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Park C, Kim M, Park JW, Kim J, Bu Y, Ko SJ. Effect of Bojanggunbi-tang and its primary constituent herbs on the gastrointestinal tract: a scoping review. Front Pharmacol 2025; 16:1543194. [PMID: 40144663 PMCID: PMC11938064 DOI: 10.3389/fphar.2025.1543194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 02/18/2025] [Indexed: 03/28/2025] Open
Abstract
Background Bojanggunbi-tang (BGT), a herbal prescription used in traditional Korean medicine, has been used to treat various gastrointestinal (GI) diseases. Methods Studies on BGT published until May 2024 were retrieved from the electronic databases of Medline, CENTRAL, Embase, AMED, CNKI, CiNii, Kmbase, KISS, NDSL, and OASIS using GI-related terms. All study types, regardless of the research method or language, were eligible for inclusion. Additional articles on Lonicera japonica, Atractylodes macrocephala, and Alisma canaliculatum, which are key components of BGT, were retrieved from the databases of Medline, CENTRAL, Embase, and Web of Science using GI-specific terms. The basic information, research models, administration methods, evaluation methods, and treatment outcomes of the selected studies were examined subsequently. Results Fourteen studies, comprising nine animal studies, one cell-based study, and four human studies, were included in the final analysis. BGT was found to exhibit anti-inflammatory effects, promote restoration of the gastrointestinal mucosa, and regulate GI motility. Analysis of the key herbal components L. japonica, A. macrocephala, and A. canaliculatum revealed that they inhibit inflammatory cytokines and oxidative substances, regulate serotonin and cholinergic pathways, and modulate intestinal microbiota. Conclusion This scoping review confirmed the therapeutic potential and mechanisms of action of BGT and its main components, L. japonica, A. macrocephala, and A. canaliculatum, thereby indicating its ability to enhance GI health. Further studies, including randomized clinical trials, must be conducted in the future to confirm these findings. Scoping review registration The study was registered in OSF, an international scoping review database: https://doi.org/10.17605/OSF.IO/ATU4S.
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Affiliation(s)
- Chaehyun Park
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea
- Department of Korean Internal Medicine, Kyung Hee University College of Korean Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
| | - Minjeong Kim
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea
- Department of Korean Internal Medicine, Kyung Hee University College of Korean Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
| | - Jae-Woo Park
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea
- Department of Korean Internal Medicine, Kyung Hee University College of Korean Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
- Department of Digestive Diseases, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Jinsung Kim
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea
- Department of Digestive Diseases, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
- Division of Digestive Diseases, Department of Korean Internal Medicine, Kyung Hee University Korean Medicine Hospital, Seoul, Republic of Korea
| | - Youngmin Bu
- Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Seok-Jae Ko
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea
- Department of Korean Internal Medicine, Kyung Hee University College of Korean Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
- Department of Digestive Diseases, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
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Jacobs I, Deleu S, Cremer J, De Hertogh G, Vermeire S, Breynaert C, Vanuytsel T, Verstockt B. Eosinophil Depletion as a Potential Therapeutic Strategy in Acute and Chronic Intestinal Inflammation Based on a Dextran Sulfate Sodium Colitis Model. Inflamm Bowel Dis 2025; 31:169-177. [PMID: 39107256 DOI: 10.1093/ibd/izae168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Indexed: 08/09/2024]
Abstract
BACKGROUND A role for eosinophils in intestinal inflammation and fibrosis in the context of inflammatory bowel disease has been suggested, yet the precise nature, whether causal or secondary remains debated. Hence, it remains unclear whether targeting eosinophils should be further explored as a treatment option in inflammatory bowel disease. METHODS Acute and chronic dextran sulfate sodium colitis was induced in wild-type C57BL/6 mice. Eosinophils were depleted by anti-CCR3 injections before colitis induction in a chronic model and after colitis onset in an acute model in order to investigate the impact of eosinophil depletion on pre-existing colitis. Inflammation was assessed using the disease activity index, macroscopic damage, and histological disease activity score. In the chronic model, fibrosis was assessed by examining colon weight/length ratio, collagen deposition through Martius Scarlet Blue staining, hydroxyproline assay, and COL1A1 expression. Protein and gene expression were assessed using the Meso Scale Discovery platform and real-time quantitative polymerase chain reaction. RESULTS In the acute and chronic colitis model, eosinophil depletion resulted in reduced disease activity and faster recovery, as observed via the total area under the curve of the disease activity index (P = .004 and P = .02, respectively), macroscopic damage score (P = .009 and P = .08, respectively), and histological disease activity score (P = .09 and P = .002, respectively). In the acute model, the accelerated recovery was accompanied by an increase in interleukin (IL)-10 (P = .03) and a decrease in IL-4 (P = .03) and IL-6 (P = .009). Colon weight/length ratio and collagen deposition were not affected by eosinophil depletion. CONCLUSIONS Eosinophil depletion prevents and decreases intestinal inflammation in a preclinical dextran sulfate sodium model without affecting fibrosis. These results pave the way for exploring eosinophil depletion as a novel treatment modality in addressing intestinal inflammation.
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Affiliation(s)
- Inge Jacobs
- Allergy and Clinical Immunology Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Sara Deleu
- Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Jonathan Cremer
- Allergy and Clinical Immunology Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Gert De Hertogh
- Translational Cell & Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium
| | - Christine Breynaert
- Allergy and Clinical Immunology Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of General Internal Medicine, UZ Leuven, Leuven, Belgium
| | - Tim Vanuytsel
- Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium
| | - Bram Verstockt
- Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium
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Halder N, Yadav S, Lal G. Neuroimmune communication of the cholinergic system in gut inflammation and autoimmunity. Autoimmun Rev 2024; 23:103678. [PMID: 39500481 DOI: 10.1016/j.autrev.2024.103678] [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: 10/01/2024] [Revised: 11/01/2024] [Accepted: 11/01/2024] [Indexed: 11/08/2024]
Abstract
Neuroimmune communication in the body forms a bridge between two central regulatory systems of the body, i.e., nervous and immune systems. The cholinergic system is a crucial modulatory neurotransmitter in the central and peripheral nervous system. It includes the neurotransmitter acetylcholine (ACh), the enzyme required for the synthesis of ACh (choline acetyltransferase, ChAT), the enzyme required for its degradation (acetylcholinesterase, AChE), and cholinergic receptors (Nicotinic acetylcholine receptors and muscarinic acetylcholine receptors). The cholinergic system in neurons is well known for its role in cognitive function, sensory perception, motor control, learning, and memory processes. It has been shown that the non-neuronal cholinergic system (NNCS) is present in various tissues and immune cells and forms a neuroimmune communications system. In the present review, we discussed the NNCS on immune cells, its role in homeostasis and inflammatory reactions in the gut, and how it can be exploited in treating inflammatory responses.
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Affiliation(s)
- Namrita Halder
- Biotechnology Research and Innovation Council-National Centre for Cell Science (BRIC-NCCS), SPPU campus, Ganeshkhind, Pune, MH-411007, India
| | - Sourabh Yadav
- Biotechnology Research and Innovation Council-National Centre for Cell Science (BRIC-NCCS), SPPU campus, Ganeshkhind, Pune, MH-411007, India
| | - Girdhari Lal
- Biotechnology Research and Innovation Council-National Centre for Cell Science (BRIC-NCCS), SPPU campus, Ganeshkhind, Pune, MH-411007, India.
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Chen Y, Chen B, Li J, Li H, Wang G, Cai X, Zhang Q, Liu X, Kan C, Wang L, Wang Z, Li HB. Alternative mRNA polyadenylation regulates macrophage hyperactivation via the autophagy pathway. Cell Mol Immunol 2024; 21:1522-1534. [PMID: 39537902 PMCID: PMC11607066 DOI: 10.1038/s41423-024-01237-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 10/31/2024] [Accepted: 11/02/2024] [Indexed: 11/16/2024] Open
Abstract
Macrophage hyperactivation is a hallmark of inflammatory diseases, yet the role of alternative polyadenylation (APA) of mRNAs in regulating innate immunity remains unclear. In this study, we focused on 3'UTR-APA and demonstrated that Nudt21, a crucial RNA-binding component of the 3'UTR-APA machinery, is significantly upregulated in various inflammatory conditions. By utilizing myeloid-specific Nudt21-deficient mice, we revealed a protective effect of Nudt21 depletion against colitis and severe hyperinflammation, primarily through diminished production of proinflammatory cytokines. Notably, Nudt21 regulates the mRNA stability of key autophagy-related genes, Map1lc3b and Ulk2, by mediating selective 3'UTR polyadenylation in activated macrophages. As a result, Nudt21-deficient macrophages display increased autophagic activity, which leads to reduced cytokine secretion. Our findings highlight an unexplored role of Nudt21-mediated 3'UTR-APA in modulating macrophage autophagy and offer new insights into the modulation of inflammation and disease progression.
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Affiliation(s)
- Yunzhu Chen
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Jiao Tong University School of Medicine - Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Baiwen Chen
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Jiao Tong University School of Medicine - Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jingyu Li
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Jiao Tong University School of Medicine - Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haixin Li
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Gaoyang Wang
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Jiao Tong University School of Medicine - Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuemin Cai
- Institute of Immunological Innovation & Translation, Chongqing Medical University, Chongqing, China
| | - Qianqian Zhang
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Jiao Tong University School of Medicine - Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoxu Liu
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Jiao Tong University School of Medicine - Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chen Kan
- School of Biological Science, The University of Manchester, Manchester, UK
| | - Lei Wang
- Department of Geriatrics, Medical Center on Aging of Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhengting Wang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hua-Bing Li
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Shanghai Jiao Tong University School of Medicine - Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Institute of Immunological Innovation & Translation, Chongqing Medical University, Chongqing, China.
- Department of Geriatrics, Medical Center on Aging of Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Medical Center on Aging, Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Chongqing International Institute for Immunology, Chongqing, China.
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Jacobs I, Deleu S, Ke BJ, Cremer J, Dilissen E, De Hertogh G, Martens T, Vanden Berghe P, Matteoli G, Vermeire S, Breynaert C, Vanuytsel T, Verstockt B. Eosinophils mitigate intestinal fibrosis while promoting inflammation in a chronic DSS colitis model and co-culture model with fibroblasts. Sci Rep 2024; 14:27133. [PMID: 39511371 PMCID: PMC11543987 DOI: 10.1038/s41598-024-78602-0] [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: 03/19/2024] [Accepted: 11/01/2024] [Indexed: 11/15/2024] Open
Abstract
Eosinophils were previously reported to play a role in intestinal inflammation and fibrosis. Whether this is as a bystander or as an active participant is still up for debate. Moreover, data describing a causal relationship between eosinophils and intestinal fibrosis are scarce. We here aimed to elucidate the role of eosinophils in the pathogenesis of intestinal inflammation and fibrosis. Therefore, we stimulated fibroblasts with (active) eosinophils or with Eosinophil Cationic Protein (ECP), and assessed fibroblast activation via flow cytometry and immunocytochemistry. We observed decreased fibroblast activation when fibroblasts were co-cultured with active eosinophils or after stimulation with ECP in comparison to monoculture conditions, but not in case of co-culturing with inactivated eosinophils. Furthermore, eosinophil depletion in a RAG-/- chronic DSS colitis model resulted in decreased inflammation, but increased development of fibrosis. In this model, we could show increased expression of the anti-inflammatory protein IL-10 and the pro-fibrotic factors IL-1β, FGF-21 and TGF-β3 in the eosinophil-depleted mice compared to the control mice. In conclusion, our in vitro data revealed an anti-fibrotic role for eosinophils. In line, in a chronic murine colitis model, we observed a pro-inflammatory, but an anti-fibrotic, role for eosinophils. Furthermore, we identified an increased presence of anti-inflammatory and pro-fibrotic cytokines in the eosinophil depleted group.
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Affiliation(s)
- Inge Jacobs
- Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium
- Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Sara Deleu
- Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Bo-Jun Ke
- Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Jonathan Cremer
- Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium
| | - Ellen Dilissen
- Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium
| | - Gert De Hertogh
- Department of Imaging and Pathology, Translational Cell & Tissue Research, KU Leuven, Leuven, Belgium
| | - Tobie Martens
- Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Cell and tissue Imaging Cluster (CIC), KU Leuven, Leuven, Belgium
| | - Pieter Vanden Berghe
- Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Cell and tissue Imaging Cluster (CIC), KU Leuven, Leuven, Belgium
| | - Gianluca Matteoli
- Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Herestraat 49, Belgium
| | - Christine Breynaert
- Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium
- Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium
| | - Tim Vanuytsel
- Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Herestraat 49, Belgium
| | - Bram Verstockt
- Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Herestraat 49, Belgium.
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Yang H, Zhou C, Nie S, Xu S, Li M, Yu Q, Wei Y, Wang X. Anti-ulcerative colitis effect of rotating magnetic field on DSS-induced mice by modulating colonic inflammatory deterioration. Mol Immunol 2024; 172:23-37. [PMID: 38865801 DOI: 10.1016/j.molimm.2024.05.011] [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: 03/25/2024] [Revised: 05/15/2024] [Accepted: 05/29/2024] [Indexed: 06/14/2024]
Abstract
Ulcerative colitis (UC) is a prevalent inflammatory disorder that emerges in the colon and rectum, exhibiting a rising global prevalence and seriously impacting the physical and mental health of patients. Significant challenges remain in UC treatment, highlighting the need for safe and effective long-term therapeutic approaches. Heralded as a promising physical treatment, the rotating magnetic field (RMF) demonstrates safety, stability, manageability, and efficiency. This study delves into RMF's potential in mitigating DSS-induced UC in mice, assessing disease activity indices (DAI) and pathological alterations such as daily body weight, fecal occult blood, colon length, and morphological changes. Besides, several indexes have been detected, including serum concentrations of pro-inflammatory cytokines (IL6, IL-17A, TNF-α, IFN-γ) and anti-inflammatory cytokines (TGF-β, IL-4, IL-10), the ratio of splenic CD3+, CD4+, and CD8+ T cells, the rate of apoptotic colonic cells, the expression of colonic inflammatory and tight junction-associated proteins. The results showed that RMF had beneficial effects on the decrease of intestinal permeability, the restoration of tight junctions, and the mitigation of mitochondrial respiratory complexes (MRCs) by attenuating inflammatory dysfunction in colons of DSS-induced UC model of mice. In conclusion, this study demonstrates that RMF attenuates colonic inflammation, enhances colonic tight junction, and alleviates MRCs impairment by regulating the equilibrium of pro-inflammatory and anti-inflammatory cytokines in UC mice, suggesting the potential application of RMF in the clinical treatment of UC.
