uncover the healing effect of friedelin, a bioactive compound against UC through bioinformatics of network pharmacology and experimental verification of UC model mice. Materials and Methods Targets of friedelin and potential mechanism of friedelin on UC were predicted through target searching, PPI network establishing, and enrichment analyzing. We explored effects of friedelin on dextran sulfate sodium (DSS)-induced colitis. Severity of UC was investigated by body weight, disease activity index (DAI), and length of the colon. Inflammation severity was examined by determination of proinflammatory and anti-inflammatory cytokines. The numbers of autophagosome around the epithelial cells were observed by autophagy inhibition via a transmission electron microscope. The expressions of autophagy-related ATG5 protein and AMPK-mTOR signaling pathway were determined by immunofluorescence staining. Results In this study, 17 potential targets of friedelin and 1111 UC-related targets were identified. 10 therapeutic targets of friedelin against UC were acquired from overlapped targets of UC and friedelin. PPI network construction filtered 14 core targets through target amplification and confidence enhancement. The results of molecular docking showed that the docking scores of the top 5 active targets were higher than the threshold values. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out, showing friedelin alleviates UC through anti-inflammatory pathways and molecular function of autophagy. Subsequently, animal-based experiments revealed the intraperitoneal injection of friedelin ameliorated DSS-induced body weight loss, DAI decrease, colon length shortening and colonic pathological damage with lower myeloperoxidase and proinflammatory cytokines (IL-1β and IL-6) and higher IL-10 levels, and more autophagosomes in transmission electron microscope results. The AMPK-mTOR signaling pathway plays important role in the friedelin's effect in autophagy as KEGG pathway result and experiment verification. Furthermore, the 3 ma validated the role of autophagy as an improvement in the friedelin's pharmacologic effect to UC model mice. Conclusions Friedelin ameliorated DSS-induced colitis in mice through of inflammatory inhibition and regulation of autophagy.
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Gomez CL, Neufeld KL. Elevated adenomatous polyposis coli in goblet cells is associated with inflammation in mouse and human colon. Exp Physiol 2020; 105:2154-2167. [PMID: 33150708 DOI: 10.1113/ep088970] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 09/21/2020] [Indexed: 11/08/2022]
Abstract
NEW FINDINGS What is the central question of this study? What is the localization and distribution pattern of adenomatous polyposis coli (APC) in intestinal epithelial cells? Does this distribution change in different regions of the colon or in the condition of inflammation? What is the main finding and its importance? Colonic epithelia from mice and humans contain a subset of goblet cells displaying high APC levels. The number of APChigh goblet cells increases in inflamed tissue, which also displays increased GRP78, indicating potential stress from mucin production. In cultured human colon cells, expression of interleukin 1 pathway components (inducers of MUC2 expression) is reduced upon APC depletion raising the potential for APC participation in an inflammatory response. ABSTRACT Adenomatous polyposis coli (APC) serves as a gatekeeper of intestinal homeostasis by promoting cellular differentiation and maintaining crypt architecture. Although appreciated as a critical colon tumour suppressor, roles for APC in disease states such as inflammation have yet to be fully delineated. This study aimed to characterize the localization of APC protein in gastrointestinal tissues from human patients with active inflammatory bowel disease and mice with dextran sodium sulfate (DSS)-induced colitis. Fluorescence immunohistochemistry revealed a subset of goblet cells with elevated Apc staining intensity in the small intestines and proximal/medial colons of mice. Upon induction of colitis with DSS, these 'APChigh ' goblet cells remained in the proximal and medial colon, but now were also observed in the distal colon. This phenotype was recapitulated in humans, with APChigh goblet cells observed only in the descending colons of patients with active ulcerative colitis. In cultured human colon cells derived from normal tissue, APC depletion reduced expression of mRNAs encoding the interleukin 1 (IL1) signalling pathway components IL1β and interleukin-1 receptor (IL1R), known regulators of Muc2 expression. Treating cancer cells lacking wild-type APC with IL1β, or induction of full-length APC in these cells led to increases in IL1R and MUC2 expression. Combining IL1β treatment with APC induction led to an increase of MUC2 expression greater than expected for additive affects, suggesting that APC sensitizes cells to IL1 signalling. These findings suggest that APC has novel roles in maintaining proper goblet cell function, thus providing further evidence for APC as an important factor in intestinal tissue homeostasis and disease.
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Affiliation(s)
- Christian L Gomez
- Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA
| | - Kristi L Neufeld
- Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA
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Xuan H, Ou A, Hao S, Shi J, Jin X. Galangin Protects against Symptoms of Dextran Sodium Sulfate-induced Acute Colitis by Activating Autophagy and Modulating the Gut Microbiota. Nutrients 2020; 12:E347. [PMID: 32013062 PMCID: PMC7071155 DOI: 10.3390/nu12020347] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 01/14/2020] [Accepted: 01/27/2020] [Indexed: 12/14/2022] Open
Abstract
Galangin is a natural flavonoid that has been reported to provide substantial health benefits. Nevertheless, little is known about the potential effects of galangin against inflammatory bowel diseases. Here, an in vivo study was performed to investigate the preventive effects of galangin against dextran sulphate sodium (DSS)-induced acute murine colitis, which mimics the symptoms of human ulcerative colitis (UC). Pre-treatment with galangin (15 mg/kg, p.o.) resulted in a significant decreased in the macroscopic signs of DSS-induced colitic symptoms, including a decreased disease activity index, prevention of the colon length shortening, and alleviation of the pathological changes occurring in the colon. Colonic pro-inflammatory mediators, including tumor necrosis factor-alpha, interleukin (IL)-1 beta, and IL-6, as well as myeloperoxidase activities were decreased following galangin pre-treatment when compared with the DSS control group. Moreover, galangin pre-treatment significantly increased the expressions of autophagy-related proteins and promoted the formation of autophagosome in the colon. Galangin pre-treatment increased the diversity of the gut microbiota, and this was accompanied by increased levels of short-chain fatty acids. These observed changes could involve the modulating effects conferred by galangin in relation to some specific bacteria populations, including the recovery of Lactobacillus spp., and increased Butyricimonas spp. Overall, these results support the use of galangin in the prevention of UC.
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Affiliation(s)
- Hongzhuan Xuan
- School of Life Science, Liaocheng University, Liaocheng 252059, China;
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, China
| | - Aiqun Ou
- College of Bee Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China;
| | - Shengyu Hao
- School of Physical Science and Information Technology, Liaocheng University, Liaocheng 252059, China;
| | - Jiajun Shi
- Department of Experimental Animals, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou 310007, China;
| | - Xiaolu Jin
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, China
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10
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Mei Y, Fang C, Ding S, Liu X, Hu J, Xu J, Mei Q. PAP-1 ameliorates DSS-induced colitis with involvement of NLRP3 inflammasome pathway. Int Immunopharmacol 2019; 75:105776. [DOI: 10.1016/j.intimp.2019.105776] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 07/11/2019] [Accepted: 07/19/2019] [Indexed: 02/07/2023]
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11
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Saleh MM, Frisbee AL, Leslie JL, Buonomo EL, Cowardin CA, Ma JZ, Simpson ME, Scully KW, Abhyankar MM, Petri WA. Colitis-Induced Th17 Cells Increase the Risk for Severe Subsequent Clostridium difficile Infection. Cell Host Microbe 2019; 25:756-765.e5. [PMID: 31003940 DOI: 10.1016/j.chom.2019.03.003] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 01/12/2019] [Accepted: 03/01/2019] [Indexed: 12/13/2022]
Abstract
Clostridium difficile infection (CDI) is the number one hospital-acquired infection in the United States. CDI is more common and severe in inflammatory bowel disease patients. Here, we studied the mechanism by which prior colitis exacerbates CDI. Mice were given dextran sulfate sodium (DSS) colitis, recovered for 2 weeks, and then were infected with C. difficile. Mortality and CDI severity were increased in DSS-treated mice compared to controls. Severe CDI is dependent on CD4+ T cells, which persist after colitis-associated inflammation subsides. Adoptive transfer of Th17 cells to naive mice is sufficient to increase CDI-associated mortality through elevated IL-17 production. Finally, in humans, the Th17 cytokines IL-6 and IL-23 associate with severe CDI, and patients with high serum IL-6 are 7.6 times more likely to die post infection. These findings establish a central role for Th17 cells in CDI pathogenesis following colitis and identify them as a potential target for preventing severe disease.
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Affiliation(s)
- Mahmoud M Saleh
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Alyse L Frisbee
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Jhansi L Leslie
- Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Erica L Buonomo
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Carrie A Cowardin
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Jennie Z Ma
- Division of Biostatistics, Department of Public Health Sciences, School of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Morgan E Simpson
- Department of Pathology, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Kenneth W Scully
- Department of Public Health Sciences, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Mayuresh M Abhyankar
- Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - William A Petri
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA; Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA; Department of Pathology, University of Virginia Health System, Charlottesville, VA 22908, USA.
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12
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Cao J, Cheng J, Xi S, Qi X, Shen S, Ge Y. Alginate/chitosan microcapsules for in-situ delivery of the protein, interleukin-1 receptor antagonist (IL-1Ra), for the treatment of dextran sulfate sodium (DSS)-induced colitis in a mouse model. Eur J Pharm Biopharm 2019; 137:112-121. [PMID: 30779979 DOI: 10.1016/j.ejpb.2019.02.011] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 12/25/2018] [Accepted: 02/15/2019] [Indexed: 12/19/2022]
Abstract
Targeted delivery of bioactive compounds such as proteins to the colon has numerous advantages for the therapeutic treatment of inflammatory bowel disease. The present study sought to fabricate alginate/chitosan microcapsules containing IL-1Ra (Alg/Chi/IL-1Ra MC) via a single-step electrospraying method. Two important factors of efficacy were measured-the pH-responsiveness of the microcapsule and the in-vitro drug release profile. The DSS-induced colitis mouse model was used to evaluate the therapeutic effect of the Alg/Chi/IL-1Ra microcapsules, with results showing the protective effect of the Alg/Chi microcapsules for the passage of IL-1Ra through the harsh environment of the upper gastrointestinal tract. This effect was owing to the pH-sensitive response of the microcapsule, which allowed the targeted release of IL-1Ra in the colon. DAI evaluation, colon length, colon tissue morphology, histologic damage scores and relative protein concentrations (MPO, TNF-α and IL-1β) demonstrated that the Alg/Chi/IL-1Ra microcapsules alleviated DSS-induced colitis in mice. The present study thus demonstrates a practical means of oral delivery of proteins, in-situ colon release, and a promising application of IL-1Ra in the treatment of autoimmune and inflammatory diseases.
