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1
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Wu X, Wang K, Li Q, Zhang Y, Wei P, Shan Y, Zhao G. Combining Single-Cell RNA Sequencing and Mendelian Randomization to Explore Novel Drug Targets for Parkinson's Disease. Mol Neurobiol 2025; 62:7380-7392. [PMID: 39890696 DOI: 10.1007/s12035-025-04700-3] [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: 01/05/2024] [Accepted: 01/11/2025] [Indexed: 02/03/2025]
Abstract
Neuroinflammation is a key pathological factor of PD, and T cells play a central role in neuroinflammatory progression. However, the causal effect of T cell-related genes on the risk of PD is still unclear. We explored single-cell RNA sequencing (scRNA-Seq) datasets of the peripheral blood T cells of PD patients and healthy controls, and screened the differentially expressed genes (DEGs) in the cytotoxic CD4 + T cells relative to the other T cell subsets. Pseudo-time series analysis, cell-cell communication analysis, and metabolic pathway analysis was performed for the cytotoxic CD4 + T cells. The DEGs were also functionally annotated through GO and KEGG pathway enrichment analyses. The MR approach was used to establish causal effects of the DEGs (exposure) on PD risk (outcome), and explore new drug targets for PD. The findings of MR analysis were further validated by Steiger filtering, bidirectional MR, Bayesian colocalization analysis, and phenotype scanning, and the GWAS data from an independent PD case-control cohort was used for external validation of the results. Finally, differences in gene expression between PD patients and healthy controls were further validated in scRNA-Seq and bulk transcriptome sequencing data. We found that increased expression of IL-32, GNLY, MT2A, and ARPC2 was significantly associated with a higher risk of PD. In contrast, the increase in ARRB2 was closely related to a lower risk of PD. IL32, GNLY, MT2A, ARRB2, and ARPC2 are the causal genes and potential drug targets of PD. Cytotoxic CD4 + T cells are likely the key effectors of PD-related neuroinflammation. These findings provide new insights into the pathogenesis and treatment options for PD, and further research and clinical trials based on the five potential drug targets and neuroinflammation are necessary.
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Affiliation(s)
- Xiaolong Wu
- Department of Neurosurgery, Xuanwu Hospital of the Capital Medical University, Beijing, 100053, China
- International Neuroscience Institute (China-INI), Beijing, 100053, China
| | - Kailiang Wang
- Department of Neurosurgery, Xuanwu Hospital of the Capital Medical University, Beijing, 100053, China.
- International Neuroscience Institute (China-INI), Beijing, 100053, China.
| | - Qinghua Li
- Department of Neurosurgery, Xuanwu Hospital of the Capital Medical University, Beijing, 100053, China
- International Neuroscience Institute (China-INI), Beijing, 100053, China
| | - Yuqing Zhang
- Department of Functional Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Penghu Wei
- Department of Neurosurgery, Xuanwu Hospital of the Capital Medical University, Beijing, 100053, China
- International Neuroscience Institute (China-INI), Beijing, 100053, China
| | - Yongzhi Shan
- Department of Neurosurgery, Xuanwu Hospital of the Capital Medical University, Beijing, 100053, China
- International Neuroscience Institute (China-INI), Beijing, 100053, China
| | - Guoguang Zhao
- Department of Neurosurgery, Xuanwu Hospital of the Capital Medical University, Beijing, 100053, China.
- International Neuroscience Institute (China-INI), Beijing, 100053, China.
- Beijing Municipal Geriatric Medical Research Center, Beijing, 100053, China.
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2
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Halvorsen S, Thomas M, Mino-Kenudson M, Kinowaki Y, Burke KE, Morgan D, Miller KC, Williams KM, Gurung J, McGoldrick J, Hopton M, Hoppe B, Samanta N, Martin S, Tirard A, Arnold BY, Tantivit J, Yarze J, Staller K, Chung DC, Villani AC, Sassi S, Khalili H. Single-cell transcriptomic characterization of microscopic colitis. Nat Commun 2025; 16:4618. [PMID: 40383833 PMCID: PMC12086216 DOI: 10.1038/s41467-025-59648-8] [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: 09/01/2022] [Accepted: 04/30/2025] [Indexed: 05/20/2025] Open
Abstract
Microscopic colitis (MC) is a chronic inflammatory disease of the large intestine and a common cause of chronic diarrhea in older adults. Here, we use single-cell RNA sequencing analysis of colonic mucosal tissue to build a cellular and molecular model for MC. Our results show that in MC, there is a substantial expansion of tissue CD8+ T cells, likely arising from local expansion following T cell receptor engagement. Within the T cell compartment, MC is characterized by a shift in CD8 tissue-resident memory T cells towards a highly cytotoxic and inflammatory phenotype and expansion of CD4+ T regulatory cells. These results provide insight into inflammatory cytokines shaping MC pathogenesis and highlight notable similarities and differences with other immune-mediated intestinal diseases, including a common upregulation of IL26 and an MC-specific upregulation of IL10. These data help identify targets against enteric T cell subsets as an effective strategy for treatment of MC.
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Affiliation(s)
- Stefan Halvorsen
- Center for Computational and Integrative Biology, Massachusetts General Hospital (MGH), Boston, MA, USA
| | - Molly Thomas
- Center for Immunology and Inflammatory Diseases, Department of Medicine, MGH, Boston, MA, USA
- Krantz Family Center for Cancer Research, Department of Medicine, MGH, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
- Harvard Medical School (HMS), Boston, MA, USA
- Division of Gastroenterology, Department of Medicine, MGH, Boston, MA, USA
| | - Mari Mino-Kenudson
- Harvard Medical School (HMS), Boston, MA, USA
- Department of Pathology, HMS, MGH, Boston, MA, USA
| | | | - Kristin E Burke
- Division of Gastroenterology, Department of Medicine, MGH, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, MGH, Boston, MA, USA
| | - David Morgan
- Clinical and Translational Epidemiology Unit, MGH, Boston, MA, USA
| | - Kaia C Miller
- Clinical and Translational Epidemiology Unit, MGH, Boston, MA, USA
- Department of Medicine, Duke University Health System, NC, Durham, USA
| | | | - Jenny Gurung
- Clinical and Translational Epidemiology Unit, MGH, Boston, MA, USA
| | | | - Megan Hopton
- Center for Computational and Integrative Biology, Massachusetts General Hospital (MGH), Boston, MA, USA
| | - Brooke Hoppe
- Center for Computational and Integrative Biology, Massachusetts General Hospital (MGH), Boston, MA, USA
| | - Nandini Samanta
- Center for Immunology and Inflammatory Diseases, Department of Medicine, MGH, Boston, MA, USA
- Krantz Family Center for Cancer Research, Department of Medicine, MGH, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
| | - Sidney Martin
- Center for Immunology and Inflammatory Diseases, Department of Medicine, MGH, Boston, MA, USA
- Krantz Family Center for Cancer Research, Department of Medicine, MGH, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
| | - Alice Tirard
- Center for Immunology and Inflammatory Diseases, Department of Medicine, MGH, Boston, MA, USA
- Krantz Family Center for Cancer Research, Department of Medicine, MGH, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
| | - Benjamin Y Arnold
- Center for Immunology and Inflammatory Diseases, Department of Medicine, MGH, Boston, MA, USA
- Krantz Family Center for Cancer Research, Department of Medicine, MGH, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
| | - Jessica Tantivit
- Center for Immunology and Inflammatory Diseases, Department of Medicine, MGH, Boston, MA, USA
- Krantz Family Center for Cancer Research, Department of Medicine, MGH, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
| | - Joseph Yarze
- Division of Gastroenterology, Department of Medicine, MGH, Boston, MA, USA
| | - Kyle Staller
- Division of Gastroenterology, Department of Medicine, MGH, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, MGH, Boston, MA, USA
| | - Daniel C Chung
- Division of Gastroenterology, Department of Medicine, MGH, Boston, MA, USA
| | - Alexandra-Chloé Villani
- Center for Immunology and Inflammatory Diseases, Department of Medicine, MGH, Boston, MA, USA
- Krantz Family Center for Cancer Research, Department of Medicine, MGH, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
- Harvard Medical School (HMS), Boston, MA, USA
| | - Slim Sassi
- Center for Computational and Integrative Biology, Massachusetts General Hospital (MGH), Boston, MA, USA
- Harvard Medical School (HMS), Boston, MA, USA
- Department of Orthopedic Surgery, MGH, Boston, MA, USA
| | - Hamed Khalili
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
- Division of Gastroenterology, Department of Medicine, MGH, Boston, MA, USA.
