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Gopalsamy RG, Antony PJ, Athesh K, Hillary VE, Montalvão MM, Hariharan G, Santana LADM, Borges LP, Gurgel RQ. Dietary essential oil components: A systematic review of preclinical studies on the management of gastrointestinal diseases. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 140:156630. [PMID: 40085990 DOI: 10.1016/j.phymed.2025.156630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 02/24/2025] [Accepted: 03/06/2025] [Indexed: 03/16/2025]
Abstract
BACKGROUND The gut is responsible for the digestion and absorption of nutrients, immune regulation, and barrier function. However, factors like poor diet, stress, and infection, can disrupt the balance of the gut microbiota and lead to intestinal inflammation and dysfunction. PURPOSE This systematic review aims to evaluate the effects of dietary plants-derived essential oil components on gut health and intestinal functions in animal models. METHODS The literature was gathered from the Scopus, Web of Science, PubMed, and Embase databases by using related search terms, such as "dietary plants", "dietary sources", "essential oils", "gut health", "intestine", "anti-inflammatory", "antioxidant", and "gut microbiota". RESULTS The results indicate that plant-derived dietary essential oil components, such as butyrolactone-I, carvacrol, cinnamaldehyde, citral, D-limonene, eugenol, farnesol, geraniol, indole, nerolidol, oleic acid, thymol, trans-anethole, vanillin, α-bisabolol, α-linolenic acid, α-pinene, α-terpineol, β-carotene, β-caryophyllene, and β-myrcene have been found to regulate gut health by influencing vital signalling pathways associated with inflammation. Dietary essential oil components modulate the expression of tumor necrosis factor alpha, interleukin 1 beta (IL-1β), interleukin (IL)-6, IL-10, inducible nitric oxide synthase, cyclooxygenase-2, toll-like receptor-4, matrix metalloproteinase, and interferon gamma in mitigating gut inflammation. The primary signalling molecules controlled by these molecules were AMP-activated protein kinase (AMPK), protein kinase B, extracellular signal-regulated kinase, c-Jun N-terminal kinase, mitogen-activated protein kinase, myeloid differentiation primary response 88, nuclear factor erythroid-2-related factor-2, and phosphoinositide 3-kinase (PI3K). Moreover, these phytochemicals have been shown to improve glucose homeostasis by regulating glucose transporter 4, glucagon-like peptide-1, peroxisome proliferator-activated receptor gamma, nuclear factor kappa B, AMPK, PI3K, and uncoupling protein-1. They can also reduce thiobarbituric acid reactive substance, malondialdehyde, and oxidative stress and enhance superoxide dismutase, catalase, and glutathione peroxidase levels. CONCLUSION In conclusion, dietary plants-derived essential oil components have the potential to mitigate inflammation and oxidative stress in the gut. However, additional clinical investigations are necessary to confirm their complete potential in improving human gut health functions.
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Affiliation(s)
- Rajiv Gandhi Gopalsamy
- Division of Phytochemistry and Drug-Design, Department of Biosciences, Rajagiri College of Social Sciences (Autonomous), Kochi, Kerala, India; Postgraduate Program of Health Sciences (PPGCS), Federal University of Sergipe, Campus Prof. João Cardoso Nascimento, Aracaju, Sergipe, Brazil
| | - Poovathumkal James Antony
- Department of Microbiology, North Bengal University, St. Joseph's College, Darjeeling, West Bengal, India
| | - Kumaraswamy Athesh
- School of Sciences, Bharata Mata College (Autonomous), Kochi, Kerala, India
| | - Varghese Edwin Hillary
- Division of Phytochemistry and Drug-Design, Department of Biosciences, Rajagiri College of Social Sciences (Autonomous), Kochi, Kerala, India
| | | | | | | | - Lysandro Pinto Borges
- Department of Pharmacy, Federal University of Sergipe, São Cristovão, Sergipe, Brazil
| | - Ricardo Queiroz Gurgel
- Postgraduate Program of Health Sciences (PPGCS), Federal University of Sergipe, Campus Prof. João Cardoso Nascimento, Aracaju, Sergipe, Brazil.
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Hong Z, Fang S, Nie H, Zhou J, Hong Y, Liu L, Zhao Q. Identification of the immune infiltration and biomarkers in ulcerative colitis based on liquid-liquid phase separation-related genes. Sci Rep 2025; 15:4484. [PMID: 39915583 PMCID: PMC11802798 DOI: 10.1038/s41598-025-89252-1] [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: 07/19/2024] [Accepted: 02/04/2025] [Indexed: 02/09/2025] Open
Abstract
Liquid-liquid phase separation (LLPS) associates with immune infiltration in multiple diseases. Nonetheless, the role of LLPS-related genes (LLPS-RGs) in immune infiltration of ulcerative colitis (UC) is still elusive. We identified the hub LLPS-RGs (DE-LLPS-RGs) (HSPB3, SLC16A1, TRIM22, SRI, PLEKHG6, GBP1, PADI2) by machine learning algorithms. Hub genes were screened that displayed high prediction accuracy of UC patients. Both the microarray and scRNA-seq datasets showed a strong correlation with immune cell infiltration and cytokines, especially GBP1, TRIM22, SRI. And qRT-PCR analysis showed that GBP1 play a pro-inflammatory role in UC. Two distinct clusters were identified, in which cluster A displayed higher immune infiltration level compared with the cluster B. The top targeted biological pathways of two clusters were distinct, glutamate receptor antagonist ranked top for cluster A while HDAC inhibitor ranked top in cluster B. External cohort and UC cell model validation indicated the similar immune infiltration levels, gene expression and cytokine expression patterns. We determined the seven high accuracy diagnostic genes of UC patients and provide a new perspective on immunoregulation in UC pathogenesis. And suggest patient stratification and candidate targets for precision treatment based on hub genes screened.
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Affiliation(s)
- Zhixing Hong
- Department of Emergency Medicine, The First People's Hospital of Linping District, Hangzhou, China
| | - Shilin Fang
- Department of Infectious Disease, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Haihang Nie
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Provincial Clinical Research Center for Intestinal and Colorectal Diseases, Wuhan, China
- Hubei Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Jingkai Zhou
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Provincial Clinical Research Center for Intestinal and Colorectal Diseases, Wuhan, China
- Hubei Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Yuntian Hong
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.
- Hubei Provincial Clinical Research Center for Intestinal and Colorectal Diseases, Wuhan, China.
- Hubei Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China.
| | - Lan Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.
- Hubei Provincial Clinical Research Center for Intestinal and Colorectal Diseases, Wuhan, China.
- Hubei Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China.
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.
- Hubei Provincial Clinical Research Center for Intestinal and Colorectal Diseases, Wuhan, China.
- Hubei Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China.
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Liu L, Davidorf B, Dong P, Peng A, Song Q, He Z. Decoding the mosaic of inflammatory bowel disease: Illuminating insights with single-cell RNA technology. Comput Struct Biotechnol J 2024; 23:2911-2923. [PMID: 39421242 PMCID: PMC11485491 DOI: 10.1016/j.csbj.2024.07.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/08/2024] [Accepted: 07/08/2024] [Indexed: 10/19/2024] Open
Abstract
Inflammatory bowel diseases (IBD), comprising ulcerative colitis (UC) and Crohn's disease (CD), are complex chronic inflammatory intestinal conditions with a multifaceted pathology, influenced by immune dysregulation and genetic susceptibility. The challenges in understanding IBD mechanisms and implementing precision medicine include deciphering the contributions of individual immune and non-immune cell populations, pinpointing specific dysregulated genes and pathways, developing predictive models for treatment response, and advancing molecular technologies. Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool to address these challenges, offering comprehensive transcriptome profiles of various cell types at the individual cell level in IBD patients, overcoming limitations of bulk RNA sequencing. Additionally, single-cell proteomics analysis, T-cell receptor repertoire analysis, and epigenetic profiling provide a comprehensive view of IBD pathogenesis and personalized therapy. This review summarizes significant advancements in single-cell sequencing technologies for enhancing our understanding of IBD, covering pathogenesis, diagnosis, treatment, and prognosis. Furthermore, we discuss the challenges that persist in the context of IBD research, including the need for longitudinal studies, integration of multiple single-cell and spatial transcriptomics technologies, and the potential of microbial single-cell RNA-seq to shed light on the role of the gut microbiome in IBD.
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Affiliation(s)
- Liang Liu
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Benjamin Davidorf
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Peixian Dong
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Alice Peng
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Qianqian Song
- Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Zhiheng He
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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Ioannidis O, Cheva A, Varnalidis I, Koutelidakis I, Papaziogas V, Christidis P, Anestiadou E, Aggelopoulos K, Mantzoros I, Pramateftakis MG, Kotidis E, Driagka B, Aggelopoulos S, Giamarellos-Bourboulis EJ. The Combined Administration of Eicosapentaenoic Acid (EPA) and Gamma-Linolenic Acid (GLA) in Experimentally Induced Colitis: An Experimental Study in Rats. J Clin Med 2024; 13:6661. [PMID: 39597805 PMCID: PMC11594508 DOI: 10.3390/jcm13226661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 10/11/2024] [Accepted: 10/18/2024] [Indexed: 11/29/2024] Open
Abstract
Background/Objectives: Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited effective treatments, prompting the need for investigation of novel therapeutic approaches. Eicosapentaenoic acid (EPA) and gamma-linolenic acid (GLA) have demonstrated potential anti-inflammatory properties, but their combined effects on UC have not been thoroughly investigated. This study aimed to evaluate the effect of the combined administration of EPA and GLA on clinical and histopathologic features of experimental UC models. Methods: Thirty-six male Wistar rats were randomized in three groups (DSS group, Ensure Plus group, and Oxepa group), with twelve rats in each group. Experimental colitis was induced by administrating dextran sulfate sodium (DSS) 8%. The DSS group received tap water, the Ensure Plus group was given a high caloric diet, and the Oxepa group received a special diet containing high levels of EPA and GLA. Disease activity index (DAI) and microscopic activity index (MAI) were measured. Inflammatory markers were calculated both in blood and large intestine, liver, spleen, and lung tissue samples. Neutrophil and macrophage populations were assessed with immunohistochemistry. Results: No significant differences in the DAI index were found between the groups, but the MAI revealed statistically significant differences (p < 0.001). While no significant differences were observed in tumor necrosis factor-alpha (TNF-α) levels, interleukin-17 (IL-17) levels in the large intestine showed statistically significant differences (p = 0.05), with the Ensure Plus and Oxepa groups displaying lower levels compared to the DSS group (p = 0.021 and p = 0.043, respectively). Significant differences in neutrophil infiltration were found in both the large intestine (p < 0.001) and lungs (p = 0.002), with the Oxepa group showing fewer cells. Similarly, significant differences in macrophage infiltration were observed in the large intestine (p = 0.038) and spleen (p < 0.001), with the Oxepa group having lower macrophage counts. Conclusions: In conclusion, the combination of EPA and GLA demonstrates local anti-inflammatory effects and improves the histopathological outcomes in UC.
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Affiliation(s)
- Orestis Ioannidis
- 4th Department of Surgery, General Hospital “George Papanikolaou”, Aristotle University of Thessaloniki, 57010 Exochi, Greece; (I.V.); (P.C.); (E.A.); (K.A.); (I.M.); (M.G.P.); (E.K.); (B.D.); (S.A.)
| | - Angeliki Cheva
- Pathology Department, Faculty of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Ioannis Varnalidis
- 4th Department of Surgery, General Hospital “George Papanikolaou”, Aristotle University of Thessaloniki, 57010 Exochi, Greece; (I.V.); (P.C.); (E.A.); (K.A.); (I.M.); (M.G.P.); (E.K.); (B.D.); (S.A.)
| | - Ioannis Koutelidakis
- 2nd Department of Surgery, G.Gennimatas General Hospital, Aristotle University of Thessaloniki, 54635 Thessaloniki, Greece; (I.K.); (V.P.)
| | - Vasileios Papaziogas
- 2nd Department of Surgery, G.Gennimatas General Hospital, Aristotle University of Thessaloniki, 54635 Thessaloniki, Greece; (I.K.); (V.P.)
| | - Panagiotis Christidis
- 4th Department of Surgery, General Hospital “George Papanikolaou”, Aristotle University of Thessaloniki, 57010 Exochi, Greece; (I.V.); (P.C.); (E.A.); (K.A.); (I.M.); (M.G.P.); (E.K.); (B.D.); (S.A.)
| | - Elissavet Anestiadou
- 4th Department of Surgery, General Hospital “George Papanikolaou”, Aristotle University of Thessaloniki, 57010 Exochi, Greece; (I.V.); (P.C.); (E.A.); (K.A.); (I.M.); (M.G.P.); (E.K.); (B.D.); (S.A.)
| | - Konstantinos Aggelopoulos
- 4th Department of Surgery, General Hospital “George Papanikolaou”, Aristotle University of Thessaloniki, 57010 Exochi, Greece; (I.V.); (P.C.); (E.A.); (K.A.); (I.M.); (M.G.P.); (E.K.); (B.D.); (S.A.)
| | - Ioannis Mantzoros
- 4th Department of Surgery, General Hospital “George Papanikolaou”, Aristotle University of Thessaloniki, 57010 Exochi, Greece; (I.V.); (P.C.); (E.A.); (K.A.); (I.M.); (M.G.P.); (E.K.); (B.D.); (S.A.)
| | - Manousos George Pramateftakis
- 4th Department of Surgery, General Hospital “George Papanikolaou”, Aristotle University of Thessaloniki, 57010 Exochi, Greece; (I.V.); (P.C.); (E.A.); (K.A.); (I.M.); (M.G.P.); (E.K.); (B.D.); (S.A.)
| | - Efstathios Kotidis
- 4th Department of Surgery, General Hospital “George Papanikolaou”, Aristotle University of Thessaloniki, 57010 Exochi, Greece; (I.V.); (P.C.); (E.A.); (K.A.); (I.M.); (M.G.P.); (E.K.); (B.D.); (S.A.)