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Affiliation(s)
- Hua Yang
- Department of Physiology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China; International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518055, China
| | - Cai Zhou
- Department of Physiology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China
| | - Shenglan Nie
- Department of Physiology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China
| | - Shuling Xu
- School of Pharmacy, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China
| | - Mengqing Li
- Department of Physiology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China
| | - Qinyao Yu
- School of Pharmacy, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China
| | - Yunpeng Wei
- Department of Physiology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China.
| | - Xiaomei Wang
- Department of Physiology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China; International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518055, China; School of Pharmacy, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China.
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Pattison LA, Cloake A, Chakrabarti S, Hilton H, Rickman RH, Higham JP, Meng MY, Paine LW, Dannawi M, Qiu L, Ritoux A, Bulmer DC, Callejo G, Smith ESJ. Digging deeper into pain: an ethological behavior assay correlating well-being in mice with human pain experience. Pain 2024; 165:1761-1773. [PMID: 38452214 PMCID: PMC11247454 DOI: 10.1097/j.pain.0000000000003190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 12/11/2023] [Accepted: 01/03/2024] [Indexed: 03/09/2024]
Abstract
ABSTRACT The pressing need for safer, more efficacious analgesics is felt worldwide. Preclinical tests in animal models of painful conditions represent one of the earliest checkpoints novel therapeutics must negotiate before consideration for human use. Traditionally, the pain status of laboratory animals has been inferred from evoked nociceptive assays that measure their responses to noxious stimuli. The disconnect between how pain is tested in laboratory animals and how it is experienced by humans may in part explain the shortcomings of current pain medications and highlights a need for refinement. Here, we survey human patients with chronic pain who assert that everyday aspects of life, such as cleaning and leaving the house, are affected by their ongoing level of pain. Accordingly, we test the impact of painful conditions on an ethological behavior of mice, digging. Stable digging behavior was observed over time in naive mice of both sexes. By contrast, deficits in digging were seen after acute knee inflammation. The analgesia conferred by meloxicam and gabapentin was compared in the monosodium iodoacetate knee osteoarthritis model, with meloxicam more effectively ameliorating digging deficits, in line with human patients finding meloxicam more effective. Finally, in a visceral pain model, the decrease in digging behavior correlated with the extent of disease. Ultimately, we make a case for adopting ethological assays, such as digging, in studies of pain in laboratory animals, which we believe to be more representative of the human experience of pain and thus valuable in assessing clinical potential of novel analgesics in animals.
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Affiliation(s)
- Luke A. Pattison
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom. Dr. Chakrabarti is now with Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. Dr. Callejo is now with Department of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain
| | - Alexander Cloake
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom. Dr. Chakrabarti is now with Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. Dr. Callejo is now with Department of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain
| | - Sampurna Chakrabarti
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom. Dr. Chakrabarti is now with Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. Dr. Callejo is now with Department of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain
| | - Helen Hilton
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom. Dr. Chakrabarti is now with Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. Dr. Callejo is now with Department of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain
| | - Rebecca H. Rickman
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom. Dr. Chakrabarti is now with Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. Dr. Callejo is now with Department of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain
| | - James P. Higham
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom. Dr. Chakrabarti is now with Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. Dr. Callejo is now with Department of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain
| | - Michelle Y. Meng
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom. Dr. Chakrabarti is now with Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. Dr. Callejo is now with Department of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain
| | - Luke W. Paine
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom. Dr. Chakrabarti is now with Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. Dr. Callejo is now with Department of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain
| | - Maya Dannawi
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom. Dr. Chakrabarti is now with Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. Dr. Callejo is now with Department of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain
| | - Lanhui Qiu
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom. Dr. Chakrabarti is now with Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. Dr. Callejo is now with Department of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain
| | - Anne Ritoux
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom. Dr. Chakrabarti is now with Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. Dr. Callejo is now with Department of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain
| | - David C. Bulmer
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom. Dr. Chakrabarti is now with Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. Dr. Callejo is now with Department of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain
| | - Gerard Callejo
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom. Dr. Chakrabarti is now with Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. Dr. Callejo is now with Department of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain
| | - Ewan St. John Smith
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom. Dr. Chakrabarti is now with Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. Dr. Callejo is now with Department of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain
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Yang C, Merlin D. Unveiling Colitis: A Journey through the Dextran Sodium Sulfate-induced Model. Inflamm Bowel Dis 2024; 30:844-853. [PMID: 38280217 PMCID: PMC11063560 DOI: 10.1093/ibd/izad312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Indexed: 01/29/2024]
Abstract
Animal models of inflammatory bowel disease (IBD) are valuable tools for investigating the factors involved in IBD pathogenesis and evaluating new therapeutic options. The dextran sodium sulfate (DSS)-induced model of colitis is arguably the most widely used animal model for studying the pathogenesis of and potential treatments for ulcerative colitis (UC), which is a primary form of IBD. This model offers several advantages as a research tool: it is highly reproducible, relatively easy to generate and maintain, and mimics many critical features of human IBD. Recently, it has also been used to study the role of gut microbiota in the development and progression of IBD and to investigate the effects of other factors, such as diet and genetics, on colitis severity. However, although DSS-induced colitis is the most popular and flexible model for preclinical IBD research, it is not an exact replica of human colitis, and some results obtained from this model cannot be directly applied to humans. This review aims to comprehensively discuss different factors that may be involved in the pathogenesis of DSS-induced colitis and the issues that should be considered when using this model for translational purposes.
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Affiliation(s)
- Chunhua Yang
- Institute for Biomedical Sciences, Digestive Disease Research Group, Georgia State University, Atlanta, GA, 30303, USA
- Atlanta Veterans Affairs Medical Center, Decatur, GA, 30033, USA
| | - Didier Merlin
- Institute for Biomedical Sciences, Digestive Disease Research Group, Georgia State University, Atlanta, GA, 30303, USA
- Atlanta Veterans Affairs Medical Center, Decatur, GA, 30033, USA
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9
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Chen Y, Jin T, Zhang M, Hong B, Jin B, Hu C, Wang J, Chen Y, Zhang L, Wang Y, Huang L. Flavokawain B inhibits NF-κB inflammatory signaling pathway activation in inflammatory bowel disease by targeting TLR2. Toxicol Appl Pharmacol 2024; 486:116922. [PMID: 38583725 DOI: 10.1016/j.taap.2024.116922] [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: 12/03/2023] [Revised: 03/11/2024] [Accepted: 04/04/2024] [Indexed: 04/09/2024]
Abstract
Inflammatory bowel disease (IBD) is characterized by recurrent inflammatory reactions in the intestinal mucosa, including ulcerative colitis (UC) and Crohn's disease (CD). The expression of Toll-like receptor 2 (TLR2) has been observed to increase during the progression of IBD. Flavokawain B (FKB), a natural chalcone with potent anti-inflammatory activity, exerts its effects through inhibition of the NF-κB pathway. In this study, we aimed to investigate the effects and mechanisms of FKB targeting TLR2 in IBD. C57BL/6 J mice were treated with 2.5% dextran sulfate sodium (DSS) for 7 days, with administration of FKB or TLR2 inhibitor C29 starting on day 2 to establish the model of IBD. In vitro, bone marrow-derived macrophages (BMDMs) were stimulated with the TLR2 agonist Pam3CSK4 to explore the therapeutic effect of FKB and its pharmacological mechanism. Compared with the model group, the FKB-treated group showed significant reductions in colitis-related injuries in the IBD mouse model, including weight gain, increased colon length and reduced inflammation. FKB decreased the formation of TLR2-MyD88 complex by targeting TLR2, leading to suppression of downstream NF-κB signaling pathway. Similar therapeutic effects were observed in the C29-treated group. Additionally, in vitro data suggested that FKB exerted its anti-inflammatory effect by targeting TLR2 and inhibiting Pam3CSK4-induced activation of the NF-κB pathway. The anti-inflammatory effects of FKB were demonstrated through drug affinity responsive target stability assay and cellular thermal shift assay, revealing its binding affinity to TLR2. By inhibiting the activation of the TLR2/NF-κB signaling pathway, FKB effectively prevented DSS-induced IBD and exhibited promising potential as a therapeutic candidate for IBD treatment.
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Affiliation(s)
- Yi Chen
- Joint Research Center on Medicine, the Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, Zhejiang, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Tianyang Jin
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Mengpei Zhang
- Joint Research Center on Medicine, the Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, Zhejiang, China
| | - Bo Hong
- Joint Research Center on Medicine, the Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, Zhejiang, China
| | - Bo Jin
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Chenghong Hu
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jiong Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yue Chen
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lingxi Zhang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yi Wang
- Joint Research Center on Medicine, the Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, Zhejiang, China; School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China.
| | - Lijiang Huang
- Joint Research Center on Medicine, the Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, Zhejiang, China.
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10
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Li J, Wu H, Zhou J, Jiang R, Zhuo Z, Yang Q, Chen H, Sha W. Ruscogenin Attenuates Ulcerative Colitis in Mice by Inhibiting Caspase-1-Dependent Pyroptosis via the TLR4/NF-κB Signaling Pathway. Biomedicines 2024; 12:989. [PMID: 38790951 PMCID: PMC11117655 DOI: 10.3390/biomedicines12050989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 04/17/2024] [Accepted: 04/27/2024] [Indexed: 05/26/2024] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic inflammatory disorders affecting the digestive tract, including ulcerative colitis and Crohn's disease. Ruscogenin, a prominent steroidal sapogenin present in radix ophiopogon japonicus, has shown a protective effect on attenuating the inflammatory response associated with inflammatory diseases, but the efficacy of ruscogenin in IBD remains unclear. The aim of this study is to explore the effect of ruscogenin on intestinal barrier dysfunction and inflammatory responses as well as the underlying mechanism in ulcerative colitis. A dextran sulfate sodium salt (DSS)-induced C57BL/6 mouse colitis model was employed for the in vivo studies, while in vitro experiments were performed in THP-1 cells and human intestinal epithelial cells involved in inducing inflammatory responses and pyroptosis using LPS/nigericin. The results indicated that ruscogenin treatment attenuated the symptoms of ulcerative colitis, reduced the release of inflammatory cytokines and the expression of pyroptosis-associated proteins, and restored the integrity of the intestinal epithelial barrier in colon tissue in mice. Moreover, ruscogenin inhibited LPS/nigericin-induced pyroptosis in THP-1 cells. Mechanically, ruscogenin inhibited NLRP3 inflammasome activation and canonical pyroptosis, at least in part, through the suppression of the TLR4/NF-κB signaling pathway. These findings might provide new insights and a solid foundation for further exploration into the therapeutic potential of ruscogenin in the treatment of IBD.
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Affiliation(s)
- Jingwei Li
- Department of Gastroenterology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; (J.L.); (R.J.); (Z.Z.); (Q.Y.)
| | - Huihuan Wu
- Department of Gastroenterology, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan 528200, China;
| | - Jialiang Zhou
- Department of Neonatal Surgery, Guangdong Women and Children Hospital, Guangzhou 511400, China
| | - Rui Jiang
- Department of Gastroenterology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; (J.L.); (R.J.); (Z.Z.); (Q.Y.)
| | - Zewei Zhuo
- Department of Gastroenterology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; (J.L.); (R.J.); (Z.Z.); (Q.Y.)
| | - Qi Yang
- Department of Gastroenterology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; (J.L.); (R.J.); (Z.Z.); (Q.Y.)
| | - Hao Chen
- Department of Gastroenterology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; (J.L.); (R.J.); (Z.Z.); (Q.Y.)
| | - Weihong Sha
- Department of Gastroenterology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; (J.L.); (R.J.); (Z.Z.); (Q.Y.)
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11
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Tao L, Dou R, Chen X, Cao Y, Dai Z, Hu Z, Ma Z, Ge X, Zhang L, Wang X. Oroxyloside protects against dextran sulfate sodium-induced colitis by inhibiting ER stress via PPARγ activation. Chin J Nat Med 2024; 22:307-317. [PMID: 38658094 DOI: 10.1016/s1875-5364(24)60615-1] [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: 06/28/2023] [Indexed: 04/26/2024]
Abstract
Ulcerative colitis (UC), a prevalent form of inflammatory bowel disease (IBD), may result from immune system dysfunction, leading to the sustained overproduction of reactive oxygen species (ROS) and subsequent cellular oxidative stress damage. Recent studies have identified both peroxisome proliferator-activated receptor-γ (PPARγ) and endoplasmic reticulum (ER) stress as critical targets for the treatment of IBD. Oroxyloside (C22H20O11), derived from the root of Scutellariabaicalensis Georgi, has traditionally been used in treating inflammatory diseases. In this study, we investigated the molecular mechanisms by which oroxyloside mitigates dextran sulfate sodium (DSS)-induced colitis. We examined the effects of oroxyloside on ROS-mediated ER stress in colitis, including the protein expressions of GRP78, p-PERK, p-eIF2α, ATF4, and CHOP, which are associated with ER stress. The beneficial impact of oroxyloside was reversed by the PPARγ antagonist GW9662 (1 mg·kg-1, i.v.) in vivo. Furthermore, oroxyloside decreased pro-inflammatory cytokines and ROS production in both bone marrow-derived macrophages (BMDM) and the mouse macrophage cell line RAW 264.7. However, PPARγ siRNA transfection blocked the anti-inflammatory effect of oroxyloside and even abolished ROS generation and ER stress activation inhibited by oroxyloside in vitro. In conclusion, our study demonstrates that oroxyloside ameliorates DSS-induced colitis by inhibiting ER stress via PPARγ activation, suggesting that oroxyloside might be a promising effective agent for IBD.