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Affiliation(s)
- Jin Cao
- School of Pharmacy, Jiangsu University, 301# Xuefu Road, Zhenjiang, Jiangsu, China
| | - Jin Cheng
- School of Pharmacy, Jiangsu University, 301# Xuefu Road, Zhenjiang, Jiangsu, China
| | - Siyu Xi
- School of Pharmacy, Jiangsu University, 301# Xuefu Road, Zhenjiang, Jiangsu, China
| | - Xueyong Qi
- School of Pharmacy, Jiangsu University, 301# Xuefu Road, Zhenjiang, Jiangsu, China
| | - Song Shen
- School of Pharmacy, Jiangsu University, 301# Xuefu Road, Zhenjiang, Jiangsu, China
| | - Yanru Ge
- School of Pharmacy, Jiangsu University, 301# Xuefu Road, Zhenjiang, Jiangsu, China.
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13
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Naz S, Battu S, Khan RA, Afroz S, Giddaluru J, Vishwakarma SK, Satti V, Habeeb MA, Khan AA, Khan N. Activation of integrated stress response pathway regulates IL-1β production through posttranscriptional and translational reprogramming in macrophages. Eur J Immunol 2019; 49:277-289. [PMID: 30578631 DOI: 10.1002/eji.201847513] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 10/27/2018] [Accepted: 12/10/2018] [Indexed: 01/06/2023]
Abstract
Immune cells sense and programme its cellular machinery appropriately to the environmental changes through the activation of cytoprotective adaptive pathway so-called the "integrated stress response (ISR)". However, the mechanisms implicated in ISR-induced protective responses are poorly understood. Here, we show that ISR activation by arsenite (Ar) results in suppression of IL-1β production in macrophages and inhibition of DSS-induced colitis in a murine model through a novel posttranscriptional and translation regulatory (PTR) mechanism. Ar triggers PTR events through eIF2α-phosphorylation, which results in the attenuation of active polysome formation leading to the accumulation of translationally stalled IL-1β mRNAs. Translationally stalled IL-1β mRNAs recruit RNA-binding proteins (TIA-1/TIAR), resulting in the formation of RBP-RNA complexes known as stress granules (SGs). The SGs bound IL-1β mRNAs might undergo degradation through induction of autophagy. Also, we show that Ar posttranslationally impairs processing and secretion of IL-1β by diminishing inflammasome activation. Altogether, this study unveils a novel mechanism of IL-1β regulation and further suggests that pharmacological activation of cytoprotective ISR pathway might provide an effective therapeutic intervention against inflammatory diseases.
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Affiliation(s)
- Saima Naz
- Central Laboratory for Stem Cell Research and Translational Medicine, Center for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad, India
| | - Srikanth Battu
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Rafiq Ahmad Khan
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Sumbul Afroz
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Jeevan Giddaluru
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Sandeep Kumar Vishwakarma
- Central Laboratory for Stem Cell Research and Translational Medicine, Center for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad, India
| | | | - Md Aejaz Habeeb
- Central Laboratory for Stem Cell Research and Translational Medicine, Center for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad, India
| | - Aleem Ahmed Khan
- Central Laboratory for Stem Cell Research and Translational Medicine, Center for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad, India
| | - Nooruddin Khan
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, India
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14
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Zakariassen HL, Bendtsen KM, Tougaard P, Hansen AK. Reduced early life mucosal integrity decreases thymic cell counts and increases local, but not thymic regulatory, T cell recruitment: Gut mucosal integrity breach and thymic T cells. EUR J INFLAMM 2019. [DOI: 10.1177/2058739218823466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Early life immune gut microbiota contact is critical for regulatory T cell–mediated oral tolerance induction. We induced a mucosal integrity breach with low dextran sulfate sodium dose right after weaning in BALB/c mice along with a standard high dose to study the impact of increased gut microbiota lymphatic tissue contact on the thymus. Both doses increased gut permeability, which caused a short-term generalized thymic involution and regulatory T cell induction in the mesenteric lymph nodes, even in the absence of clinically apparent inflammation in the low-dose group. The thymic regulatory T cells resisted thymic involution. In the low-dose group, we found acutely altered gut mobilization patterns characterized by changed gut-homing marker CD103 expression on mesenteric lymph node CD4+ T cells as well as on mature CD8+ T cells and developing CD4−/CD8− thymocytes. Furthermore, CD218a (IL-18-receptor-a) expression was acutely decreased on both mature CD8+ T cells and regulatory T cells, while increased on the mesenteric lymph node CD8+ T cells, indicating a direct link between the thymus and the mesenteric lymph nodes with CD218a in a functional role in thymic involution. Acute and non-persisting regulatory responses in the mesenteric lymph nodes were induced in the form of a relative regulatory T cell increase. We saw no changes in total thymic regulatory T cells and thus the thymus does not seem to play a major role of in the regulatory immunity induced by increased gut microbiota lymphatic tissue contact around weaning, which in our study primarily was located to the gut.
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Affiliation(s)
- Hannah Louise Zakariassen
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Katja Maria Bendtsen
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Peter Tougaard
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Axel Kornerup Hansen
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
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15
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Qu S, Shen Y, Wang M, Wang X, Yang Y. Suppression of miR-21 and miR-155 of macrophage by cinnamaldehyde ameliorates ulcerative colitis. Int Immunopharmacol 2018; 67:22-34. [PMID: 30530166 DOI: 10.1016/j.intimp.2018.11.045] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 11/07/2018] [Accepted: 11/27/2018] [Indexed: 02/07/2023]
Abstract
Ulcerative colitis (UC) is a major form of inflammatory bowel disease which involved mucosal immune dysfunction. Cinnamaldehyde (CA) is major active compound from cinnamon, a useful traditional medicine in Asia which shows superior antibacterial and anti-inflammatory activity. In this study, we investigated the effects of CA on UC both in vivo and in vitro. We showed that CA attenuated the symptoms of DSS-induced colitis, including loss of body weights, disease activity index (DAI), shortening of the colon lengths and infiltration of inflammatory cells. Moreover, CA decreased the pro-inflammatory cytokines and NLRP3 inflammasome, miR-21 and miR-155 in colon tissues, in addition, the percentage of macrophages was reduced based on the surface marker F4/80 and IL-10 secretion in CA-treated group, suggesting that the CA ameliorate the UC via activation of macrophage. Herein, the effects of CA on macrophage cells were examined in vitro. We found that CA reduced the level of proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, in the activation of RAW264.7, human macrophage-like cells U937, and primary peritoneal macrophages. Furthermore, the suppression of NLRP3 inflammasome, miR-21 and miR-155 was also found in CA-treated LPS-stimulated RAW264.7 cells. CA also reduced the production of reactive oxygen species, the phosphorylation of AKT, mTOR and COX2 protein level in the RAW264.7. Meanwhile, data revealed that transferred miR-21 or miR-155 inhibitor suppressed levels of IL-1β and IL-6, whereas miR-21 or miR-155 mimics increased expressions of these, and CA suppressed these expressions. Our results indicate that CA could ameliorate DSS-induced colitis through inhibition of NLRP3 inflammasome activation and miR-21 and miR-155 levels in colons and macrophage, suggesting that CA might be a potentially effective drug for UC.
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Affiliation(s)
- Shulan Qu
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yunhui Shen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Mengjie Wang
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiaoyu Wang
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Yifu Yang
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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16
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Impellizzeri D, Siracusa R, Cordaro M, Peritore AF, Gugliandolo E, Mancuso G, Midiri A, Di Paola R, Cuzzocrea S. Therapeutic potential of dinitrobenzene sulfonic acid (DNBS)-induced colitis in mice by targeting IL-1β and IL-18. Biochem Pharmacol 2018; 155:150-161. [PMID: 29963998 DOI: 10.1016/j.bcp.2018.06.029] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 06/27/2018] [Indexed: 01/01/2023]
Abstract
Interleukin (IL)-1 and IL-18 belong to the IL-1 family of ligands, and their receptors are members of the IL-1 receptor family. Both cytokines drive an extensive range of pro-inflammatory networks in many cell types using common signal transduction cascades. Anyway, differences in signaling pathways exist. With this aim in mind, we investigated by using transgenic mice the mechanisms through the simultaneous deficiency of both IL-1β and IL-18 could be more protective compared to blocking the single cytokine IL-1β or IL-18 during colitis. Colitis was provoked in mice by instillation of dinitrobenzene sulfonic acid (DNBS) in the colon. The results indicated that single knockout (KO) mice of IL-1β or IL-18, and double KO mice of both IL-1β and IL-18 were hyporesponsive to DNBS-induced colitis compared to wild type (WT) mice, in which double KO were less sensitive than single KO mice. Moreover, treatment with Anakinra (IL-1R antagonist) also ameliorated colitis, in views of macroscopic and histological alteration, infiltration of neutrophils or Th1 cells, oxidative and nitrosative stress. Anakinra more significantly reduced cyclooxygenase (COX-2) and nuclear factor (NF-κB) levels as well as IKB-α degradation compared to blocking IL-18. On the contrary, the absence of IL-18 reduced p-ERK and p-p38 mitogen-activated protein kinase (MAPKs) in a more significant way compared to blocking IL-1β. Thus, the double KO increased the protective effects against colon inflammation maybe because different converging inflammatory pathways are being inhibited. In conclusion, the blocking of both IL-1β and IL-18 function may be advantageous in the treatment of IBD or inflammatory diseases.
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Affiliation(s)
- Daniela Impellizzeri
- Department of Chemical Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres 31, 98166 Messina, Italy
| | - Rosalba Siracusa
- Department of Chemical Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres 31, 98166 Messina, Italy
| | - Marika Cordaro
- Department of Chemical Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres 31, 98166 Messina, Italy
| | - Alessio Filippo Peritore
- Department of Chemical Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres 31, 98166 Messina, Italy
| | - Enrico Gugliandolo
- Department of Chemical Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres 31, 98166 Messina, Italy
| | - Giuseppe Mancuso
- Department of Human Pathology, University of Messina, 98125 Messina, Italy
| | - Angelina Midiri
- Department of Human Pathology, University of Messina, 98125 Messina, Italy
| | - Rosanna Di Paola
- Department of Chemical Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres 31, 98166 Messina, Italy
| | - Salvatore Cuzzocrea
- Department of Chemical Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres 31, 98166 Messina, Italy; Manchester Biomedical Research Centre, Manchester Royal Infirmary, School of Medicine, University of Manchester, Manchester, United Kingdom.