| | - Barbara Driagka
- 4th Department of Surgery, General Hospital “George Papanikolaou”, Aristotle University of Thessaloniki, 57010 Exochi, Greece; (I.V.); (P.C.); (E.A.); (K.A.); (I.M.); (M.G.P.); (E.K.); (B.D.); (S.A.)
| | - Stamatios Aggelopoulos
- 4th Department of Surgery, General Hospital “George Papanikolaou”, Aristotle University of Thessaloniki, 57010 Exochi, Greece; (I.V.); (P.C.); (E.A.); (K.A.); (I.M.); (M.G.P.); (E.K.); (B.D.); (S.A.)
| | - Evangelos J. Giamarellos-Bourboulis
- 4th Department of Internal Medicine, National and Kapodistrian University of Athens Medical School, “Attikon” Hospital, 12462 Athens, Greece;
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Ohara D, Takeuchi Y, Hirota K. Type 17 immunity: novel insights into intestinal homeostasis and autoimmune pathogenesis driven by gut-primed T cells. Cell Mol Immunol 2024; 21:1183-1200. [PMID: 39379604 PMCID: PMC11528014 DOI: 10.1038/s41423-024-01218-x] [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: 04/15/2024] [Accepted: 09/11/2024] [Indexed: 10/10/2024] Open
Abstract
The IL-23 signaling pathway in both innate and adaptive immune cells is vital for orchestrating type 17 immunity, which is marked by the secretion of signature cytokines such as IL-17, IL-22, and GM-CSF. These proinflammatory mediators play indispensable roles in maintaining intestinal immune equilibrium and mucosal host defense; however, their involvement has also been implicated in the pathogenesis of chronic inflammatory disorders, such as inflammatory bowel diseases and autoimmunity. However, the implications of type 17 immunity across diverse inflammation models are complex. This review provides a comprehensive overview of the multifaceted roles of these cytokines in maintaining gut homeostasis and in perturbing gut barrier integrity, leading to acute and chronic inflammation in various models of gut infection and colitis. Additionally, this review focuses on type 17 immunity interconnecting multiple organs in autoimmune conditions, with a particular emphasis on the pathogenesis of autoimmune arthritis and neuroinflammation driven by T cells primed within the gut microenvironment.
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Affiliation(s)
- Daiya Ohara
- Laboratory of Integrative Biological Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Yusuke Takeuchi
- Laboratory of Integrative Biological Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Keiji Hirota
- Laboratory of Integrative Biological Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
- ImmunoSensation Cluster of Excellence, University of Bonn, Bonn, Germany.
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Gobert AP, Latour YL, McNamara KM, Hawkins CV, Williams KJ, Asim M, Barry DP, Allaman MM, Delgado AG, Milne GL, Zhao S, Piazuelo MB, Washington MK, Coburn LA, Wilson KT. The reverse transsulfuration pathway affects the colonic microbiota and contributes to colitis in mice. Amino Acids 2024; 56:63. [PMID: 39427081 PMCID: PMC11490428 DOI: 10.1007/s00726-024-03423-4] [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: 04/10/2024] [Accepted: 10/05/2024] [Indexed: 10/21/2024]
Abstract
Cystathionine γ-lyase (CTH) is a critical enzyme in the reverse transsulfuration pathway, the major route for the metabolism of sulfur-containing amino acids, notably converting cystathionine to cysteine. We reported that CTH supports gastritis induced by the pathogen Helicobacter pylori. Herein our aim was to investigate the role of CTH in colonic inflammation. First, we found that CTH is induced in the colon mucosa in mice with dextran sulfate sodium-induced colitis. Expression of CTH was completely absent in the colon of Cth-/- mice. We observed that clinical and histological parameters are ameliorated in Cth-deficient mice compared to wild-type animals. However, Cth deletion had no effect on tumorigenesis and the level of dysplasia in mice treated with azoxymethane-DSS, as a reliable model of colitis-associated carcinogenesis. Mechanistically, we determined that the deletion of the gene Slc7a11 encoding for solute carrier family 7 member 11, the transporter of the anionic form of cysteine, does not affect DSS colitis. Lastly, we found that the richness and diversity of the fecal microbiota were significantly increased in Cth-/- mice compared to both WT and Slc7a11-/- mice. In conclusion, our data suggest that the enzyme CTH represents a target for clinical intervention in patients with inflammatory bowel disease, potentially by beneficially reshaping the composition of the gut microbiota.
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Affiliation(s)
- Alain P Gobert
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Program in Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Yvonne L Latour
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Kara M McNamara
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Program in Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Caroline V Hawkins
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Kamery J Williams
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Mohammad Asim
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Daniel P Barry
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Margaret M Allaman
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Alberto G Delgado
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Ginger L Milne
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Shilin Zhao
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - M Blanca Piazuelo
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - M Kay Washington
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Lori A Coburn
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Program in Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, 37232, USA
| | - Keith T Wilson
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
- Program in Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, 37232, USA.
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Wen C, Chen D, Zhong R, Peng X. Animal models of inflammatory bowel disease: category and evaluation indexes. Gastroenterol Rep (Oxf) 2024; 12:goae021. [PMID: 38634007 PMCID: PMC11021814 DOI: 10.1093/gastro/goae021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 02/12/2024] [Accepted: 02/29/2024] [Indexed: 04/19/2024] Open
Abstract
Inflammatory bowel disease (IBD) research often relies on animal models to study the etiology, pathophysiology, and management of IBD. Among these models, rats and mice are frequently employed due to their practicality and genetic manipulability. However, for studies aiming to closely mimic human pathology, non-human primates such as monkeys and dogs offer valuable physiological parallels. Guinea pigs, while less commonly used, present unique advantages for investigating the intricate interplay between neurological and immunological factors in IBD. Additionally, New Zealand rabbits excel in endoscopic biopsy techniques, providing insights into mucosal inflammation and healing processes. Pigs, with their physiological similarities to humans, serve as ideal models for exploring the complex relationships between nutrition, metabolism, and immunity in IBD. Beyond mammals, non-mammalian organisms including zebrafish, Drosophila melanogaster, and nematodes offer specialized insights into specific aspects of IBD pathology, highlighting the diverse array of model systems available for advancing our understanding of this multifaceted disease. In this review, we conduct a thorough analysis of various animal models employed in IBD research, detailing their applications and essential experimental parameters. These include clinical observation, Disease Activity Index score, pathological assessment, intestinal barrier integrity, fibrosis, inflammatory markers, intestinal microbiome, and other critical parameters that are crucial for evaluating modeling success and drug efficacy in experimental mammalian studies. Overall, this review will serve as a valuable resource for researchers in the field of IBD, offering insights into the diverse array of animal models available and their respective applications in studying IBD.
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Affiliation(s)
- Changlin Wen
- Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, Sichuan, P. R. China
| | - Dan Chen
- Acupuncture and Moxibustion School of Teaching, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P. R. China
| | - Rao Zhong
- Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, Sichuan, P. R. China
| | - Xi Peng
- Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, Sichuan, P. R. China
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Wu Z, Li Y, Jiang M, Sang L, Chang B. Selenium Yeast Alleviates Dextran Sulfate Sodium-Induced Chronic Colitis in Mice by Reducing Proinflammatory Cytokines and Regulating the Gut Microbiota and Their Metabolites. J Inflamm Res 2024; 17:2023-2037. [PMID: 38577691 PMCID: PMC10992675 DOI: 10.2147/jir.s449335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 02/29/2024] [Indexed: 04/06/2024] Open
Abstract
Background Inflammatory bowel disease (IBD) is a chronic recurrent gastrointestinal inflammatory disease. Selenium has been reported to have therapeutic potential in IBD. Selenium yeast is a common selenium supplement that is convenient to access. This study explored the effect of selenium yeast on dextran sulfate sodium- (DSS-)induced chronic colitis in mice. Methods Mice were randomly divided into four groups: the control group, selenium yeast group, chronic colitis group, and chronic colitis+selenium yeast group (n=6). Mice were killed on the 26th day. The disease activity index (DAI) score and histological damage score were calculated. Cytokines, serum selenium, colonic tissue selenium, gut microbiota and their metabolites short-chain fatty acids (SCFAs) were evaluated. Results Selenium yeast lowered IL-1β, IL-6, TNF-α, IL-17A, IL-22 and IFN-γ (P<0.05). In addition, selenium yeast significantly elevated Turicibacter, Bifidobacterium, Allobaculum, Prevotella, Halomonas, Adlercreutzia (P<0.05), and butyric acid (P<0.05). Conclusion Selenium yeast could improve DSS-induced chronic colitis in mice by regulating cytokines, gut microbiota and their metabolites.
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Affiliation(s)
- Zeyu Wu
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China
| | - Yan Li
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China
| | - Min Jiang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China
| | - Lixuan Sang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China
| | - Bing Chang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China
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9
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Liu Y, Ouyang Y, You W, Liu W, Cheng Y, Mai X, Shen Z. Physiological roles of human interleukin-17 family. Exp Dermatol 2024; 33:e14964. [PMID: 37905720 DOI: 10.1111/exd.14964] [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: 06/08/2023] [Revised: 10/08/2023] [Accepted: 10/13/2023] [Indexed: 11/02/2023]
Abstract
Interleukin-17 s (IL-17s) are well-known proinflammatory cytokines, and their antagonists perform excellently in the treatment of inflammatory skin diseases such as psoriasis. However, their physiological functions have not been given sufficient attention by clinicians. IL-17s can protect the host from extracellular pathogens, maintain epithelial integrity, regulate cognitive processes and modulate adipocyte activity through distinct mechanisms. Here, we present a systematic review concerning the physiological functions of IL-17s. Our goal is not to negate the therapeutic effect of IL-17 antagonists, but to ensure their safe use and reasonably explain the possible adverse events that may occur in their application.
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Affiliation(s)
- Yucong Liu
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Ye Ouyang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Wanchun You
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Wenqi Liu
- Department of Dermatology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Yufan Cheng
- Department of Dermatology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Xinming Mai
- Medical School, Shenzhen University, Shenzhen, China
| | - Zhu Shen
- Department of Dermatology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
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10
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Xian S, Zhu J, Wang Y, Song H, Wang H. Oral liposomal delivery of an activatable budesonide prodrug reduces colitis in experimental mice. Drug Deliv 2023; 30:2183821. [PMID: 36861451 PMCID: PMC9987780 DOI: 10.1080/10717544.2023.2183821] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/03/2023] Open
Abstract
Inflammatory bowel disease (IBD) is one of the most common intestinal disorders, with increasing global incidence and prevalence. Numerous therapeutic drugs are available but require intravenous administration and are associated with high toxicity and insufficient patient compliance. Here, an oral liposome that entraps the activatable corticosteroid anti-inflammatory budesonide was developed for efficacious and safe IBD therapy. The prodrug was produced via the ligation of budesonide with linoleic acid linked by a hydrolytic ester bond, which was further constrained into lipid constituents to form colloidal stable nanoliposomes (termed budsomes). Chemical modification with linoleic acid augmented the compatibility and miscibility of the resulting prodrug in lipid bilayers to provide protection from the harsh environment of the gastrointestinal tract, while liposomal nanoformulation enables preferential accumulation to inflamed vasculature. Hence, when delivered orally, budsomes exhibited high stability with low drug release in the stomach in the presence of ultra-acidic pH but released active budesonide after accumulation in inflamed intestinal tissues. Notably, oral administration of budsomes demonstrated favorable anti-colitis effect with only ∼7% mouse body weight loss, whereas at least ∼16% weight loss was observed in other treatment groups. Overall, budsomes exhibited higher therapeutic efficiency than free budesonide treatment and potently induced remission of acute colitis without any adverse side effects. These data suggest a new and reliable approach for improving the efficacy of budesonide. Our in vivo preclinical data demonstrate the safety and increased efficacy of the budsome platform for IBD treatment, further supporting clinical evaluation of this orally efficacious budesonide therapeutic.
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Affiliation(s)
- Shiyun Xian
- The First Affiliated Hospital, National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, P.R. China.,Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province, P.R. China
| | - Jiabin Zhu
- Department of Pharmacy, The Obstetrics and Gynecology Hospital of Fudan University, Shanghai, P.R. China
| | - Yuchen Wang
- The First Affiliated Hospital, National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, P.R. China
| | - Haihan Song
- Central Lab, Shanghai Key Laboratory of Pathogenic Fungi Medical Testing, Shanghai Pudong New Area People's Hospital, Shanghai, P.R. China
| | - Hangxiang Wang
- The First Affiliated Hospital, National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, P.R. China.,Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province, P.R. China
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11
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Zhou X, Gou K, Xu J, Jian L, Luo Y, Li C, Guan X, Qiu J, Zou J, Zhang Y, Zhong X, Zeng T, Zhou Y, Xiao Y, Yang X, Chen W, Gao P, Liu C, Zhou Y, Tao L, Liu X, Cen X, Chen Q, Sun Q, Luo Y, Zhao Y. Discovery and Optimization of Novel hDHODH Inhibitors for the Treatment of Inflammatory Bowel Disease. J Med Chem 2023; 66:14755-14786. [PMID: 37870434 DOI: 10.1021/acs.jmedchem.3c01365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2023]
Abstract
As a key rate-limiting enzyme in the de novo synthesis of pyrimidine nucleotides, human dihydroorotate dehydrogenase (hDHODH) is considered a known target for the treatment of autoimmune diseases, including inflammatory bowel disease (IBD). Herein, BAY 41-2272 with a 1H-pyrazolo[3,4-b]pyridine scaffold was identified as an hDHODH inhibitor by screening an active compound library containing 5091 molecules. Further optimization led to 2-(1-(2-chloro-6-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-cyclopropylpyrimidin-4-amine (w2), which was found to be the most promising and drug-like compound with potent inhibitory activity against hDHODH (IC50 = 173.4 nM). Compound w2 demonstrated acceptable pharmacokinetic characteristics and alleviated the severity of acute ulcerative colitis induced by dextran sulfate sodium in a dose-dependent manner. Notably, w2 exerted better therapeutic effects on ulcerative colitis than hDHODH inhibitor vidofludimus and Janus kinase (JAK) inhibitor tofacitinib. Taken together, w2 is a promising hDHODH inhibitor for the treatment of IBD and deserves to be developed as a preclinical candidate.