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Affiliation(s)
- Lei Tao
- Nanjing Institute for Food and Drug Control, Nanjing 211198, China.
| | - Renjie Dou
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Xueming Chen
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Yu Cao
- Nanjing Institute for Food and Drug Control, Nanjing 211198, China
| | - Zhen Dai
- Nanjing Institute for Food and Drug Control, Nanjing 211198, China
| | - Ziyan Hu
- Nanjing Institute for Food and Drug Control, Nanjing 211198, China
| | - Zhi Ma
- Nanjing Institute for Food and Drug Control, Nanjing 211198, China
| | - Xiaoming Ge
- Nanjing Institute for Food and Drug Control, Nanjing 211198, China
| | - Ling Zhang
- Nanjing Institute for Food and Drug Control, Nanjing 211198, China
| | - Xiaoping Wang
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
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12
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Zhu F, Zhi Y, Li Y, Niu H, Ren S. The Mechanism of Polygonum Hydropiper L-Coptis Chinensis in the Treatment of Ulcerative Colitis Based on Network Pharmacology and Experimental Validation. FRONT BIOSCI-LANDMRK 2024; 29:93. [PMID: 38538280 DOI: 10.31083/j.fbl2903093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 01/16/2024] [Accepted: 01/31/2024] [Indexed: 01/05/2025]
Abstract
BACKGROUND Polygonum hydropiper L (PH) was widely used to treat dysentery, gastroenteritis, diarrhea and other diseases. Coptis chinensis (CC) had the effects of clearing dampness-heat, purging fire, and detoxifying. Study confirmed that flavonoids in PH and alkaloids in CC alleviated inflammation to inhibit the development of intestinal inflammation. However, how PH-CC affects UC was unclear. Therefore, the aim of this study is to analyze the mechanism of PH-CC on ulcerative colitis (UC) through network pharmacology and in vivo experiments. METHODS The active ingredients and targets of PH-CC and targets of UC were screened based on related databases. The core targets of PH-CC on UC was predicted by protein-protein interaction network (PPI), and then the Gene Ontology-biological processes (GO-BP) function enrichment analysis was conducted using the Database for Annotation, Visualization and Integrated Discovery (DAVID) database. The binding activity between pyroptosis proteins, core targets and effective ingredients were verified based on molecular docking technology. Finally, combined with the results of network pharmacology and literature research, the mechanism of PH-CC against UC was verified by in vivo experiments. RESULTS There were 23 active components and 191 potential targets in PH-CC, 5275 targets in UC, and 141 co-targets. GO-BP functional analysis of 141 co-targets showed that the first 20 biological processes were closely related to inflammation and lipopolysaccharide (LPS) stimulation. Furthermore, core targets had good binding activity with the corresponding compounds. Animal experiment indicated that PH-CC effectively prevented weight loss in UC mice, reduced the disease activity index (DAI) score, maintained colon length, suppressed myeloperoxidase (MPO) activity, inhibited pyroptosis protein expression, and downregulated the levels of IL-18 and IL-1β to alleviate intestinal inflammation. CONCLUSIONS The results of network pharmacology and animal experiments showed that PH-CC suppressed the inflammatory response, restored colon morphology, and inhibited pyroptosis in UC mice. Thus, PH-CC may improve UC by regulating the NOD-like receptor protein domain 3 (NLRP3)/Caspase-1 signaling pathway.
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Affiliation(s)
- Feifei Zhu
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Key Laboratory for Research and Development of Tropical Herbs, Haikou Key Laboratory of Li Nationality Medicine, School of Pharmacy, Hainan Medical University, 571199 Haikou, Hainan, China
| | - Yunyun Zhi
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Key Laboratory for Research and Development of Tropical Herbs, Haikou Key Laboratory of Li Nationality Medicine, School of Pharmacy, Hainan Medical University, 571199 Haikou, Hainan, China
| | - Yonghui Li
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Key Laboratory for Research and Development of Tropical Herbs, Haikou Key Laboratory of Li Nationality Medicine, School of Pharmacy, Hainan Medical University, 571199 Haikou, Hainan, China
| | - Haiyan Niu
- Department of Pathology, The First Affiliated Hospital of Hainan Medical University, 570102 Haikou, Hainan, China
| | - Shouzhong Ren
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Key Laboratory for Research and Development of Tropical Herbs, Haikou Key Laboratory of Li Nationality Medicine, School of Pharmacy, Hainan Medical University, 571199 Haikou, Hainan, China
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13
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Labib M, Wang Z, Kim Y, Lin S, Abdrabou A, Yousefi H, Lo PY, Angers S, Sargent EH, Kelley SO. Identification of druggable regulators of cell secretion via a kinome-wide screen and high-throughput immunomagnetic cell sorting. Nat Biomed Eng 2024; 8:263-277. [PMID: 38012306 DOI: 10.1038/s41551-023-01135-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 10/16/2023] [Indexed: 11/29/2023]
Abstract
The identification of genetic regulators of cell secretions is challenging because it requires the sorting of a large number of cells according to their secretion patterns. Here we report the development and applicability of a high-throughput microfluidic method for the analysis of the secretion levels of large populations of immune cells. The method is linked with a kinome-wide loss-of-function CRISPR screen, immunomagnetically sorting the cells according to their secretion levels, and the sequencing of their genomes to identify key genetic modifiers of cell secretion. We used the method, which we validated against flow cytometry for cytokines secreted from primary mouse CD4+ (cluster of differentiation 4-positive) T cells, to discover a subgroup of highly co-expressed kinase-coding genes that regulate interferon-gamma secretion by these cells. We validated the function of the kinases identified using RNA interference, CRISPR knockouts and kinase inhibitors and confirmed the druggability of selected kinases via the administration of a kinase inhibitor in an animal model of colitis. The technique may facilitate the discovery of regulatory mechanisms for immune-cell activation and of therapeutic targets for autoimmune diseases.
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Affiliation(s)
- Mahmoud Labib
- Peninsula Medical School, Faculty of Health, University of Plymouth, Plymouth, UK
- Department of Chemistry, Northwestern University, Evanston, IL, USA
- Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Zongjie Wang
- Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA
| | - Yunhye Kim
- Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Sichun Lin
- Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Abdalla Abdrabou
- Robert H. Laurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
| | - Hanie Yousefi
- Department of Chemistry, Northwestern University, Evanston, IL, USA
| | - Pei-Ying Lo
- Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA
| | - Stéphane Angers
- Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada
- Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
- Donnelly Centre for Cellular and Biomolecular Research, Toronto, Ontario, Canada
| | - Edward H Sargent
- Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA
- Department of Electrical & Computer Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Shana O Kelley
- Department of Chemistry, Northwestern University, Evanston, IL, USA.
- Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada.
- Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA.
- Robert H. Laurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA.
- Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
- Donnelly Centre for Cellular and Biomolecular Research, Toronto, Ontario, Canada.
- Institute for Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
- Chan Zuckerberg Biohub Chicago, Chicago, IL, USA.
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14
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Gold MS, Loeza-Alcocer E. Experimental colitis-induced visceral hypersensitivity is attenuated by GABA treatment in mice. Am J Physiol Gastrointest Liver Physiol 2024; 326:G252-G263. [PMID: 38193198 PMCID: PMC11211035 DOI: 10.1152/ajpgi.00012.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 12/21/2023] [Accepted: 12/26/2023] [Indexed: 01/10/2024]
Abstract
Ulcerative colitis (UC) is linked with inflammation of the large intestine due to an overactive response of the colon-immune system. UC is associated with weight loss, rectal bleeding, diarrhea, and abdominal pain. Given that γ-amino butyric acid (GABA) suppresses immune cell activity and the excitability of colonic afferents, and that there is a decrease in colonic GABA during UC, we hypothesized that UC pain is due to a decrease in the inhibition of colonic afferents. Thus, restoring GABA in the colon will attenuate inflammatory hypersensitivity. We tested this hypothesis in a mouse model of colitis. Colon inflammation was induced with seven days of dextran sodium sulfate (DSS, 3%) in the drinking water. GABA (40 mg/kg) was administered orally for the same period as DSS, and body weight, colon length, colon permeability, clinical progression of colitis (disease activity index or DAI), and colon histological score (HS) were assessed to determine the effects of GABA on colitis. A day after the end of GABA treatment, visceral sensitivity was assessed with balloon distention (of the colon)-evoked visceromotor response and colon samples were collected for the measurement of GABA and cytokines. Treatment with GABA reduced the DSS-induced increase in the colon permeability, DAI, HS, and decrease in body weight and colon length. Furthermore, GABA inhibited the DSS-induced increase in the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-12 (IL-12), and increased the expression of the anti-inflammatory cytokine IL-10 in the colon tissue. Importantly, GABA reduced DSS-induced visceral hypersensitivity. These data suggest that increasing gastrointestinal levels of GABA may be useful for the treatment of colitis.NEW & NOTEWORTHY GABA treatment reduces the severity of colitis and inflammation and produces inhibition of visceral hypersensitivity in colon-inflamed mice. These results raise the promising possibility that GABA treatment may be an effective therapeutic strategy for the management of symptoms associated with colitis. However, clinical studies are required to corroborate whether this mouse-model data translates to human colon.
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Affiliation(s)
- Michael S Gold
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
| | - Emanuel Loeza-Alcocer
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
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15
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Ji ZH, He S, Xie WY, Zhao PS, Ren WZ, Gao W, Yuan B. Agaricus blazei Polysaccharide Alleviates DSS-Induced Colitis in Mice by Modulating Intestinal Barrier and Remodeling Metabolism. Nutrients 2023; 15:4877. [PMID: 38068735 PMCID: PMC10707896 DOI: 10.3390/nu15234877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 11/15/2023] [Accepted: 11/20/2023] [Indexed: 12/18/2023] Open
Abstract
Ulcerative colitis (UC) is a chronic noninfectious intestinal disease that severely affects patients' quality of life. Agaricus blazei Murrill polysaccharide (ABP) is an effective active ingredient extracted from Agaricus blazei Murrill (ABM). It has good efficacy in inhibiting tumor cell growth, lowering blood pressure, and improving atherosclerosis. However, its effect on colitis is unclear. The aim of this study was to analyze the protective effects and potential mechanisms of ABP against dextran sulfate sodium (DSS)-induced acute colitis in mice. The results showed that dietary supplementation with ABP significantly alleviated DSS-induced colitis symptoms, inflammatory responses, and oxidative stress. Meanwhile, ABP intervention was able to maintain the integrity of the intestinal mechanical barrier by promoting the expression of ZO-1 and Occludin tight junction proteins and facilitating mucus secretion. Moreover, 16S rRNA sequencing results suggested that ABP intervention was able to alleviate DSS-induced gut microbiota disruption, and nontargeted metabolomics results indicated that ABP was able to remodel metabolism. In conclusion, these results demonstrate that dietary supplementation with ABP alleviated DSS-induced acute colitis by maintaining intestinal barrier integrity and remodeling metabolism. These results improve our understanding of ABP function and provide a theoretical basis for the use of dietary supplementation with ABP for the prevention of ulcerative colitis.
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Affiliation(s)
- Zhong-Hao Ji
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China
- Department of Basic Medicine, Changzhi Medical College, Changzhi 046000, China
| | - Song He
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China
| | - Wen-Yin Xie
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China
| | - Pei-Sen Zhao
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China
| | - Wen-Zhi Ren
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China
| | - Wei Gao
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China
| | - Bao Yuan
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun 130062, China
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16
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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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17
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Gan F, Lin Z, Tang J, Chen X, Huang K. Deoxynivalenol at No-Observed Adverse-Effect Levels Aggravates DSS-Induced Colitis through the JAK2/STAT3 Signaling Pathway in Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:4144-4152. [PMID: 36847760 DOI: 10.1021/acs.jafc.3c00252] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
The etiology of inflammatory bowel diseases (IBDs) involves complex genetic and environmental factors such as mycotoxin contamination. Deoxynivalenol (DON), a well-known mycotoxin, contaminates food and feed and can induce intestinal injury and inflammatory response. The dose of DON in many foods is also below the limit, although the dose of DON exceeds the limit. The present study aims to evaluate the effects of the nontoxic dose of DON on colitis induced by dextran sodium sulfate (DSS) and the mechanism in mice. The results showed a nontoxic dose of DON at 50 μg/kg bw per day exacerbated DSS-induced colitis in mice as demonstrated by increased disease activity index, decreased colon length, increased morphological damage, decreased occludin and mucoprotein 2 expression, increased IL-1β and TNF-α expression, and decreased IL-10 expression. DON at 50 μg/kg bw per day enhanced JAK2/STAT3 phosphorylation induced by DSS. Adding JAK2 inhibitor AG490 attenuated the aggravating effects of DON on DSS-induced colitis by reversing the morphological damage, occludin and mucoprotein 2 expression increased, IL-1β and TNF-α expression increased, and IL-10 expression decreased. Taken together, a nontoxic dose of DON could aggravate DSS-induced colitis via the JAK2/STAT3 signaling pathway. This suggests that DON, below the standard limit dose, is also a risk for IBD and may be harmful to the health of humans and animals, which could provide the basis for establishing limits for DON.
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Affiliation(s)
- Fang Gan
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095 Jiangsu Province, China
- Institute of Animal Nutritional Health, Nanjing Agricultural University, Nanjing 210095 Jiangsu Province, China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095 Jiangsu Province, China
| | - Ziman Lin
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095 Jiangsu Province, China
- Institute of Animal Nutritional Health, Nanjing Agricultural University, Nanjing 210095 Jiangsu Province, China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095 Jiangsu Province, China
| | - Jiangyu Tang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095 Jiangsu Province, China
- Institute of Animal Nutritional Health, Nanjing Agricultural University, Nanjing 210095 Jiangsu Province, China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095 Jiangsu Province, China
| | - Xingxiang Chen
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095 Jiangsu Province, China
- Institute of Animal Nutritional Health, Nanjing Agricultural University, Nanjing 210095 Jiangsu Province, China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095 Jiangsu Province, China
| | - Kehe Huang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095 Jiangsu Province, China
- Institute of Animal Nutritional Health, Nanjing Agricultural University, Nanjing 210095 Jiangsu Province, China
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095 Jiangsu Province, China
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18
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de Andrade STQ, Guidugli TI, Borrego A, Rodrigues BLC, Fernandes NCCDA, Guerra JM, de Sousa JG, Starobinas N, Jensen JR, Cabrera WHK, De Franco M, Ibañez OM, Massa S, Ribeiro OG. Slc11a1 gene polymorphism influences dextran sulfate sodium (DSS)-induced colitis in a murine model of acute inflammation. Genes Immun 2023; 24:71-80. [PMID: 36792680 PMCID: PMC10110460 DOI: 10.1038/s41435-023-00199-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 01/26/2023] [Accepted: 02/02/2023] [Indexed: 02/17/2023]
Abstract
Ulcerative Colitis (UC) is an inflammatory disease characterized by colonic mucosal lesions associated with an increased risk of carcinogenesis. UC pathogenesis involves environmental and genetic factors. Genetic studies have indicated the association of gene variants coding for the divalent metal ion transporter SLC11A1 protein (formerly NRAMP1) with UC susceptibility in several animal species. Two mouse lines were genetically selected for high (AIRmax) or low (AIRmin) acute inflammatory responses (AIR). AIRmax is susceptible, and AIRmin is resistant to DSS-induced colitis and colon carcinogenesis. Furthermore, AIRmin mice present polymorphism of the Slc11a1 gene. Here we investigated the possible modulating effect of the Slc11a1 R and S variants in DSS-induced colitis by using AIRmin mice homozygous for Slc11a1 R (AIRminRR) or S (AIRminSS) alleles. We evaluated UC by the disease activity index (DAI), considering weight loss, diarrhea, blood in the anus or feces, cytokines, histopathology, and cell populations in the distal colon epithelium. AIRminSS mice have become susceptible to DSS effects, with higher DAI, IL6, G-CSF, and MCP-1 production and morphological and colon histopathological alterations than AIRminRR mice. The results point to a role of the Slc11a1 S allele in DSS colitis induction in the genetic background of AIRmin mice.