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17
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Abron JD, Singh NP, Price RL, Nagarkatti M, Nagarkatti PS, Singh UP. Genistein induces macrophage polarization and systemic cytokine to ameliorate experimental colitis. PLoS One 2018; 13:e0199631. [PMID: 30024891 PMCID: PMC6053137 DOI: 10.1371/journal.pone.0199631] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 06/11/2018] [Indexed: 12/11/2022] Open
Abstract
Mucosal changes in Crohn’s disease (CD) and ulcerative colitis (UC), two major forms of inflammatory bowel disease (IBD), are characterized by a prominent infiltration of inflammatory cells including lymphocytes, macrophages, T cells and neutrophils. The precise etiology of IBD is unknown but it involves a complex interplay of factors associated with the immune system, environment, host genotype and enteric commensal bacteria. As there is no known safe cure for IBD, natural alternative therapeutic options without side effects are urgently needed. To this end, Soy-based foods, which have been eaten for centuries in Asian countries, have potential benefits, including lowering the incidence of coronary heart disease, atherosclerosis, type-2 diabetes, allergic response, and autoimmune diseases. This study describes the effect of Soy isoflavons 4', 5, 7 Trihydroxyisoflavone (genistein) on dextran sodium sulphate (DSS) induced experimental colitis. The extent and severity of disease was analyzed through body weight, histopathological analysis, cellular immune response, systemic cytokine levels, and inflammation score using a disease activity index. Genistein treatment significantly attenuated DSS-induced colitis severity and resulted in increase in body weight, colon length and reduction in inflammation score. Genistein also skews M1 macrophages towards the M2 phenotype. Further, gen also reduced the systemic cytokine levels as compared to vehicle control. This serves as the first detailed study towards natural soya based product that shows the polarization of M1 towards M2 macrophages, and reduction of systemic cytokine in part to attenuate the colitis symptoms. Thus, our work demonstrates that genistein, a soya compound, may be useful for the treatment of IBD.
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Affiliation(s)
- Jessicca D. Abron
- Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC
| | - Narendra P. Singh
- Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC
| | - Robert L. Price
- Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC, United States of America
| | - Mitzi Nagarkatti
- Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC
| | - Prakash S. Nagarkatti
- Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC
| | - Udai P. Singh
- Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC
- * E-mail:
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18
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Monajemi M, Pang YCF, Bjornson S, Menzies SC, van Rooijen N, Sly LM. Malt1 blocks IL-1β production by macrophages in vitro and limits dextran sodium sulfate-induced intestinal inflammation in vivo. J Leukoc Biol 2018; 104:557-572. [PMID: 29901822 DOI: 10.1002/jlb.3vma0118-019r] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 05/03/2018] [Accepted: 05/15/2018] [Indexed: 01/02/2023] Open
Abstract
This study tested the hypothesis that Malt1 deficiency in macrophages contributes to dextran sodium sulfate (DSS)-induced intestinal inflammation in Malt1-deficient mice. In people, combined immunodeficiency caused by a homozygous mutation in the MALT1 gene is associated with increased susceptibility to bacterial infections and chronic inflammation, including severe inflammation along the gastrointestinal tract. The consequences of Malt1 deficiency have largely been attributed to its role in lymphocytes, but Malt1 is also expressed in macrophages, where it is activated downstream of TLR4 and dectin-1. The effect of Malt1 deficiency in murine macrophages and its contribution to DSS-induced colitis have not been investigated. Our objectives were to compare the susceptibility of Malt1+/+ and Malt1-/- mice to DSS-induced colitis, to determine the contribution of macrophages to DSS-induced colitis in Malt1-/- mice, and to assess the effect of innate immune stimuli on Malt1-/- macrophage inflammatory responses. We found that Malt1 deficiency exacerbates DSS-induced colitis in mice, accompanied by higher levels of IL-1β, and that macrophages and IL-1 signaling contribute to pathology in Malt1-/- mice. Malt1-/- macrophages produce more IL-1β in response to either TLR4 or dectin-1 ligation, whereas inhibition of Malt1 proteolytic (paracaspase) activity blocked IL-1β production. TLR4 or dectin-1 stimulation induced Malt1 protein levels but decreased its paracaspase activity. Taken together, these data support the hypothesis that Malt1-/- macrophages contribute to increased susceptibility of Malt1-/- mice to DSS-induced colitis, which is dependent on IL-1 signaling. Increased IL-1β production by MALT1-deficient macrophages may also contribute to chronic inflammation in people deficient in MALT1.
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Affiliation(s)
- Mahdis Monajemi
- Department of Pediatrics, Division of Gastroenterology, BC Children's Hospital Research Institute, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Yvonne C F Pang
- Department of Pediatrics, Division of Gastroenterology, BC Children's Hospital Research Institute, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Saelin Bjornson
- Department of Pediatrics, Division of Gastroenterology, BC Children's Hospital Research Institute, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Susan C Menzies
- Department of Pediatrics, Division of Gastroenterology, BC Children's Hospital Research Institute, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Nico van Rooijen
- Department of Molecular Cell Biology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Laura M Sly
- Department of Pediatrics, Division of Gastroenterology, BC Children's Hospital Research Institute, The University of British Columbia, Vancouver, British Columbia, Canada
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19
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Perera AP, Fernando R, Shinde T, Gundamaraju R, Southam B, Sohal SS, Robertson AAB, Schroder K, Kunde D, Eri R. MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice. Sci Rep 2018; 8:8618. [PMID: 29872077 PMCID: PMC5988655 DOI: 10.1038/s41598-018-26775-w] [Citation(s) in RCA: 227] [Impact Index Per Article: 32.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 03/01/2018] [Indexed: 12/28/2022] Open
Abstract
MCC950 a potent, highly specific small molecule inhibitor of canonical and noncanonical activation of NLRP3 inflammasome has been evaluated in a multitude of NLRP3 driven inflammatory diseases. However, the effect of MCC950 on colonic inflammation has not yet been reported. In the present study we investigated the effect of MCC950 in a spontaneous chronic colitis mouse model Winnie, which mimics human ulcerative colitis. Oral administration of 40 mg/kg MCC950 commencing at Winnie week seven for three weeks significantly improved body weight gain, colon length, colon weight to body weight ratio, disease activity index and histopathological scores. MCC950 significantly suppressed release of proinflammatory cytokines IL-1β, IL-18, IL1-α, IFNγ, TNF-α, IL6, IL17, chemokine MIP1a and Nitric Oxide in colonic explants. Moreover, MCC950 resulted in a significant decrease of IL-1β release and activation of caspase-1 in colonic explants and macrophage cells isolated from Winnie. Complete inhibition with MCC950 in Winnie colonic explants shows, for the first time, the contribution of inflammatory effects resulting exclusively from canonical and noncanonical NLRP3 inflammasome activation in colitis. Taken together, our results illustrate the efficacy of MCC950 in the treatment of murine ulcerative colitis and provides avenue for a potential novel therapeutic agent for human inflammatory bowel diseases.
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Affiliation(s)
| | - Ruchira Fernando
- Department of Pathology, Launceston General Hospital, Launceston, TAS, Australia
| | - Tanvi Shinde
- School of Health Sciences, University of Tasmania, Launceston, TAS, Australia
| | - Rohit Gundamaraju
- School of Health Sciences, University of Tasmania, Launceston, TAS, Australia
| | - Benjamin Southam
- School of Health Sciences, University of Tasmania, Launceston, TAS, Australia
| | | | - Avril A B Robertson
- Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD, Australia
| | - Kate Schroder
- Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD, Australia
| | - Dale Kunde
- School of Health Sciences, University of Tasmania, Launceston, TAS, Australia
| | - Rajaraman Eri
- School of Health Sciences, University of Tasmania, Launceston, TAS, Australia.
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Battu S, Afroz S, Giddaluru J, Naz S, Huang W, Khumukcham SS, Khan RA, Bhat SY, Qureshi IA, Manavathi B, Khan AA, August A, Hasnain SE, Khan N. Amino acid starvation sensing dampens IL-1β production by activating riboclustering and autophagy. PLoS Biol 2018; 16:e2005317. [PMID: 29621237 PMCID: PMC5903674 DOI: 10.1371/journal.pbio.2005317] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 04/17/2018] [Accepted: 03/05/2018] [Indexed: 11/22/2022] Open
Abstract
Activation of the amino acid starvation response (AAR) increases lifespan and acute stress resistance as well as regulates inflammation. However, the underlying mechanisms remain unclear. Here, we show that activation of AAR pharmacologically by Halofuginone (HF) significantly inhibits production of the proinflammatory cytokine interleukin 1β (IL-1β) and provides protection from intestinal inflammation in mice. HF inhibits IL-1β through general control nonderepressible 2 kinase (GCN2)–dependent activation of the cytoprotective integrated stress response (ISR) pathway, resulting in rerouting of IL-1β mRNA from translationally active polysomes to inactive ribocluster complexes—such as stress granules (SGs)—via recruitment of RNA-binding proteins (RBPs) T cell–restricted intracellular antigen-1(TIA-1)/TIA-1–related (TIAR), which are further cleared through induction of autophagy. GCN2 ablation resulted in reduced autophagy and SG formation, which is inversely correlated with IL-1β production. Furthermore, HF diminishes inflammasome activation through suppression of reactive oxygen species (ROS) production. Our study unveils a novel mechanism by which IL-1β is regulated by AAR and further suggests that administration of HF might offer an effective therapeutic intervention against inflammatory diseases. Reduced intake of food (also known as dietary restriction) without malnutrition has been shown to benefit health in humans and animals, including an increase in life expectancy, metabolic fitness, and resistance to acute stress. Recent studies have attributed the benefits associated with dietary restriction to the reduced intake of amino acids. However, the underlying mechanisms through which amino acid restriction regulates various homeostatic processes are poorly defined. Here, we show that activation of amino acid starvation response (AAR) by the small molecule Halofuginone (HF) results in a significant inhibition of production of interleukin 1β (IL-1β), a proinflammatory mediator. We find that AAR provides protection from intestinal inflammation–associated pathology in a mouse model of colitis through a novel mechanism involving the formation of riboclusters (groups of RNA-binding proteins (RBPs) and stalled mRNA complexes) and autophagy. We further show that HF-mediated inhibition in IL-1β production is dependent on general control nonderepressible 2 kinase (GCN2), an amino acid deprivation sensor. This study provides the mechanisms regulating AAR-induced benefits in the context of inflammation and further suggests that the administration of HF might offer an effective therapeutic intervention against inflammatory diseases in mammals.