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Affiliation(s)
- Xia Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Green Pharmaceutical Technology Key Laboratory of Luzhou, Central Nervous System Drug Key Laboratory of Sichuan Province, Department of Medicinal Chemistry, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
| | - Kun Gou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jing Xu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lunan Jian
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yuan Luo
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Chungen Li
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xinqi Guan
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jiahao Qiu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jiao Zou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yu Zhang
- School of Medicine, Tibet University, Lhasa 850000, China
| | - Xi Zhong
- West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Ting Zeng
- West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yue Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yuzhou Xiao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xinyu Yang
- West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Weijie Chen
- West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Ping Gao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Chunqi Liu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yang Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lei Tao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xingchen Liu
- West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Xiaobo Cen
- National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qiang Chen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qingxiang Sun
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Department of Pulmonary and Critical Care Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Youfu Luo
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yinglan Zhao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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12
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Wang L, Zhang H, Tang F, Yan H, Feng W, Liu J, Wang Y, Tan Y, Chen H. Therapeutic Effects of Valeriana jatamansi on Ulcerative Colitis: Insights into Mechanisms of Action through Metabolomics and Microbiome Analysis. J Proteome Res 2023; 22:2669-2682. [PMID: 37475705 DOI: 10.1021/acs.jproteome.3c00237] [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] [Indexed: 07/22/2023]
Abstract
Ulcerative colitis (UC), belonging to inflammatory bowel disease (IBD), is a chronic and relapsing inflammatory disorder of the gastrointestinal tract, which has not been completely cured in patients so far. Valeriana jatamansi is a Chinese medicine used clinically to treat "diarrhea," which is closely related to UC. This study was to elucidate the therapeutic effects of V. jatamansi extract (VJE) on dextran sodium sulfate (DSS)-induced UC in mice and its underlying mechanism. In this work, VJE effectively ameliorates the symptoms and histopathological scores and reduces the production of inflammatory factors in UC mice. The colon untargeted metabolomics analysis and 16S rDNA sequencing showed remarkable differences in colon metabolite profiles and intestinal microbiome composition between the control and DSS groups, and VJE intervention can reduce these differences. Thirty-two biomarkers were found and modulated the primary pathways including pyrimidine metabolism, arginine biosynthesis, and glutathione metabolism. Meanwhile, twelve significant taxa of gut microbiota were found. Moreover, there is a close relationship between endogenous metabolites and intestinal flora. These findings suggested that VJE ameliorates UC by inhibiting inflammatory factors, recovering intestinal maladjustment, and regulating the interaction between intestinal microbiota and host metabolites. Therefore, the intervention of V. jatamansi is a potential therapeutic treatment for UC.
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Affiliation(s)
- Lixia Wang
- Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
| | - Hai Zhang
- Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
| | - Fei Tang
- Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
| | - Hongling Yan
- Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
| | - Wuwen Feng
- Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
| | - Juan Liu
- Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
| | - Yulan Wang
- Singapore Phenome Center, Lee Kong Chian School of Medicine, Nanyang Technological University, 639798 Singapore
| | - Yuzhu Tan
- Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
| | - Hulan Chen
- Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
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13
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Kim WK, Min SG, Kwon H, Park S, Jo MJ, Ko G. Lactobacillus rhamnosus KBL2290 Ameliorates Gut Inflammation in a Mouse Model of Dextran Sulfate Sodium-Induced Colitis. J Microbiol 2023; 61:673-682. [PMID: 37314676 DOI: 10.1007/s12275-023-00061-5] [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: 02/10/2023] [Revised: 05/12/2023] [Accepted: 05/16/2023] [Indexed: 06/15/2023]
Abstract
Ulcerative colitis, a major form of inflammatory bowel disease (IBD) associated with chronic colonic inflammation, may be induced via overreactive innate and adaptive immune responses. Restoration of gut microbiota abundance and diversity is important to control the pathogenesis. Lactobacillus spp., well-known probiotics, ameliorate IBD symptoms via various mechanisms, including modulation of cytokine production, restoration of gut tight junction activity and normal mucosal thickness, and alterations in the gut microbiota. Here, we studied the effects of oral administration of Lactobacillus rhamnosus (L. rhamnosus) KBL2290 from the feces of a healthy Korean individual to mice with DSS-induced colitis. Compared to the dextran sulfate sodium (DSS) + phosphate-buffered saline control group, the DSS + L. rhamnosus KBL2290 group evidenced significant improvements in colitis symptoms, including restoration of body weight and colon length, and decreases in the disease activity and histological scores, particularly reduced levels of pro-inflammatory cytokines and an elevated level of anti-inflammatory interleukin-10. Lactobacillus rhamnosus KBL2290 modulated the levels of mRNAs encoding chemokines and markers of inflammation; increased regulatory T cell numbers; and restored tight junction activity in the mouse colon. The relative abundances of genera Akkermansia, Lactococcus, Bilophila, and Prevotella increased significantly, as did the levels of butyrate and propionate (the major short-chain fatty acids). Therefore, oral L. rhamnosus KBL2290 may be a useful novel probiotic.
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Affiliation(s)
- Woon-Ki Kim
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, 08826, Republic of Korea.
- Institute of Health and Environment, Seoul National University, Seoul, 08826, Republic of Korea.
| | - Sung-Gyu Min
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, 08826, Republic of Korea
| | - Heeun Kwon
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, 08826, Republic of Korea
| | - SungJun Park
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, 08826, Republic of Korea
- N-Bio, Seoul National University, Seoul, 08826, Republic of Korea
- KoBioLabs, Inc., Seoul, 13488, Republic of Korea
| | - Min Jung Jo
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, 08826, Republic of Korea
| | - GwangPyo Ko
- Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, 08826, Republic of Korea.
- Institute of Health and Environment, Seoul National University, Seoul, 08826, Republic of Korea.
- N-Bio, Seoul National University, Seoul, 08826, Republic of Korea.
- KoBioLabs, Inc., Seoul, 13488, Republic of Korea.
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14
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Zeng J, Li M, Zhao Q, Chen M, Zhao L, Wei S, Yang H, Zhao Y, Wang A, Shen J, Du F, Chen Y, Deng S, Wang F, Zhang Z, Li Z, Wang T, Wang S, Xiao Z, Wu X. Small molecule inhibitors of RORγt for Th17 regulation in inflammatory and autoimmune diseases. J Pharm Anal 2023; 13:545-562. [PMID: 37440911 PMCID: PMC10334362 DOI: 10.1016/j.jpha.2023.05.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 05/05/2023] [Accepted: 05/16/2023] [Indexed: 07/15/2023] Open
Abstract
As a ligand-dependent transcription factor, retinoid-associated orphan receptor γt (RORγt) that controls T helper (Th) 17 cell differentiation and interleukin (IL)-17 expression plays a critical role in the progression of several inflammatory and autoimmune conditions. An emerging novel approach to the therapy of these diseases thus involves controlling the transcriptional capacity of RORγt to decrease Th17 cell development and IL-17 production. Several RORγt inhibitors including both antagonists and inverse agonists have been discovered to regulate the transcriptional activity of RORγt by binding to orthosteric- or allosteric-binding sites in the ligand-binding domain. Some of small-molecule inhibitors have entered clinical evaluations. Therefore, in current review, the role of RORγt in Th17 regulation and Th17-related inflammatory and autoimmune diseases was highlighted. Notably, the recently developed RORγt inhibitors were summarized, with an emphasis on their optimization from lead compounds, efficacy, toxicity, mechanisms of action, and clinical trials. The limitations of current development in this area were also discussed to facilitate future research.
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Affiliation(s)
- Jiuping Zeng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646000, China
| | - Qianyun Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
| | - Meijuan Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Long Zhao
- Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Shulin Wei
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
| | - Huan Yang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646000, China
| | - Anqi Wang
- School of Medicine, Chengdu University, Chengdu, 610106, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646000, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646000, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646000, China
| | - Shuai Deng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646000, China
| | - Fang Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
| | - Zhuo Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, China
| | - Zhi Li
- Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Tiangang Wang
- Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Shengpeng Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, China
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15
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Koshida K, Ito M, Yakabe K, Takahashi Y, Tai Y, Akasako R, Kimizuka T, Takano S, Sakamoto N, Haniuda K, Ogawa S, Kimura S, Kim YG, Hase K, Harada Y. Dysfunction of Foxp3 + Regulatory T Cells Induces Dysbiosis of Gut Microbiota via Aberrant Binding of Immunoglobulins to Microbes in the Intestinal Lumen. Int J Mol Sci 2023; 24:8549. [PMID: 37239894 PMCID: PMC10218244 DOI: 10.3390/ijms24108549] [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: 04/11/2023] [Revised: 05/08/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
Abstract
Foxp3+ regulatory T (Treg) cells prevent excessive immune responses against dietary antigens and commensal bacteria in the intestine. Moreover, Treg cells contribute to the establishment of a symbiotic relationship between the host and gut microbes, partly through immunoglobulin A. However, the mechanism by which Treg cell dysfunction disturbs the balanced intestinal microbiota remains unclear. In this study, we used Foxp3 conditional knockout mice to conditionally ablate the Foxp3 gene in adult mice and examine the relationship between Treg cells and intestinal bacterial communities. Deletion of Foxp3 reduced the relative abundance of Clostridia, suggesting that Treg cells have a role in maintaining Treg-inducing microbes. Additionally, the knockout increased the levels of fecal immunoglobulins and immunoglobulin-coated bacteria. This increase was due to immunoglobulin leakage into the gut lumen as a result of loss of mucosal integrity, which is dependent on the gut microbiota. Our findings suggest that Treg cell dysfunction leads to gut dysbiosis via aberrant antibody binding to the intestinal microbes.
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Affiliation(s)
- Kouhei Koshida
- Laboratory of Pharmaceutical Immunology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan; (K.K.); (M.I.)
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University, Tokyo 105-8512, Japan (S.K.); (K.H.)
| | - Mitsuki Ito
- Laboratory of Pharmaceutical Immunology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan; (K.K.); (M.I.)
| | - Kyosuke Yakabe
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University, Tokyo 105-8512, Japan (S.K.); (K.H.)
- Research Center for Drug Discovery, Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University, Tokyo 105-8512, Japan;
| | - Yoshimitsu Takahashi
- Laboratory of Pharmaceutical Immunology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan; (K.K.); (M.I.)
| | - Yuki Tai
- Laboratory of Pharmaceutical Immunology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan; (K.K.); (M.I.)
| | - Ryouhei Akasako
- Laboratory of Pharmaceutical Immunology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan; (K.K.); (M.I.)
| | - Tatsuki Kimizuka
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University, Tokyo 105-8512, Japan (S.K.); (K.H.)
- Research Center for Drug Discovery, Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University, Tokyo 105-8512, Japan;
| | - Shunsuke Takano
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University, Tokyo 105-8512, Japan (S.K.); (K.H.)
| | - Natsumi Sakamoto
- Laboratory of Pharmaceutical Immunology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan; (K.K.); (M.I.)
| | - Kei Haniuda
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Shuhei Ogawa
- Division of Integrated Research, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda 278-0022, Japan;
| | - Shunsuke Kimura
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University, Tokyo 105-8512, Japan (S.K.); (K.H.)
| | - Yun-Gi Kim
- Research Center for Drug Discovery, Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University, Tokyo 105-8512, Japan;
| | - Koji Hase
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University, Tokyo 105-8512, Japan (S.K.); (K.H.)
- The Institute of Fermentation Sciences (IFeS), Faculty of Food and Agricultural Sciences, Fukushima University, Fukushima 960-1296, Japan
| | - Yohsuke Harada
- Laboratory of Pharmaceutical Immunology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan; (K.K.); (M.I.)
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16
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Venkataraman B, Almarzooqi S, Raj V, Bhongade BA, Patil RB, Subramanian VS, Attoub S, Rizvi TA, Adrian TE, Subramanya SB. Molecular Docking Identifies 1,8-Cineole (Eucalyptol) as A Novel PPARγ Agonist That Alleviates Colon Inflammation. Int J Mol Sci 2023; 24:ijms24076160. [PMID: 37047133 PMCID: PMC10094723 DOI: 10.3390/ijms24076160] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/10/2023] [Accepted: 03/17/2023] [Indexed: 04/14/2023] Open
Abstract
Inflammatory bowel disease, comprising Crohn's disease (CD) and ulcerative colitis (UC), is often debilitating. The disease etiology is multifactorial, involving genetic susceptibility, microbial dysregulation, abnormal immune activation, and environmental factors. Currently, available drug therapies are associated with adverse effects when used long-term. Therefore, the search for new drug candidates to treat IBD is imperative. The peroxisome proliferator-activated receptor-γ (PPARγ) is highly expressed in the colon. PPARγ plays a vital role in regulating colonic inflammation. 1,8-cineole, also known as eucalyptol, is a monoterpene oxide present in various aromatic plants which possess potent anti-inflammatory activity. Molecular docking and dynamics studies revealed that 1,8-cineole binds to PPARγ and if it were an agonist, that would explain the anti-inflammatory effects of 1,8-cineole. Therefore, we investigated the role of 1,8-cineole in colonic inflammation, using both in vivo and in vitro experimental approaches. Dextran sodium sulfate (DSS)-induced colitis was used as the in vivo model, and tumor necrosis factor-α (TNFα)-stimulated HT-29 cells as the in vitro model. 1,8-cineole treatment significantly decreased the inflammatory response in DSS-induced colitis mice. 1,8-cineole treatment also increased nuclear factor erythroid 2-related factor 2 (Nrf2) translocation into the nucleus to induce potent antioxidant effects. 1,8-cineole also increased colonic PPARγ protein expression. Similarly, 1,8-cineole decreased proinflammatory chemokine production and increased PPARγ protein expression in TNFα-stimulated HT-29 cells. 1,8-cineole also increased PPARγ promoter activity time-dependently. Because of its potent anti-inflammatory effects, 1,8-cineole may be valuable in treating IBD.