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Affiliation(s)
| | | | - Andrea Borrego
- Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil
| | | | | | | | | | - Nancy Starobinas
- Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil
| | | | | | | | | | - Solange Massa
- Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil
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19
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Fermented Glutinous Rice Extract Mitigates DSS-Induced Ulcerative Colitis by Alleviating Intestinal Barrier Function and Improving Gut Microbiota and Inflammation. Antioxidants (Basel) 2023; 12:antiox12020336. [PMID: 36829894 PMCID: PMC9951866 DOI: 10.3390/antiox12020336] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/19/2023] [Accepted: 01/30/2023] [Indexed: 02/04/2023] Open
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease caused by various factors, including intestinal inflammation and barrier dysfunction. Herein, we determined the effects of fermented glutinous rice (FGR) on the expression of tight junction proteins and levels of inflammation and apoptosis in the dextran sodium sulfate (DSS)-induced acute colitis model. FGR was orally administered once per day to C57BL/6J mice with colitis induced by 5% DSS in drinking water. FGR administration recovered DSS-induced body weight loss and irregularly short colon lengths. FGR inhibited the DSS-induced decrease in FITC-dextran (FD)-4 permeability and myeloperoxidase activity. Moreover, FGR treatment repaired the reduction of zonula occluden-1 (ZO-1) and occludin expression and the increase in claudin-2 expression in colonic tissue relative to that following DSS administration. FGR treatment significantly recovered expression of cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β, in serum or respective mRNA expression in colonic tissue relative to that following DSS administration. FGR regulated levels of oxidative stress-related factors, such as malondialdehyde and glutathione, and the activity of catalase and superoxide dismutase in the colon tissue of the DSS-induced acute colitis mice model. Furthermore, FGR treatment inhibited apoptosis by reducing the activity of caspase-3 and the ratio of Bcl-2 associated X (Bax)/B-cell lymphoma 2 (Bcl-2). Collectively, FGR treatment protected the intestinal barrier from dysfunction and inhibited inflammation and apoptosis in DSS-induced colitis. Therefore, FGR may decrease the inflammatory response and be a candidate for treating and prevention inflammatory bowel disease by protecting the intestinal integrity.
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20
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Peters LA, Friedman JR, Stojmirovic A, Hagen J, Houten S, Dodatko T, Amaro MP, Restrepo P, Chai Z, Rodrigo Mora J, Raymond HA, Curran M, Dobrin R, Das A, Xiong H, Schadt EE, Argmann C, Losic B. A temporal classifier predicts histopathology state and parses acute-chronic phasing in inflammatory bowel disease patients. Commun Biol 2023; 6:95. [PMID: 36694043 PMCID: PMC9873918 DOI: 10.1038/s42003-023-04469-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 01/12/2023] [Indexed: 01/25/2023] Open
Abstract
Previous studies have conducted time course characterization of murine colitis models through transcriptional profiling of differential expression. We characterize the transcriptional landscape of acute and chronic models of dextran sodium sulfate (DSS) and adoptive transfer (AT) colitis to derive temporal gene expression and splicing signatures in blood and colonic tissue in order to capture dynamics of colitis remission and relapse. We identify sub networks of patient-derived causal networks that are enriched in these temporal signatures to distinguish acute and chronic disease components within the broader molecular landscape of IBD. The interaction between the DSS phenotype and chronological time-point naturally defines parsimonious temporal gene expression and splicing signatures associated with acute and chronic phases disease (as opposed to ordinary time-specific differential expression/splicing). We show these expression and splicing signatures are largely orthogonal, i.e. affect different genetic bodies, and that using machine learning, signatures are predictive of histopathological measures from both blood and intestinal data in murine colitis models as well as an independent cohort of IBD patients. Through access to longitudinal multi-scale profiling from disease tissue in IBD patient cohorts, we can apply this machine learning pipeline to generation of direct patient temporal multimodal regulatory signatures for prediction of histopathological outcomes.
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Affiliation(s)
- Lauren A. Peters
- grid.59734.3c0000 0001 0670 2351Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Joshua R. Friedman
- grid.476706.40000 0004 7647 0615Spark Therapeutics, Philadelphia, PA USA ,grid.497530.c0000 0004 0389 4927Janssen Research & Development, LLC, Spring House, Philadelphia, PA USA
| | - Aleksandar Stojmirovic
- grid.497530.c0000 0004 0389 4927Janssen Research & Development, LLC, Spring House, Philadelphia, PA USA
| | - Jacob Hagen
- grid.59734.3c0000 0001 0670 2351Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Sander Houten
- grid.59734.3c0000 0001 0670 2351Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Tetyana Dodatko
- grid.59734.3c0000 0001 0670 2351Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Mariana P. Amaro
- grid.59734.3c0000 0001 0670 2351Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Paula Restrepo
- grid.59734.3c0000 0001 0670 2351Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Zhi Chai
- grid.59734.3c0000 0001 0670 2351Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - J. Rodrigo Mora
- grid.497530.c0000 0004 0389 4927Janssen Research & Development, LLC, Spring House, Philadelphia, PA USA ,grid.479574.c0000 0004 1791 3172Moderna, Cambridge, MA USA
| | - Holly A. Raymond
- grid.497530.c0000 0004 0389 4927Janssen Research & Development, LLC, Spring House, Philadelphia, PA USA
| | - Mark Curran
- grid.497530.c0000 0004 0389 4927Janssen Research & Development, LLC, Spring House, Philadelphia, PA USA
| | - Radu Dobrin
- grid.497530.c0000 0004 0389 4927Janssen Research & Development, LLC, Spring House, Philadelphia, PA USA ,Pathos AI, Berwyn, PA USA
| | - Anuk Das
- grid.497530.c0000 0004 0389 4927Janssen Research & Development, LLC, Spring House, Philadelphia, PA USA
| | - Huabao Xiong
- grid.59734.3c0000 0001 0670 2351Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Eric E. Schadt
- grid.59734.3c0000 0001 0670 2351Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Carmen Argmann
- grid.59734.3c0000 0001 0670 2351Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Bojan Losic
- grid.59734.3c0000 0001 0670 2351Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA ,grid.511203.4Present Address: Guardant Health, Redwood City, CA USA
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21
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Ahmad T, Ishaq M, Karpiniec S, Park A, Stringer D, Singh N, Ratanpaul V, Wolfswinkel K, Fitton H, Caruso V, Eri R. Oral Macrocystis pyrifera Fucoidan Administration Exhibits Anti-Inflammatory and Antioxidant Properties and Improves DSS-Induced Colitis in C57BL/6J Mice. Pharmaceutics 2022; 14:2383. [PMID: 36365201 PMCID: PMC9693024 DOI: 10.3390/pharmaceutics14112383] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/27/2022] [Accepted: 10/31/2022] [Indexed: 07/30/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a complex and multifactorial disorder characterised by relapsing and remitting inflammation of the intestinal tract. Oxidative stress (OS) is the result of an imbalance between production and accumulation of reactive oxygen species (ROS), which has been associated with inflammatory responses and implicated in the exacerbation of IBD. Fucoidan, a sulfated polysaccharide from brown seaweed, is a well-known anti-inflammatory agent and emerging evidence indicates that fucoidan extracts from Macrocystis pyrifera (MPF and DP-MPF) may also modulate oxidative stress. This study investigated the impact of fucoidan extracts, MPF and DP-MPF in a dextran sodium sulphate (DSS)-induced mouse model of acute colitis. 3% DSS was administered in C57BL/6J male mice over a period of 7 days, and MPF and DP-MPF were co-administered orally at a dose of 400 mg/kg body weight. Our results indicated that MPF and DP-MPF significantly prevented body weight loss, improved the disease activity index (DAI), restored colon lengths, reduced the wet colon weight, reduced spleen enlargement, and improved the overall histopathological score. Consistent with the reported anti-inflammatory functions, fucoidan extracts, MPF and DP-MPF significantly reduced the colonic levels of myeloperoxidase (MPO), nitric oxide (NO), malondialdehyde (MDA) and increased the levels of antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT). In addition, MPF and DP-MPF significantly inhibited levels of pro-inflammatory cytokines in colon-derived tissues. Collectively, our results indicate that MPF and DP-MPF exhibited anti-inflammatory and antioxidant effects representing a promising therapeutic strategy for the cure of IBD.
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Affiliation(s)
- Tauseef Ahmad
- College of Health and Medicine, University of Tasmania, Newnham, TAS 7248, Australia
| | - Muhammad Ishaq
- School of Pharmacy and Pharmacology, University of Tasmania, Hobart, TAS 7001, Australia
| | | | - Ahyoung Park
- Marinova Pty Ltd., Cambridge, TAS 7170, Australia
| | | | - Neeraj Singh
- College of Health and Medicine, University of Tasmania, Newnham, TAS 7248, Australia
| | - Vishal Ratanpaul
- School of Science, RMIT University, Bundoora West Campus, Plenty Road, Melbourne, VIC 3083, Australia
| | - Karen Wolfswinkel
- Department of Pathology, Launceston General Hospital (LGH), Launceston, TAS 7250, Australia
| | | | - Vanni Caruso
- School of Pharmacy and Pharmacology, University of Tasmania, Hobart, TAS 7001, Australia
- Istituto di Formazione e Ricerca in Scienze Algologiche (ISAL), Torre Pedrera, 47922 Rimini, Italy
| | - Rajaraman Eri
- College of Health and Medicine, University of Tasmania, Newnham, TAS 7248, Australia
- School of Science, RMIT University, Bundoora West Campus, Plenty Road, Melbourne, VIC 3083, Australia
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22
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Devi S, Kapila R, Kapila S. A novel gut inflammatory rat model by laparotomic injection of peptidoglycan from Staphylococcus aureus. Arch Microbiol 2022; 204:684. [DOI: 10.1007/s00203-022-03294-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 09/21/2022] [Accepted: 10/18/2022] [Indexed: 11/16/2022]
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23
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Ma X, Di Q, Li X, Zhao X, Zhang R, Xiao Y, Li X, Wu H, Tang H, Quan J, Wu Z, Xiao W, Chen W. Munronoid I Ameliorates DSS-Induced Mouse Colitis by Inhibiting NLRP3 Inflammasome Activation and Pyroptosis Via Modulation of NLRP3. Front Immunol 2022; 13:853194. [PMID: 35865528 PMCID: PMC9296101 DOI: 10.3389/fimmu.2022.853194] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 06/07/2022] [Indexed: 12/31/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) are increasingly common diseases characterized by chronic and relapsing inflammation of the gastrointestinal tract. NLRP3 might be a crucial regulator of the homeostatic balance of the intestine, but its upregulation leads to pyroptosis. Munronoid I is extracted and purified from Munronia sinica, which has shown an anti-inflammatory effect, but the efficacy of Munronoid I in IBD remains unproven. In this study, we attempted to determine the effect of Munronoid I on NLRP3 to regulate the inflammasome activation and pyroptosis in IBD. Our data demonstrated that Munronoid I treatment attenuated DSS-induced body weight loss, pathological injury of the colon, the production of IL-1β and IL-18, and the expression of pyroptosis-associated proteins in colon tissue in mice. Moreover, Munronoid I inhibited LPS/ATP-induced pyroptosis in mouse peritoneal macrophages, MODE-K cells, and DSS-induced pyroptosis in mouse colonic epithelial cells, and decreased the release of inflammatory cytokines IL-1β and IL-18 in mouse peritoneal macrophages. Mechanically, Munronoid I could suppress the NLRP3 inflammasome activation and pyroptosis by promoting the K48-linked ubiquitination and NLRP3 degradation. It is suggested that Munronoid I might be a potential therapeutic candidate for IBD.
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Affiliation(s)
- Xingyu Ma
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Qianqian Di
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Xiaoli Li
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, China
| | - Xibao Zhao
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Ruihan Zhang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, China
| | - Yue Xiao
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Xunwei Li
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Han Wu
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Haimei Tang
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Jiazheng Quan
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Zherui Wu
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Weilie Xiao
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, China
- *Correspondence: Weilie Xiao, ; Weilin Chen,
| | - Weilin Chen
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
- *Correspondence: Weilie Xiao, ; Weilin Chen,
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24
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Loeza-Alcocer E, Gold MS. Peripheral GABAA receptor signaling contributes to visceral hypersensitivity in a mouse model of colitis. Pain 2022; 163:1402-1413. [PMID: 34726659 PMCID: PMC9056586 DOI: 10.1097/j.pain.0000000000002526] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 09/16/2021] [Indexed: 11/26/2022]
Abstract
ABSTRACT Pain is a common and debilitating symptom of inflammatory bowel disease (IBD). Based on evidence that peripheral GABAA receptor (GAR) inhibition plays an important role in establishing colonic afferent excitability and nociceptive threshold, we hypothesized that the increase in pain associated with IBD is due to, at least in part, a decrease in peripheral GAR-mediated inhibition. Acute colitis was induced with 5 days of dextran sodium sulfate (DSS, 3%) in the drinking water. Visceral sensitivity was assessed with the visceromotor response (VMR) evoked with balloon distention of the colon in control and DSS-treated mice before and after intracolonic administration of GAR agonist muscimol, the high-affinity GAR preferring agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol (THIP), the GAR positive allosteric modulator diazepam, or the GAR antagonists gabazine and bicuculline. Low concentrations of muscimol or THIP increased the VMR in DSS-treated mice but not in control mice. However, high concentrations of muscimol decreased the VMR in both control and DSS-treated mice. Diazepam decreased the VMR in both DSS-treated and control mice. By contrast, at a concentration of gabazine that blocks only low-affinity GAR, there was no effect on the VMR in either DSS-treated or control mice, but at concentrations of the antagonist that block low-affinity and high-affinity GAR, the VMR was increased in control mice and decreased in DSS-treated mice. Furthermore, bicuculline increased the VMR in control mice but decreased it in DSS-treated mice. These data suggest that activating of low-affinity GAR or blocking high-affinity GAR may be effective therapeutic strategies for the management of pain in IBD.