- Clinical and Translational Epidemiology Unit, MGH, Boston, MA, USA.
- Institute of Environmental Medicine, Nutrition Epidemiology, Karolinska Institutet, Stockholm, Sweden.
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3
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Kim SH, White Z, Gainullina A, Kang S, Kim J, Dominguez JR, Choi Y, Cabrera I, Plaster M, Takahama M, Czepielewski RS, Yeom J, Gunzer M, Hay N, David O, Chevrier N, Sano T, Kim KW. IL-10 sensing by lung interstitial macrophages prevents bacterial dysbiosis-driven pulmonary inflammation and maintains immune homeostasis. Immunity 2025; 58:1306-1326.e7. [PMID: 40306274 DOI: 10.1016/j.immuni.2025.04.004] [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: 02/02/2024] [Revised: 10/02/2024] [Accepted: 04/03/2025] [Indexed: 05/02/2025]
Abstract
Crosstalk between the immune system and the microbiome is critical for maintaining immune homeostasis. Here, we examined this communication and the impact of immune-suppressive IL-10 signaling on pulmonary homeostasis. We found that IL-10 sensing by interstitial macrophages (IMs) is required to prevent spontaneous lung inflammation. Loss of IL-10 signaling in IMs initiated an inflammatory cascade through the activation of classical monocytes and CD4+ T cell subsets, leading to chronic lung inflammation with age. Analyses of antibiotic-treated and germ-free mice established that lung inflammation in the animals lacking IL-10 signaling was triggered by commensal bacteria. 16S rRNA sequencing revealed Delftia acidovorans and Rhodococcus erythropolis as potential drivers of lung inflammation. Intranasal administration of these bacteria or transplantation of human fecal microbiota elicited lung inflammation in gnotobiotic Il10-deficient mice. These findings highlight that IL-10 sensing by IMs contributes to pulmonary homeostasis by preventing lung inflammation caused by commensal dysbiosis.
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Affiliation(s)
- Seung Hyeon Kim
- Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, USA
| | - Zachary White
- Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL, USA
| | | | - Soeun Kang
- Department of Biochemistry and Genetics, University of Illinois College of Medicine, Chicago, IL, USA
| | - Jiseon Kim
- Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, USA
| | - Joseph R Dominguez
- Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, USA
| | - Yeonwoo Choi
- Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, USA
| | - Ivan Cabrera
- Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL, USA
| | - Madison Plaster
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA
| | - Michihiro Takahama
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA
| | - Rafael S Czepielewski
- Immunology Center of Georgia, Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, USA; Georgia Cancer Center, Augusta University, Augusta, GA, USA
| | - Jinki Yeom
- Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University, Seoul, Republic of Korea
| | - Matthias Gunzer
- Institute for Experimental Immunology and Imaging, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany
| | - Nissim Hay
- Department of Biochemistry and Genetics, University of Illinois College of Medicine, Chicago, IL, USA; University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, USA
| | - Odile David
- University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, USA; Department of Pathology, University of Illinois College of Medicine, Chicago, IL, USA
| | - Nicolas Chevrier
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA
| | - Teruyuki Sano
- Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL, USA; University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, USA.
| | - Ki-Wook Kim
- Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, USA; University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, USA.
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4
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DiDonato M, Simpson CT, Vo T, Knuth M, Geierstanger B, Jamontt J, Jones DH, Fathman JW, DeLarosa D, Junt T, Picard D, Sommer U, Bagger M, Peters E, Meeusen S, Spraggon G. A novel interleukin-10 antibody graft to treat inflammatory bowel disease. Structure 2025; 33:475-488.e7. [PMID: 39798572 DOI: 10.1016/j.str.2024.12.010] [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] [Revised: 11/19/2024] [Accepted: 12/12/2024] [Indexed: 01/15/2025]
Abstract
Inflammatory bowel disease (IBD) consists of chronic conditions that severely impact a patient's health and quality of life. Interleukin-10 (IL-10), a potent anti-inflammatory cytokine has strong genetic links to IBD susceptibility and has shown strong efficacy in IBD rodent models, suggesting it has great therapeutic potential. However, when tested in clinical trials for IBD, recombinant human IL-10 (rhIL-10) showed weak and inconsistent efficacy due to its short half-life and pro-inflammatory properties that counteract the anti-inflammatory efficacy. Here we present an engineered, IL-10, antibody-graft therapeutic (GFT-IL10M) designed to rectify these issues. GFT-IL10M combines the half-life extension properties of a monoclonal IgG antibody with altered IL-10 cell-type selective signaling, retaining desirable signaling on monocytes while reducing unwanted signaling on T, natural killer (NK), and B cells. Our structural and biochemical results indicate that the altered IL-10 topology in GFT-IL10M leads to a predominantly anti-inflammatory profile, potentially altering cell-type specific signaling patterns and extending half-life.