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Affiliation(s)
- Srikanth Battu
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
| | - Sumbul Afroz
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
| | - Jeevan Giddaluru
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
| | - Saima Naz
- Centre for Liver Research and Diagnostics, Central Laboratory for Stem Cell Research and Translational Medicine, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad, Telangana, India
| | - Weishan Huang
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America
| | | | - Rafiq Ahmad Khan
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
| | - Saleem Yousuf Bhat
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
| | - Insaf Ahmed Qureshi
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
| | - Bramanandam Manavathi
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
| | - Aleem Ahmed Khan
- Centre for Liver Research and Diagnostics, Central Laboratory for Stem Cell Research and Translational Medicine, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad, Telangana, India
| | - Avery August
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America
| | - Seyed Ehtesham Hasnain
- JH-Institute of Molecular Medicine, Jamia Hamdard University, Hamdard Nagar, New Delhi, India
- Molecular Infection and Functional Biology Laboratory, Kusuma School of Biological Sciences, Indian Institute of Technology, New Delhi, India
- Dr Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India
| | - Nooruddin Khan
- Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
- * E-mail:
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21
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IL-1R2 deficiency suppresses dextran sodium sulfate-induced colitis in mice via regulation of microbiota. Biochem Biophys Res Commun 2018; 496:934-940. [DOI: 10.1016/j.bbrc.2018.01.116] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 01/17/2018] [Indexed: 12/15/2022]
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22
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Van Welden S, Selfridge AC, Hindryckx P. Intestinal hypoxia and hypoxia-induced signalling as therapeutic targets for IBD. Nat Rev Gastroenterol Hepatol 2017; 14:596-611. [PMID: 28853446 DOI: 10.1038/nrgastro.2017.101] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Tissue hypoxia occurs when local oxygen demand exceeds oxygen supply. In chronic inflammatory conditions such as IBD, the increased oxygen demand by resident and gut-infiltrating immune cells coupled with vascular dysfunction brings about a marked reduction in mucosal oxygen concentrations. To counter the hypoxic challenge and ensure their survival, mucosal cells induce adaptive responses, including the activation of hypoxia-inducible factors (HIFs) and modulation of nuclear factor-κB (NF-κB). Both pathways are tightly regulated by oxygen-sensitive prolyl hydroxylases (PHDs), which therefore represent promising therapeutic targets for IBD. In this Review, we discuss the involvement of mucosal hypoxia and hypoxia-induced signalling in the pathogenesis of IBD and elaborate in detail on the role of HIFs, NF-κB and PHDs in different cell types during intestinal inflammation. We also provide an update on the development of PHD inhibitors and discuss their therapeutic potential in IBD.
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Affiliation(s)
- Sophie Van Welden
- Department of Gastroenterology, Ghent University, De Pintelaan 185, 1K12-E, 9000 Ghent, Belgium
| | - Andrew C Selfridge
- Robarts Clinical Trials West, 4350 Executive Drive 210, San Diego, California 92121, USA
| | - Pieter Hindryckx
- Department of Gastroenterology, Ghent University, De Pintelaan 185, 1K12-E, 9000 Ghent, Belgium
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23
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Song EM, Jung SA, Lee KE, Jang JY, Lee KH, Tae CH, Moon CM, Joo YH, Kim SE, Jung HK, Shim KN. The Therapeutic Efficacy of Tonsil-derived Mesenchymal Stem Cells in Dextran Sulfate Sodium-induced Acute Murine Colitis Model. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2017; 69:119-128. [PMID: 28239080 DOI: 10.4166/kjg.2017.69.2.119] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Background/Aims Mesenchymal stem cells (MSCs) are multipotent progenitor cells currently under investigation for its efficacy as the treatment for inflammatory bowel disease. In this study, we evaluated the efficacy of tonsil-derived mesenchymal stem cells (T-MSCs) as a novel source of mesenchymal stem cells and traced their localization in a murine model of acute colitis induced by dextran sulfate sodium (DSS). Methods C57BL/6 mice were randomly assigned to the following three groups: the normal control group, DSS colitis group (DSS+phosphate buffered saline), and T-MSC group (DSS+T-MSCs, 1×106). The severity of colitis was assessed by determining the severity of symptoms of colitis, colon length, histopathologic grade, and levels of inflammatory cytokines. T-MSCs labeled with PKH26 were traced in vivo. Results The T-MSC group, compared with the DSS colitis group, showed a significantly lower disease activity index (11.3±1.5 vs. 8.3±1.9, p=0.015) at sacrifice and less reduction of body weight (-17.1±5.0% vs. -8.1±6.9%, p=0.049). In the T-MSC group, the histologic colitis score was significantly decreased compared with the DSS colitis group (22.6±3.8 vs. 17.0±3.4, p=0.039). IL-6 and IL-1β, the pro-inflammatory cytokines, were also significantly reduced after a treatment with T-MSCs. In vivo tracking revealed no PKH26-labelled T-MSCs in the colonic tissue of mice with acute colitis. Conclusions In the acute colitis model, we demonstrated that the administration of T-MSCs ameliorates inflammatory symptoms and histology. Moreover, the anti-inflammatory activities of T-MSCs were independent of gut homing.
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Affiliation(s)
- Eun Mi Song
- Department of Internal Medicine, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Sung Ae Jung
- Department of Internal Medicine, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Ko Eun Lee
- Department of Internal Medicine, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Ji Young Jang
- Department of Internal Medicine, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Kang Hoon Lee
- Department of Internal Medicine, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Chung Hyun Tae
- Department of Internal Medicine, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Chang Mo Moon
- Department of Internal Medicine, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Yang Hee Joo
- Department of Internal Medicine, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Seong Eun Kim
- Department of Internal Medicine, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Hye Kyung Jung
- Department of Internal Medicine, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Ki Nam Shim
- Department of Internal Medicine, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
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Young Cho J, Yeon Kim H, Me Kim H, Na Song H, Hong E, Hwang JK, Sook Chun H. Standardized ethanolic extract of the rhizome of Curcuma xanthorrhiza prevents murine ulcerative colitis by regulation of inflammation. J Funct Foods 2017. [DOI: 10.1016/j.jff.2017.01.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
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Gálvez-Llompart M, Recio MC, García-Domenech R, Gálvez J. Molecular topology: a strategy to identify novel compounds against ulcerative colitis. Mol Divers 2016; 21:219-234. [PMID: 27734189 DOI: 10.1007/s11030-016-9706-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 09/26/2016] [Indexed: 12/27/2022]
Abstract
In the present paper, a strategy to identify novel compounds against ulcerative colitis (UC) by molecular topology (MT) is presented. Several quantitative structure-activity relationship (QSAR) models based on molecular topology have been developed to predict inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha ([Formula: see text]) mediated anti-ulcerative colitis (UC) activity and protective activity against a dextran sulfate sodium (DSS)-induced UC model. Each one has been used for the screening of four previously selected compounds as potential therapeutic agents for UC: alizarin-3-methyliminodiacetic acid (AMA), Calcein, (+)-dibenzyl-L-tartrate, and Ro 41-0960. These four compounds were then tested in vitro and in vivo and confirmed AMA and Ro 41-0960 as the best lead candidates for further development against UC.
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Affiliation(s)
- María Gálvez-Llompart
- Molecular Connectivity and Drug Design Research Unit, Department of Physical Chemistry, Faculty of Pharmacy, University of Valencia, Avd, V.A. Estellés, Burjassot, 46100, Valencia, Spain. .,Department of Pharmacology, Faculty of Pharmacy, University of Valencia, Avd, V.A. Estellés, Burjassot, 46100, Valencia, Spain.
| | - Maria C Recio
- Department of Pharmacology, Faculty of Pharmacy, University of Valencia, Avd, V.A. Estellés, Burjassot, 46100, Valencia, Spain
| | - Ramón García-Domenech
- Molecular Connectivity and Drug Design Research Unit, Department of Physical Chemistry, Faculty of Pharmacy, University of Valencia, Avd, V.A. Estellés, Burjassot, 46100, Valencia, Spain
| | - Jorge Gálvez
- Molecular Connectivity and Drug Design Research Unit, Department of Physical Chemistry, Faculty of Pharmacy, University of Valencia, Avd, V.A. Estellés, Burjassot, 46100, Valencia, Spain
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Toyonaga T, Matsuura M, Mori K, Honzawa Y, Minami N, Yamada S, Kobayashi T, Hibi T, Nakase H. Lipocalin 2 prevents intestinal inflammation by enhancing phagocytic bacterial clearance in macrophages. Sci Rep 2016; 6:35014. [PMID: 27734904 PMCID: PMC5062163 DOI: 10.1038/srep35014] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 09/21/2016] [Indexed: 01/03/2023] Open
Abstract
Lipocalin 2 (Lcn2), also called neutrophil gelatinase B-associated lipocalin (NGAL), is an anti-microbial peptide originally identified in neutrophil granules. Although Lcn2/NGAL expression is increased in the inflamed intestinal tissues of patients with inflammatory bowel disease, the role of Lcn2/NGAL in the development of intestinal inflammation remains unclear. Here we investigated the role of Lcn2/NGAL in intestinal inflammation using a spontaneous mouse colitis model, interleukin-10 knock out (IL-10 KO) mice. Lcn2 expression in the colonic tissues of IL-10 KO mice increased with the development of colitis. Lcn2/IL-10 double-KO mice showed a more rapid onset and development of colitis compared to IL-10 KO mice. Lcn2 enhanced phagocytic bacterial clearance in macrophages in vitro after infection with Escherichia coli. Transfer of Lcn2-repleted macrophages prevented the development of colitis in Lcn2/IL-10 double-KO mice in vivo. Our findings revealed that Lcn2 prevents the development of intestinal inflammation. One crucial factor seems to be the enhancement of phagocytic bacterial clearance in macrophages by Lcn2.