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Affiliation(s)
- Balaji Venkataraman
- Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
- Zayed Bin Sultan Center for Health Sciences, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Saeeda Almarzooqi
- Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Vishnu Raj
- Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Bhoomendra A Bhongade
- Department of Pharmaceutical Chemistry, RAK College of Pharmacy, RAK Medical & Health Sciences University, Ras Al Khaimah P.O. Box 11172, United Arab Emirates
| | - Rajesh B Patil
- Department of Pharmaceutical Chemistry, Sinhgad College of Pharmacy, Vadgaon (BK), Pune 411 041, India
| | | | - Samir Attoub
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Tahir A Rizvi
- Zayed Bin Sultan Center for Health Sciences, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Thomas E Adrian
- Department of Basic Medical Sciences, College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai P.O. Box 505055, United Arab Emirates
| | - Sandeep B Subramanya
- Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
- Zayed Bin Sultan Center for Health Sciences, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
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17
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Yang WL, Qiu W, Zhang T, Xu K, Gu ZJ, Zhou Y, Xu HJ, Yang ZZ, Shen B, Zhao YL, Zhou Q, Yang Y, Li W, Yang PY, Yang YG. Nsun2 coupling with RoRγt shapes the fate of Th17 cells and promotes colitis. Nat Commun 2023; 14:863. [PMID: 36792629 PMCID: PMC9932167 DOI: 10.1038/s41467-023-36595-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 02/07/2023] [Indexed: 02/17/2023] Open
Abstract
T helper 17 (Th17) cells are a subset of CD4+ T helper cells involved in the inflammatory response in autoimmunity. Th17 cells secrete Th17 specific cytokines, such as IL-17A and IL17-F, which are governed by the master transcription factor RoRγt. However, the epigenetic mechanism regulating Th17 cell function is still not fully understood. Here, we reveal that deletion of RNA 5-methylcytosine (m5C) methyltransferase Nsun2 in mouse CD4+ T cells specifically inhibits Th17 cell differentiation and alleviates Th17 cell-induced colitis pathogenesis. Mechanistically, RoRγt can recruit Nsun2 to chromatin regions of their targets, including Il17a and Il17f, leading to the transcription-coupled m5C formation and consequently enhanced mRNA stability. Our study demonstrates a m5C mediated cell intrinsic function in Th17 cells and suggests Nsun2 as a potential therapeutic target for autoimmune disease.
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Affiliation(s)
- Wen-Lan Yang
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.,Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Weinan Qiu
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.,Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100101, China.,Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ting Zhang
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.,Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China
| | - Kai Xu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Zi-Juan Gu
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100101, China.,National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, 100101, China
| | - Yu Zhou
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China
| | - Heng-Ji Xu
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhong-Zhou Yang
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, Nanjing University Medical School, 210093, Nanjing, China
| | - Bin Shen
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China
| | - Yong-Liang Zhao
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Qi Zhou
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Ying Yang
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China. .,Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 101408, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Wei Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. .,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Peng-Yuan Yang
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Yun-Gui Yang
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China. .,Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 101408, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, 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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Chen ZA, Ma HH, Wang Y, Tian H, Mi JW, Yao DM, Yang CJ. Integrated multiple microarray studies by robust rank aggregation to identify immune-associated biomarkers in Crohn's disease based on three machine learning methods. Sci Rep 2023; 13:2694. [PMID: 36792688 PMCID: PMC9931764 DOI: 10.1038/s41598-022-26345-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 12/13/2022] [Indexed: 02/17/2023] Open
Abstract
Crohn's disease (CD) is a complex autoimmune disorder presumed to be driven by complex interactions of genetic, immune, microbial and even environmental factors. Intrinsic molecular mechanisms in CD, however, remain poorly understood. The identification of novel biomarkers in CD cases based on larger samples through machine learning approaches may inform the diagnosis and treatment of diseases. A comprehensive analysis was conducted on all CD datasets of Gene Expression Omnibus (GEO); our team then used the robust rank aggregation (RRA) method to identify differentially expressed genes (DEGs) between controls and CD patients. PPI (protein‒protein interaction) network and functional enrichment analyses were performed to investigate the potential functions of the DEGs, with molecular complex detection (MCODE) identifying some important functional modules from the PPI network. Three machine learning algorithms, support vector machine-recursive feature elimination (SVM-RFE), random forest (RF), and least absolute shrinkage and selection operator (LASSO), were applied to determine characteristic genes, which were verified by ROC curve analysis and immunohistochemistry (IHC) using clinical samples. Univariable and multivariable logistic regression were used to establish a machine learning score for diagnosis. Single-sample GSEA (ssGSEA) was performed to examine the correlation between immune infiltration and biomarkers. In total, 5 datasets met the inclusion criteria: GSE75214, GSE95095, GSE126124, GSE179285, and GSE186582. Based on RRA integrated analysis, 203 significant DEGs were identified (120 upregulated genes and 83 downregulated genes), and MCODE revealed some important functional modules in the PPI network. Machine learning identified LCN2, REG1A, AQP9, CCL2, GIP, PROK2, DEFA5, CXCL9, and NAMPT; AQP9, PROK2, LCN2, and NAMPT were further verified by ROC curves and IHC in the external cohort. The final machine learning score was defined as [Expression level of AQP9 × (2.644)] + [Expression level of LCN2 × (0.958)] + [Expression level of NAMPT × (1.115)]. ssGSEA showed markedly elevated levels of dendritic cells and innate immune cells, such as macrophages and NK cells, in CD, consistent with the gene enrichment results that the DEGs are mainly involved in the IL-17 signaling pathway and humoral immune response. The selected biomarkers analyzed by the RRA method and machine learning are highly reliable. These findings improve our understanding of the molecular mechanisms of CD pathogenesis.
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Affiliation(s)
- Zi-An Chen
- grid.452702.60000 0004 1804 3009Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000 Hebei China ,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000 Hebei China
| | - Hui-hui Ma
- grid.452702.60000 0004 1804 3009Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000 Hebei China ,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000 Hebei China
| | - Yan Wang
- grid.452702.60000 0004 1804 3009Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000 Hebei China ,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000 Hebei China
| | - Hui Tian
- grid.452702.60000 0004 1804 3009Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000 Hebei China ,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000 Hebei China
| | - Jian-wei Mi
- grid.452702.60000 0004 1804 3009Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000 Hebei China ,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000 Hebei China
| | - Dong-Mei Yao
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China. .,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000, Hebei, China.
| | - Chuan-Jie Yang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China. .,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, 050000, Hebei, China.
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20
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Ariki S, Ozaka S, Sachi N, Chalalai T, Soga Y, Fukuda C, Kagoshima Y, Ekronarongchai S, Mizukami K, Kamiyama N, Murakami K, Kobayashi T. GM-CSF-producing CCR2 + CCR6 + Th17 cells are pathogenic in dextran sodium sulfate-induced colitis model in mice. Genes Cells 2023; 28:267-276. [PMID: 36641236 DOI: 10.1111/gtc.13008] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/09/2023] [Accepted: 01/12/2023] [Indexed: 01/15/2023]
Abstract
Although excessive immune responses by Th17 cells, a helper T cell subset, are implicated in the pathogenesis of inflammatory bowel disease (IBD), the mechanism by which its localization in an inflamed colon is regulated remains unclear. Chemokines and their receptors are involved in the pathogenesis of IBD, however, the relative significance of each receptor on Th17 cells remains unknown. We generated C-C motif chemokine receptor 2 (CCR2) knockout (KO) and CCR6 KO mice in the syngeneic background using the CRISPR/Cas9 system and found that the phenotypes of experimental colitis worsened in both mutant mice. Surprisingly, the phenotype of colitis in CCR2/CCR6-double knockout (CCR2/6 DKO) mice was opposite to that of the single-deficient mice, with significantly milder experimental colitis (p < .05). The same was true for the symptoms in CCR6 KO mice, but not in wild type mice treated with a CCR2 inhibitor, propagermanium. Colonic CCR2+ CCR6+ Th17 cells produced a potentially pathogenic cytokine GM-CSF whose levels in the gut were significantly reduced in CCR2/6 DKO mice (p < .05). These results suggest that GM-CSF-producing CCR2+ CCR6+ Th17 cells are pathogenic and are attracted to the inflamed colon by either CCR2 or CCR6 gradient, which subsequently exacerbates experimental colitis in mice.
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Affiliation(s)
- Shimpei Ariki
- Department of Infectious Disease Control, Oita University, Oita, Japan.,Department of Gastroenterology, Oita University, Oita, Japan
| | - Sotaro Ozaka
- Department of Infectious Disease Control, Oita University, Oita, Japan.,Department of Gastroenterology, Oita University, Oita, Japan
| | - Nozomi Sachi
- Department of Infectious Disease Control, Oita University, Oita, Japan
| | | | - Yasuhiro Soga
- Department of Infectious Disease Control, Oita University, Oita, Japan
| | - Chiaki Fukuda
- Department of Infectious Disease Control, Oita University, Oita, Japan
| | - Yomei Kagoshima
- Department of Infectious Disease Control, Oita University, Oita, Japan.,Department of Gastroenterology, Oita University, Oita, Japan
| | | | - Kazuhiro Mizukami
- Department of Gastroenterology, Oita University, Oita, Japan.,Hospital Clinical Training Institute for Interns, Faculty of Medicine, Oita University, Oita, Japan
| | - Naganori Kamiyama
- Department of Infectious Disease Control, Oita University, Oita, Japan
| | | | - Takashi Kobayashi
- Department of Infectious Disease Control, Oita University, Oita, Japan.,Research Center for GLOBAL and LOCAL Infectious Diseases, Oita, Japan
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21
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Sinigrin Attenuates the Dextran Sulfate Sodium-induced Colitis in Mice by Modulating the MAPK Pathway. Inflammation 2023; 46:787-807. [PMID: 36622573 DOI: 10.1007/s10753-022-01780-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/09/2022] [Accepted: 12/28/2022] [Indexed: 01/10/2023]
Abstract
Ulcerative colitis (UC) is an intestinal inflammatory disease characterised by the loss of intestinal crypts, edema, mucosal ulceration, and infiltration of inflammatory cells in the mucosa. The current study aimed to investigate the protective and therapeutic effects of sinigrin and underlying mechanisms in a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis. DSS-induced colitis models were used to demonstrate sinigrin's therapeutic/protective action. Mice were orally administered with sinigrin (15 mg/kg or 30 mg/kg) for a period of 12 days in both prophylactic and therapeutic models. Animal weights, stool consistency, and bleeding parameters were measured throughout the experimental period. After the experimental period, colon lengths were measured, and colon tissues were harvested to determine the levels of oxidative stress-inducing factors (nitrates and MDA levels) and anti-oxidant components (GSH, SOD, and catalase). Furthermore, gene expression analysis, IL-17 levels, and inflammatory marker expressions were measured using RT-qPCR, ELISA, and immunohistochemical methods respectively. Furthermore, histopathological observations and elucidation of the mechanism of action were determined using H&E analysis and Western blot analysis. Sinigrin treatment (in both prophylactic and therapeutic models) significantly mitigated the DSS-induced body weight loss, attenuated the colon length shrinkage, and improved the disease index score (p < 0.001). Further results revealed that sinigrin's protective/therapeutic effect is associated with a significant attenuation of pro‑inflammatory cytokine production (p < 0.001), reversing the anti-oxidant enzyme levels (p < 0.001) and substantial improvement (2 folds) of the disruption of the colonic morphology in colon tissues compared to DSS control. Immunohistochemical analysis showed that sinigrin treatment remarkably reduced the DSS-induced myeloperoxidase, neutrophil elastase, and CD68 expression in colon tissues. Additionally, sinigrin successfully abrogated the DSS-induced IL-17 levels (p < 0.001) and improved the colonic barrier in colon tissues. Overall, these results demonstrated that sinigrin exerts protective and therapeutic effects on DSS‑induced colitis, by enhancing the anti-oxidant enzymes and suppressing the intestinal inflammatory cascade of markers by regulating the MAPK pathway.
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22
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Okamura Y, Kono T, Sakai M, Hikima JI. Evolutional perspective and functional characteristics of interleukin-17 in teleosts. FISH & SHELLFISH IMMUNOLOGY 2023; 132:108496. [PMID: 36526158 DOI: 10.1016/j.fsi.2022.108496] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/10/2022] [Accepted: 12/13/2022] [Indexed: 06/17/2023]
Abstract
Interleukin (IL)-17 is a proinflammatory cytokine and plays essential roles in adaptive and innate immune responses against bacterial and fungal infections. Especially in mammalian mucosal tissues, it is well known that innate immune responses via IL-17A and IL-17F, such as the production of antimicrobial peptides, are very important for microbiota control. In contrast, interesting insights into the functions of IL-17 have recently been reported in several teleost species, although little research has been conducted on teleost IL-17. In the present review, we focused on current insights on teleost IL-17 and speculated on the different or consensus parts of teleost IL-17 signaling compared to that of mammals. This review focuses on the role of teleost IL-17 in intestinal immunity. We expect that this review will encourage a further understanding of the roles and importance of IL-17 signaling in teleosts.
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Affiliation(s)
- Yo Okamura
- Department of Immunology, School of Medicine, University of Washington, Seattle, WA, 98109, USA
| | - Tomoya Kono
- Department of Biochemistry and Applied Biosciences, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan
| | - Masahiro Sakai
- Department of Biochemistry and Applied Biosciences, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan
| | - Jun-Ichi Hikima
- Department of Biochemistry and Applied Biosciences, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan.