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Affiliation(s)
- Michael DiDonato
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
| | - Carolina Turk Simpson
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
| | - Todd Vo
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
| | - Mark Knuth
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
| | - Bernhard Geierstanger
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
| | | | - David H Jones
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
| | - John W Fathman
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
| | - Donnie DeLarosa
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
| | - Tobias Junt
- Novartis Biomedical Research, Novartis Campus, Basel, Switzerland
| | - Damien Picard
- Novartis Biomedical Research, Novartis Campus, Basel, Switzerland
| | - Ulrike Sommer
- Novartis Biomedical Research, Novartis Campus, Basel, Switzerland
| | - Morten Bagger
- Novartis Biomedical Research, Novartis Campus, Basel, Switzerland
| | - Eric Peters
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
| | - Shelly Meeusen
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
| | - Glen Spraggon
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
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5
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Ranjan P, Goswami SK, Dutta RK, Colin K, Pal HC, Zhang Q, Lal H, Prasad R, Verma SK. Hypertrophic heart failure promotes gut dysbiosis and gut leakage in interleukin 10-deficient mice. Am J Physiol Heart Circ Physiol 2025; 328:H447-H459. [PMID: 39854049 DOI: 10.1152/ajpheart.00323.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 06/10/2024] [Accepted: 01/02/2025] [Indexed: 01/26/2025]
Abstract
Heart failure (HF) is a leading cause of death worldwide. We have shown that pressure overload (PO)-induced inflammatory cell recruitment leads to heart failure in IL-10 knockout (KO) mice. However, it is unclear whether PO-induced inflammatory cells also target the gut mucosa, causing gut dysbiosis and leakage. We hypothesized that transverse aortic constriction (TAC) exacerbates immune cell homing to the gut (small intestine and colon), promoting dysbiosis and gut leakage in IL-10 KO mice. HF was induced in 8- to 10-wk-old C57BL/6J wild-type (WT) and B6.129P2-Il10tm1Cgn/J mutant (IL-10 KO) male and female mice by TAC and cardiac function was measured using visual sonics VEVO 3100. Fourteen days post-TAC, levels of monocytes, macrophages, neutrophils, and proinflammatory cytokines were measured in blood and gut. Gut dysbiosis was assessed via 16S rRNA sequencing in feces at 56 days post-TAC. IL-10 KO mice showed worsened cardiac dysfunction post-TAC. TAC worsened monocytes, and neutrophils infiltration in systemic circulation and facilitated their homing to the gut in IL-10 KO mice. Intriguingly, proinflammatory cytokines level was increased in blood, and gut of IL-10 KO mice following TAC. Furthermore, IL-10 expression was reduced in the colon of WT mice post-TAC. Moreover, TAC exacerbated gut dysbiosis in IL-10 KO mice. Finally, an impaired intestinal permeability was noted in IL-10 KO mice post-TAC. In conclusion, TAC-induced systemic inflammation leads to gut dysbiosis and impaired gut permeability in IL-10 KO mice, indicating IL-10's potential role in regulating intestinal integrity and microbiota balance during heart failure.NEW & NOTEWORTHY IL-10, crucial for systemic inflammation regulation and gut mucosal homeostasis, was investigated using IL-10 knockout (KO) mice. Exacerbated gut inflammation was observed post-transverse aortic constriction (TAC) in IL-10-depleted mice, whereas wild-type (WT) mice showed reduced IL-10 gene expression in colon and ileum. TAC induced gut dysbiosis and leakage in IL-10 KO mice, suggesting a link between enhanced inflammatory signaling in heart failure and multi-organ damage via gut dysbiosis and leakage.
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Affiliation(s)
- Prabhat Ranjan
- Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Sumanta Kumar Goswami
- Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Roshan Kumar Dutta
- Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Karen Colin
- Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, United States
- Division of Clinical Immunology and Rheumatology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Harish Chandra Pal
- Division of Clinical Immunology and Rheumatology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Qinkun Zhang
- Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Hind Lal
- Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Ram Prasad
- Department of Ophthalmology and Visual Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Suresh Kumar Verma
- Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, United States
- Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, Alabama, United States
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6
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Yu Y, Ba X, Li T, Xu W, Zhao J, Zhang N, Zhao Y, Wang T, Zhang X, Wang X, Bai B, Wang B. PTPN22 and the pathogenesis of ulcerative colitis: Insights into T cell differentiation and the JAK/STAT signaling pathway. Cell Signal 2025; 127:111551. [PMID: 39643025 DOI: 10.1016/j.cellsig.2024.111551] [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: 04/30/2024] [Revised: 10/20/2024] [Accepted: 12/01/2024] [Indexed: 12/09/2024]
Abstract
70 % of the ulcerative colitis (UC) linked gene loci are associated with other autoimmune or immunodeficient diseases. The phosphatase activity of PTPN22 can regulate the development of T cells and contribute to regulate the level of inflammation in autoimmune diseases. We produced PTPN22-CS thymus-specific transgenic mice, which suppressed PTPN22 enzyme activity in the thymocytes. Overexpressed PTPN22-CS facilitated the development of the thymocytes towards CD4+T cells and resulted in an increased proportion of the Th1 and Treg cells in the UC mesenteric lymph nodes. PTPN22-CS promoted the activation of the JAK/STAT signaling pathway in the Th1 and Treg cells that localized in the colon, resulting in an excessive production of inflammatory mediators such as IL-2 and IFN-γ. Consequently, PTPN22-CS contributes to the inflammatory response of ulcerative colitis. In summary, the tyrosine phosphatase activity of PTPN22 plays a role in modulating UC by regulating T cell differentiation and modulating the JAK/STAT signaling pathway, thereby influencing the inflammatory response in colonic. These findings provide new insight into the association between PTPN22 and the pathogenesis of UC.
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Affiliation(s)
- Yang Yu
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Xinlei Ba
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Tong Li
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Wenying Xu
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Jiahui Zhao
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China
| | - Na Zhang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Yanjiao Zhao
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China
| | - Tao Wang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Xiaonan Zhang
- Department of Pathophysiology, Bengbu Medical University, Longzihu, Bengbu, 233030, Anhui, PR China..
| | - Xipeng Wang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China
| | - Bin Bai
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Bing Wang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
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7
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Nicolle S, Barker M, Barrett J, Campbell M, Wojno-Picon J, Atkinson SJ, Aylott H, Kessedjian H, He Y, Messenger C, Roberts E, Spitzfaden C, Le J, Zinn N, Werner T, Dümpelfeld B, Bantscheff M, Somers DO, Reid H, Thang K, Gobbetti T, Lewis HD. Phenotype-Led Identification of IL-10 Upregulators in Human CD4 + T-cells and Elucidation of Their Pharmacology as Highly Selective CDK8/CDK19 Inhibitors. J Med Chem 2025; 68:1883-1900. [PMID: 39780505 DOI: 10.1021/acs.jmedchem.4c02630] [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: 01/11/2025]
Abstract
Therapeutics promoting the endogenous production of IL-10 have the potential to restore homeostasis in inflammatory disorders such as inflammatory bowel disease (IBD). Here we describe the identification of a series of IL-10 upregulators based on a pyrimidyl-piperidine scaffold through a high throughput phenotypic CD4+ T-cell multiplex assay. In vitro optimization of the initial hit yielded a lead with good potency and an in vitro clearance profile, compound 3-7, which additionally demonstrated efficacy in a murine endotoxin challenge PK-PD mechanistic model. Target deconvolution efforts identified compound 3-7 as a highly selective CDK8/19 inhibitor, and crystallographic studies unveiled its binding mode to the CDK8/Cyclin-C complex, characterized by an unusual water-mediated hydrogen bond to the kinase hinge region.