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Affiliation(s)
- Takahiko Toyonaga
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, 5-9-1, Shirokane, Minato-ku, Tokyo, 108-8642, Japan
| | - Minoru Matsuura
- Department of Gastroenterology &Hepatology, Graduate School of Medicine, Kyoto University, 54 shogoin, Kawahara-cho, Sakyo-ku, Kyoto, 606-8397, Japan
| | - Kiyoshi Mori
- School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, 422-8526, Japan
| | - Yusuke Honzawa
- Department of Gastroenterology &Hepatology, Graduate School of Medicine, Kyoto University, 54 shogoin, Kawahara-cho, Sakyo-ku, Kyoto, 606-8397, Japan
| | - Naoki Minami
- Department of Gastroenterology &Hepatology, Graduate School of Medicine, Kyoto University, 54 shogoin, Kawahara-cho, Sakyo-ku, Kyoto, 606-8397, Japan
| | - Satoshi Yamada
- Department of Gastroenterology &Hepatology, Graduate School of Medicine, Kyoto University, 54 shogoin, Kawahara-cho, Sakyo-ku, Kyoto, 606-8397, Japan
| | - Taku Kobayashi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, 5-9-1, Shirokane, Minato-ku, Tokyo, 108-8642, Japan
| | - Toshifumi Hibi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, 5-9-1, Shirokane, Minato-ku, Tokyo, 108-8642, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan
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Cazarin CBB, Rodriguez-Nogales A, Algieri F, Utrilla MP, Rodríguez-Cabezas ME, Garrido-Mesa J, Guerra-Hernández E, Braga PADC, Reyes FGR, Maróstica MR, Gálvez J. Intestinal anti-inflammatory effects of Passiflora edulis peel in the dextran sodium sulphate model of mouse colitis. J Funct Foods 2016. [DOI: 10.1016/j.jff.2016.08.020] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
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Elshaer D, Begun J. The role of barrier function, autophagy, and cytokines in maintaining intestinal homeostasis. Semin Cell Dev Biol 2016; 61:51-59. [PMID: 27565684 DOI: 10.1016/j.semcdb.2016.08.018] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Revised: 08/10/2016] [Accepted: 08/22/2016] [Indexed: 02/06/2023]
Abstract
Intestinal homeostasis is maintained through the interplay of the intestinal mucosa, local and systemic immune factors, and the microbial content of the gut. The cellular processes of autophagy, endoplasmic reticulum stress, the unfolded protein response and regulation of reactive oxygen species production are required to maintain a balance between pro-inflammatory responses against potential pathogens and a tolerogenic response towards commensal bacteria. Intestinally active cytokines regulate innate immune pathways and cellular pathways within the gut mucosa. Disruption of these processes, or alterations in the cytokine milieu, can result in an improper response to the commensal gut microbial community leading to inappropriate inflammation characteristic of conditions such as inflammatory bowel disease.
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Affiliation(s)
- Dana Elshaer
- Immunity, Infection and Inflammation Program, Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.
| | - Jakob Begun
- Immunity, Infection and Inflammation Program, Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia; University of Queensland School of Medicine, Brisbane, Queensland, Australia.
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Dimethyl fumarate ameliorates dextran sulfate sodium-induced murine experimental colitis by activating Nrf2 and suppressing NLRP3 inflammasome activation. Biochem Pharmacol 2016; 112:37-49. [DOI: 10.1016/j.bcp.2016.05.002] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 05/04/2016] [Indexed: 02/07/2023]
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Somani S, Zambad S, Modi K. Mangiferin attenuates DSS colitis in mice: Molecular docking and in vivo approach. Chem Biol Interact 2016; 253:18-26. [PMID: 27125760 DOI: 10.1016/j.cbi.2016.04.033] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 04/05/2016] [Accepted: 04/24/2016] [Indexed: 01/07/2023]
Abstract
Inflammation, oxidative stress and altered mucosal barrier permeability are potential etiopathological or triggering factors for inflammatory bowel disease (IBD). In this study, the therapeutic potential of Mangiferin was investigated in vivo in mouse model of colitis and also attempts were made to understand mechanistic insights of Mangiferin in IBD. In present study, colitis was induced by administration of 5% DSS for 11 days, followed by 3 days of DSS free period. On day 14, animals were sacrificed and colon tissues were taken for biochemical and histological analysis. Therapeutic treatment with Mangiferin after colitis induction (i.e. day 5) ameliorated symptoms of colitis (presence of blood in stools, body weight loss and diarrhea) as evidenced by reduced DAI score, attenuated the levels of catalase (CAT), reduced glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), myeloperoxidase (MPO). It also decreased the colonic pro-inflammatory mediators tumor necrosis factor (TNF-α), interleukin 1β (IL-1β) levels, matrix metalloproteinase-9 (MMP-9) activity and histopathological score. Molecular docking of Mangiferin against TNF-α and MMP-9 was evaluated using GLIDE software. Mangiferin demonstrated the glide score of -8.04 kcal/mol for TNF-α and -9.97 kcal/mol for MMP-9, which indicated its binding potential with TNF-α and MMP-9. In conclusion, Mangiferin reduces colonic damage in a murine model of colitis, alleviates the oxidative and inflammatory events partly through directly influencing the activity of TNF-α and MMP-9 and therefore might have therapeutic usefulness in the management of inflammatory bowel disease.
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Affiliation(s)
- Sahil Somani
- Department of Pharmacology, Torrent Pharmaceuticals Ltd, Gandhinagar, Gujarat, India; Department of Pharmacology, School of Pharmacy, RK University, Rajkot, India.
| | - Shitalkumar Zambad
- Department of Pharmacology, Torrent Pharmaceuticals Ltd, Gandhinagar, Gujarat, India.
| | - Ketan Modi
- Department of Pharmacology, B K Mody Government Pharmacy College, Rajkot, India.
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Du Q, Wang Q, Fan H, Wang J, Liu X, Wang H, Wang Y, Hu R. Dietary cholesterol promotes AOM-induced colorectal cancer through activating the NLRP3 inflammasome. Biochem Pharmacol 2016; 105:42-54. [DOI: 10.1016/j.bcp.2016.02.017] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Accepted: 02/23/2016] [Indexed: 12/12/2022]
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Choi KC, Cho SW, Kook SH, Chun SR, Bhattarai G, Poudel SB, Kim MK, Lee KY, Lee JC. Intestinal anti-inflammatory activity of the seeds of Raphanus sativus L. in experimental ulcerative colitis models. JOURNAL OF ETHNOPHARMACOLOGY 2016; 179:55-65. [PMID: 26721217 DOI: 10.1016/j.jep.2015.12.045] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Revised: 12/08/2015] [Accepted: 12/21/2015] [Indexed: 06/05/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Water extract of Raphanus sativus L. (RSL) seeds was traditionally used to treat digestive inflammatory complaints in Korean culture. RSL seeds exerted antioxidant, anti-inflammatory, and anti-septic functions, suggesting their pharmacological potential for the treatment of inflammatory pathologies associated with oxidative stress such as inflammatory bowel disease. AIM OF THIS STUDY We evaluated the intestinal anti-inflammatory effects of RSL seed water extract (RWE) in experimental rat models of trinitrobenzenesulphonic acid (TNBS)- or dextran sodium sulfate (DSS)-induced colitis. MATERIALS AND METHODS RWE was characterized by determining the content of sinapic acid as a reference material and then assayed in the DSS and TNBS models of rat colitis. Male Sprague-Dawley rats were divided into 10 groups (n=7/group): non-colitic control, DSS or TNBS control, DSS colitis groups treated with RWE (100mg/kg) or mesalazine (25mg/kg), and TNBS colitis groups treated with various doses (10, 40, 70, and 100mg/kg) of RWE or mesalazine (25mg/kg). RWE or mesalazine treatment started the same day of colitis induction and rats were sacrificed 24h after the last treatment followed by histological and biochemical analyses. RESULTS Oral administration with RWE suppressed intestinal inflammatory damages in both DSS- and TNBS-induced colitic rats. The treatment with 100mg/kg RWE recovered intestinal damages caused by TNBS or DSS to levels similar to that of mesalazine, decreasing the activity of myeloperoxidase activity and the secretion of tumor necrosis factor (TNF)-α and interleukin (IL)-1β. RWE treatment inhibited malondialdehyde production and glutathione reduction in colon of colitis rats. The administration of RWE at dose of 100mg/kg also suppressed the TNBS- or DSS-stimulated expression of TNF-α, IL-1β, monocyte chemotactic protein-1, inducible nitric oxide, and intercellular adhesion molecule-1. Furthermore, RWE inhibited p38 kinase and DNA-nuclear factor-κB binding activities, both of which were stimulated in the colitic rats. CONCLUSIONS The current findings show that RWE ameliorates intestinal oxidative and inflammatory damages in DSS and TNBS models of rat colitis, suggesting its beneficial use for the treatment of intestinal inflammatory disorders.
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Affiliation(s)
- Ki-Choon Choi
- Grassland and Forage Division, National Institute of Animal Science, RDA, Cheonan, Chungnam 330-801, South Korea.
| | - Seong-Wan Cho
- Department of Pharmaceutical Engineering, Konyang University, Nonsan 320-711, South Korea.
| | - Sung-Ho Kook
- Research Center of Bioactive Materials and Institute for Molecular Biology and Genetics, Chonbuk National University, Jeonju 561-756, South Korea; Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju 561-756, South Korea.
| | - Sa-Ra Chun
- Research Center of Bioactive Materials and Institute for Molecular Biology and Genetics, Chonbuk National University, Jeonju 561-756, South Korea.
| | - Govinda Bhattarai
- Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju 561-756, South Korea.
| | - Sher Bahadur Poudel
- Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju 561-756, South Korea.
| | - Min-Kook Kim
- Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju 561-756, South Korea.
| | - Kyung-Yeol Lee
- Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju 561-756, South Korea.
| | - Jeong-Chae Lee
- Research Center of Bioactive Materials and Institute for Molecular Biology and Genetics, Chonbuk National University, Jeonju 561-756, South Korea; Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju 561-756, South Korea.