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23
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Tao S, Wang X, Yang X, Liu Y, Fu Z, Zhang L, Wang Z, Ni J, Shuai Z, Pan H. COVID-19 and inflammatory bowel disease crosstalk: From emerging association to clinical proposal. J Med Virol 2022; 94:5640-5652. [PMID: 35971954 PMCID: PMC9538900 DOI: 10.1002/jmv.28067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/29/2022] [Accepted: 08/10/2022] [Indexed: 01/08/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause coronavirus disease 2019 (COVID-19), an acute respiratory inflammation that has emerged worldwide since December 2019, and it quickly became a global epidemic. Inflammatory bowel disease (IBD) is a group of chronic nonspecific intestinal inflammatory diseases whose etiology has not been elucidated. The two have many overlapping symptoms in clinical presentation, such as abdominal pain, diarrhea, pneumonia, etc. Imbalance of the autoimmune system in IBD patients and long-term use of immunosuppressive drugs may increase the risk of infection; and systemic symptoms caused by COVID-19 may also induce or exacerbate intestinal inflammation. It has been found that the SARS-CoV-2 receptor angiotensin converting enzyme 2, which is highly expressed in the lung and intestine, is an inflammatory protective factor, and is downregulated and upregulated in COVID-19 and IBD, respectively, suggesting that there may be a coregulatory pathway. In addition, the immune activation pattern of COVID-19 and the cytokine storm in the inflammatory response have similar roles in IBD, indicating that the two diseases may influence each other. Therefore, this review aimed to address the following research questions: whether SARS-CoV-2 infection leads to the progression of IBD; whether IBD increases the risk of COVID-19 infection and poor prognosis; possible common mechanisms and genetic cross-linking between the two diseases; new treatment and care strategies for IBD patients, and the feasibility and risk of vaccination in the context of the COVID-19 epidemic.
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Affiliation(s)
- Sha‐Sha Tao
- Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical UniversityHefeiAnhuiChina
| | - Xin‐Yi Wang
- Department of Radiation Oncology, The First Affiliated Hospital of Anhui Medical University, First Clinical Medical CollegeAnhui Medical UniversityHefeiAnhuiChina
| | - Xiao‐Ke Yang
- Department of Rheumatology and ImmunologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiAnhuiChina
| | - Yu‐Chen Liu
- Department of Otolaryngology, Head, and Neck SurgeryThe First Affiliated Hospital of Anhui Medical UniversityHefeiAnhuiChina
| | - Zi‐Yue Fu
- Department of Clinical Medicine, The Second School of Clinical MedicineAnhui Medical UniversityHefeiAnhuiChina
| | - Li‐Zhi Zhang
- Department of Clinical Medicine, The First School of Clinical MedicineAnhui Medical UniversityHefeiAnhuiChina
| | - Zhi‐Xin Wang
- Department of Rheumatology and ImmunologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiAnhuiChina
| | - Jing Ni
- Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical UniversityHefeiAnhuiChina
| | - Zong‐Wen Shuai
- Department of Rheumatology and ImmunologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiAnhuiChina
| | - Hai‐Feng Pan
- Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical UniversityHefeiAnhuiChina
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24
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Khan A, Khan A, Shal B, Aziz A, Ahmad S, Amin MU, Ahmed MN, Zia-Ur-Rehman, Khan S. Ameliorative effect of two structurally divergent hydrazide derivatives against DSS-induced colitis by targeting Nrf2 and NF-κB signaling in mice. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2022; 395:1167-1188. [PMID: 35851927 DOI: 10.1007/s00210-022-02272-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 07/08/2022] [Indexed: 11/27/2022]
Abstract
The environmental factors and genetic vulnerability trigger the inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn's disease. Furthermore, the oxidative stress and inflammatory cytokines have been implicated in the aggravation of the IBDs. The aim of the present study was to investigate the effect of N-(benzylidene)-2-((2-hydroxynaphthalen-1-yl)diazenyl)benzohydrazides (NCHDH and NTHDH) compounds against the DSS-induced colitis in mice. The colitis was induced by 5% dextran sulfate sodium (DSS) dissolved in normal saline for 5 days. The effect of the NCHDH and NTHDH on the behavioral, biochemical, histological, and immunohistological parameters was assessed. The NCHDH and NTHDH treatment improved the behavioral parameters such as food intake, disease activity index, and diarrhea score significantly compared to DSS control. The NCHDH and NTHDH treatments significantly increased the antioxidant enzymes, whereas oxidative stress markers were markedly reduced. Similarly, the NCHDH and NTHDH treatments significantly suppressed the activity of nitric oxide (NO), myeloperoxidase (MPO), and eosinophil peroxidase (EPO). The histological studies showed a significant reduction in inflammation, immune cell infiltration, and fibrosis in the NCHDH- and NTHDH-treated groups. The immunohistochemical results demonstrated that NCHDH and NTHDH treatments markedly increase the expression level of Nrf2, HO-1 (hemeoxygenase-1), TRX (thioredoxin reductase), and IκB compared to the DSS-induced group. In the same way, the NCHDH and NTHDH significantly reduced the NF-κB and COX-2 (cyclooxygenase-2) expression levels. The NCHDH and NTHDH treatment significantly improved the symptoms associated with colitis via inducing antioxidants and attenuating oxidative stress markers.
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Affiliation(s)
- Ashrafullah Khan
- Pharmacological Sciences Research Laboratory, Department of Pharmacy, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, 45320, Pakistan
- Faculty of Pharmaceutical Sciences, Abasyn University, Peshawar, 25000, KPK, Pakistan
| | - Adnan Khan
- Pharmacological Sciences Research Laboratory, Department of Pharmacy, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Bushra Shal
- Pharmacological Sciences Research Laboratory, Department of Pharmacy, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Abdul Aziz
- Department of Chemistry, The University of Azad Jammu and Kashmir, Muzaffarabad, 13100, Pakistan
| | - Sajjad Ahmad
- Department of Health and Biological Sciences, Abasyn University, Peshawar, 25000, Pakistan
| | - Muhammad Usman Amin
- Faculty of Pharmaceutical Sciences, Abasyn University, Peshawar, 25000, KPK, Pakistan
| | - Muhammad Naeem Ahmed
- Department of Chemistry, The University of Azad Jammu and Kashmir, Muzaffarabad, 13100, Pakistan
| | - Zia-Ur-Rehman
- Department of Chemistry, Quaid-I-Azam University, Islamabad, Pakistan
| | - Salman Khan
- Pharmacological Sciences Research Laboratory, Department of Pharmacy, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad, 45320, Pakistan.
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25
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Liang X, Xie Y, Liu X, Xu H, Ren H, Tang S, Liu Q, Huang M, Shao X, Li C, Zhou Y, Geng M, Xie Z, Liu H. Discovery of Novel Imidazo[4,5- c]quinoline Derivatives to Treat Inflammatory Bowel Disease (IBD) by Inhibiting Multiple Proinflammatory Signaling Pathways and Restoring Intestinal Homeostasis. J Med Chem 2022; 65:11949-11969. [PMID: 36053746 DOI: 10.1021/acs.jmedchem.2c00390] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
As a complex pathogenesis driven by immune inflammatory factors and intestinal microbiota, the treatment of inflammatory bowel disease (IBD) may rely on the comprehensive regulation of these important pathogenic factors to reach a favorable therapeutic effect. In the current study, we discovered a series of imidazo[4,5-c]quinoline derivatives that potently and simultaneously inhibited two primary proinflammatory signaling pathways JAK/STAT and NF-κB. Especially, lead compound 8l showed potent inhibitory activities against interferon-stimulated genes (IC50: 3.3 nM) and NF-κB pathways (IC50: 150.7 nM) and decreased the release of various proinflammatory factors at the nanomolar level, including IL-6, IL-8, IL-1β, TNF-α, IL-12, and IFN-γ. In vivo, 8l produced a strong anti-inflammatory activity in both dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced acute enteritis models and restored the structural composition of gut microbiota. Collectively, this study provided valuable lead compounds for the treatment of IBD and revealed the great anti-inflammatory potential of the simultaneous suppression of JAK/STAT and NF-κB signals.
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Affiliation(s)
- Xuewu Liang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai201203, China.,University of Chinese Academy of Sciences, Beijing100049, China
| | - Yongle Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai201203, China.,University of Chinese Academy of Sciences, Beijing100049, China
| | - Xuyi Liu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai201203, China.,University of Chinese Academy of Sciences, Beijing100049, China
| | - Hui Xu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai201203, China.,University of Chinese Academy of Sciences, Beijing100049, China
| | - Hairu Ren
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou310024, China
| | - Shuai Tang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai201203, China.,University of Chinese Academy of Sciences, Beijing100049, China
| | - Qi Liu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai201203, China.,University of Chinese Academy of Sciences, Beijing100049, China
| | - Min Huang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai201203, China.,University of Chinese Academy of Sciences, Beijing100049, China
| | - Xueqing Shao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai201203, China.,University of Chinese Academy of Sciences, Beijing100049, China
| | - Chunpu Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai201203, China.,University of Chinese Academy of Sciences, Beijing100049, China
| | - Yu Zhou
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai201203, China.,University of Chinese Academy of Sciences, Beijing100049, China
| | - Meiyu Geng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai201203, China.,University of Chinese Academy of Sciences, Beijing100049, China
| | - Zuoquan Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai201203, China.,University of Chinese Academy of Sciences, Beijing100049, China
| | - Hong Liu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai201203, China.,University of Chinese Academy of Sciences, Beijing100049, China.,School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou310024, China
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26
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Inflammatory Bowel Disease: A Review of Pre-Clinical Murine Models of Human Disease. Int J Mol Sci 2022; 23:ijms23169344. [PMID: 36012618 PMCID: PMC9409205 DOI: 10.3390/ijms23169344] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/15/2022] [Accepted: 08/17/2022] [Indexed: 12/11/2022] Open
Abstract
Crohn’s disease (CD) and ulcerative colitis (UC) are both highly inflammatory diseases of the gastrointestinal tract, collectively known as inflammatory bowel disease (IBD). Although the cause of IBD is still unclear, several experimental IBD murine models have enabled researchers to make great inroads into understanding human IBD pathology. Here, we discuss the current pre-clinical experimental murine models for human IBD, including the chemical-induced trinitrobenzene sulfonic acid (TNBS) model, oxazolone and dextran sulphate sodium (DSS) models, the gene-deficient I-kappa-B kinase gamma (Iκκ-γ) and interleukin(IL)-10 models, and the CD4+ T-cell transfer model. We offer a comprehensive review of how these models have been used to dissect the etiopathogenesis of disease, alongside their limitations. Furthermore, the way in which this knowledge has led to the translation of experimental findings into novel clinical therapeutics is also discussed.
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27
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He S, Azar DA, Esfahani FN, Azar GA, Shazly T, Saeidi N. Mechanoscopy: A Novel Device and Procedure for in vivo Detection of Chronic Colitis in Mice. Inflamm Bowel Dis 2022; 28:1143-1150. [PMID: 35325126 PMCID: PMC9340527 DOI: 10.1093/ibd/izac046] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Gut stiffening caused by fibrosis plays a critical role in the progression of inflammatory bowel disease (IBD) and colon cancer. Previous studies have characterized the biomechanical response of healthy and pathological gut, with most measurements obtained ex vivo. METHODS Here, we developed a device and accompanying procedure for in vivo quantification of gut stiffness, termed mechanoscopy. Mechanoscopy includes a flexible balloon catheter, pressure sensor, syringe pump, and control system. The control system activates the balloon catheter and performs automated measurements of the gut stress-strain biomechanical response. RESULTS A gut stiffness index (GSI) is identified based on the slope of the obtained stress-strain response. Using a colitis mouse model, we demonstrated that GSI positively correlates with the extent of gut fibrosis, the severity of mucosal damage, and the infiltration of immune cells. Furthermore, a critical strain value is suggested, and GSI efficiently detects pathological gut fibrotic stiffening when the strain exceeds this value. CONCLUSIONS Based on these results, we envision that mechanoscopy and GSI will facilitate the clinical diagnosis of IBD.
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Affiliation(s)
| | | | - Farid Nasr Esfahani
- Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
- Shriners Hospital for Children, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Golara A Azar
- Department of Electrical Engineering and Computer Sciences, University of California Los Angeles, Los Angeles, CA, USA
| | - Tarek Shazly
- Department of Mechanical Engineering, University of South Carolina, Columbia, SC, USA
| | - Nima Saeidi
- Address correspondence to: Nima Saeidi, 51 Blossom St., Room 207, Boston, MA, 02114, USA ()
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28
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Madecassic acid alleviates colitis-associated colorectal cancer by blocking the recruitment of myeloid-derived suppressor cells via the inhibition of IL-17 expression in γδT17 cells. Biochem Pharmacol 2022; 202:115138. [PMID: 35700756 DOI: 10.1016/j.bcp.2022.115138] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 06/03/2022] [Accepted: 06/07/2022] [Indexed: 11/20/2022]
Abstract
INTRODUCTION Madecassic acid (MA), a triterpene compound isolated from Centella Asiatica herbs, has previously been shown to attenuate colitis induced by DSS in mice. In the present study, we address whether and how MA ameliorates colitis-associated colorectal cancer (CAC), which accounts for a considerable proportion of colorectal cancer. METHODS CAC was induced by AOM/DSS in mice, and MA was administered orally once a day. To identify the source cells of IL-17 and the target cells for MA reducing the expression of IL-17 in the colons of CAC mice, single-cell suspensions were prepared from the colons of CAC mice and analyzed by flow cytometry. An adoptive transfer experiment was performed to verify the importance of the decreasing γδT17 cell population in the anti-CAC effect of MA. RESULTS Oral administration of MA reduced the burden and incidence of tumors in the CAC mice. MA decreased the number of MDSCs in the colon tissues of CAC mice and ameliorated anti-tumor immune responses. MA could prevent the migration of MDSCs by inhibiting the activation of γδT17 cells and the expression of chemokines. The population of activated-γδT17 cells in the tumor microenvironment of CAC mice positively correlated with the number of MDSCs and tumors as well as tumor load. Moreover, the anti-CAC effect of MA was significantly counteracted by the adoptive transfer of γδT17 cells. CONCLUSIONS MA alleviates CAC by blocking the recruitment of MDSCs to increase the population of anti-tumor immune cells in tumor microenvironment via inhibition of the activation of γδT17 cells.