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Affiliation(s)
- Simon Nicolle
- Medicine Design, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Mike Barker
- Medicine Design, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K
| | - John Barrett
- In Vitro In Vivo Translation, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Matthew Campbell
- Medicine Design, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K
| | | | - Stephen J Atkinson
- Medicine Design, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Helen Aylott
- Medicine Design, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K
| | | | - Yanan He
- Medicine Development and Supply, GlaxoSmithKline R&D Hub, 1250 South Collegeville Road, Upper Providence, Pennsylvania 19426, United States
| | - Cassie Messenger
- Medicine Design, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Emma Roberts
- Medicine Design, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Claus Spitzfaden
- Medicine Design, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Joelle Le
- Medicine Design, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Nico Zinn
- Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg 69117, Germany
| | - Thilo Werner
- Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg 69117, Germany
| | - Birgit Dümpelfeld
- Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg 69117, Germany
| | - Marcus Bantscheff
- Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg 69117, Germany
| | - Don O Somers
- Medicine Design, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Heather Reid
- Immunology Research Unit GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Kevin Thang
- Immunology Research Unit GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Thomas Gobbetti
- Immunology Research Unit GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K
| | - Huw D Lewis
- Immunology Research Unit GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K
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Bezzio C, Brinch D, Ribaldone DG, Cappello M, Ruzzon N, Vernero M, Scalvini D, Loy L, Donghi S, Ciminnisi S, Manes G, Armuzzi A, Saibeni S. Prevalence, Risk Factors and Association with Clinical Outcomes of Malnutrition and Sarcopenia in Inflammatory Bowel Disease: A Prospective Study. Nutrients 2024; 16:3983. [PMID: 39683376 DOI: 10.3390/nu16233983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 11/16/2024] [Accepted: 11/19/2024] [Indexed: 12/18/2024] Open
Abstract
INTRODUCTION The prevalences of malnutrition and sarcopenia in patients with IBD are not precisely known, and nutritional assessment is not standardized. We assessed the prevalence and risk factors of these conditions in outpatients and their impact on clinical outcomes. METHODS This prospective longitudinal study considered patients who had IBD for at least one year, were attending a tertiary IBD center, and were followed for the subsequent year. RESULTS In a sample of 158 consecutive patients (96 with Crohn's disease and 62 with ulcerative colitis), the prevalence of malnutrition, according to GLIM criteria, was 13.3%. For identifying patients at risk of malnutrition, the Malnutrition Universal Screening Tool demonstrated better accuracy, (sensitivity 88.9 (65.3-98.6) and specificity 90.2 (83.8-93.4)) than the SaskIBD-NR questionnaire (sensitivity 69.3 (41.1-86.7) and specificity 60.9 (60.9-76.8)). The prevalence of sarcopenia was 34.2%. Considering clinical outcomes, sarcopenia at baseline was significantly associated with hospital admission within a year (p = 45.2% vs. 20.3%, 0.026). CONCLUSIONS Malnutrition and sarcopenia were present in about one-third of IBD patients. Awareness should be raised among physicians caring for IBD patients about the need to evaluate patients' nutritional statuses to help patients achieve a better quality of life.
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Affiliation(s)
- Cristina Bezzio
- IBD Centre, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy
| | - Daniele Brinch
- Gastroenterology Unit, Rho Hospital, ASST Rhodense, 20017 Rho, Italy
| | - Davide Giuseppe Ribaldone
- Division of Gastroenterology, Department of Medical Sciences, Università di Torino, 10126 Turin, Italy
| | - Maria Cappello
- Gastroenterology and Hepatology Section, ProMiSe Department, University of Palermo, 90100 Palermo, Italy
| | - Natalie Ruzzon
- Gastroenterology Unit, Rho Hospital, ASST Rhodense, 20017 Rho, Italy
| | - Marta Vernero
- Division of Gastroenterology, Department of Medical Sciences, Università di Torino, 10126 Turin, Italy
| | - Davide Scalvini
- Experimental Medicine, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Laura Loy
- IBD Centre, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy
| | - Sofia Donghi
- Gastroenterology Unit, Rho Hospital, ASST Rhodense, 20017 Rho, Italy
| | - Stefania Ciminnisi
- Gastroenterology and Hepatology Section, ProMiSe Department, University of Palermo, 90100 Palermo, Italy
| | - Gianpiero Manes
- Gastroenterology Unit, Rho Hospital, ASST Rhodense, 20017 Rho, Italy
| | - Alessandro Armuzzi
- IBD Centre, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy
| | - Simone Saibeni
- Gastroenterology Unit, Rho Hospital, ASST Rhodense, 20017 Rho, Italy
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9
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Wang ZQ, Zhang JY, Tang X, Zhou JB. Hypoglycemic drugs, circulating inflammatory proteins, and gallbladder diseases: A mediation mendelian randomization study. Diabetes Res Clin Pract 2024; 217:111882. [PMID: 39366640 DOI: 10.1016/j.diabres.2024.111882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 08/31/2024] [Accepted: 10/01/2024] [Indexed: 10/06/2024]
Abstract
BACKGROUND The relationship of hypoglycemic drugs, inflammatory proteins and gallbladder diseases remain unknown. METHODS Four hypoglycemic drugs were selected as exposure: glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter 2 inhibitors (SGLT-2i), and metformin. The outcome were two gallbladder diseases: cholecystitis and cholelithiasis. Mendelian Randomization (MR) was employed to determine the association between hypoglycemic drugs and gallbladder diseases. RESULTS DPP-4i and SGLT-2i had no effect on cholecystitis and cholelithiasis. However, a causal relationship was found between inhibition of ETFDH gene, a target of metformin expressed in cultured fibroblasts, and cholelithiasis (OR: 0.84, 95 %CI: (0.72,0.97), p = 0.021), as well as between GLP1R expression in the brain caudate basal ganglia and cholecystitis (OR: 1.29, 95 %CI: (1.11,1.49), p = 0.001). The effect of ETFDH inhibition on cholelithiasis through Interleukin-10 receptor subunit beta (IL-10RB) levels and Neurotrophin-3 (NT-3) levels, with a mediated proportion of 8 % and 8 %, respectively. CONCLUSION Metformin plays a protective role in cholelithiasis, while GLP-1RA have a harmful effect on the risk of cholecystitis. Metformin may reduce the risk of cholelithiasis by modulating the levels of Neurotrophin-3 (NT-3) and Interleukin-10 receptor subunit beta (IL-10RB). Further clinical and mechanistic studies are required to confirm these findings.
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Affiliation(s)
- Zi-Qi Wang
- Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Jin-Yan Zhang
- Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | | | - Jian-Bo Zhou
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
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10
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Haag SM, Xie S, Eidenschenk C, Fortin JP, Callow M, Costa M, Lun A, Cox C, Wu SZ, Pradhan RN, Lock J, Kuhn JA, Holokai L, Thai M, Freund E, Nissenbaum A, Keir M, Bohlen CJ, Martin S, Geiger-Schuller K, Hejase HA, Yaspan BL, Melo Carlos S, Turley SJ, Murthy A. Systematic perturbation screens identify regulators of inflammatory macrophage states and a role for TNF mRNA m6A modification. Nat Genet 2024; 56:2493-2505. [PMID: 39443811 DOI: 10.1038/s41588-024-01962-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 09/26/2024] [Indexed: 10/25/2024]
Abstract
Macrophages exhibit remarkable functional plasticity, a requirement for their central role in tissue homeostasis. During chronic inflammation, macrophages acquire sustained inflammatory 'states' that contribute to disease, but there is limited understanding of the regulatory mechanisms that drive their generation. Here we describe a systematic functional genomics approach that combines genome-wide phenotypic screening in primary murine macrophages with transcriptional and cytokine profiling of genetic perturbations in primary human macrophages to uncover regulatory circuits of inflammatory states. This process identifies regulators of five distinct states associated with key features of macrophage function. Among these regulators, loss of the N6-methyladenosine (m6A) writer components abolishes m6A modification of TNF transcripts, thereby enhancing mRNA stability and TNF production associated with multiple inflammatory pathologies. Thus, phenotypic characterization of primary murine and human macrophages describes the regulatory circuits underlying distinct inflammatory states, revealing post-transcriptional control of TNF mRNA stability as an immunosuppressive mechanism in innate immunity.