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Garlic oil inhibits dextran sodium sulfate-induced ulcerative colitis in rats. Life Sci 2016; 146:40-51. [PMID: 26780265 DOI: 10.1016/j.lfs.2016.01.012] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 12/11/2015] [Accepted: 01/07/2016] [Indexed: 01/20/2023]
Abstract
AIMS Garlic oil (GO) is used for centuries in folk medicine as a therapy for many diseases including inflammatory disorders. Recently, it has exhibited potent anti-oxidant, anti-inflammatory and immunomodulatory effects. Consequently, we evaluated the possible protective effect of GO in a rat model of colitis, induced by dextran sulfate sodium (DSS). MAIN METHODS Colitis induced by allowing rats a free access to drinking water containing 5% DSS for 7 days, from day 1 to day 7. GO was administered orally in doses of 25, 50 and 100mg/kg/day. Mesalazine used as a standard medication in a dose of 15 mg/kg/day. All animals fasted for 2h, 1h before and 1h after giving the treatment, which introduced daily for 7 days, from day 1 to day 7, at 10:00 to 11:00 A.M. Animal body, and colonic weights, colonic myeloperoxidase (MPO), and superoxide dismutase (SOD) activities, colonic reduced-glutathione (GSH), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-10 levels, macroscopic and microscopic changes of colonic tissues were evaluated. KEY FINDINGS GO treatment significantly suppressed the elevated colonic weight, MPO activity, MDA, TNF-α and IL-1β levels. However, it potentiated the decrease body weight, colonic SOD activity, GSH and IL-10 levels. Moreover, it ameliorated the marked macroscopic and microscopic changes of colonic mucosa in a dose dependent manner. SIGNIFICANCE Garlic oil inhibits DSS-induced colitis in rats may be through its anti-oxidant, anti-inflammatory and immunomodulatory properties. Therefore, GO could be a promising protective agent recommended for UC patients.
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Deciphering the crosstalk among IL-1 and IL-10 family cytokines in intestinal immunity. Trends Immunol 2015; 36:471-8. [PMID: 26184648 DOI: 10.1016/j.it.2015.06.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2015] [Revised: 06/18/2015] [Accepted: 06/19/2015] [Indexed: 12/16/2022]
Abstract
The IL-1 and IL-10 family cytokines are important regulators of intestinal immunity. Whereas these cytokines have protective roles in response to mucosal damage or infection, they also contribute to pathology in certain settings. How these cytokines function to maintain intestinal homoeostasis, and under what circumstances they contribute to disease is poorly understood. Recent studies have revealed a multi-layered regulatory network wherein IL-1 and IL-10 family cytokines impact each other's production. The workings of this network vary in different intestinal regions, reflecting the influence of resident microbiota and the distribution of distinct immune cell populations in different regions of the intestine. We review these findings here, and discuss them in the context of the current understanding of the functions of these cytokine families in health and disease. We further highlight important areas of future investigation.
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Zhao B, Qi Z, Li Y, Wang C, Fu W, Chen YG. The non-muscle-myosin-II heavy chain Myh9 mediates colitis-induced epithelium injury by restricting Lgr5+ stem cells. Nat Commun 2015; 6:7166. [PMID: 25968904 DOI: 10.1038/ncomms8166] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 04/13/2015] [Indexed: 11/09/2022] Open
Abstract
Lgr5+ stem cells are crucial to gut epithelium homeostasis, and therapies targeting these cells hold promise for treatment of gastrointestinal diseases. Here we report that the non-muscle-myosin-II (NMII) heavy chain Myh9 accumulates at epithelial injury sites in mice distal colon treated with dextran sulphate sodium (DSS). Gut-epithelium-specific Myh9 monoallelic deletion alleviates DSS-induced colonic crypt damage and acute colitis. Consistently, the NMII inhibitor blebbistatin can improve the survival of Lgr5+ stem cells and the growth of Lgr5 organoids. Mechanistically, inhibition of NMII by blebbistatin or Myh9 monoallelic deletion activates Akt through Rac1 and PAK1, which is essential for the survival and pluripotency of Lgr5+ cells. These results establish a critical role of the Myh9-Rac1-PAK1-Akt pathway in the maintenance of Lgr5+ stem cells. As blebbistatin can mitigate DSS-induced colitis and preserve Lgr5+ colonic stem cells in vivo, our findings provide a potential therapeutic intervention of gastrointestinal epithelium injury and degenerative diseases.
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Affiliation(s)
- Bing Zhao
- The State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Zhen Qi
- The State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yehua Li
- The State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Chongkai Wang
- Department of General Surgery, Peking University Third Hospital, Beijing 100191, China
| | - Wei Fu
- Department of General Surgery, Peking University Third Hospital, Beijing 100191, China
| | - Ye-Guang Chen
- The State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
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Guo W, Sun Y, Liu W, Wu X, Guo L, Cai P, Wu X, Wu X, Shen Y, Shu Y, Gu Y, Xu Q. Small molecule-driven mitophagy-mediated NLRP3 inflammasome inhibition is responsible for the prevention of colitis-associated cancer. Autophagy 2015; 10:972-85. [PMID: 24879148 DOI: 10.4161/auto.28374] [Citation(s) in RCA: 184] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Nonresolving inflammation in the intestine predisposes individuals to the development of colitis-associated cancer (CAC). Inflammasomes are thought to mediate intestinal homeostasis, and their dysregulation contributes to inflammatory bowel diseases and CAC. However, few agents have been reported to reduce CAC by targeting inflammasomes. Here we show that the small molecule andrographolide (Andro) protects mice against azoxymethane/dextran sulfate sodium-induced colon carcinogenesis through inhibiting the NLRP3 inflammasome. Administration of Andro significantly attenuated colitis progression and tumor burden. Andro also inhibited NLRP3 inflammasome activation in macrophages both in vivo and in vitro, as indicated by reduced expression of cleaved CASP1, disruption of NLRP3-PYCARD-CASP1 complex assembly, and lower IL1B secretion. Importantly, Andro was found to trigger mitophagy in macrophages, leading to a reversed mitochondrial membrane potential collapse, which in turn inactivated the NLRP3 inflammasome. Moreover, downregulation of the PIK3CA-AKT1-MTOR-RPS6KB1 pathway accounted for Andro-induced autophagy. Finally, Andro-driven inhibition of the NLRP3 inflammasome and amelioration of murine models for colitis and CAC were significantly blocked by BECN1 knockdown, or by various autophagy inhibitors. Taken together, our findings demonstrate that mitophagy-mediated NLRP3 inflammasome inhibition by Andro is responsible for the prevention of CAC. Our data may help guide decisions regarding the use of Andro in patients with inflammatory bowel diseases, which ultimately reduces the risk of CAC.
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Affiliation(s)
- Wenjie Guo
- State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; Nanjing University; Nanjing, China; School of Pharmacy; Jiangsu University; Zhenjiang, China
| | - Yang Sun
- State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; Nanjing University; Nanjing, China
| | - Wen Liu
- State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; Nanjing University; Nanjing, China
| | - Xingxin Wu
- State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; Nanjing University; Nanjing, China
| | - Lele Guo
- State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; Nanjing University; Nanjing, China
| | - Peifen Cai
- Department of Oncology; First Affiliated Hospital of Nanjing Medical University; Nanjing, China
| | - Xuefeng Wu
- State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; Nanjing University; Nanjing, China
| | - Xudong Wu
- State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; Nanjing University; Nanjing, China
| | - Yan Shen
- State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; Nanjing University; Nanjing, China
| | - Yongqian Shu
- Department of Oncology; First Affiliated Hospital of Nanjing Medical University; Nanjing, China
| | - Yanhong Gu
- Department of Oncology; First Affiliated Hospital of Nanjing Medical University; Nanjing, China
| | - Qiang Xu
- State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; Nanjing University; Nanjing, China
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Guo W, Liu W, Jin B, Geng J, Li J, Ding H, Wu X, Xu Q, Sun Y, Gao J. Asiatic acid ameliorates dextran sulfate sodium-induced murine experimental colitis via suppressing mitochondria-mediated NLRP3 inflammasome activation. Int Immunopharmacol 2014; 24:232-238. [PMID: 25523461 DOI: 10.1016/j.intimp.2014.12.009] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Revised: 11/20/2014] [Accepted: 12/04/2014] [Indexed: 12/14/2022]
Abstract
In the present study, the effect of asiatic acid, a natural triterpenoid compound, on murine experimental colitis induced by dextran sulfate sodium (DSS) and its possible mechanism were examined in vivo and vitro. Oral administration of asiatic acid dose-dependently attenuated the loss of body weight and shortening of colon length induced by DSS. The disease activity index, histopathologic scores of musco and myeloperoxidase activity were also significantly reduced by asiatic acid treatment. Protein and mRNA levels of DSS-induced pro-inflammatory cytokines in colon, including TNF-α, IL-1β, IL-6 and IFN-γ, were markedly suppressed by asiatic acid. At the same time, decreased activation of caspase-1 in peritoneal macrophages was detected in asiatic acid-treated mice, which suggested that the NLRP3 inflammasome activation was suppressed. In addition, we also found that asiatic acid dose-dependently inhibited IL-1β secretion, caspase-1 activation as well as inflammasome assembling in vitro. Furthermore, the mechanism of asiatic acid was related to the inhibition of mitochondrial reactive oxygen species generation and prevention of mitochondrial membrane potential collapse. Taken together, our results demonstrate the ability of asiatic acid to inhibit NLRP3 inflammasome activation and its potential usage in the treatment of inflammatory bowel diseases.
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Affiliation(s)
- Wenjie Guo
- School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Han Kou Road, Nanjing 210093, China
| | - Wen Liu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Han Kou Road, Nanjing 210093, China
| | - Biao Jin
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Han Kou Road, Nanjing 210093, China
| | - Ji Geng
- School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China
| | - Jing Li
- School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China
| | - Hongqun Ding
- School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China
| | - Xuefeng Wu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Han Kou Road, Nanjing 210093, China
| | - Qiang Xu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Han Kou Road, Nanjing 210093, China.
| | - Yang Sun
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Han Kou Road, Nanjing 210093, China.
| | - Jing Gao
- School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China.
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Abstract
Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disorder of the colonic mucosa, and its etiology remains unclear. Animal models are commonly used to study UC, including the murine model of colitis induced with dextran sulfate sodium (DSS). The murine model of DSS-induced colitis is well appreciated and widely used because of its simplicity, cheapness and high success rate. DSS-induced colitis has many similarities to human UC in location, clinical and histological features. In view of its indispensable position in the study of UC, we provide a brief overview of the animal model of DSS-induced colitis in terms of its features, modelling methods, pathogenesis and influencing factors.