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Affiliation(s)
- Emanuel Loeza-Alcocer
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Michael S Gold
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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25
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Yaghoubi A, Amel Jamehdar S, Reza Akbari Eidgahi M, Ghazvini K. Evaluation of the therapeutic effect of melittin peptide on the ulcerative colitis mouse model. Int Immunopharmacol 2022; 108:108810. [DOI: 10.1016/j.intimp.2022.108810] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 04/13/2022] [Accepted: 04/25/2022] [Indexed: 12/27/2022]
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26
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Wu G, Zhang D, Yang L, Wu Q, Yuan L. MicroRNA-200c-5p targets NIMA Related Kinase 7 (NEK7) to inhibit NOD-like receptor 3 (NLRP3) inflammasome activation, MODE-K cell pyroptosis, and inflammatory bowel disease in mice. Mol Immunol 2022; 146:57-68. [DOI: 10.1016/j.molimm.2022.03.121] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 03/21/2022] [Accepted: 03/27/2022] [Indexed: 12/30/2022]
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27
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Bergmann CA, Beltran S, Vega-Letter AM, Murgas P, Hernandez MF, Gomez L, Labrador L, Cortés BI, Poblete C, Quijada C, Carrion F, Woehlbier U, Manque PA. The Autophagy Protein Pacer Positively Regulates the Therapeutic Potential of Mesenchymal Stem Cells in a Mouse Model of DSS-Induced Colitis. Cells 2022; 11:cells11091503. [PMID: 35563809 PMCID: PMC9101276 DOI: 10.3390/cells11091503] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 04/14/2022] [Accepted: 04/21/2022] [Indexed: 02/01/2023] Open
Abstract
Mesenchymal stem cells (MSC) have emerged as a promising tool to treat inflammatory diseases, such as inflammatory bowel disease (IBD), due to their immunoregulatory properties. Frequently, IBD is modeled in mice by using dextran sulfate sodium (DSS)-induced colitis. Recently, the modulation of autophagy in MSC has been suggested as a novel strategy to improve MSC-based immunotherapy. Hence, we investigated a possible role of Pacer, a novel autophagy enhancer, in regulating the immunosuppressive function of MSC in the context of DSS-induced colitis. We found that Pacer is upregulated upon stimulation with the pro-inflammatory cytokine TNFα, the main cytokine released in the inflammatory environment of IBD. By modulating Pacer expression in MSC, we found that Pacer plays an important role in regulating the autophagy pathway in this cell type in response to TNFα stimulation, as well as in regulating the immunosuppressive ability of MSC toward T-cell proliferation. Furthermore, increased expression of Pacer in MSC enhanced their ability to ameliorate the symptoms of DSS-induced colitis in mice. Our results support previous findings that autophagy regulates the therapeutic potential of MSC and suggest that the augmentation of autophagic capacity in MSC by increasing Pacer levels may have therapeutic implications for IBD.
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Affiliation(s)
- Cristian A. Bergmann
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
| | - Sebastian Beltran
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
- Escuela de Tecnología Médica, Universidad Mayor, Santiago 7500000, Chile
| | - Ana Maria Vega-Letter
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago 7620001, Chile;
- Centro de Investigación e Innovación Biomédica, Universidad de los Andes, Santiago 7620157, Chile
| | - Paola Murgas
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
- Escuela de Tecnología Médica, Universidad Mayor, Santiago 7500000, Chile
- Escuela de Biotecnología, Facultad de Ciencias, Universidad Mayor, Santiago 7500000, Chile
| | - Maria Fernanda Hernandez
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
| | - Laura Gomez
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
| | - Luis Labrador
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
| | - Bastián I. Cortés
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
| | - Cristian Poblete
- Laboratorio de Morfofisiopatología y Citodiagnóstico, Escuela de Tecnología Médica, Facultad de Ciencias, Universidad Mayor, Santiago 7500000, Chile;
| | - Cristobal Quijada
- Servicio de Anatomía Patológica, Hospital Clínico de la Universidad de Chile, Santiago 8380456, Chile;
| | - Flavio Carrion
- Programa de Inmunología Translacional, Facultad de Medicina, Universidad del Desarrollo Clínica Alemana, Santiago 7590943, Chile;
- Departamento de Investigación, Postgrado y Educación Contínua (DIPEC), Facultad de Ciencias de la Salud, Universidad del Alba, Santiago 8320000, Chile
| | - Ute Woehlbier
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
- Escuela de Biotecnología, Facultad de Ciencias, Universidad Mayor, Santiago 7500000, Chile
- Correspondence: (U.W.); (P.A.M.)
| | - Patricio A. Manque
- Center for Integrative Biology (CIB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile; (C.A.B.); (S.B.); (P.M.); (M.F.H.); (L.G.); (L.L.); (B.I.C.)
- Center for Genomics and Bioinformatics (CGB), Faculty of Science, Universidad Mayor, Santiago 7500000, Chile
- Centro de Oncologia de Precision (COP), Escuela de Medicina, Universidad Mayor, Santiago 7500000, Chile
- Correspondence: (U.W.); (P.A.M.)
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Xun Y, Yan F, Zhu H, Feng L, Zhang D, Xue Y, He F, Wang S. Oral Administration of Lactobacillus paracasei N1115 on Neonatal Mice Prevents the Intestinal Inflammation in Adulthood. Lett Appl Microbiol 2022; 75:330-337. [PMID: 35485997 DOI: 10.1111/lam.13729] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 04/10/2022] [Accepted: 04/25/2022] [Indexed: 11/28/2022]
Abstract
Colonization and development of gut microbiota during early life stage plays a key regulatory role in the establishment of the host-microbial relationship, which was conducive to progressing host immunity and maintaining health throughout the adulthood life span. This study was aimed to evaluate the protective effect from inflammatory bowel disease (IBD) in adulthood based on the early intervention of Lactobacillus paracasei N1115 (LP N1115) occurs after birth. LP N1115 treatment was carried out during two weeks in postnatal mice. Then the dextran sodium sulfate (DSS) induced colitis model mice were established in adulthood, and the status of intestinal tissues was detected. Results showed the decreased severity of intestinal tissue injury, cell apoptosis and proinflammatory cytokines expression in DSS-induced model with LP N1115 early intervention. Therefore, intake of LP N1115 in neonatal mice have played the long-term healthy role in prevention of intestinal injury and inflammation in adulthood.
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Affiliation(s)
- Yiping Xun
- Junlebao Dairy Group Co., Ltd., Shijiazhuang, Hebei, P. R. China
| | - Fang Yan
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Hong Zhu
- Junlebao Dairy Group Co., Ltd., Shijiazhuang, Hebei, P. R. China
| | - Lili Feng
- Junlebao Dairy Group Co., Ltd., Shijiazhuang, Hebei, P. R. China
| | - Dong Zhang
- Junlebao Dairy Group Co., Ltd., Shijiazhuang, Hebei, P. R. China
| | - Yuling Xue
- Junlebao Dairy Group Co., Ltd., Shijiazhuang, Hebei, P. R. China
| | - Fang He
- Department of nutrition, Food safety and Toxicology, West China school of Public health, Sichuan University, Chengdu, Sichuan, P. R. China
| | - Shijie Wang
- Junlebao Dairy Group Co., Ltd., Shijiazhuang, Hebei, P. R. China.,Department of nutrition, Food safety and Toxicology, West China school of Public health, Sichuan University, Chengdu, Sichuan, P. R. China
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29
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Yang L, Wu G, Wu Q, Peng L, Yuan L. METTL3 overexpression aggravates LPS-induced cellular inflammation in mouse intestinal epithelial cells and DSS-induced IBD in mice. Cell Death Dis 2022; 8:62. [PMID: 35165276 PMCID: PMC8844074 DOI: 10.1038/s41420-022-00849-1] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 01/12/2022] [Accepted: 01/25/2022] [Indexed: 11/09/2022]
Abstract
The inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the intestine. Dysregulated cytokine secretion and signal transduction mechanisms via intestinal epithelial cells are involved in IBD pathogenesis, in which the transcription factor NF-κB plays a critical role. In this study, METTL3, which plays a key role in inflammation regulation, has been recognized significantly up-regulated in IBD samples, DSS-induced IBD mice, and LPS-treated MODE-K cells. Within LPS-treated MODE-K cells, METTL3 knockdown promoted cell viability, inhibited cell apoptosis, decreased apoptotic caspase3/9 cleavage, and decreased the levels of proinflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-18) and inflammatory enzymes (COX-2 and iNOS). Under the same conditions, METTL3 knockdown inhibited, whereas METTL3 overexpression promoted p65 phosphorylation in MODE-K cells; NF-κB inhibitor JSH-23 partially abolished the promotive effects of METTL3 overexpression upon p65 phosphorylation. Consistently, the effects of METTL3 overexpression upon LPS-stimulated MODE-K cells were partially abolished by JSH-23. Lastly, METTL3 knockdown in DSS-induced IBD mice significantly ameliorated DSS-induced IBD and inhibited DSS-induced p65 phosphorylation. In conclusion, METTL3 overexpression aggravates LPS-induced cellular inflammation in mouse intestinal epithelial cells and DSS-induced IBD in mice. The NF-κB signaling might be involved, and the regulatory mechanism remains to be investigated in our future study.
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Affiliation(s)
- Lichao Yang
- Department of Geriatric Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Guotao Wu
- Department of Geriatric Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qiang Wu
- Department of Geriatric Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Liangxin Peng
- Department of Geriatric Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lianwen Yuan
- Department of Geriatric Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
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30
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Maltz RM, Marte-Ortiz P, Rajasekera TA, Loman BR, Gur TL, Bailey MT. Stressor-Induced Increases in Circulating, but Not Colonic, Cytokines Are Related to Anxiety-like Behavior and Hippocampal Inflammation in a Murine Colitis Model. Int J Mol Sci 2022; 23:ijms23042000. [PMID: 35216112 PMCID: PMC8877477 DOI: 10.3390/ijms23042000] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 01/31/2022] [Accepted: 02/08/2022] [Indexed: 01/27/2023] Open
Abstract
Stressor exposure increases colonic inflammation. Because inflammation leads to anxiety-like behavior, we tested whether stressor exposure in mice recovering from dextran-sulfate-sodium (DSS)-induced colitis enhances anxiety-like behavior. Mice received 2% DSS for five consecutive days prior to being exposed to a social-disruption (SDR) stressor (or being left undisturbed). After stressor exposure, their behavior was tested and colitis was assessed via histopathology and via inflammatory-cytokine measurement in the serum and colon. Cytokine and chemokine mRNA levels in the colon, mesenteric lymph nodes (MLNs), hippocampus, and amygdala were measured with RT-PCR. SDR increased anxiety-like behaviors, which correlated with serum and hippocampal IL-17A. The stressor also reduced IL-1β, CCL2, and iNOS in the colonic tissue, but increased iNOS, IFNγ, IL-17A, and TNFα in the MLNs. A network analysis indicated that reductions in colonic iNOS were related to elevated MLN iNOS and IFNγ. These inflammatory markers were related to serum and hippocampal IL-17A and associated with anxiety-like behavior. Our data suggest that iNOS may protect against extra-colonic inflammation, and when suppressed during stress it is associated with elevated MLN IFNγ, which may coordinate gut-to-brain inflammation. Our data point to hippocampal IL-17A as a key correlate of anxiety-like behavior.
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Affiliation(s)
- Ross M. Maltz
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Department of Pediatrics, The Ohio State Wexner Medical Center, Columbus, OH 43210, USA;
- The Center for Microbial Pathogenesis, The Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA; (P.M.-O.); (B.R.L.)
- Oral and Gastrointestinal Microbiology Research Affinity Group, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Correspondence: ; Tel.: +1-614-722-5116; Fax: +1-614-722-2979
| | - Pedro Marte-Ortiz
- The Center for Microbial Pathogenesis, The Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA; (P.M.-O.); (B.R.L.)
| | - Therese A. Rajasekera
- Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (T.A.R.); (T.L.G.)
- Department of Psychiatry & Behavioral Health, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Brett R. Loman
- The Center for Microbial Pathogenesis, The Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA; (P.M.-O.); (B.R.L.)
| | - Tamar L. Gur
- Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (T.A.R.); (T.L.G.)
- Department of Psychiatry & Behavioral Health, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Michael T. Bailey
- Department of Pediatrics, The Ohio State Wexner Medical Center, Columbus, OH 43210, USA;
- The Center for Microbial Pathogenesis, The Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA; (P.M.-O.); (B.R.L.)
- Oral and Gastrointestinal Microbiology Research Affinity Group, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (T.A.R.); (T.L.G.)
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Utilizing Sphingomyelinase Sensitizing Liposomes in Imaging Intestinal Inflammation in Dextran Sulfate Sodium-Induced Murine Colitis. Biomedicines 2022; 10:biomedicines10020413. [PMID: 35203622 PMCID: PMC8962329 DOI: 10.3390/biomedicines10020413] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 02/05/2022] [Accepted: 02/06/2022] [Indexed: 02/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gastrointestinal tract, resulting in severe symptoms. At the moment, the goal of medical treatments is to reduce inflammation. IBD is treated with systemic anti-inflammatory compounds, but they have serious side effects. The treatment that is most efficient and causes the fewest side effects would be the delivery of the drugs on the disease site. This study aimed to investigate the suitability of sphingomyelin (SM) containing liposomes to specifically target areas of inflammation in dextran sulfate sodium-induced murine colitis. Sphingomyelin is a substrate to the sphingomyelinase enzyme, which is only present outside cells in cell stress, like inflammation. When sphingomyelin consisting of liposomes is predisposed to the enzyme, it causes the weakening of the membrane structure. We demonstrated that SM-liposomes are efficiently taken up in intestinal macrophages, indicating their delivery potential. Furthermore, our studies showed that sphingomyelinase activity and release are increased in a dextran sulfate sodium-induced IBD mouse model. The enzyme appearance in IBD disease was also traced in intestine samples of the dextran sulfate sodium-treated mice and human tissue samples. The results from the IBD diseased animals, treated with fluorescently labeled SM-liposomes, demonstrated that the liposomes were taken up preferentially in the inflamed colon. This uptake efficiency correlated with sphingomyelinase activity.
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Kojima F, Sekiya H, Hioki Y, Kashiwagi H, Kubo M, Nakamura M, Maehana S, Imamichi Y, Yuhki KI, Ushikubi F, Kitasato H, Ichikawa T. Facilitation of colonic T cell immune responses is associated with an exacerbation of dextran sodium sulfate-induced colitis in mice lacking microsomal prostaglandin E synthase-1. Inflamm Regen 2022; 42:1. [PMID: 34983695 PMCID: PMC8725565 DOI: 10.1186/s41232-021-00188-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 12/07/2021] [Indexed: 12/24/2022] Open
Abstract
Background Microsomal prostaglandin E synthase-1 (mPGES-1) is a key enzyme that acts downstream of cyclooxygenase and plays a major role in inflammation by converting prostaglandin (PG) H2 to PGE2. The present study investigated the effect of genetic deletion of mPGES-1 on the development of immunologic responses to experimental colitis induced by dextran sodium sulfate (DSS), a well-established model of inflammatory bowel disease (IBD). Methods Colitis was induced in mice lacking mPGES-1 (mPGES-1−/− mice) and wild-type (WT) mice by administering DSS for 7 days. Colitis was assessed by body weight loss, diarrhea, fecal bleeding, and histological features. The colonic expression of mPGES-1 was determined by real-time PCR, western blotting, and immunohistochemistry. The impact of mPGES-1 deficiency on T cell immunity was determined by flow cytometry and T cell depletion in vivo. Results After administration of DSS, mPGES-1−/− mice exhibited more severe weight loss, diarrhea, and fecal bleeding than WT mice. Histological analysis further showed significant exacerbation of colonic inflammation in mPGES-1−/− mice. In WT mice, the colonic expression of mPGES-1 was highly induced on both mRNA and protein levels and colonic PGE2 increased significantly after DSS administration. Additionally, mPGES-1 protein was localized in the colonic mucosal epithelium and infiltrated inflammatory cells in underlying connective tissues and the lamina propria. The abnormalities consistent with colitis in mPGES-1−/− mice were associated with higher expression of colonic T-helper (Th)17 and Th1 cytokines, including interleukin 17A and interferon-γ. Furthermore, lack of mPGES-1 increased the numbers of Th17 and Th1 cells in the lamina propria mononuclear cells within the colon, even though the number of suppressive regulatory T cells also increased. CD4+ T cell depletion effectively reduced symptoms of colitis as well as colonic expression of Th17 and Th1 cytokines in mPGES-1−/− mice, suggesting the requirement of CD4+ T cells in the exacerbation of DSS-induced colitis under mPGES-1 deficiency. Conclusions These results demonstrate that mPGES-1 is the main enzyme responsible for colonic PGE2 production and deficiency of mPGES-1 facilitates the development of colitis by affecting the development of colonic T cell–mediated immunity. mPGES-1 might therefore impact both the intestinal inflammation and T cell–mediated immunity associated with IBD. Supplementary Information The online version contains supplementary material available at 10.1186/s41232-021-00188-1.