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Affiliation(s)
| | - Shiqi Xie
- Genentech Inc., South San Francisco, CA, USA
| | | | | | | | - Mike Costa
- Genentech Inc., South San Francisco, CA, USA
| | - Aaron Lun
- Genentech Inc., South San Francisco, CA, USA
| | - Chris Cox
- Genentech Inc., South San Francisco, CA, USA
| | - Sunny Z Wu
- Genentech Inc., South San Francisco, CA, USA
| | | | - Jaclyn Lock
- Genentech Inc., South San Francisco, CA, USA
- Sana Biotechnology Inc., South San Francisco, CA, USA
| | - Julia A Kuhn
- Genentech Inc., South San Francisco, CA, USA
- Alector Therapeutics, South San Francisco, CA, USA
| | | | - Minh Thai
- Genentech Inc., South San Francisco, CA, USA
| | | | | | - Mary Keir
- Genentech Inc., South San Francisco, CA, USA
| | | | | | | | | | | | | | | | - Aditya Murthy
- Genentech Inc., South San Francisco, CA, USA.
- Gilead Sciences, Foster City, CA, USA.
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11
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Huang Z, Liu B, Xiao L, Liao M, Huang L, Zhao X, Ma K, Wang R, Ji F, Li W, Huang L, Xie L. Effects of breast-fed infants-derived Limosilactobacillus reuteri and Bifidobacterium breve ameliorate DSS-induced colitis in mice. iScience 2024; 27:110902. [PMID: 39351200 PMCID: PMC11439849 DOI: 10.1016/j.isci.2024.110902] [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: 04/15/2024] [Revised: 07/11/2024] [Accepted: 09/04/2024] [Indexed: 10/04/2024] Open
Abstract
Studies have shown that breastfeeding can reduce the risk and severity of inflammatory bowel disease (IBD) in children and adults. Probiotics in breast milk have also been isolated and their effects on IBD have been studied. However, based on current evidence, the exact efficacy and mechanisms of probiotics in the treatment of IBD cannot be determined. In this study, Bifidobacterium breve FPHC4024 (BB FPHC4024) and Limosilactobacillus reuteri FPHC2951 (LR FPHC2951) were isolated from feces of exclusively breastfed healthy infants and administered by gavage to dextran sulfate sodium (DSS)-induced IBD mice. The results showed that LR FPHC2951 improved the symptoms of DSS-induced IBD, increased the expression of interleukin (IL)-10 mRNA and upregulated the abundance of Verrucomicrobiaceae Akkermansia. Combined with Kyoto Encyclopedia of Genes and Genomes (KEGG)-based Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) function prediction results, we hypothesized that LR FPHC2951 improved DSS-induced colitis symptoms in mice by increasing of IL-10 mRNA, altering the structure of intestinal flora, and reducing proinflammatory pathways and enhancing pathways associated with anti-inflammatory and intestinal protection.
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Affiliation(s)
- Zhipeng Huang
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
| | - Bingdong Liu
- State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
- Department of Endocrinology and Metabolism, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Lanlin Xiao
- State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
| | - Miaomiao Liao
- State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
| | - Liujing Huang
- Medical Affairs Department, Guangzhou Betrue Technology Co., Ltd. Guangzhou 510700, China
| | - Xiaogan Zhao
- Nanjing Agricultural University College of Food Science and Technology, Nanjing, Jiangsu, China
| | - Kai Ma
- Jiangsu New-bio Biotechnology Co., Ltd., Jiangyin, China
| | - Runxin Wang
- Jiangsu New-bio Biotechnology Co., Ltd., Jiangyin, China
| | - Feng Ji
- Jiangsu New-bio Biotechnology Co., Ltd., Jiangyin, China
| | - Wei Li
- Nanjing Agricultural University College of Food Science and Technology, Nanjing, Jiangsu, China
| | - Liping Huang
- Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Liwei Xie
- State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
- College of Life and Health Sciences, Guangdong Industry Polytechnic University, Guangzhou, Guangdong 510300, China
- Department of Endocrinology and Metabolism, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Department of Internal Medicine, Shunde Women and Children’s Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, Guangdong, China
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12
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Uvarova AN, Zheremyan EA, Ustiugova AS, Murashko MM, Bogomolova EA, Demin DE, Stasevich EM, Kuprash DV, Korneev KV. Autoimmunity-Associated SNP rs3024505 Disrupts STAT3 Binding in B Cells, Leading to IL10 Dysregulation. Int J Mol Sci 2024; 25:10196. [PMID: 39337678 PMCID: PMC11432243 DOI: 10.3390/ijms251810196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 09/11/2024] [Accepted: 09/20/2024] [Indexed: 09/30/2024] Open
Abstract
Interleukin 10 (IL10) is a major anti-inflammatory cytokine that acts as a master regulator of the immune response. A single nucleotide polymorphism rs3024505(C/T), located downstream of the IL10 gene, is associated with several aggressive inflammatory diseases, including systemic lupus erythematosus, Sjögren's syndrome, Crohn's disease, and ulcerative colitis. In such autoimmune pathologies, IL10-producing B cells play a protective role by decreasing the level of inflammation and restoring immune homeostasis. This study demonstrates that rs3024505 is located within an enhancer that augments the activity of the IL10 promoter in a reporter system based on a human B cell line. The common rs3024505(C) variant creates a functional binding site for the transcription factor STAT3, whereas the risk allele rs3024505(T) disrupts STAT3 binding, thereby reducing the IL10 promoter activity. Our findings indicate that B cells from individuals carrying the minor rs3024505(T) allele may produce less IL10 due to the disrupted STAT3 binding site, contributing to the progression of inflammatory pathologies.