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Xilei san ameliorates experimental colitis in rats by selectively degrading proinflammatory mediators and promoting mucosal repair. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2014; 2014:569587. [PMID: 25120575 PMCID: PMC4120479 DOI: 10.1155/2014/569587] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Accepted: 06/28/2014] [Indexed: 12/29/2022]
Abstract
Xilei san (XLS), a herbal preparation widely used in China for erosive and ulcerative diseases, has been shown to be effective in ulcerative colitis (UC). The present experiments were conducted to assess its efficacy and determine its mechanism of action in a rat model that resembles human UC. The model was induced by adding 4% dextran sulfate sodium (DSS) to the rats' drinking water for 7 days. XLS was administered daily by retention enema from day 2 to day 7; the rats were sacrificed on day 8. The colon tissues were obtained for further experiments. A histological damage score and the activity of tissue myeloperoxidase were used to evaluate the severity of the colitis. The colonic cytokine levels were detected in a suspension array, and epithelial proliferation was assessed using Ki-67 immunohistochemistry. Intrarectal administration of XLS attenuated the DSS-induced colitis, as evidenced by a reduction in both the histological damage score and myeloperoxidase activity. It also decreased the levels of proinflammatory cytokines, but increased the mucosal repair-related cytokines. In addition, the epithelial Ki-67 expression was upregulated by XLS. These results suggest that XLS attenuates DSS-induced colitis by degrading proinflammatory mediators and promoting mucosal repair. XLS could be a potential topical treatment for human UC.
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IL-10 modulates DSS-induced colitis through a macrophage-ROS-NO axis. Mucosal Immunol 2014; 7:869-78. [PMID: 24301657 PMCID: PMC4045662 DOI: 10.1038/mi.2013.103] [Citation(s) in RCA: 144] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Accepted: 10/27/2013] [Indexed: 02/06/2023]
Abstract
Breakdown of the epithelial barrier because of toxins or other insults leads to severe colitis. Interleukin-10 (IL-10) is a critical regulator of this, yet its cellular targets and mechanisms of action are not resolved. We address this here. Mice with a macrophage-selective deletion of IL-10Rα (IL-10Rα(Mdel)) developed markedly enhanced dextran sodium sulfate (DSS)-induced colitis that did not significantly differ from disease in IL-10(-/-) or IL-10Rα(-/-) mice; no impact of IL-10Rα deficiency in other lineages was observed. IL-10Rα(Mdel) colitis was associated with increased mucosal barrier disruption in the setting of intact epithelial regeneration. Lamina propria macrophages (LPMφs) did not show numerical or phenotypic differences from controls, or a competitive advantage over wild-type cells. Proinflammatory cytokine production, and particularly tumor necrosis factor-α (TNF-α), was increased, although TNF-α neutralization failed to reveal a defining role for this cytokine in the aggravated disease. Rather, IL-10Rα(Mdel) LPMφs produced substantially greater levels of nitric oxide (NO) and reactive oxygen species (ROS) than controls. Inhibition of these had modest effects in wild-type mice, although they dramatically reduced colitis severity in IL-10Rα(Mdel) mice, and largely eliminated the differential effect of DSS in them. Therefore, the palliative actions of IL-10 in DSS-induced colitis predominantly results from its macrophage-specific effects. Downregulation of NO and ROS production are central to the protective actions of IL-10.
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The complex role of inflammasomes in the pathogenesis of Inflammatory Bowel Diseases - lessons learned from experimental models. Cytokine Growth Factor Rev 2014; 25:715-30. [PMID: 24803013 DOI: 10.1016/j.cytogfr.2014.04.003] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Accepted: 04/04/2014] [Indexed: 02/08/2023]
Abstract
Inflammasomes are a large family of multiprotein complexes recognizing pathogen-associated molecular pattern molecules (PAMPs) and damage-associated molecular patterns (DAMPs). This leads to caspase-1 activation, promoting the secretion of mature IL-1β, IL-18 and under certain conditions even induce pyroptosis. Inflammatory Bowel Diseases (IBD) is associated with alterations in microbiota composition, inappropriate immune responses and genetic predisposition associated to bacterial sensing and autophagy. Besides their acknowledged role in mounting microbial induced host responses, a crucial role in maintenance of intestinal homeostasis was revealed in inflammasome deficient mice. Further, abnormal activation of these functions appears to contribute to the pathology of intestinal inflammation including IBD and colitis-associated cancer. Herein, the current literature implicating the inflammasomes, microbiota and IBD is comprehensively reviewed.
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Nagib MM, Tadros MG, ELSayed MI, Khalifa AE. Anti-inflammatory and anti-oxidant activities of olmesartan medoxomil ameliorate experimental colitis in rats. Toxicol Appl Pharmacol 2013; 271:106-13. [DOI: 10.1016/j.taap.2013.04.026] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Revised: 04/27/2013] [Accepted: 04/30/2013] [Indexed: 01/15/2023]
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ZHAO JING, HONG TIE, DONG MAN, MENG YIXIAO, MU JIAYE. Protective effect of myricetin in dextran sulphate sodium-induced murine ulcerative colitis. Mol Med Rep 2012; 7:565-70. [DOI: 10.3892/mmr.2012.1225] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2012] [Accepted: 11/16/2012] [Indexed: 11/06/2022] Open
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Iwaya H, Lee JS, Yamagishi S, Shinoki A, Lang W, Thawornkuno C, Kang HK, Kumagai Y, Suzuki S, Kitamura S, Hara H, Okuyama M, Mori H, Kimura A, Ishizuka S. The delay in the development of experimental colitis from isomaltosyloligosaccharides in rats is dependent on the degree of polymerization. PLoS One 2012; 7:e50658. [PMID: 23209802 PMCID: PMC3510184 DOI: 10.1371/journal.pone.0050658] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2012] [Accepted: 10/23/2012] [Indexed: 12/25/2022] Open
Abstract
Background Isomaltosyloligosaccharides (IMO) and dextran (Dex) are hardly digestible in the small intestine and thus influence the luminal environment and affect the maintenance of health. There is wide variation in the degree of polymerization (DP) in Dex and IMO (short-sized IMO, S-IMO; long-sized IMO, L-IMO), and the physiological influence of these compounds may be dependent on their DP. Methodology/Principal Findings Five-week-old male Wistar rats were given a semi-purified diet with or without 30 g/kg diet of the S-IMO (DP = 3.3), L-IMO (DP = 8.4), or Dex (DP = 1230) for two weeks. Dextran sulfate sodium (DSS) was administered to the rats for one week to induce experimental colitis. We evaluated the clinical symptoms during the DSS treatment period by scoring the body weight loss, stool consistency, and rectal bleeding. The development of colitis induced by DSS was delayed in the rats fed S-IMO and Dex diets. The DSS treatment promoted an accumulation of neutrophils in the colonic mucosa in the rats fed the control, S-IMO, and L-IMO diets, as assessed by a measurement of myeloperoxidase (MPO) activity. In contrast, no increase in MPO activity was observed in the Dex-diet-fed rats even with DSS treatment. Immune cell populations in peripheral blood were also modified by the DP of ingested saccharides. Dietary S-IMO increased the concentration of n-butyric acid in the cecal contents and the levels of glucagon-like peptide-2 in the colonic mucosa. Conclusion/Significance Our study provided evidence that the physiological effects of α-glucosaccharides on colitis depend on their DP, linkage type, and digestibility.
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Affiliation(s)
- Hitoshi Iwaya
- Graduate School of Agriculture, Hokkaido University, Sapporo, Japan
| | - Jae-Sung Lee
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
| | - Shinya Yamagishi
- Graduate School of Agriculture, Hokkaido University, Sapporo, Japan
| | - Aki Shinoki
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
| | - Weeranuch Lang
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
| | | | - Hee-Kwon Kang
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
| | - Yuya Kumagai
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
| | - Shiho Suzuki
- Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan
| | - Shinichi Kitamura
- Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan
| | - Hiroshi Hara
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
| | - Masayuki Okuyama
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
| | - Haruhide Mori
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
| | - Atsuo Kimura
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
| | - Satoshi Ishizuka
- Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
- * E-mail:
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Moussa L, Bézirard V, Salvador-Cartier C, Bacquié V, Lencina C, Lévêque M, Braniste V, Ménard S, Théodorou V, Houdeau E. A low dose of fermented soy germ alleviates gut barrier injury, hyperalgesia and faecal protease activity in a rat model of inflammatory bowel disease. PLoS One 2012; 7:e49547. [PMID: 23166707 PMCID: PMC3498131 DOI: 10.1371/journal.pone.0049547] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Accepted: 10/10/2012] [Indexed: 12/19/2022] Open
Abstract
Pro-inflammatory cytokines like macrophage migration inhibitory factor (MIF), IL-1β and TNF-α predominate in inflammatory bowel diseases (IBD) and TNBS colitis. Increased levels of serine proteases activating protease-activated receptor 2 (PAR-2) are found in the lumen and colonic tissue of IBD patients. PAR-2 activity and pro-inflammatory cytokines impair epithelial barrier, facilitating the uptake of luminal aggressors that perpetuate inflammation and visceral pain. Soy extracts contain phytoestrogens (isoflavones) and serine protease inhibitors namely Bowman-Birk Inhibitors (BBI). Since estrogens exhibit anti-inflammatory and epithelial barrier enhancing properties, and that a BBI concentrate improves ulcerative colitis, we aimed to evaluate if a fermented soy germ extract (FSG) with standardized isoflavone profile and stable BBI content exert cumulative or synergistic protection based on protease inhibition and estrogen receptor (ER)-ligand activity in colitic rats. Female rats received orally for 15 d either vehicle or FSG with or without an ER antagonist ICI 182.780 before TNBS intracolonic instillation. Macroscopic and microscopic damages, myeloperoxidase activity, cytokine levels, intestinal paracellular permeability, visceral sensitivity, faecal proteolytic activity and PAR-2 expression were assessed 24 h, 3 d and 5 d post-TNBS. FSG treatment improved the severity of colitis, by decreasing the TNBS-induced rise in gut permeability, visceral sensitivity, faecal proteolytic activity and PAR-2 expression at all post-TNBS points. All FSG effects were reversed by the ICI 182.780 except the decrease in faecal proteolytic activity and PAR-2 expression. In conclusion, the anti-inflammatory properties of FSG treatment result from two distinct but synergic pathways i.e an ER-ligand and a PAR-2 mediated pathway, providing rationale for potential use as adjuvant therapy in IBD.