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Affiliation(s)
- Fumiaki Kojima
- Department of Pharmacology, Kitasato University School of Allied Health Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan. .,Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan. .,Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan.
| | - Hiroki Sekiya
- Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan
| | - Yuka Hioki
- Department of Pharmacology, Kitasato University School of Allied Health Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan
| | - Hitoshi Kashiwagi
- Department of Pharmacology, Asahikawa Medical University, 2-1-1-1 Midorigaoka higashi, Asahikawa, 078-8510, Japan
| | - Makoto Kubo
- Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan.,Division of Clinical Immunology, Graduate School of Medical Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0373, Japan
| | - Masaki Nakamura
- Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan.,Department of Environmental Microbiology, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan
| | - Shotaro Maehana
- Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan.,Department of Environmental Microbiology, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan
| | - Yoshitaka Imamichi
- Department of Pharmacology, Asahikawa Medical University, 2-1-1-1 Midorigaoka higashi, Asahikawa, 078-8510, Japan
| | - Koh-Ichi Yuhki
- Department of Pharmacology, Asahikawa Medical University, 2-1-1-1 Midorigaoka higashi, Asahikawa, 078-8510, Japan
| | - Fumitaka Ushikubi
- Department of Pharmacology, Asahikawa Medical University, 2-1-1-1 Midorigaoka higashi, Asahikawa, 078-8510, Japan
| | - Hidero Kitasato
- Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan.,Department of Environmental Microbiology, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan
| | - Takafumi Ichikawa
- Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan.,Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, Sagamihara, 252-0373, Japan
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Seo H, Seong H, Kim GY, Jo YM, Cheon SW, Song Y, Ryu BH, Kang H, Han NS. Development of Anti-inflammatory Probiotic Limosilactobacillus reuteri EFEL6901 as Kimchi Starter: in vitro and In vivo Evidence. Front Microbiol 2021; 12:760476. [PMID: 34899643 PMCID: PMC8656428 DOI: 10.3389/fmicb.2021.760476] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 11/03/2021] [Indexed: 11/13/2022] Open
Abstract
The use of probiotic starters can improve the sensory and health-promoting properties of fermented foods. In this study, we developed an anti-inflammatory probiotic starter, Limosilactobacillus reuteri EFEL6901, for use in kimchi fermentation. The EFEL6901 strain was safe for use in foods and was stable under human gastrointestinal conditions. In in vitro experiments, EFEL6901 cells adhered well to colonic epithelial cells and decreased nitric oxide production in lipopolysaccharide-induced macrophages. In in vivo experiments, oral administration of EFEL6901 to DSS-induced colitis mice models significantly alleviated the observed colitis symptoms, prevented body weight loss, lowered the disease activity index score, and prevented colon length shortening. Analysis of these results indicated that EFEL6901 played a probiotic role by preventing the overproduction of pro-inflammatory cytokines, improving gut barrier function, and up-regulating the concentrations of short-chain fatty acids. In addition, EFEL6901 made a fast growth in a simulated kimchi juice and it synthesized similar amounts of metabolites in nabak-kimchi comparable to a commercial kimchi. This study demonstrates that EFEL6901 can be used as a suitable kimchi starter to promote gut health and product quality.
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Affiliation(s)
- Hee Seo
- Brain Korea 21 Center for Bio-Resource Development, Division of Animal, Horticultural, and Food Sciences, Chungbuk National University, Cheongju, South Korea
| | - Hyunbin Seong
- Brain Korea 21 Center for Bio-Resource Development, Division of Animal, Horticultural, and Food Sciences, Chungbuk National University, Cheongju, South Korea
| | - Ga Yun Kim
- Brain Korea 21 Center for Bio-Resource Development, Division of Animal, Horticultural, and Food Sciences, Chungbuk National University, Cheongju, South Korea
| | - Yu Mi Jo
- Brain Korea 21 Center for Bio-Resource Development, Division of Animal, Horticultural, and Food Sciences, Chungbuk National University, Cheongju, South Korea
| | - Seong Won Cheon
- Brain Korea 21 Center for Bio-Resource Development, Division of Animal, Horticultural, and Food Sciences, Chungbuk National University, Cheongju, South Korea
| | - Youngju Song
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul, South Korea
| | - Byung Hee Ryu
- Fresh Food Research Division, Food BU, Daesang Corporation Research Institute, Icheon, South Korea
| | - Hee Kang
- Humanitas College, Kyung Hee University, Yongin, South Korea
| | - Nam Soo Han
- Brain Korea 21 Center for Bio-Resource Development, Division of Animal, Horticultural, and Food Sciences, Chungbuk National University, Cheongju, South Korea
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Shan W, Zhang W, Xue F, Ma Y, Dong L, Wang T, Zheng Y, Feng D, Chang M, Yuan G, Wang X. Schistosoma japonicum peptide SJMHE1 inhibits acute and chronic colitis induced by dextran sulfate sodium in mice. Parasit Vectors 2021; 14:455. [PMID: 34488863 PMCID: PMC8422783 DOI: 10.1186/s13071-021-04977-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 08/24/2021] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Harnessing helminth-based immunoregulation is a novel therapeutic strategy for many immune dysfunction disorders, including inflammatory bowel diseases (IBDs). We previously identified a small molecule peptide from Schistosoma japonicum and named it SJMHE1. SJMHE1 can suppress delayed-type hypersensitivity, collagen-induced arthritis and asthma in mice. In this study, we assessed the effects of SJMHE1 on dextran sulfate sodium (DSS)-induced acute and chronic colitis. METHODS Acute and chronic colitis were induced in C57BL/6 mice by DSS, following which the mice were injected with an emulsifier SJMHE1 or phosphate-buffered saline. The mice were then examined for body weight loss, disease activity index, colon length, histopathological changes, cytokine expression and helper T (Th) cell subset distribution. RESULTS SJMHE1 treatment significantly suppressed DSS-induced acute and chronic colitis, improved disease activity and pathological damage to the colon and modulated the expression of pro-inflammatory and anti-inflammatory cytokines in splenocytes and the colon. In addition, SJMHE1 treatment reduced the percentage of Th1 and Th17 cells and increased the percentage of Th2 and regulatory T (Treg) cells in the splenocytes and mesenteric lymph nodes of mice with acute colitis. Similarly, SJMHE1 treatment upregulated the expression of interleukin-10 (IL-10) mRNA, downregulated the expression of IL-17 mRNA and modulated the Th cell balance in mice with chronic colitis. CONCLUSIONS Our data show that SJMHE1 provided protection against acute and chronic colitis by restoring the immune balance. As a small molecule, SJMHE1 might be a novel agent for the treatment of IBDs without immunogenicity concerns.
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Affiliation(s)
- Wenqi Shan
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.,Department of Pediatrics, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Wenzhe Zhang
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.,Department of Blood Transfusion, The Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Fei Xue
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.,Department of Pediatrics, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yongbin Ma
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.,Department of Central Laboratory, Jintan Hospital, Jiangsu University, Jintan, Jiangsu, China
| | - Liyang Dong
- Department of Nuclear Medicine and Institute of Oncology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Ting Wang
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yu Zheng
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Dingqi Feng
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Ming Chang
- Department of Pediatrics, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.
| | - Guoyue Yuan
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.
| | - Xuefeng Wang
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China. .,Department of Nuclear Medicine and Institute of Oncology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.
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Azizian-Farsani F, Osuchowski M, Abedpoor N, Forootan FS, Derakhshan M, Nasr-Esfahani MH, Sheikhha MH, Ghaedi K. Anti-inflammatory and -apoptotic effects of a long-term herbal extract treatment on DSS-induced colitis in mice fed with high AGEs-fat diet. Nutr Metab (Lond) 2021; 18:77. [PMID: 34380504 PMCID: PMC8359107 DOI: 10.1186/s12986-021-00603-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 07/23/2021] [Indexed: 01/11/2023] Open
Abstract
Background Obesity is associated with many comorbidities including inflammatory bowel disease (IBD). We investigated prophylactic effects of an herbal extract (HE) on the DSS-induced colitis mice challenged with high AGEs-fat diet 60% (HFD). Methods Six-week-old C57BL/6 male mice were fed with either HFD (8 groups, 6 mice in each group), or normal diet (ND) (8 groups, 6 mice in each group). After 6 weeks, animals received HE (combination of turmeric, ginger, boswellia and cat’s claw extract) for 7 weeks in three doses (high dose (0.6 mg/g); low dose (0.15 mg/g) and mid dose (0.3 mg/g)). Next, mice were subjected to 2.5% DSS in drinking water. Control mice received ND and instead of HE and DSS they received distilled water. Obesity index markers were determined, H&E staining and TUNEL assay evaluated apoptosis. Colonic expressions of IL-6, RAGE, AGER1, Sirt1, Bax, Bcl2, ZO-1 and P53 were determined.
Results HE ameliorated colitis in HFD mice by reducing colonic myeloperoxidase activity (by 2.3-fold), macrophage accumulation (by 2.6-fold) and mRNA expression of IL-6 (by 2.3-fold) in HFD mice. Moreover, HE restored ZO-1 (by 2.7-fold), prevented apoptosis and maintained immune homeostasis. HE reduced activation of NF-κB protein (by 1.3-fold) through decreasing RAGE (by 1.93-fold) and up-regulation of Sirt1 (by 7.71-fold) and prevented down-regulation of DDOST (by 6.6-fold) in HFD mice. Conclusions HE ameliorated colitis in prophylactic in HFD mice and it was, at least partly, due to the restoration of the gut integrity, suppression of inflammation and apoptosis via modulation of colonic Sirt1, RAGE and DDOST signaling. Graphic abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s12986-021-00603-x.
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Affiliation(s)
| | - Marcin Osuchowski
- Ludwig Boltzmann Institute for Clinical and Experimental Traumatology in AUVA Research Center, Vienna, Austria.
| | - Navid Abedpoor
- Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Royan, Salman Streets, 816513-1378, Isfahan, Iran
| | - Farzad Seyed Forootan
- Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Royan, Salman Streets, 816513-1378, Isfahan, Iran.,Legal Medicine research Center, Legal Medicine Organization, Tehran, Iran
| | - Maryam Derakhshan
- Department of Pathology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Hossein Nasr-Esfahani
- Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Royan, Salman Streets, 816513-1378, Isfahan, Iran.
| | - Mohammad Hasan Sheikhha
- Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. .,Biotechnology Research Center, International Campus, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
| | - Kamran Ghaedi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Hezar Jerib Ave., Azadi Sq., 81746-73441, Isfahan, Iran.
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Asgharzadeh F, Hashemzadeh A, Rahmani F, Yaghoubi A, Nazari SE, Avan A, Mehr SMH, Soleimanpour S, Khazaei M. Cerium oxide nanoparticles acts as a novel therapeutic agent for ulcerative colitis through anti-oxidative mechanism. Life Sci 2021; 278:119500. [PMID: 33862111 DOI: 10.1016/j.lfs.2021.119500] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 03/25/2021] [Accepted: 03/30/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Cerium (IV) oxide (CeO2) exhibit anti-inflammatory activity via scavenge free radicals and decreasing the oxygen species (ROS) production. Here we aimed to exhibit the therapeutic effect of this nanoparticle in experimental colitis models. METHODS Cerium oxide nanoparticles (CeONPs) were synthesized via using UiO-66 as a precursor. We used dextran sodium sulfate (DSS) to induce colitis in experimental models to investigate the anti-inflammatory effect of CeONPs. Colitis models are divided into four groups to receive the treatment, including control, colitis, cerium oxide, and sulfasalazine. We evaluated the therapeutic effects of CeONPs for the increased colitis clinical symptoms and attenuated the histological damage to colon tissue in colitis. RESULT This nanoparticle was significantly able to reduce the clinical symptoms of colitis. Moreover, CeONPs can enhance the disease activity index such as body lose weight, diarrhea, rectal bleeding, colon length, and spleen weight. Moreover, CeONPs showed a significant reduction in the histological characteristics of the colitis models. CONCLUSION These results suggest that CeONPs can be considered as promising therapeutic agents in treating the ulcerative colitis.
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Affiliation(s)
- Fereshteh Asgharzadeh
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Hashemzadeh
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farzad Rahmani
- Department of Biochemistry, Faculty of Medicine, Iranshahr University of Medical Sciences, Iranshahr, Iran
| | - Atieh Yaghoubi
- Antimicrobial Resistance Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Microbiology and Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyedeh Elnaz Nazari
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hasanian Mehr
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Biochemistry, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saman Soleimanpour
- Antimicrobial Resistance Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Microbiology and Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Majid Khazaei
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Qin Y, Yu Y, Yang C, Wang Z, Yang Y, Wang C, Zheng Q, Li D, Xu W. Atractylenolide I Inhibits NLRP3 Inflammasome Activation in Colitis-Associated Colorectal Cancer via Suppressing Drp1-Mediated Mitochondrial Fission. Front Pharmacol 2021; 12:674340. [PMID: 34335248 PMCID: PMC8320763 DOI: 10.3389/fphar.2021.674340] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 06/18/2021] [Indexed: 01/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) is an important high-risk factor that promotes the occurrence and development of colon cancer. Research on the mechanism of regulating NLRP3 can provide potential targets for treating NLRP3 inflammasome–related diseases and changing the inflammatory potential of immune cells. In this study, the effects of atractylenolide I on colitis-associated CRC (caCRC) and inflammasome activation were investigated both in vivo and in vitro. Furthermore, the role of atractylenolide I on Drp1-mediated mitochondrial fission was analyzed via Western blotting and transmission electron microscopy (TEM). Moreover, the Drp1 overexpression lentiviral vector was used to study the role of Drp1 on the signaling mechanisms of atractylenolide I. Atractylenolide I treatment significantly reduced the cell viability of human HCT116 and SW480 cells and induced apoptosis, and effectively inhibited colon tumors in the AOM/DSS mouse model. The reduction of NLRP3 inflammasome activation and excessive fission of mitochondria mediated by Drp1 were associated with the administration of atractylenolide I. Upregulation of Drp1 reversed the inhibitory effect of atractylenolide I on the activation of NLRP3 inflammasomes. Overexpressing the Drp1 expression counteracted the restraint of atractylenolide I on the release of IL-1β of LPS/DSS-stimulated BMDMs. Atractylenolide I inhibited NLRP3 and caspase-1 expression in mice BMDMs, with no influence in the Drp1-overexpressed BMDMs. These results demonstrated that atractylenolide I inhibits NLRP3 inflammasome activation in colitis-associated colorectal cancer via suppressing Drp1-mediated mitochondrial fission.