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Affiliation(s)
- Aksinya N. Uvarova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Laboratory of Intracellular Signaling in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Elina A. Zheremyan
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Laboratory of Intracellular Signaling in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Alina S. Ustiugova
- Laboratory of Intracellular Signaling in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Matvey M. Murashko
- Laboratory of Intracellular Signaling in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Moscow Center for Advanced Studies, 123592 Moscow, Russia
| | - Elvina A. Bogomolova
- Laboratory of Intracellular Signaling in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Moscow Center for Advanced Studies, 123592 Moscow, Russia
| | - Denis E. Demin
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Laboratory of Intracellular Signaling in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Ekaterina M. Stasevich
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Laboratory of Intracellular Signaling in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Moscow Center for Advanced Studies, 123592 Moscow, Russia
| | - Dmitry V. Kuprash
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Laboratory of Intracellular Signaling in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Kirill V. Korneev
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Laboratory of Intracellular Signaling in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
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13
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Ge R, Zhang L, Yang Y, Chen K, Li C. Arpc2 integrates ecdysone and juvenile hormone metabolism to influence metamorphosis and reproduction in Tribolium castaneum. PEST MANAGEMENT SCIENCE 2024; 80:3734-3742. [PMID: 38477435 DOI: 10.1002/ps.8076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 02/29/2024] [Accepted: 03/13/2024] [Indexed: 03/14/2024]
Abstract
BACKGROUND Actin-related protein 2/3 complex regulates actin polymerization and the formation of branched actin networks. However, the function and evolutionary relationship of this complex subunit 2 (Arpc2) has been poorly understood in insects. RESULTS To address these issues, we performed comprehensive analysis of Arpc2 in Tribolium castaneum. Phylogenetic analysis revealed that Arpc2 was originated from one ancestral gene in animals but evolved independently between vertebrates and insects after species differentiation. T. castaneum Arpc2 has a 906-bp coding sequence and consists of 4 exons. Arpc2 transcripts were abundantly detected in embryos and pupae but less so in larvae and adults, while it had high expression in the gut, fat body and head but low expression in the epidermis of late-stage larvae. Knockdown of it at the late larval stage inhibited the pupation and resulted in arrested larvae. Silencing it in 1-day pupae impaired eclosion, which caused adult wings to fail to close. Injection of Arpc2 dsRNAs into 5-day pupae made adults have smaller testis and ovary and could not lay eggs. The expression of vitellogenin 1 (Vg1), Vg2 and Vg receptor (VgR) was downregulated after knocking down Arpc2 5 days post-adult emergence. Arpc2 silencing reduced 20-hydroxyecdysone titer by affecting the enzymes of its biosynthesis and catabolism but increased juvenile biosynthesis via upregulating JHAMT3 expression. CONCLUSION Our results indicate that Arpc2 is associated with the metamorphosis and reproduction by integrating ecdysone and juvenile hormone metabolism in T. castaneum. This study provides theoretical basis for developing Arpc2 as a potential RNA interference target for pest control. © 2024 Society of Chemical Industry.
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Affiliation(s)
- Runting Ge
- School of Life Sciences, Jiangsu University, Zhenjiang, China
| | - Ling Zhang
- School of Life Sciences, Jiangsu University, Zhenjiang, China
| | - Yanhua Yang
- School of Life Sciences, Jiangsu University, Zhenjiang, China
| | - Keping Chen
- School of Life Sciences, Jiangsu University, Zhenjiang, China
| | - Chengjun Li
- School of Life Sciences, Jiangsu University, Zhenjiang, China
- Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
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14
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Li B, Hu P, Liang H, Zhao X, Zhang A, Xu Y, Zhang B, Zhang J. Evaluating the causal effect of circulating proteome on the risk of inflammatory bowel disease-related traits using Mendelian randomization. Front Immunol 2024; 15:1434369. [PMID: 39144148 PMCID: PMC11321985 DOI: 10.3389/fimmu.2024.1434369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 07/17/2024] [Indexed: 08/16/2024] Open
Abstract
Objective This study sought to identify circulating proteins causally linked to Inflammatory Bowel Disease (IBD) traits through a Mendelian Randomization (MR) analytical framework. Methods Using a large-scale, two-sample MR approach, we estimated the genetic links of numerous plasma proteins with IBD and its subtypes, leveraging information from the Inflammatory Bowel Disease Genetics Consortium. To assess the robustness of MR findings, methods like Bayesian colocalization, and Steiger filtering analysis, evaluation of protein-altering variants. Further insights into IBD's underlying mechanisms and therapeutic targets were gleaned from single-cell sequencing analyses, protein-protein interaction assessments, pathway enrichment analyses, and evaluation of drug targets. Results By cis-only MR analysis, we identified 83 protein-phenotype associations involving 27 different proteins associated with at least one IBD subtype. Among these proteins, DAG1, IL10, IL12B, IL23R, MST1, STAT3 and TNFRSF6B showed overlapping positive or negative associations in all IBD phenotypes. Extending to cis + trans MR analysis, we further identified 117 protein-feature associations, including 44 unique proteins, most of which were not detected in the cis-only analysis. In addition, by performing co-localization analysis and Steiger filtering analysis on the prioritized associations, we further confirmed the causal relationship between these proteins and the IBD phenotype and verified the exact causal direction from the protein to the IBD-related feature. Conclusion MR analysis facilitated the identification of numerous circulating proteins associated with IBD traits, unveiling protein-mediated mechanisms and promising therapeutic targets.
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Affiliation(s)
- Beining Li
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
- The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Ping Hu
- Department of Orthopedic, Tianjin Medical University General Hospital, Tianjin, China
| | - Hongyan Liang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Xingliang Zhao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Aiting Zhang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Yingchong Xu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Bin Zhang
- Department of Orthopedic, Tianjin Medical University General Hospital, Tianjin, China
| | - Jie Zhang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
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15
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Ge J, Li M, Yao J, Guo J, Li X, Li G, Han X, Li Z, Liu M, Zhao J. The potential of EGCG in modulating the oral-gut axis microbiota for treating inflammatory bowel disease. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 130:155643. [PMID: 38820660 DOI: 10.1016/j.phymed.2024.155643] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 04/07/2024] [Accepted: 04/13/2024] [Indexed: 06/02/2024]
Abstract
Inflammatory bowel disease (IBD) is a recurrent chronic intestinal disorder that includes ulcerative colitis (UC) and Crohn's disease (CD). Its pathogenesis involves intricate interactions between pathogenic microorganisms, native intestinal microorganisms, and the intestinal immune system via the oral-gut axis. The strong correlation observed between oral diseases and IBD indicates the potential involvement of oral pathogenic microorganisms in IBD development. Consequently, therapeutic strategies targeting the proliferation, translocation, intestinal colonization and exacerbated intestinal inflammation of oral microorganisms within the oral-gut axis may partially alleviate IBD. Tea consumption has been identified as a contributing factor in reducing IBD, with epigallocatechin gallate (EGCG) being the primary bioactive compound used for IBD treatment. However, the precise mechanism by which EGCG mediates microbial crosstalk within the oral-gut axis remains unclear. In this review, we provide a comprehensive overview of the diverse oral microorganisms implicated in the pathogenesis of IBD and elucidate their colonization pathways and mechanisms. Subsequently, we investigated the antibacterial properties of EGCG and its potential to attenuate microbial translocation and colonization in the gut, emphasizing its role in attenuating exacerbations of IBD. We also elucidated the toxic and side effects of EGCG. Finally, we discuss current strategies for enhancing EGCG bioavailability and propose novel multi-targeted nano-delivery systems for the more efficacious management of IBD. This review elucidates the role and feasibility of EGCG-mediated modulation of the oral-gut axis microbiota in the management of IBD, contributing to a better understanding of the mechanism of action of EGCG in the treatment of IBD and the development of prospective treatment strategies.