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Affiliation(s)
- Lara Moussa
- Neuro-Gastroenterology and Nutrition, Institut National de la Recherche Agronomique, UMR1331 Toxalim, INRA/INPT/UPS, Toulouse, France
- GENIBIO, Lorp-Sentaraille, France
| | - Valérie Bézirard
- Neuro-Gastroenterology and Nutrition, Institut National de la Recherche Agronomique, UMR1331 Toxalim, INRA/INPT/UPS, Toulouse, France
| | - Christel Salvador-Cartier
- Neuro-Gastroenterology and Nutrition, Institut National de la Recherche Agronomique, UMR1331 Toxalim, INRA/INPT/UPS, Toulouse, France
| | - Valérie Bacquié
- Neuro-Gastroenterology and Nutrition, Institut National de la Recherche Agronomique, UMR1331 Toxalim, INRA/INPT/UPS, Toulouse, France
| | - Corinne Lencina
- Neuro-Gastroenterology and Nutrition, Institut National de la Recherche Agronomique, UMR1331 Toxalim, INRA/INPT/UPS, Toulouse, France
| | - Mathilde Lévêque
- Neuro-Gastroenterology and Nutrition, Institut National de la Recherche Agronomique, UMR1331 Toxalim, INRA/INPT/UPS, Toulouse, France
| | - Viorica Braniste
- Neuro-Gastroenterology and Nutrition, Institut National de la Recherche Agronomique, UMR1331 Toxalim, INRA/INPT/UPS, Toulouse, France
| | - Sandrine Ménard
- Neuro-Gastroenterology and Nutrition, Institut National de la Recherche Agronomique, UMR1331 Toxalim, INRA/INPT/UPS, Toulouse, France
| | - Vassilia Théodorou
- Neuro-Gastroenterology and Nutrition, Institut National de la Recherche Agronomique, UMR1331 Toxalim, INRA/INPT/UPS, Toulouse, France
| | - Eric Houdeau
- Neuro-Gastroenterology and Nutrition, Institut National de la Recherche Agronomique, UMR1331 Toxalim, INRA/INPT/UPS, Toulouse, France
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Pre-treatment with IL-1β enhances the efficacy of MSC transplantation in DSS-induced colitis. Cell Mol Immunol 2012; 9:473-81. [PMID: 23085948 DOI: 10.1038/cmi.2012.40] [Citation(s) in RCA: 174] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been used experimentally for treating inflammatory disorders, partly due to their immunosuppressive properties. Although interleukin-1β (IL-1β) is one of the most important inflammatory mediators, growing evidence indicates that IL-1β signaling elicits the immunosuppressive properties of MSCs. However, it remains unclear how IL-1β signaling accomplishes this activity. Here, we focus on the therapeutic efficacy of IL-1β-primed MSCs in the dextran sulfate sodium (DSS)-induced colitis model, in addition to the underlining mechanisms. We first found that IL-1β-primed MSCs, without any observable phenotype change in vitro, significantly attenuated the development of DSS-induced murine colitis. Moreover, IL-1β-primed MSCs modulated the balance of immune cells in the spleen and the mesenteric lymph nodes (MLNs) through elevating cyclooxygenase-2 (COX-2), IL-6 and IL-8 expression and influencing the polarization of peritoneal macrophages. Importantly, IL-1β-primed MSCs possessed an enhanced ability to migrate to the inflammatory site of the gut via upregulation of chemokine receptor type 4 (CXCR4) expression. In summary, IL-1β-primed MSCs have improved efficacy in treating DSS-induced colitis, which at least partly depends on their increased immunosuppressive capacities and enhanced migration ability.
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47
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Akiyama S, Nesumi A, Maeda-Yamamoto M, Uehara M, Murakami A. Effects of anthocyanin-rich tea "Sunrouge" on dextran sodium sulfate-induced colitis in mice. Biofactors 2012; 38:226-33. [PMID: 22422705 DOI: 10.1002/biof.1008] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2011] [Accepted: 01/27/2012] [Indexed: 12/23/2022]
Abstract
Sunrouge, an anthocyanin-rich tea, has similar levels of catechins as "Yabukita," the most popular green tea cultivar consumed in Japan. Green tea polyphenols (GTPs) have attracted interest due to their potent antioxidative activities combined with a lack of side effects in humans at normal consumption levels. However, we previously reported that high doses (0.5 and 1%) of dietary GTPs can result in deterioration of colitis and failed to prevent colon carcinogenesis in inflamed colons. In the present study, we determined the inhibitory effects of Sunrouge on colitis in dextran sodium sulfate (DSS)-treated and untreated control mice. Five-week-old female ICR mice were administered a single dose of Yabukita or Sunrouge (extracts in 1 mL distilled water) via a stomach tube for 3 weeks. After 1 week of treatment, the mice were divided into four groups (two Yabukita and two Sunrouge groups) and given drinking water with or without 3% DSS for 2 weeks, then they were euthanized. Those treated with DSS developed watery diarrhea and bloody stools, and showed body weight loss, spleen hypertrophy, and shortening of the colon, as well as deteriorations in survival rate, liver function, colon mucosal interleukin-1β level and expression of phase II detoxification enzyme mRNA. Sunrouge improved these DSS-induced symptoms, at least in part, whereas Yabukita showed either no effect or adverse effects in regard to some those parameters. It is suggested that the differences between Yabukita and Sunrouge on DSS-induced colitis might be due to the high levels of anthocyanins found in Sunrouge tea.
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Affiliation(s)
- Satoko Akiyama
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Japan
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Okayasu I. Development of ulcerative colitis and its associated colorectal neoplasia as a model of the organ-specific chronic inflammation-carcinoma sequence. Pathol Int 2012; 62:368-80. [DOI: 10.1111/j.1440-1827.2012.02807.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Abdelouhab K, Rafa H, Toumi R, Bouaziz S, Medjeber O, Touil-Boukoffa C. Mucosal intestinal alteration in experimental colitis correlates with nitric oxide production by peritoneal macrophages: effect of probiotics and prebiotics. Immunopharmacol Immunotoxicol 2012; 34:590-7. [PMID: 22211319 DOI: 10.3109/08923973.2011.641971] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease (IBD) consists mainly of Ulcerative colitis (UC) and Crohn disease (CD). Although its aetiology is still not clearly established, it is thought to be due to overly aggressive immune response to enteric bacteria in genetically predisposed individuals. Manipulating the microbiota using probiotics or prebiotics is considered as a promising field of new therapeutic strategies used to attenuate immune disorders observed during IBD. The production of nitric oxide (NO) seems to be implicated in IBD pathogenesis. In our study, an acute UC was induced in Swiss mice using 3% Dextran Sulfate Sodium (DSS). The preventive effects of "Ultrabiotique®" (a probiotic) and inulin (a prebiotic) on the colitis were investigated. The production of NO was evaluated in the supernatants of peritoneal macrophages (pMφ) cultures. Colonic mucosa histology was subsequently examined. Results showed severe acute UC after administration of DSS. High levels of NO in pMφ cultures were also observed compared to control samples. These findings correlated with a significant destruction of the colonic mucosa. Oral administration of Ultrabiotique® or inulin decreased the severity of DSS-induced colitis. These treatments lead to a decrease in NO levels in pMφ cultures. A considerable reduction of colonic lesions was also noticed. Our findings suggest the involvement of NO in experimental UC pathogenesis. Pre- and pro-biotics, as discussed herein, seem to have an anti-inflammatory effect.
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Affiliation(s)
- Katia Abdelouhab
- Department of Biological Sciences, Laboratory of Cellular and Molecular Biology, Cytokines and NOSynthases Group, USTHB, Algiers, Algeria
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Huff KR, Akhtar LN, Fox AL, Cannon JA, Smith PD, Smythies LE. Extracellular matrix-associated cytokines regulate CD4+ effector T-cell responses in the human intestinal mucosa. Mucosal Immunol 2011; 4:420-7. [PMID: 21228771 PMCID: PMC3118864 DOI: 10.1038/mi.2010.86] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Extracellular matrix (stroma) regulation of mucosal T-cell function is incompletely understood. In this study, we uncovered a role for intestinal stromal products in the innate regulation of effector T cells. Stroma-conditioned media (S-CM) derived from the normal human intestinal stroma (transforming growth factor-β (TGF-β)(hi)/interleukin (IL)-6(lo)/IL-1β(lo)) significantly downregulated T-cell proliferation and interferon-γ (IFN-γ) production compared with S-CM derived from the inflamed Crohn's mucosa (TGF-β(hi)/IL-6(hi)/IL-1β(hi)). Antibody neutralization studies showed that TGF-β in normal S-CM inhibited T-cell proliferation and IFN-γ production, whereas IL-6 plus IL-1β in Crohn's S-CM promoted T-cell proliferation, and IL-1β alone promoted IFN-γ and IL-17 release. Importantly, normal S-CM inhibited T-bet expression, whereas Crohn's S-CM activated signal transducer and activator of transcription 3, suggesting that discordant T-cell responses are regulated at the transcription factor and signaling levels. These findings implicate stromal TGF-β in the downregulation of T-cell 2 responses in the normal intestinal mucosa, and stromal IL-6 and IL-1β in the promotion of Th1 and Th17 responses in the inflamed Crohn's mucosa, suggesting an innate regulatory function for the intestinal extracellular matrix.
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Affiliation(s)
- Kayci R. Huff
- Department of Medicine (Gastroenterology), University of Alabama at Birmingham, Birmingham, AL
| | | | - Anna L. Fox
- Department of Medicine (Gastroenterology), University of Alabama at Birmingham, Birmingham, AL
| | - Jamie A. Cannon
- Department of Surgery (Gastrointestinal), University of Alabama at Birmingham, Birmingham, AL
| | - Phillip D. Smith
- Department of Medicine (Gastroenterology), University of Alabama at Birmingham, Birmingham, AL
- Department of VA Medical Center, Birmingham, AL
| | - Lesley E. Smythies
- Department of Medicine (Gastroenterology), University of Alabama at Birmingham, Birmingham, AL
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