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29
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Schuster C, Kiaf B, Hatzihristidis T, Ruckdeschel A, Nieves-Bonilla J, Ishikawa Y, Zhao B, Zheng P, Love PE, Kissler S. CD5 Controls Gut Immunity by Shaping the Cytokine Profile of Intestinal T Cells. Front Immunol 2022; 13:906499. [PMID: 35720357 PMCID: PMC9201032 DOI: 10.3389/fimmu.2022.906499] [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: 03/28/2022] [Accepted: 05/10/2022] [Indexed: 02/03/2023] Open
Abstract
CD5 is constitutively expressed on all T cells and is a negative regulator of lymphocyte function. However, the full extent of CD5 function in immunity remains unclear. CD5 deficiency impacts thymic selection and extra-thymic regulatory T cell generation, yet CD5 knockout was reported to cause no immune pathology. Here we show that CD5 is a key modulator of gut immunity. We generated mice with inducible CD5 knockdown (KD) in the autoimmune-prone nonobese diabetic (NOD) background. CD5 deficiency caused T cell-dependent wasting disease driven by chronic gut immune dysregulation. CD5 inhibition also exacerbated acute experimental colitis. Mechanistically, loss of CD5 increased phospho-Stat3 levels, leading to elevated IL-17A secretion. Our data reveal a new facet of CD5 function in shaping the T cell cytokine profile.
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Affiliation(s)
- Cornelia Schuster
- Joslin Diabetes Center, Harvard Medical School, Boston, MA, United States
| | - Badr Kiaf
- Joslin Diabetes Center, Harvard Medical School, Boston, MA, United States
| | - Teri Hatzihristidis
- Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Anna Ruckdeschel
- Joslin Diabetes Center, Harvard Medical School, Boston, MA, United States
| | | | - Yuki Ishikawa
- Joslin Diabetes Center, Harvard Medical School, Boston, MA, United States
| | - Bin Zhao
- Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Peilin Zheng
- Rudolf Virchow Center for Experimental Biomedicine, Wurzburg, Germany
| | - Paul E. Love
- Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Stephan Kissler
- Joslin Diabetes Center, Harvard Medical School, Boston, MA, United States,*Correspondence: Stephan Kissler,
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30
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Abstract
The interleukin-23 [IL-23] cytokine, derived predominantly from macrophages and dendritic cells in response to microbial stimulation, has emerged as a critical promoter of chronic intestinal inflammation. Genome-wide association studies linking variants in IL23R to disease protection, bolstered by experimental evidence from colitis models, and the successful application of therapies against the IL-12/IL-23 shared p40 subunit in the treatment of inflammatory bowel disease [IBD] all provide compelling evidence of a crucial role for IL-23 in disease pathogenesis. Moreover, targeting the p19 subunit specific for IL-23 has shown considerable promise in recent phase 2 studies in IBD. The relative importance of the diverse immunological pathways downstream of IL-23 in propagating mucosal inflammation in the gut, however, remains contentious. Here we review current understanding of IL-23 biology and explore its pleiotropic effects on T cells, and innate lymphoid, myeloid and intestinal epithelial cells in the context of the pathogenesis of IBD. We furthermore discuss these pathways in the light of recent evidence from clinical trials and indicate emerging targets amenable to therapeutic intervention and translation into clinical practice.
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Affiliation(s)
- Gavin W Sewell
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
| | - Arthur Kaser
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
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31
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α-Bisabolol Mitigates Colon Inflammation by Stimulating Colon PPAR-γ Transcription Factor: In Vivo and In Vitro Study. PPAR Res 2022; 2022:5498115. [PMID: 35465355 PMCID: PMC9020997 DOI: 10.1155/2022/5498115] [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: 11/24/2021] [Revised: 03/08/2022] [Accepted: 03/18/2022] [Indexed: 12/13/2022] Open
Abstract
The incidence and prevalence of inflammatory bowel disease (IBD, Crohn’s disease, and ulcerative colitis) are increasing worldwide. The etiology of IBD is multifactorial, including genetic predisposition, dysregulated immune response, microbial dysbiosis, and environmental factors. However, many of the existing therapies are associated with marked side effects. Therefore, the development of new drugs for IBD treatment is an important area of investigation. Here, we investigated the anti-inflammatory effects of α-bisabolol, a naturally occurring monocyclic sesquiterpene alcohol present in many aromatic plants, in colonic inflammation. To address this, we used molecular docking and dynamic studies to understand how α-bisabolol interacts with PPAR-γ, which is highly expressed in the colonic epithelium: in vivo (mice) and in vitro (RAW264.7 macrophages and HT-29 colonic adenocarcinoma cells) models. The molecular docking and dynamic analysis revealed that α-bisabolol interacts with PPAR-γ, a nuclear receptor protein that is highly expressed in the colon epithelium. Treatment with α-bisabolol in DSS-administered mice significantly reduced Disease Activity Index (DAI), myeloperoxidase (MPO) activity, and colonic length and protected the microarchitecture of the colon. α-Bisabolol treatment also reduced the expression of proinflammatory cytokines (IL-6, IL1β, TNF-α, and IL-17A) at the protein and mRNA levels. The expression of COX-2 and iNOS inflammatory mediators were reduced along with tissue nitrite levels. Furthermore, α-bisabolol decreased the phosphorylation of activated mitogen-activated protein kinase (MAPK) signaling and nuclear factor kappa B (NFκB) proteins and enhanced colon epithelial PPAR-γ transcription factor expression. However, the PPAR-α and β/δ expression was not altered, indicating α-bisabolol is a specific stimulator of PPAR-γ. α-Bisabolol also increased the PPAR-γ transcription factor expression but not PPAR-α and β/δ in pretreated in LPS-stimulated RAW264.7 macrophages. α-Bisabolol significantly decreased the expression of proinflammatory chemokines (CXCL-1 and IL-8) mRNA in HT-29 cells treated with TNF-α and HT-29 PPAR-γ promoter activity. These results demonstrate that α-bisabolol mitigates colonic inflammation by inhibiting MAPK signaling and stimulating PPAR-γ expression.
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32
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Vaghari-Tabari M, Targhazeh N, Moein S, Qujeq D, Alemi F, Majidina M, Younesi S, Asemi Z, Yousefi B. From inflammatory bowel disease to colorectal cancer: what's the role of miRNAs? Cancer Cell Int 2022; 22:146. [PMID: 35410210 PMCID: PMC8996392 DOI: 10.1186/s12935-022-02557-3] [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: 08/24/2021] [Accepted: 03/21/2022] [Indexed: 12/27/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease with relapse and remission periods. Ulcerative colitis and Crohn's disease are two major forms of the disease. IBD imposes a lot of sufferings on the patient and has many consequences; however, the most important is the increased risk of colorectal cancer, especially in patients with Ulcerative colitis. This risk is increased with increasing the duration of disease, thus preventing the progression of IBD to cancer is very important. Therefore, it is necessary to know the details of events contributed to the progression of IBD to cancer. In recent years, the importance of miRNAs as small molecules with 20-22 nucleotides has been recognized in pathophysiology of many diseases, in which IBD and colorectal cancer have not been excluded. As a result, the effectiveness of these small molecules as therapeutic target is hopefully confirmed. This paper has reviewed the related studies and findings about the role of miRNAs in the course of events that promote the progression of IBD to colorectal carcinoma, as well as a review about the effectiveness of some of these miRNAs as therapeutic targets.
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Affiliation(s)
- Mostafa Vaghari-Tabari
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Niloufar Targhazeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheila Moein
- Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
| | - Forough Alemi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidina
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Simin Younesi
- Schoole of Health and Biomedical Sciences, RMIT University, Melborne, VIC, Australia
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran.
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Mukhopadhyay S, Saha S, Chakraborty S, Prasad P, Ghosh A, Aich P. Differential colitis susceptibility of Th1- and Th2-biased mice: A multi-omics approach. PLoS One 2022; 17:e0264400. [PMID: 35263357 PMCID: PMC8906622 DOI: 10.1371/journal.pone.0264400] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 02/09/2022] [Indexed: 01/08/2023] Open
Abstract
The health and economic burden of colitis is increasing globally. Understanding the role of host genetics and metagenomics is essential to establish the molecular basis of colitis pathogenesis. In the present study, we have used a common composite dose of DSS to compare the differential disease severity response in C57BL/6 (Th1 biased) and BALB/c (Th2 biased) mice with zero mortality rates. We employed multi-omics approaches and developed a newer vector analysis approach to understand the molecular basis of the disease pathogenesis. In the current report, comparative transcriptomics, metabonomics, and metagenomics analyses revealed that the Th1 background of C57BL/6 induced intense inflammatory responses throughout the treatment period. On the contrary, the Th2 background of BALB/c resisted severe inflammatory responses by modulating the host’s inflammatory, metabolic, and gut microbial profile. The multi-omics approach also helped us discover some unique metabolic and microbial markers associated with the disease severity. These biomarkers could be used in diagnostics.
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Affiliation(s)
- Sohini Mukhopadhyay
- School of Biological Sciences, National Institute of Science Education and Research (NISER), HBNI, Khurdha, Odisha, India
- Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, India
| | - Subha Saha
- Institute of Life Sciences, NALCO Square, Bhubaneswar, Odisha, India
| | - Subhayan Chakraborty
- Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, India
- School of Chemical Sciences, National Institute of Science Education and Research (NISER), HBNI, Khurdha, Odisha, India
| | - Punit Prasad
- Institute of Life Sciences, NALCO Square, Bhubaneswar, Odisha, India
| | - Arindam Ghosh
- Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, India
- School of Chemical Sciences, National Institute of Science Education and Research (NISER), HBNI, Khurdha, Odisha, India
| | - Palok Aich
- School of Biological Sciences, National Institute of Science Education and Research (NISER), HBNI, Khurdha, Odisha, India
- Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, India
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34
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Linh H, Iwata Y, Senda Y, Sakai-Takemori Y, Nakade Y, Oshima M, Yoneda-Nakagawa S, Ogura H, Sato K, Minami T, Kitajima S, Toyama T, Yamamura Y, Miyakawa T, Hara A, Shimizu M, Furuichi K, Sakai N, Yamada H, Asanuma K, Matsushima K, Wada T. Intestinal Bacterial Translocation Contributes to Diabetic Kidney Disease. J Am Soc Nephrol 2022; 33:1105-1119. [PMID: 35264456 PMCID: PMC9161796 DOI: 10.1681/asn.2021060843] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 02/22/2022] [Indexed: 11/03/2022] Open
Abstract
Background In recent years, many studies have focused on the intestinal environment to elucidate pathogenesis of various diseases, including kidney diseases. Impairment of the intestinal barrier function, the "leaky gut," reportedly contributes to pathological processes in some disorders. Mitochondrial antiviral signaling protein (MAVS), a component of innate immunity, maintains intestinal integrity. The effects of disrupted intestinal homeostasis associated with MAVS signaling in diabetic kidney disease remains unclear. Methods To evaluate the contribution of intestinal barrier impairment to kidney injury under diabetic conditions, we induced diabetic kidney disease in wild-type and MAVS knockout mice through unilateral nephrectomy and streptozotocin treatment. We then assessed effects on the kidney, intestinal injuries, and bacterial translocation. Results MAVS knockout diabetic mice showed more severe glomerular and tubular injuries compared with wild-type diabetic mice. Owing to impaired intestinal integrity, the presence of intestine-derived Klebsiella oxytoca and elevated IL-17 were detected in the circulation and kidneys of diabetic mice, especially in diabetic MAVS knockout mice. Stimulation of tubular epithelial cells with K. oxytoca activated MAVS pathways and the phosphorylation of Stat3 and ERK1/2, leading to the production of kidney injury molecule-1 (KIM-1). Nevertheless, MAVS inhibition induced inflammation in the intestinal epithelial cells and KIM-1 production in tubular epithelial cells under K. oxytoca supernatant or IL-17 stimulation. Treatment with neutralizing anti-IL-17 antibody treatment had renoprotective effects. In contrast, lipopolysaccharide administration accelerated kidney injury in the murine diabetic kidney disease model. Conclusions Impaired MAVS signaling both in the kidney and intestine contributes to the disrupted homeostasis, leading to diabetic kidney disease progression. Controlling intestinal homeostasis may offer a novel therapeutic approach for this condition.
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Affiliation(s)
- Hoang Linh
- H Linh, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Yasunori Iwata
- Y Iwata, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Yasuko Senda
- Y Senda, Division of Infection Control, Kanazawa University Hospital, Kanazawa, Japan
| | - Yukiko Sakai-Takemori
- Y Sakai-Takemori, Division of Infection Control, Kanazawa University Hospital, Kanazawa, Japan
| | - Yusuke Nakade
- Y Nakade, Division of Infection Control, Kanazawa University Hospital, Kanazawa, Japan
| | - Megumi Oshima
- M Oshima, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Shiori Yoneda-Nakagawa
- S Yoneda-Nakagawa, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Hisayuki Ogura
- H Ogura, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Koichi Sato
- K Sato, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Taichiro Minami
- T Minami, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Shinji Kitajima
- S Kitajima, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Tadashi Toyama
- T Toyama, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Yuta Yamamura
- Y Yamamura, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Taro Miyakawa
- T Miyakawa, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Akinori Hara
- A Hara, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Miho Shimizu
- M Shimizu, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Kengo Furuichi
- K Furuichi, Division of Nephrology, Kanazawa Medical University School of Medicine Graduate School of Medicine, Kahoku-gun, Japan
| | - Norihiko Sakai
- N Sakai, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Hiroyuki Yamada
- H Yamada, Department of Nephrology, Chiba University Graduate School of Medicine School of Medicine, Chiba, Japan
| | - Katsuhiko Asanuma
- K Asanuma, Department of Nephrology, Chiba University Graduate School of Medicine School of Medicine, Chiba, Japan
| | - Kouji Matsushima
- K Matsushima, Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute of Biomedical Sciences, Tokyo University of Science, Shinjuku-ku, Japan
| | - Takashi Wada
- T Wada, Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
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Kelly L, McGrath S, Rodgers L, McCall K, Tulunay Virlan A, Dempsey F, Crichton S, Goodyear CS. Annexin-A1; the culprit or the solution? Immunology 2022; 166:2-16. [PMID: 35146757 PMCID: PMC9426623 DOI: 10.1111/imm.13455] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 12/23/2021] [Accepted: 01/24/2022] [Indexed: 11/30/2022] Open
Abstract
Annexin‐A1 has a well‐defined anti‐inflammatory role in the innate immune system, but its function in adaptive immunity remains controversial. This glucocorticoid‐induced protein has been implicated in a range of inflammatory conditions and cancers, as well as being found to be overexpressed on the T cells of patients with autoimmune disease. Moreover, the formyl peptide family of receptors, through which annexin‐A1 primarily signals, has also been implicated in these diseases. In contrast, treatment with recombinant annexin‐A1 peptides resulted in suppression of inflammatory processes in murine models of inflammation. This review will focus on what is currently known about annexin‐A1 in health and disease and discuss the potential of this protein as a biomarker and therapeutic target.