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Affiliation(s)
- Jiaming Ge
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Tianjin Key Laboratory of Intelligent TCM Diagnosis and Treatment Technology and Equipment, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Mengyuan Li
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Tianjin Key Laboratory of Intelligent TCM Diagnosis and Treatment Technology and Equipment, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Jingwen Yao
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Tianjin Key Laboratory of Intelligent TCM Diagnosis and Treatment Technology and Equipment, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Jinling Guo
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Tianjin Key Laboratory of Intelligent TCM Diagnosis and Treatment Technology and Equipment, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xiankuan Li
- Tianjin Key Laboratory of Intelligent TCM Diagnosis and Treatment Technology and Equipment, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Gang Li
- State Key Laboratory of Precision Measurement Technology and Instruments, Tianjin University, Tianjin 300072, China
| | - Xiangli Han
- Department of Geriatric, Fourth Teaching Hospital of Tianjin University of TCM, Tianjin 300450, China
| | - Zheng Li
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Tianjin Key Laboratory of Intelligent TCM Diagnosis and Treatment Technology and Equipment, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Tianjin Key Laboratory of Intelligent and Green Pharmaceuticals for Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Ming Liu
- Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, 236 Baidi Road, Nankai District, Tianjin 300192, China.
| | - Jing Zhao
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Tianjin Key Laboratory of Intelligent TCM Diagnosis and Treatment Technology and Equipment, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Tianjin Key Laboratory of Intelligent and Green Pharmaceuticals for Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
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16
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McKelvey M, Uddin MB, Palani S, Shao S, Sun K. IL-10 Counteracts IFN-γ to Alleviate Acute Lung Injury in a Viral-Bacterial Superinfection Model. Am J Respir Cell Mol Biol 2024; 71:110-120. [PMID: 38574279 PMCID: PMC11225870 DOI: 10.1165/rcmb.2023-0437oc] [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: 12/10/2023] [Accepted: 04/03/2024] [Indexed: 04/06/2024] Open
Abstract
Immune activation is essential for lung control of viral and bacterial infection, but an overwhelming inflammatory response often leads to the onset of acute respiratory distress syndrome. IL-10 plays a crucial role in regulating the balance between antimicrobial immunity and immunopathology. In the present study, we investigated the role of IL-10 in acute lung injury induced by influenza A virus and methicillin-resistant Staphylococcus aureus coinfection. This unique coinfection model resembles patients with acute pneumonia undergoing appropriate antibiotic therapies. Using global IL-10 and IL-10 receptor gene-deficient mice, as well as in vivo neutralizing antibodies, we show that IL-10 deficiency promotes IFN-γ-dominant cytokine responses and triggers acute animal death. Interestingly, this extreme susceptibility is fully preventable by IFN-γ neutralization during coinfection. Further studies using mice with Il10ra deletion in selective myeloid subsets reveal that IL-10 primarily acts on mononuclear phagocytes to prevent IFN-γ/TNF-α hyperproduction and acute mortality. Importantly, this antiinflammatory IL-10 signaling is independent of its inhibitory effect on antiviral and antibacterial defense. Collectively, our results demonstrate a key mechanism of IL-10 in preventing hypercytokinemia and acute respiratory distress syndrome pathogenesis by counteracting the IFN-γ response.
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Affiliation(s)
| | - Md Bashir Uddin
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas
| | - Sunil Palani
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas
| | - Shengjun Shao
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas
| | - Keer Sun
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas
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17
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Iske J, El Fatimy R, Nian Y, Ghouzlani A, Eskandari SK, Cetina Biefer HR, Vasudevan A, Elkhal A. NAD + prevents septic shock-induced death by non-canonical inflammasome blockade and IL-10 cytokine production in macrophages. eLife 2024; 12:RP88686. [PMID: 38372712 PMCID: PMC10942599 DOI: 10.7554/elife.88686] [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] [Indexed: 02/20/2024] Open
Abstract
Septic shock is characterized by an excessive inflammatory response depicted in a cytokine storm that results from invasive bacterial, fungi, protozoa, and viral infections. Non-canonical inflammasome activation is crucial in the development of septic shock promoting pyroptosis and proinflammatory cytokine production via caspase-11 and gasdermin D (GSDMD). Here, we show that NAD+ treatment protected mice toward bacterial and lipopolysaccharide (LPS)-induced endotoxic shock by blocking the non-canonical inflammasome specifically. NAD+ administration impeded systemic IL-1β and IL-18 production and GSDMD-mediated pyroptosis of macrophages via the IFN-β/STAT-1 signaling machinery. More importantly, NAD+ administration not only improved casp-11 KO (knockout) survival but rendered wild type (WT) mice completely resistant to septic shock via the IL-10 signaling pathway that was independent from the non-canonical inflammasome. Here, we delineated a two-sided effect of NAD+ blocking septic shock through a specific inhibition of the non-canonical inflammasome and promoting immune homeostasis via IL-10, underscoring its unique therapeutic potential.
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Affiliation(s)
- Jasper Iske
- Division of Transplant Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical SchoolBostonUnited States
- Department of Cardiothoracic and Vascular Surgery, Germany Heart Center BerlinBerlinGermany
| | - Rachid El Fatimy
- Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical SchoolBostonUnited States
- Institute of Biological Sciences (ISSB-P), Mohammed VI Polytechnic UniversityBenguerirMorocco
| | - Yeqi Nian
- Institute of Transplant Medicine, Tianjin First Central Hospital, Nankai UniversityTianjinChina
| | - Amina Ghouzlani
- NAD Immunology Laboratory, Huntington Medical Research InstitutesPasadenaUnited States
| | - Siawosh K Eskandari
- Department of Internal Medicine, University of GroningenGroningenNetherlands
| | - Hector Rodriguez Cetina Biefer
- Division of Transplant Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical SchoolBostonUnited States
- Department of Cardiac Surgery, Stadtspital Zurich TriemliZurichSwitzerland
| | - Anju Vasudevan
- Department of Neurosciences, Angiogenesis and Brain Development Laboratory, Huntington Medical Research InstitutesPasadenaUnited States
| | - Abdallah Elkhal
- Division of Transplant Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical SchoolBostonUnited States
- NAD Immunology Laboratory, Huntington Medical Research InstitutesPasadenaUnited States
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18
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Mukherjee T, Kumar N, Chawla M, Philpott DJ, Basak S. The NF-κB signaling system in the immunopathogenesis of inflammatory bowel disease. Sci Signal 2024; 17:eadh1641. [PMID: 38194476 DOI: 10.1126/scisignal.adh1641] [Citation(s) in RCA: 33] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 12/11/2023] [Indexed: 01/11/2024]
Abstract
Inflammatory bowel disease (IBD) is an idiopathic, chronic condition characterized by episodes of inflammation in the gastrointestinal tract. The nuclear factor κB (NF-κB) system describes a family of dimeric transcription factors. Canonical NF-κB signaling is stimulated by and enhances inflammation, whereas noncanonical NF-κB signaling contributes to immune organogenesis. Dysregulation of NF-κB factors drives various inflammatory pathologies, including IBD. Signals from many immune sensors activate NF-κB subunits in the intestine, which maintain an equilibrium between local microbiota and host responses. Genetic association studies of patients with IBD and preclinical mouse models confirm the importance of the NF-κB system in host defense in the gut. Other studies have investigated the roles of these factors in intestinal barrier function and in inflammatory gut pathologies associated with IBD. NF-κB signaling modulates innate and adaptive immune responses and the production of immunoregulatory proteins, anti-inflammatory cytokines, antimicrobial peptides, and other tolerogenic factors in the intestine. Furthermore, genetic studies have revealed critical cell type-specific roles for NF-κB proteins in intestinal immune homeostasis, inflammation, and restitution that contribute to the etiopathology of IBD-associated manifestations. Here, we summarize our knowledge of the roles of these NF-κB pathways, which are activated in different intestinal cell types by specific ligands, and their cross-talk, in fueling aberrant intestinal inflammation. We argue that an in-depth understanding of aberrant immune signaling mechanisms may hold the key to identifying predictive or prognostic biomarkers and developing better therapeutics against inflammatory gut pathologies.