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Affiliation(s)
- Yao Qin
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
| | - Yanwei Yu
- Yantai Hospital of Traditional Chinese Medicine, Yantai, China
| | - Chendong Yang
- Yantai Hospital of Traditional Chinese Medicine, Yantai, China
| | - Zhuien Wang
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
| | - Yi Yang
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
| | - Chongxu Wang
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
| | - Qiusheng Zheng
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
| | - Defang Li
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
| | - Wenjuan Xu
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
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Playford RJ, Weiser MJ, Marchbank T. Methods to improve efficacy of orally administered bioactive peptides using bovine colostrum as an exemplar. PLoS One 2021; 16:e0253422. [PMID: 34138960 PMCID: PMC8211160 DOI: 10.1371/journal.pone.0253422] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 06/07/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Oral administration of bioactive peptides has potential clinical advantages, but its applicability is limited due to gastric and pancreatic enzyme proteolysis. OBJECTIVE To examine whether the co-packaging of bovine colostrum (BC), a rich source of IgG, immune and growth factors, with the food additives trehalose (carbohydrate), stearine (fat), casein (protein present in BC) or soy flour (plant based with high protease inhibitory activity) enhances the stability of BC against digestion. DESIGN Samples alone and in combination (BC+ 10% wt/wt trehalose, stearine, casein or soy) were exposed to HCl/pepsin, followed by trypsin and chymotrypsin ("CT"). Assessment of proliferation used gastric AGS cells (Alamar blue), IgG function measured bovine IgG anti-E.coli binding and ELISAs quantified growth factor constituents. In vivo bioassay assessed ability of BC alone or with soy to reduce injury caused by dextran sodium sulphate (DSS, 4% in drinking water, 7 days, test products started 2 days prior to DSS). RESULTS Proliferative activity of BC reduced 61% following HCl/pepsin and CT exposure. This was truncated 50% if soy was co-present, and also protected against loss of total IgG, IgG E.coli binding, TGFβ, lactoferrin and EGF (all P<0.01 vs BC alone). Co-packaging with trehalose was ineffective in preventing digestion whereas casein or stearine provided some intermediate protective effects. Rats given BC alone showed beneficial effects on weight gain, disease activity index, tissue histology and colonic MPO. Soy alone was ineffective. BC+ soy combination showed the greatest benefit with a dose of 7 mg/kg (6.4 BC + 0.6 soy flour) having the same degree of benefit as using 20 mg/kg BC alone. CONCLUSION Soy, and to a lesser extent casein, enhanced the biostability of BC against digestive enzymes. Co-packaging of BC with other food products such as soy flour could result in a decreased dose being required, improving cost-effectiveness and patient compliance.
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Affiliation(s)
- Raymond John Playford
- Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine, Queen Mary, University of London, London, United Kingdom
- Department of R&D, PanTheryx Inc, Boulder, CO, United States of America
| | | | - Tania Marchbank
- Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine, Queen Mary, University of London, London, United Kingdom
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Marchbank T, ten Bruggencate SJM, Playford RJ. Protease Inhibitors Protect Bovine Colostrum or Chicken Egg Growth Factors from Pancreatic Enzyme Digestion in AGS Cells or Colitic Rats. J Nutr 2021; 151:3036-3044. [PMID: 34132332 PMCID: PMC8485905 DOI: 10.1093/jn/nxab197] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/20/2021] [Accepted: 05/25/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Bovine colostrum (BC) and chicken egg contain proteins possessing growth factor activity. Epidermal growth factor (EGF) provides much of the pro-reparative activity within BC. Clinical use of orally administered peptide growth factors is hampered by digestion from pancreatic proteases. OBJECTIVES We examined whether adding a protease inhibitor [soybean trypsin inhibitor (SBTI) or ovomucoid] protected bioactivity of BC ± egg or EGF alone against pancreatic digestion using in vitro and in vivo models. METHODS BC, egg, or EGF alone or in combination with trypsin inhibitors were tested for proliferative (Alamar blue) activity using human gastric adenocarcinoma (AGS) cells, prior to and after incubation with HCl/pepsin and trypsin/chymotrypsin. Data were analyzed using 2-factor ANOVA. Eight groups (n = 10) of adult female Sprague-Dawley rats (mean: 188.3 ± 0.8 g) received 20 mg/kg/d of BC + egg, 100 μg/d of EGF, 5 mg/d ovomucoid, or 10.8 mg/d SBTI, alone or in combination (in 1 mL 3% NaHCO3) by gavage for 9 d and dextran sodium sulfate (DSS; 5% in drinking water) for the final 7 d. Histology, microscopic damage score, and myeloperoxidase (MPO) were assessed and analyzed using 1-factor ANOVA. RESULTS Proliferative activities of BC, egg, or EGF were reduced 40-57% by HCl/pepsin exposure and further reduced 14-24% by chymotrypsin/trypsin. Co-addition of SBTI or ovomucoid truncated the decrease in proliferative bioactivity caused by chymotrypsin/trypsin by 54-100% (P < 0.01). In vivo study showed oral EGF alone or protease inhibitors given alone were ineffective in reducing DSS damage, whereas SBTI with EGF or ovomucoid with BC + egg improved protective effects on weight gain, disease activity score, colonic MPO, and histology damage by 3-4-fold (P < 0.01). CONCLUSIONS Studies using AGS, cells, and Sprague-Dawley rats showed the protease inhibitors ovomucoid and SBTI protected BC, egg, and EGF against loss of bioactivity due to pancreatic enzymes and, when given with NaHCO3, enhanced colonic protection against DSS damage.
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Affiliation(s)
- Tania Marchbank
- Centre of Immunobiology, Blizard Institute, Barts and The London School of Medicine, Queen Mary, University of London, London, United Kingdom
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Hashiesh HM, Sharma C, Goyal SN, Sadek B, Jha NK, Kaabi JA, Ojha S. A focused review on CB2 receptor-selective pharmacological properties and therapeutic potential of β-caryophyllene, a dietary cannabinoid. Biomed Pharmacother 2021; 140:111639. [PMID: 34091179 DOI: 10.1016/j.biopha.2021.111639] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 04/12/2021] [Accepted: 04/19/2021] [Indexed: 02/06/2023] Open
Abstract
The endocannabinoid system (ECS), a conserved physiological system emerged as a novel pharmacological target for its significant role and potential therapeutic benefits ranging from neurological diseases to cancer. Among both, CB1 and CB2R types, CB2R have received attention for its pharmacological effects as antioxidant, anti-inflammatory, immunomodulatory and antiapoptotic that can be achieved without causing psychotropic adverse effects through CB1R. The ligands activate CB2R are of endogenous, synthetic and plant origin. In recent years, β-caryophyllene (BCP), a natural bicyclic sesquiterpene in cannabis as well as non-cannabis plants, has received attention due to its selective agonist property on CB2R. BCP has been well studied in a variety of pathological conditions mediating CB2R selective agonist property. The focus of the present manuscript is to represent the CB2R selective agonist mediated pharmacological mechanisms and therapeutic potential of BCP. The present narrative review summarizes insights into the CB2R-selective pharmacological properties and therapeutic potential of BCP such as cardioprotective, hepatoprotective, neuroprotective, nephroprotective, gastroprotective, chemopreventive, antioxidant, anti-inflammatory, and immunomodulator. The available evidences suggest that BCP, can be an important candidate of plant origin endowed with CB2R selective properties that may provide a pharmacological rationale for its pharmacotherapeutic application and pharmaceutical development like a drug. Additionally, given the wide availability in edible plants and dietary use, with safety, and no toxicity, BCP can be promoted as a nutraceutical and functional food for general health and well-being. Further, studies are needed to explore pharmacological and pharmaceutical opportunities for therapeutic and preventive applications of use of BCP in human diseases.
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Affiliation(s)
- Hebaallah Mamdouh Hashiesh
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates
| | - Charu Sharma
- Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates
| | - Sameer N Goyal
- Shri Vile Parle Kelvani Mandal's Institute of Pharmacy, Dhule 424001, Maharashtra, India
| | - Bassem Sadek
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology, Sharda University, Greater Noida, Uttar Pradesh 201310, India
| | - Juma Al Kaabi
- Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates; Zayed Bin Sultan Al Nahyan Center for Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates.
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Pabari RM, Tambuwala MM, Lajczak-McGinley N, Aljabali A, Kirby BP, Keely S, Ramtoola Z. Novel polyurethane based particulate formulations of infliximab reduce inflammation in DSS induced murine model of colitis - A preliminary study. Int J Pharm 2021; 604:120717. [PMID: 34015378 DOI: 10.1016/j.ijpharm.2021.120717] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/13/2021] [Accepted: 05/13/2021] [Indexed: 11/19/2022]
Abstract
Our recent study showed that novel infliximab (INF) loaded polyesterurethane (INF-PU) and INF-PU-PEG particulate formulations reduced inflammation in an in-vitro epithelial inflammation model. In this study we investigated therapeutic potential of novel INF-PU and INF-PU-PEG particulate formulations to reduce inflammation in a dextran sodium sulfate (DSS) induced murine model of colitis. Severity of colitis was assessed by measurement of disease activity index (DAI) score, inflammatory markers (neutrophil infiltration, TNFα) and histological score. Treatment groups orally administered with INF-PU and INF-PU-PEG particulate formulations showed improvement in the clinical signs of colitis, similar to that observed with intraperitoneally administered INF, in both, moderate and severe DSS induced colitis model. This was related to a significant reduction in inflammatory cytokines, resulting in a significant reduction in histological score (ANOVA; p < 0.05), indicative of mucosal healing, a key goal of IBD therapy. This could be attributed to its targeted delivery to the inflamed colon and higher permeation of these particulate formulations across the inflamed colonic mucosa, as observed by the confocal images, resulting in local inhibition of TNFα at its site of production. These promising preliminary results warrant further investigation of orally administered INF and its novel particulate formulations in a wider preclinical study.
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Affiliation(s)
- Ritesh M Pabari
- RCSI, University of Medicine and Health Sciences, Dublin, Ireland.
| | - Murtaza M Tambuwala
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, County, Londonderry BT52 1SA, Northern Ireland, United Kingdom
| | | | - Alaa Aljabali
- Faculty of Pharmacy, Department of Pharmaceutical Sciences, Yarmouk University, Irbid, Jordan
| | - Brian P Kirby
- RCSI, University of Medicine and Health Sciences, Dublin, Ireland
| | - Stephen Keely
- Department of Molecular Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
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Guan D, Wang Z, Huo J, Xu S, Lam KP. Bruton's tyrosine kinase regulates gut immune homeostasis through attenuating Th1 response. Cell Death Dis 2021; 12:431. [PMID: 33931590 PMCID: PMC8087775 DOI: 10.1038/s41419-021-03702-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 03/29/2021] [Accepted: 03/30/2021] [Indexed: 12/25/2022]
Abstract
Inflammatory bowel disease (IBD) is driven by multiple genetic and environmental risk factors. Patients with mutations in Bruton’s tyrosine kinase (BTK) is known to manifest high prevalence of intestinal disorders including IBD. Although BTK mediates the signaling of various immune receptors, little is known how BTK maintains the homeostasis of the gut immune system. Here, we show that BTK-deficiency promotes IBD progression in a mouse model of colitis. Interestingly, the increased colitis susceptibility of BTK-deficient mice is not caused by gut microbiota changes but rather arises from enhanced pro-inflammatory Th1 response. More importantly, we find the heightened Th1 response in BTK-deficient mice to result from both T cell-extrinsic and -intrinsic mechanisms. BTK-deficient dendritic cells secret elevated levels of the Th1-polarizing cytokine IL-12 and BTK-deficient T cells are inherently more prone to Th1 differentiation. Thus, BTK plays critical roles in maintaining gut immune homeostasis and preventing inflammation via regulating T-cell polarization.
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Affiliation(s)
- Di Guan
- NUS Graduate School for Integrative Sciences & Engineering (NGS), National University of Singapore, Singapore, Singapore.,Bioprocessing Technology Institute, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore
| | - Zixi Wang
- Bioprocessing Technology Institute, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.,Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jianxin Huo
- Bioprocessing Technology Institute, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.,Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore
| | - Shengli Xu
- Bioprocessing Technology Institute, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore. .,Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore. .,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Kong-Peng Lam
- NUS Graduate School for Integrative Sciences & Engineering (NGS), National University of Singapore, Singapore, Singapore. .,Bioprocessing Technology Institute, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore. .,Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. .,Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.
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Yaghoubi A, Davoodi J, Asgharzadeh F, Rezaie S, Nazari E, Khazaei M, Soleimanpour S. Therapeutic effect of an anti-tuberculosis agent, isoniazid, and its nano-isoform in ulcerative colitis. Int Immunopharmacol 2021; 96:107577. [PMID: 33812254 DOI: 10.1016/j.intimp.2021.107577] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 03/04/2021] [Accepted: 03/08/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Isoniazid (INH) is well known as a first-line anti-tuberculosis, while some studies demonstrate that it has anti-inflammatory activity via a different mechanism such as inhibitionthe production of IL-1, ROS, activation of PPARγ expression, inhibition of the transcriptional regulatory activity of NF-κB and AP-1. The aim of this study, investigate the anti-inflammatory effect of INH and INH combined with Sulfasalazine-loaded nanoparticles (NPs) in the ulcerative colitis mouse model. METHODS To investigate the anti-inflammatory effect of INH and NPs in the ulcerative colitis mice model, we evaluated the effect of INH clinical symptoms and colonic mucosal histology in colitis. RESULT The present study demonstrates that combination therapy of INH with sulfasalazine as well as NPs reduces the symptom of ulcerative colitis and improved disease activity index include body lose weight, diarrhea, rectal bleeding, colonic length, spleen weight, and colon histopathological score in DSS-induced colitis mice model. CONCLUSION Our results suggest that the nanoforms of INH with sulfasalazine enhances the therapeutic effect of the drugs in the treatment of ulcerative colitis.