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Affiliation(s)
- Lauren Kelly
- Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, Scotland, UK
| | - Sarah McGrath
- Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, Scotland, UK
| | - Lewis Rodgers
- Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, Scotland, UK
| | - Kathryn McCall
- Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, Scotland, UK
| | - Aysin Tulunay Virlan
- Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, Scotland, UK
| | - Fiona Dempsey
- Medannex Ltd, 1 Lochrin Square, Fountainbridge, Edinburgh, EH3 9QA
| | - Scott Crichton
- Medannex Ltd, 1 Lochrin Square, Fountainbridge, Edinburgh, EH3 9QA
| | - Carl S Goodyear
- Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, Scotland, UK
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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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Zhou C, Wu D, Jawale C, Li Y, Biswas PS, McGeachy MJ, Gaffen SL. Divergent functions of IL-17-family cytokines in DSS colitis: Insights from a naturally-occurring human mutation in IL-17F. Cytokine 2021; 148:155715. [PMID: 34587561 PMCID: PMC8627693 DOI: 10.1016/j.cyto.2021.155715] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 09/13/2021] [Accepted: 09/15/2021] [Indexed: 01/06/2023]
Abstract
The IL-17 family is structurally distinct from other cytokine subclasses. IL-17A and IL-17F, the most closely related of this family, form homodimers and an IL-17AF heterodimer. While IL-17A and IL-17F exhibit similar activities in many settings, in others their functions are divergent. To better understand the function of IL-17F in vivo, we created mice harboring a mutation in Il17f originally described in humans with unexplained chronic mucosal candidiasis (Ser-65-Leu). We evaluated Il17fS65L/S65L mice in DSS-colitis, as this is one of the few settings where IL-17A and IL-17F exhibit opposing activities. Specifically, IL-17A is protective of the gut epithelium, a finding that was revealed when trials of anti-IL-17A biologics in Crohn's disease failed and recapitulated in many mouse models of colitis. In contrast, mice lacking IL-17F are resistant to DSS-colitis, partly attributable to alterations in intestinal microbiota that mobilize Tregs. Here we report that Il17fS65L/S65L mice do not phenocopy Il17f-/- mice in DSS colitis, but rather exhibited a worsening disease phenotype much like Il17a-/- mice. Gut inflammation in Il17fS65L/S65L mice correlated with reduced Treg accumulation and lowered intestinal levels of Clostridium cluster XIV. Unexpectedly, the protective DSS-colitis phenotype in Il17f-/- mice could be reversed upon co-housing with Il17fS65L/S65L mice, also correlating with Clostridium cluster XIV levels in gut. Thus, the Il17fS65L/S65L phenotype resembles an IL-17A deficiency more closely than IL-17F deficiency in the setting of DSS colitis.
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Affiliation(s)
- Chunsheng Zhou
- Dept of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Dongwen Wu
- Dept of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA; The Xiangya Hospital, Gastrointestinal Department, Central South University, Changsha, Hunan, PR China
| | - Chetan Jawale
- Dept of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Yang Li
- Dept of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Partha S Biswas
- Dept of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mandy J McGeachy
- Dept of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Sarah L Gaffen
- Dept of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
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Li TX, Liang JX, Liu LL, Shi FC, Jia XW, Li MH, Xu CP. Novel kojic acid derivatives with anti-inflammatory effects from Aspergillus versicolor. Fitoterapia 2021; 154:105027. [PMID: 34492330 DOI: 10.1016/j.fitote.2021.105027] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/30/2021] [Accepted: 09/01/2021] [Indexed: 11/29/2022]
Abstract
Two novel kojic acid derivatives, kojicones A and B (1 and 2), along with the precursors kojic acid (3) and (2R,4R)-4-hydroxy-5-methoxy-2,4-dimethyl-2- [(2R)-2-methylbutyryloxy]-5-cyclohexen-1,3-dione (4), were isolated from a fungal strain Aspergillus versicolor. Their structures and absolute configurations were accurately confirmed by HRESIMS data, NMR analysis, and electronic circular dichroism (ECD) calculations. Kojicones A and B were the first examples of kojic acid adducts with cyclohexen-1,3-dione possessing unprecedented tricycle skeletons. Compounds 1-3 were found to have inhibition on the NO production of murine RAW 264.7 cells. They can also reduce the mRNA expression of four cytokines (IL-6, IL-1β, TNF-α, and iNOS) and promote the expression of IL-4 at 20 μM. Moreover, kojic acid (3) could treat the DSS (dextran sulfate sodium)-induced colitis on mice with the effectiveness similar to that of the positive control. The results suggested that kojic acid and its derivatives could be a promising anti-inflammatory source for the medicinal and cosmetic industry.
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Affiliation(s)
- Tian-Xiao Li
- College of Food and Biological Engineering, Zhengzhou University of Light Industry, Zhengzhou 450002, China
| | - Jia-Xin Liang
- College of Food and Biological Engineering, Zhengzhou University of Light Industry, Zhengzhou 450002, China
| | - Lu-Lu Liu
- Technical Center of China Tobacco Sichuan Industrial Co., Ltd., Chengdu 610051, China
| | - Feng-Cheng Shi
- Technical Center of China Tobacco Sichuan Industrial Co., Ltd., Chengdu 610051, China
| | - Xue-Wei Jia
- College of Food and Biological Engineering, Zhengzhou University of Light Industry, Zhengzhou 450002, China
| | - Ming-Hui Li
- College of Life Sciences, Anhui Normal University, Wuhu 241000, China.
| | - Chun-Ping Xu
- College of Food and Biological Engineering, Zhengzhou University of Light Industry, Zhengzhou 450002, China.
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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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40
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Wang R, Chen T, Wang Q, Yuan XM, Duan ZL, Feng ZY, Ding Y, Bu F, Shi GP, Chen YG. Total Flavone of Abelmoschus manihot Ameliorates Stress-Induced Microbial Alterations Drive Intestinal Barrier Injury in DSS Colitis. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:2999-3016. [PMID: 34267502 PMCID: PMC8276878 DOI: 10.2147/dddt.s313150] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 06/19/2021] [Indexed: 12/15/2022]
Abstract
Purpose Total flavone of Abelmoschus manihot (TFA), the effective constituents extracted from Flos Abelmoschus Manihot, has been reported to inhibit inflammation. However, the effect of TFA on ulcerative colitis (UC) progression in patients with depression is unknown. The purpose of our research was to explore the anti-UC effects of TFA in the context of depression in mice with UC by regulating the gut microbiota to drive the intestinal barrier. Methods In this study, chronic stress (CS) and dextran sodium sulfate (DSS) were used to induce depression and UC, respectively, in C57BL/6J mice. Fecal microbiota transplantation (FMT) was used to evaluate how treating mice modeling UC and depression with TFA effected their gut microbiota. Results Our results showed that TFA effectively improved UC aggravated by CS. In addition, TFA treatment improved the depression-like phenotype, the disturbed gut microbiota, and the intestinal barrier function in CS mice. It is worth noting that FMT from the CS mice to the receptor group further aggravated the damage of the intestinal barrier and the disturbance of the gut microbiota in the recipient DSS mice, thus further aggravating UC, however, treatment of the intervention of TFA in the CS fecal microbiota transplant with TFA also played its therapeutic outcome. Conclusion Taken together, our results show that CS disrupts the gut microbiota, triggers intestinal barrier injury and aggravates DSS colitis, while TFA is a promising drug for the treatment of UC in patients with depression.
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Affiliation(s)
- Rong Wang
- Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, People's Republic of China
| | - Tuo Chen
- Department of General Surgery, Affiliated hospital of Yangzhou university, Yangzhou, Jiangsu, 225000, People's Republic of China
| | - Qiong Wang
- Central Laboratory, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People's Republic of China
| | - Xiao-Min Yuan
- Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, People's Republic of China
| | - Zheng-Lan Duan
- Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, People's Republic of China
| | - Ze-Yu Feng
- Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, People's Republic of China
| | - Yang Ding
- Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, People's Republic of China
| | - Fan Bu
- Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, People's Republic of China
| | - Guo-Ping Shi
- Collaborative Innovation Center for Cancer Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, People's Republic of China
| | - Yu-Gen Chen
- Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, People's Republic of China
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Yang S, Park JS, Hwang SH, Cho KH, Na HS, Choi J, Jhun J, Kim SJ, Lee BI, Park SH, Cho ML. Metformin-Inducible Small Heterodimer Partner Interacting Leucine Zipper Protein Ameliorates Intestinal Inflammation. Front Immunol 2021; 12:652709. [PMID: 34211461 PMCID: PMC8239434 DOI: 10.3389/fimmu.2021.652709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 05/07/2021] [Indexed: 12/02/2022] Open
Abstract
Small heterodimer partner interacting leucine zipper protein (SMILE) is an orphan nuclear receptor and a member of the bZIP family of proteins. We investigated the mechanism by which SMILE suppressed the development of inflammatory bowel disease (IBD) using a DSS-induced colitis mouse model and peripheral blood mononuclear cells (PBMCs) from patients with ulcerative colitis (UC). Metformin, an antidiabetic drug and an inducer of AMPK, upregulated the level of SMILE in human intestinal epithelial cells and the number of SMILE-expressing cells in colon tissues from DSS-induced colitis mice compared to control mice. Overexpression of SMILE using a DNA vector reduced the severity of DSS-induced colitis and colitis-associated intestinal fibrosis compared to mock vector. Furthermore, SMILE transgenic mice showed ameliorated DSS-induced colitis compared with wild-type mice. The mRNA levels of SMILE and Foxp3 were downregulated and SMILE expression was positively correlated with Foxp3 in PBMCs from patients with UC and an inflamed mucosa. Metformin increased the levels of SMILE, AMPK, and Foxp3 but decreased the number of interleukin (IL)-17–producing T cells among PBMCs from patients with UC. These data suggest that SMILE exerts a therapeutic effect on IBD by modulating IL-17 production.
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Affiliation(s)
- SeungCheon Yang
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Jin-Sil Park
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Sun-Hee Hwang
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Keun-Hyung Cho
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Hyun Sik Na
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - JeongWon Choi
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Jooyeon Jhun
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Seung-Jun Kim
- Division of Gastroenterology, Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Bo-In Lee
- Division of Gastroenterology, Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Sung-Hwan Park
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Mi-La Cho
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul, South Korea
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Garo LP, Ajay AK, Fujiwara M, Gabriely G, Raheja R, Kuhn C, Kenyon B, Skillin N, Kadowaki-Saga R, Saxena S, Murugaiyan G. MicroRNA-146a limits tumorigenic inflammation in colorectal cancer. Nat Commun 2021; 12:2419. [PMID: 33893298 PMCID: PMC8065171 DOI: 10.1038/s41467-021-22641-y] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 03/24/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic inflammation can drive tumor development. Here, we have identified microRNA-146a (miR-146a) as a major negative regulator of colonic inflammation and associated tumorigenesis by modulating IL-17 responses. MiR-146a-deficient mice are susceptible to both colitis-associated and sporadic colorectal cancer (CRC), presenting with enhanced tumorigenic IL-17 signaling. Within myeloid cells, miR-146a targets RIPK2, a NOD2 signaling intermediate, to limit myeloid cell-derived IL-17-inducing cytokines and restrict colonic IL-17. Accordingly, myeloid-specific miR-146a deletion promotes CRC. Moreover, within intestinal epithelial cells (IECs), miR-146a targets TRAF6, an IL-17R signaling intermediate, to restrict IEC responsiveness to IL-17. MiR-146a within IECs further suppresses CRC by targeting PTGES2, a PGE2 synthesis enzyme. IEC-specific miR-146a deletion therefore promotes CRC. Importantly, preclinical administration of miR-146a mimic, or small molecule inhibition of the miR-146a targets, TRAF6 and RIPK2, ameliorates colonic inflammation and CRC. MiR-146a overexpression or miR-146a target inhibition represent therapeutic approaches that limit pathways converging on tumorigenic IL-17 signaling in CRC.
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Affiliation(s)
- Lucien P Garo
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Boston University School of Medicine, Boston, MA, USA
| | - Amrendra K Ajay
- Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Mai Fujiwara
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Galina Gabriely
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Radhika Raheja
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Chantal Kuhn
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Brendan Kenyon
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Nathaniel Skillin
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Ryoko Kadowaki-Saga
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Shrishti Saxena
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Gopal Murugaiyan
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
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43
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Sun Y, Wang Q, Wang Y, Ren W, Cao Y, Li J, Zhou X, Fu W, Yang J. Sarm1-mediated neurodegeneration within the enteric nervous system protects against local inflammation of the colon. Protein Cell 2021; 12:621-638. [PMID: 33871822 PMCID: PMC8310542 DOI: 10.1007/s13238-021-00835-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 03/01/2021] [Indexed: 12/13/2022] Open
Abstract
Axonal degeneration is one of the key features of neurodegenerative disorders. In the canonical view, axonal degeneration destructs neural connections and promotes detrimental disease defects. Here, we assessed the enteric nervous system (ENS) of the mouse, non-human primate, and human by advanced 3D imaging. We observed the profound neurodegeneration of catecholaminergic axons in human colons with ulcerative colitis, and similarly, in mouse colons during acute dextran sulfate sodium-induced colitis. However, we unexpectedly revealed that blockage of such axonal degeneration by the Sarm1 deletion in mice exacerbated the colitis condition. In contrast, pharmacologic ablation or chemogenetic inhibition of catecholaminergic axons suppressed the colon inflammation. We further showed that the catecholaminergic neurotransmitter norepinephrine exerted a pro-inflammatory function by enhancing the expression of IL-17 cytokines. Together, this study demonstrated that Sarm1-mediated neurodegeneration within the ENS mitigated local inflammation of the colon, uncovering a previously-unrecognized beneficial role of axonal degeneration in this disease context.