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Affiliation(s)
- Atieh Yaghoubi
- Antimicrobial Resistance Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Microbiology and Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Javid Davoodi
- Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fereshteh Asgharzadeh
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sajad Rezaie
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Elnaz Nazari
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Saman Soleimanpour
- Antimicrobial Resistance Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Microbiology and Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Li S, Wang T, Wu B, Fu W, Xu B, Pamuru RR, Kennett M, Vanamala JKP, Reddivari L. Anthocyanin-containing purple potatoes ameliorate DSS-induced colitis in mice. J Nutr Biochem 2021; 93:108616. [PMID: 33705951 DOI: 10.1016/j.jnutbio.2021.108616] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 12/19/2020] [Accepted: 02/04/2021] [Indexed: 12/13/2022]
Abstract
Ulcerative colitis (UC), a major form of inflammatory bowel disease (IBD), is on the rise worldwide. Approximately three million people suffer from IBD in the United States alone, but the current therapeutic options (e.g., corticosteroids) come with adverse side effects including reduced ability to fight infections. Thus, there is a critical need for developing effective, safe and evidence-based food products with anti-inflammatory activity. This study evaluated the antiinflammatory potential of purple-fleshed potato using a dextran sodium sulfate (DSS) murine model of colitis. Mice were randomly assigned to control (AIN-93G diet), P15 (15% purple-fleshed potato diet) and P25 (25% purple-fleshed potato diet) groups. Colitis was induced by 2% DSS administration in drinking water for six days. The results indicated that purple-fleshed potato supplementation suppressed the DSS-induced reduction in body weight and colon length as well as the increase in spleen and liver weights. P15 and P25 diets suppressed the elevation in the intestinal permeability, colonic MPO activity, mRNA expression and protein levels of pro-inflammatory interleukins IL-6 and IL-17, the relative abundance of specific pathogenic bacteria such as Enterobacteriaceae, Escherichia coli (E. coli) and pks+ E. coli, and the increased flagellin levels induced by DSS treatment. P25 alone suppressed the elevated systemic MPO levels in DSS-exposed mice, and elevated the relative abundance of Akkermansia muciniphila (A. muciniphila) as well as attenuated colonic mRNA expression level of IL-17 and the protein levels of IL-6 and IL-1β. Therefore, the purple-fleshed potato has the potential to aid in the amelioration of UC symptoms.
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Affiliation(s)
- Shiyu Li
- Department of Food Science, Purdue University, West Lafayette, Indiana, USA
| | - Tianmin Wang
- Department of Plant Science, Penn State University, University Park, Pennsylvania, USA
| | - Binning Wu
- Department of Plant Science, Penn State University, University Park, Pennsylvania, USA
| | - Wenyi Fu
- Department of Food Science, Purdue University, West Lafayette, Indiana, USA
| | - Baojun Xu
- Food Science and Technology Program, BNU-HKBU United International College, Zhuhai, Guangdong, China
| | - Ramachandra Reddy Pamuru
- Department of Food Science, Penn State University, UniversityPark, Pennsylvania, USA; Department of Biochemistry, Yogi Vemana University, Kadapa, Andhra Pradesh, India
| | - Mary Kennett
- Department of Veterinary and Biomedical Sciences, Penn State University, University Park, Pennsylvania, USA
| | - Jairam K P Vanamala
- Department of Food Science, Penn State University, UniversityPark, Pennsylvania, USA
| | - Lavanya Reddivari
- Department of Food Science, Purdue University, West Lafayette, Indiana, USA.
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45
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Single Donor FMT Reverses Microbial/Immune Dysbiosis and Induces Clinical Remission in a Rat Model of Acute Colitis. Pathogens 2021; 10:pathogens10020152. [PMID: 33540919 PMCID: PMC7913212 DOI: 10.3390/pathogens10020152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/27/2021] [Accepted: 01/28/2021] [Indexed: 12/14/2022] Open
Abstract
Deviation in the gut microbial composition is involved in various pathologies, including inflammatory bowel disease (IBD). Faecal microbiota transplant (FMT) can act as a promising approach to treat IBD by which changes in microbiome can be reversed and homeostasis restored. Therefore, the aim of this study was to investigate the effect of FMT on the remission of acute inflammatory response using dextran sulfate sodium (DSS)-induced rat colitis model. Faecal microbial communities were analysed using the 16S rRNA approach, and clinical manifestations together with histological/haematological/biochemical/immunological analyses were assessed. Our study demonstrated significant shifts in the dominant species of microbiota under inflammatory conditions induced by DSS and evident restoration effect of FMT treatment on microbial composition. These faecal microbial alterations in FMT-treated rats led to a relative restoration of colon length, and a significant decrease in both epithelium damage and disease severity, which was reflected in lower serum pro-inflammatory cytokine levels. Haematological/biochemical parameters in DSS-treated animals showed signs of anaemia with a significant reduction in red blood cell count together with increasing levels of total bilirubin, creatinine and phosphorus suggesting potential protective effect of FMT. These results support FMT as a valuable therapeutic strategy to control inflammation during acute colitis.
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46
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Kim W, Jang JH, Zhong X, Seo H, Surh YJ. 15-Deoxy-△ 12,14-Prostaglandin J 2 Promotes Resolution of Experimentally Induced Colitis. Front Immunol 2021; 12:615803. [PMID: 33633749 PMCID: PMC7901909 DOI: 10.3389/fimmu.2021.615803] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 01/04/2021] [Indexed: 12/14/2022] Open
Abstract
Uncontrolled macrophage functions cause failure to resolve gut inflammation and has been implicated in the pathogenesis of inflammatory bowel disease (IBD). 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of endogenous lipid mediators formed from arachidonic acid during the inflammatory process, has been reported to terminate inflammation. However, the pro-resolving effect of 15d-PGJ2 on intestinal inflammation and underlying molecular mechanisms remain largely unknown. In the present study, we examined the effects of 15d-PGJ2 on the resolution of dextran sulfate sodium (DSS)-induced murine colitis that mimics human IBD. Pharmacologic inhibition of prostaglandin D synthase (PGDS) responsible for the synthesis of 15d-PGJ2 hampered resolution of inflammation in the colonic mucosa of mice treated with DSS. Notably, intraperitoneal injection of 15d-PGJ2 accelerated the resolution of experimentally induced colitis. 15d-PGJ2 treatment reduced the number of neutrophils and M1 macrophages, while it increased the proportion of M2 macrophages. Moreover, 15d-PGJ2 treated mice exhibited the significantly reduced proportion of macrophages expressing the pro-inflammatory cytokine, IL-6 with concomitant suppression of STAT3 phosphorylation in the colonic mucosa of mice administered 2.5% DSS in drinking water. Taken together, these findings clearly indicate that 15d-PGJ2, endogenously generated from arachidonic acid by cyclooxygenase-2 and PGDS activities in inflamed tissue, promotes resolution of intestinal colitis.
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Affiliation(s)
- Wonki Kim
- Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Jeong-Hoon Jang
- Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Xiancai Zhong
- Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Hyungseok Seo
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea
| | - Young-Joon Surh
- Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.,Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.,Cancer Research Institute, Seoul National University, Seoul, South Korea
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47
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Manicassamy S, Prasad PD, Swafford D. Mouse Models of Colitis-Associated Colon Cancer. Methods Mol Biol 2021; 2224:133-146. [PMID: 33606212 DOI: 10.1007/978-1-0716-1008-4_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Crohn's disease (CD) and ulcerative colitis are two main clinically defined forms of chronic inflammatory bowel disease (IBD). Chronic intestinal inflammation is inextricably linked to colitis-associated colon carcinogenesis (CAC). Patients with ulcerative colitis (UC) and Crohn's disease (CD) have an increased risk of colon cancer. Our understanding of IBD and IBD-associated colon carcinogenesis depends largely on rodent models. AOM-DSS-induced colitis-associated colon cancer in mice is the most widely used and accepted model that can recapitulate the human IBD-associated colon cancer. Here, we have provided detailed protocols of this mouse model of experimentally induced chronic intestinal inflammation-associated colon cancer. We will also discuss the protocols for the isolation and analysis of inflammatory immune cells from the colon.
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Affiliation(s)
- Santhakumar Manicassamy
- Georgia Cancer Center, Augusta University, Augusta, GA, USA. .,Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA. .,Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.
| | - Puttur D Prasad
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA
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48
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Song C, Chen J, Li X, Yang R, Cao X, Zhou L, Zhou Y, Ying H, Zhang Q, Sun Y. Limonin ameliorates dextran sulfate sodium-induced chronic colitis in mice by inhibiting PERK-ATF4-CHOP pathway of ER stress and NF-κB signaling. Int Immunopharmacol 2020; 90:107161. [PMID: 33168409 DOI: 10.1016/j.intimp.2020.107161] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 10/22/2020] [Accepted: 10/28/2020] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammation regulated by intricate mechanisms. Limonin, a natural tetracyclic triterpenoid compound, possesses multiple bioactivities including anti-inflammation, anti-cancer and so on. However, the therapeutic potential and the underlying mechanism of limonin on IBD remain unclear. Here, we probe into the effect of limonin on chronic colitis induced by dextran sulfate sodium (DSS) and illustrated the potential mechanisms. We found that limonin relieved the risk and severity of DSS-induced chronic colitis in mice through various aspects including increasing body weight and colon length, decreasing the mortality rate, inhibiting MPO activity and improving colon pathology. Limonin also decreased the production of proinflammatory cytokines TNF-α, IL-1β, IL-6 and the expression of inflammatory proteins COX-2, iNOS in colon tissues from DSS-induced colitis mice. Moreover, limonin attenuated DSS-induced chronic colitis by inhibiting PERK-ATF4-CHOP pathway of endoplasmic reticulum (ER) stress and NF-κB signaling. In vitro, limonin not only decreased LPS-induced higher production of pro-inflammatory cytokines and inflammatory proteins mentioned above by inhibiting NF-κB signaling in macrophage cells RAW264.7, but also suppressed PERK-ATF4-CHOP pathway of ER stress. In summary, our study demonstrated that limonin mitigated DSS-induced chronic colitis via inhibiting PERK-ATF4-CHOP pathway of ER stress and NF-κB signaling. All of this study provides the possibility for limonin as an effective drug for chronic colitis of IBD in the future.
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Affiliation(s)
- Changqin Song
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China; College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China
| | - Jiaxi Chen
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China
| | - Xiaotian Li
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, People's Republic of China
| | - Runyu Yang
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China
| | - Xiaomei Cao
- Department of Pharmacology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, People's Republic of China
| | - Lvqi Zhou
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China
| | - Yanfen Zhou
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China
| | - Hanjie Ying
- College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China
| | - Qi Zhang
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China.
| | - Yang Sun
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China.
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49
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Yashiro T, Yura S, Tobita A, Toyoda Y, Kasakura K, Nishiyama C. Pterostilbene reduces colonic inflammation by suppressing dendritic cell activation and promoting regulatory T cell development. FASEB J 2020; 34:14810-14819. [PMID: 32964554 DOI: 10.1096/fj.202001502r] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/21/2020] [Accepted: 08/24/2020] [Indexed: 12/31/2022]
Abstract
Dendritic cells (DCs) and T cells play important roles in immune regulation, and modulating their function is an approach for developing preventive or therapeutic strategies against immune disorders. Herein, the effect of pterostilbene (PSB) (3',5'-dimethoxy-resveratrol)-a resveratrol-related polyphenol found in blueberries-on immune regulation was evaluated. Using an in vitro co-culture system, PSB was found to exert the strongest inhibitory effect among all tested resveratrol derivatives on DC-mediated T cell proliferation; moreover, PSB treatment decreased the Th1 and Th17 populations and increased the regulatory T cell (Treg) population. Upon co-stimulation with anti-CD3 and anti-CD28 antibodies, PSB inhibited CD4+ T cell proliferation and differentiation into Th1 cells. Additionally, PSB acted on DCs to suppress the lipopolysaccharide-induced transactivation of genes encoding antigen presentation-related molecules and inflammatory cytokines by attenuating the DNA-binding ability of the transcription factor PU.1. Furthermore, PSB promoted DC-mediated Foxp3+ Treg differentiation, and PU.1 knockdown increased DC-induced Treg activity. Oral administration of PSB alleviated the symptoms of dextran sulfate sodium-induced colitis and decreased tumor necrosis factor-α expression in mice. Thus, PSB treatment ameliorates colonic inflammation.
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Affiliation(s)
- Takuya Yashiro
- Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Tokyo, Japan
| | - Shiori Yura
- Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Tokyo, Japan
| | - Akari Tobita
- Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Tokyo, Japan
| | - Yuki Toyoda
- Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Tokyo, Japan
| | - Kazumi Kasakura
- Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Tokyo, Japan
| | - Chiharu Nishiyama
- Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Tokyo, Japan
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50
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Grondin JA, Kwon YH, Far PM, Haq S, Khan WI. Mucins in Intestinal Mucosal Defense and Inflammation: Learning From Clinical and Experimental Studies. Front Immunol 2020; 11:2054. [PMID: 33013869 PMCID: PMC7500085 DOI: 10.3389/fimmu.2020.02054] [Citation(s) in RCA: 242] [Impact Index Per Article: 48.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 07/28/2020] [Indexed: 12/24/2022] Open
Abstract
Throughout the gastrointestinal (GI) tract, a distinct mucus layer composed of highly glycosylated proteins called mucins plays an essential role in providing lubrication for the passage of food, participating in cell signaling pathways and protecting the host epithelium from commensal microorganisms and invading pathogens, as well as toxins and other environmental irritants. These mucins can be broadly classified into either secreted gel-forming mucins, those that provide the structural backbone for the mucus barrier, or transmembrane mucins, those that form the glycocalyx layer covering the underlying epithelial cells. Goblet cells dispersed among the intestinal epithelial cells are chiefly responsible for the synthesis and secretion of mucins within the gut and are heavily influenced by interactions with the immune system. Evidence from both clinical and animal studies have indicated that several GI conditions, including inflammatory bowel disease (IBD), colorectal cancer, and numerous enteric infections are accompanied by considerable changes in mucin quality and quantity. These changes include, but are not limited to, impaired goblet cell function, synthesis dysregulation, and altered post-translational modifications. The current review aims to highlight the structural and functional features as well as the production and immunological regulation of mucins and the impact these key elements have within the context of barrier function and host defense in intestinal inflammation.
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Affiliation(s)
- Jensine A Grondin
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Yun Han Kwon
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Parsa Mehraban Far
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Sabah Haq
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Waliul I Khan
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
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