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Affiliation(s)
- Yue Sun
- State Key Laboratory of Membrane Biology, School of Life Sciences, Center for Life Sciences, Peking University, Beijing, 100871, China
| | - Qi Wang
- State Key Laboratory of Membrane Biology, School of Life Sciences, Center for Life Sciences, Peking University, Beijing, 100871, China
| | - Yi Wang
- State Key Laboratory of Membrane Biology, School of Life Sciences, Center for Life Sciences, Peking University, Beijing, 100871, China
| | - Wenran Ren
- School of Medicine, Tsinghua University, Beijing, 100084, China
| | - Ying Cao
- State Key Laboratory of Membrane Biology, School of Life Sciences, Center for Life Sciences, Peking University, Beijing, 100871, China
| | - Jiali Li
- IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China.,Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
| | - Xin Zhou
- Department of General Surgery, Peking University Third Hospital, Beijing, 100191, China
| | - Wei Fu
- Department of General Surgery, Peking University Third Hospital, Beijing, 100191, China
| | - Jing Yang
- State Key Laboratory of Membrane Biology, School of Life Sciences, Center for Life Sciences, Peking University, Beijing, 100871, China. .,IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China. .,Chinese Institute for Brain Research, Beijing, 102206, China. .,Shenzhen Bay Laboratory, Institute of Molecular Physiology, Shenzhen, 518055, China.
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44
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CD101 as an indicator molecule for pathological changes at the interface of host-microbiota interactions. Int J Med Microbiol 2021; 311:151497. [PMID: 33773220 DOI: 10.1016/j.ijmm.2021.151497] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 02/22/2021] [Accepted: 03/16/2021] [Indexed: 11/21/2022] Open
Abstract
Intestinal microbiota signal to local and distant tissues in the body. Thus, they also regulate biochemical, metabolic and immunological processes in the gut and in the pancreas. Vice versa, eating habits or the immune system of the host shape the intraluminal microbiota. Disruptions of these versatile host-microbiota interactions underlie the pathogenesis of complex immune-mediated disorders such as inflammatory bowel disease (IBD) or type 1 diabetes (T1D). Consequently, dysbiosis and increased intestinal permeability associated with both disorders change the biology of underlying tissues, as evidenced, for example, by an altered expression of surface markers such as CD101 on immune cells located at these dynamic host-microbiota interfaces. CD101, a heavily glycosylated member of the immunoglobulin superfamiliy, is predominantly detected on myeloid cells, intraepithelial lymphocytes (IELs) and regulatory T cells (Tregs) in the gut. The expression of CD101 on both myeloid cells and T lymphocytes protects from experimental enterocolitis and T1D. The improved outcome of both diseases is associated with an anti-inflammatory cytokine profile and a reduced expansion of T cells. However, distinct bacteria suppress the expression of CD101 on myeloid cells, similar as does inflammation on T cells. Thus, the reduced CD101 expression in T1D and IBD patients might be a consequence of an altered composition of the intestinal microbiota, enhanced bacterial translocation and a subsequent primining of local and systemic inflammatory immune responses.
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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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Zhou BG, Liu FC, Zhao HM, Zhang XY, Wang HY, Liu DY. Regulatory effect of Zuojin Pill on correlation with gut microbiota and Treg cells in DSS-induced colitis. JOURNAL OF ETHNOPHARMACOLOGY 2020; 262:113211. [PMID: 32739566 DOI: 10.1016/j.jep.2020.113211] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 06/20/2020] [Accepted: 07/22/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE As a classic prescription and commercial Chinese patent medicine, Zuojin Pill (ZJP) has been used to treat ulcerative colitis (UC) effectively for many years. However, its mechanism of action remains unclear. AIM OF THE STUDY METHODS: Mice with dextran-sulfate-sodium-induced colitis were treated with ZJP for 7 d. In the present study, the therapeutic effect of ZJP was evaluated by macroscopic and microscopic observation; regulatory T (Treg) cells and their subsets were analyzed by flow cytometry; and the composition of gut microbiota was tested by 16S rRNA analysis. Activation of the phosphoinostide 3-kinase (PI3K)/Akt signaling pathway was observed by western blotting. RESULTS The pathological damage was attenuated and expression of proinflammatory cytokines was decreased. While the diversity of intestinal microflora was regulated, the relative abundance of Actinobacteria, and Sphingobacteriia was modified. Meanwhile, the level of CD4+CD25+Foxp3+ and PD-L1+ Treg cells improved. These changes maintained a positive correlation which was analyzed statistically. Our results also showed that ZJP inhibited activation of the PI3K/Akt signaling pathway. CONCLUSIONS ZJP regulates crosstalk between intestinal microflora and Treg cells to attenuate experimental colitis via the PI3K/Akt signaling pathway.
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Affiliation(s)
- Bu-Gao Zhou
- Office of Academic Research, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, Jiangxi Province, China.
| | - Fu-Chun Liu
- Department of Postgraduate, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, Jiangxi Province, China.
| | - Hai-Mei Zhao
- College of Traditional Chinese Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, Jiangxi Province, China.
| | - Xiao-Yun Zhang
- Department of Postgraduate, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, Jiangxi Province, China.
| | - Hai-Yan Wang
- Doctoral Candidate of 2017, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, Jiangxi Province, China.
| | - Duan-Yong Liu
- Science and Technology College, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, Jiangxi Province, China; Formula-Pattern Research Center of Jiangxi, Nanchang, 330004, Jiangxi Province, China.
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Tachibana M, Watanabe N, Koda Y, Oya Y, Kaminuma O, Katayama K, Fan Z, Sakurai F, Kawabata K, Hiroi T, Mizuguchi H. Ablation of IL-17A leads to severe colitis in IL-10-deficient mice: implications of myeloid-derived suppressor cells and NO production. Int Immunol 2020; 32:187-201. [PMID: 31755523 PMCID: PMC7067553 DOI: 10.1093/intimm/dxz076] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 11/20/2019] [Indexed: 12/18/2022] Open
Abstract
IL-10 is an immune regulatory cytokine and its genetic defect leads to gastrointestinal inflammation in humans and mice. Moreover, the IL-23/Th17 axis is known to be involved in these inflammatory disorders. IL-17A, a representative cytokine produced by Th17 cells, has an important role for the pathological process of inflammatory diseases. However, the precise function of IL-17A in inflammatory bowel disease (IBD) remains controversial. In this study, we evaluated the effect of IL-17A on colitis in IL-10-deficient (Il10−/−) mice. Mice lacking both IL-10 and IL-17A (Il10−/−Il17a−/−) suffered from fatal wasting and manifested more severe colitis compared with Il10−/−Il17a+/− mice. Moreover, we found that CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) accumulated in the bone marrow, spleen and peripheral blood of Il10−/−Il17a−/− mice. These MDSCs highly expressed inducible nitric oxide synthase (iNOS) (Nos2) and suppressed the T-cell response in vitro in a NOS-dependent manner. In correlation with these effects, the concentration of nitric oxide was elevated in the serum of Il10−/−Il17a−/− mice. Surprisingly, the severe colitis observed in Il10−/−Il17a−/− mice was ameliorated in Il10−/−Il17a−/−Nos2−/− mice. Our findings suggest that IL-17A plays suppressive roles against spontaneous colitis in Il10−/− mice in an iNOS-dependent manner and inhibits MDSC differentiation and/or proliferation.
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Affiliation(s)
- Masashi Tachibana
- Laboratory of Biochemistry and Molecular Biology, Osaka University, Osaka, Japan.,Project for Vaccine and Immune Regulation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.,Global Center for Medical Engineering and Informatics, Osaka University, Osaka, Japan
| | - Nobumasa Watanabe
- Department of Genome Medicine, Allergy and Immunology Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Yuzo Koda
- Laboratory of Biochemistry and Molecular Biology, Osaka University, Osaka, Japan
| | - Yukako Oya
- Laboratory of Biochemistry and Molecular Biology, Osaka University, Osaka, Japan
| | - Osamu Kaminuma
- Department of Genome Medicine, Allergy and Immunology Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Kazufumi Katayama
- Laboratory of Biochemistry and Molecular Biology, Osaka University, Osaka, Japan
| | - Zifei Fan
- Laboratory of Biochemistry and Molecular Biology, Osaka University, Osaka, Japan
| | - Fuminori Sakurai
- Laboratory of Biochemistry and Molecular Biology, Osaka University, Osaka, Japan
| | - Kenji Kawabata
- Laboratory of Stem Cell Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Takachika Hiroi
- Department of Genome Medicine, Allergy and Immunology Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Hiroyuki Mizuguchi
- Laboratory of Biochemistry and Molecular Biology, Osaka University, Osaka, Japan.,Global Center for Medical Engineering and Informatics, Osaka University, Osaka, Japan.,Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan.,Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, Japan
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48
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Bifidobacterium longum subsp. longum YS108R fermented milk alleviates DSS induced colitis via anti-inflammation, mucosal barrier maintenance and gut microbiota modulation. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.104153] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
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49
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Inhibition of the activation of γδT17 cells through PPARγ-PTEN/Akt/GSK3β/NFAT pathway contributes to the anti-colitis effect of madecassic acid. Cell Death Dis 2020; 11:752. [PMID: 32929062 PMCID: PMC7490397 DOI: 10.1038/s41419-020-02969-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/20/2020] [Accepted: 08/27/2020] [Indexed: 12/15/2022]
Abstract
Type-17 immune response, mediated mainly by IL-17, plays a critical role in ulcerative colitis. Previously, we showed that madecassic acid (MA), the main active ingredient of Centella asiatica herbs for anti-colitis effect, ameliorated dextran sulfate sodium (DSS)-induced mouse colitis through reducing the level of IL-17. Here, we explore the effect of MA on the activation of γδT17 cells, an alternative source of IL-17 in colitis. In DSS-induced colitis mice, oral administration of MA decreased the number of γδT17 cells and attenuated the inflammation in the colon, and the anti-colitis effect of MA was significantly counteracted by redundant γδT17 cells, suggesting that the decrease in γδT17 cells is important for the anti-colitis effect of MA. In vitro, MA could inhibit the activation but not the proliferation of γδT17 cells at concentrations without evident cytotoxicity. Antibody microarray profiling showed that the inhibition of MA on the activation of γδT17 cells involved PPARγ–PTEN/Akt/GSK3β/NFAT signals. In γδT17 cells, MA could reduce the nuclear localization of NFATc1 through inhibiting Akt phosphorylation to promote GSK3β activation. Moreover, it was confirmed that MA inhibited the Akt/GSK3β/NFATc1 pathway and the activation of γδT17 cells through activating PPARγ to increase PTEN expression and phosphorylation. The correlation between activation of PPARγ, decrease in γδT17 cell number, and amelioration of colitis by MA was validated in mice with DSS-induced colitis. In summary, these findings reveal that MA inhibits the activation of γδT17 cells through PPARγ–PTEN/Akt/GSK3β/NFAT pathway, which contributes to the amelioration of colitis.
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50
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Peng H, Ning H, Wang Q, Lai J, Wei L, Stumpo DJ, Blackshear PJ, Fu M, Hou R, Hoft DF, Liu J. Tristetraprolin Regulates T H17 Cell Function and Ameliorates DSS-Induced Colitis in Mice. Front Immunol 2020; 11:1952. [PMID: 32922402 PMCID: PMC7457025 DOI: 10.3389/fimmu.2020.01952] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 07/20/2020] [Indexed: 02/05/2023] Open
Abstract
TH17 cells have been extensively investigated in inflammation, autoimmune diseases, and cancer. The precise molecular mechanisms for TH17 cell regulation, however, remain elusive, especially regulation at the post-transcriptional level. Tristetraprolin (TTP) is an RNA-binding protein important for degradation of the mRNAs encoding several proinflammatory cytokines. With newly generated T cell-specific TTP conditional knockout mice (CD4CreTTPf/f), we found that aging CD4CreTTPf/f mice displayed an increase of IL-17A in serum and spontaneously developed chronic skin inflammation along with increased effector TH17 cells in the affected skin. TTP inhibited TH17 cell development and function by promoting IL-17A mRNA degradation. In a DSS-induced colitis model, CD4CreTTPf/f mice displayed severe colitis and had more TH17 cells and serum IL-17A compared with wild-type mice. Furthermore, neutralization of IL-17A reduced the severity of colitis. Our results reveal a new mechanism for regulating TH17 function and TH17-mediated inflammation post-transcriptionally by TTP, suggests that TTP might be a novel therapeutic target for the treatment of TH17-mediated diseases.
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Affiliation(s)
- Hui Peng
- Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis University, St. Louis, MO, United States
| | - Huan Ning
- Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis University, St. Louis, MO, United States
| | - Qinghong Wang
- Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis University, St. Louis, MO, United States
| | - Jinping Lai
- Department of Pathology, Saint Louis University School of Medicine, Saint Louis University, St. Louis, MO, United States
| | - Lin Wei
- Department of Immunology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, China
| | - Deborah J. Stumpo
- National Institute of Environmental Health Sciences, Research Triangle, NC, United States
| | - Perry J. Blackshear
- National Institute of Environmental Health Sciences, Research Triangle, NC, United States
| | - Mingui Fu
- Shock/Trauma Research Center and Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, United States
| | - Rong Hou
- Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis University, St. Louis, MO, United States
| | - Daniel F. Hoft
- Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis University, St. Louis, MO, United States
| | - Jianguo Liu
- Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis University, St. Louis, MO, United States
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