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Affiliation(s)
- Tapas Mukherjee
- Systems Immunology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Naveen Kumar
- Systems Immunology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
| | - Meenakshi Chawla
- Systems Immunology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
| | - Dana J Philpott
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Soumen Basak
- Systems Immunology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
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19
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Mishra Y, Mishra V, Aljabali AAA, El-Tanani M, Naikoo GA, Charbe N, Chava SR, Tambuwala MM. 3D Printed Personalized Colon-targeted Tablets: A Novel Approach in Ulcerative Colitis Management. Curr Drug Deliv 2024; 21:1211-1225. [PMID: 37718525 DOI: 10.2174/1567201821666230915150544] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 07/19/2023] [Accepted: 08/03/2023] [Indexed: 09/19/2023]
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD) are two types of idiopathic inflammatory bowel disease (IBD) that are increasing in frequency and incidence worldwide, particularly in highly industrialized countries. Conventional tablets struggle to effectively deliver anti-inflammatory drugs since the inflammation is localized in different areas of the colon in each patient. The goal of 3D printing technology in pharmaceutics is to create personalized drug delivery systems (DDS) that are tailored to each individual's specific needs. This review provides an overview of existing 3D printing processes, with a focus on extrusion-based technologies, which have received the most attention. Personalized pharmaceutical products offer numerous benefits to patients worldwide, and 3D printing technology is becoming more affordable every day. Custom manufacturing of 3D printed tablets provides innovative ideas for developing a tailored colon DDS. In the future, 3D printing could be used to manufacture personalized tablets for UC patients based on the location of inflammation in the colon, resulting in improved therapeutic outcomes and a better quality of life.
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Affiliation(s)
- Yachana Mishra
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara (Punjab)-144411, India
| | - Vijay Mishra
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara (Punjab)-144411, India
| | - Alaa A A Aljabali
- Faculty of Pharmacy, Department of Pharmaceutics & Pharmaceutical Technology, Yarmouk University, Irbid 21163, Jordan
| | - Mohamed El-Tanani
- Pharmacological and Diagnostic Research Centre, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan
| | - Gowhar A Naikoo
- Department of Mathematics and Sciences, College of Arts and Applied Sciences, Dhofar University, Salalah PC 211, Oman
| | - Nitin Charbe
- Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics (Lake Nona), University of Florida, Orlando, FL, USA
| | | | - Murtaza M Tambuwala
- Lincoln Medical School, University of Lincoln, Brayford Pool Campus, Lincoln LN6 7TS. United Kingdom
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20
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Sosna B, Aebisher D, Myśliwiec A, Dynarowicz K, Bartusik-Aebisher D, Oleś P, Cieślar G, Kawczyk-Krupka A. Selected Cytokines and Metalloproteinases in Inflammatory Bowel Disease. Int J Mol Sci 2023; 25:202. [PMID: 38203373 PMCID: PMC10779120 DOI: 10.3390/ijms25010202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a collective term for two diseases: ulcerative colitis (UC) and Crohn's disease (CD). There are many factors, e.g., genetic, environmental and immunological, that increase the likelihood of these diseases. Indicators of IBDs include extracellular matrix metalloproteinases (MMPs). The aim of this review is to present data on the role of selected cytokines and metalloproteinases in IBD. In recent years, more and more transcriptomic studies are emerging. These studies are improving the characterization of the cytokine microenvironment inside inflamed tissue. It is observed that the levels of several cytokines are consistently increased in inflamed tissue in IBD, both in UC and CD. This review shows that MMPs play a major role in the pathology of inflammatory processes, cancer, and IBD. IBD-associated inflammation is associated with increased expression of MMPs and reduced ability of tissue inhibitors of metalloproteinases (TIMPs) to inhibit their action. In IBD patients in tissues that are inflamed, MMPs are produced in excess and TIMP activity is not sufficient to block MMPs. This review is based on our personal selection of the literature that was retrieved by a selective search in PubMed using the terms "Inflammatory bowel disease" and "pathogenesis of Inflammatory bowel diseases" that includes systematic reviews, meta-analyses, and clinical trials. The involvement of the immune system in the pathophysiology of IBD is reviewed in terms of the role of the cytokines and metalloproteinases involved.
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Affiliation(s)
- Barbara Sosna
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - David Aebisher
- Department of Photomedicine and Physical Chemistry, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland;
| | - Angelika Myśliwiec
- Center for Innovative Research in Medical and Natural Sciences, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland; (A.M.); (K.D.)
| | - Klaudia Dynarowicz
- Center for Innovative Research in Medical and Natural Sciences, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland; (A.M.); (K.D.)
| | - Dorota Bartusik-Aebisher
- Department of Biochemistry and General Chemistry, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland;
| | - Piotr Oleś
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - Grzegorz Cieślar
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - Aleksandra Kawczyk-Krupka
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
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21
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Li X, Morel JD, Benegiamo G, Poisson J, Bachmann A, Rapin A, Sulc J, Williams E, Perino A, Schoonjans K, Bou Sleiman M, Auwerx J. Genetic and dietary modulators of the inflammatory response in the gastrointestinal tract of the BXD mouse genetic reference population. eLife 2023; 12:RP87569. [PMID: 37855835 PMCID: PMC10586803 DOI: 10.7554/elife.87569] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2023] Open
Abstract
Inflammatory gut disorders, including inflammatory bowel disease (IBD), can be impacted by dietary, environmental, and genetic factors. While the incidence of IBD is increasing worldwide, we still lack a complete understanding of the gene-by-environment interactions underlying inflammation and IBD. Here, we profiled the colon transcriptome of 52 BXD mouse strains fed with a chow or high-fat diet (HFD) and identified a subset of BXD strains that exhibit an IBD-like transcriptome signature on HFD, indicating that an interplay of genetics and diet can significantly affect intestinal inflammation. Using gene co-expression analyses, we identified modules that are enriched for IBD-dysregulated genes and found that these IBD-related modules share cis-regulatory elements that are responsive to the STAT2, SMAD3, and REL transcription factors. We used module quantitative trait locus analyses to identify genetic loci associated with the expression of these modules. Through a prioritization scheme involving systems genetics in the mouse and integration with external human datasets, we identified Muc4 and Epha6 as the top candidates mediating differences in HFD-driven intestinal inflammation. This work provides insights into the contribution of genetics and diet to IBD risk and identifies two candidate genes, MUC4 and EPHA6, that may mediate IBD susceptibility in humans.
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Affiliation(s)
- Xiaoxu Li
- Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de LausanneLausanneSwitzerland
| | - Jean-David Morel
- Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de LausanneLausanneSwitzerland
| | - Giorgia Benegiamo
- Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de LausanneLausanneSwitzerland
| | - Johanne Poisson
- Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de LausanneLausanneSwitzerland
| | - Alexis Bachmann
- Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de LausanneLausanneSwitzerland
| | - Alexis Rapin
- Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de LausanneLausanneSwitzerland
| | - Jonathan Sulc
- Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de LausanneLausanneSwitzerland
| | - Evan Williams
- Luxembourg Centre for Systems Biomedicine, University of LuxembourgEsch-sur-AlzetteLuxembourg
| | - Alessia Perino
- Laboratory of Metabolic Signaling, Institute of Bioengineering, École Polytechnique Fédérale de LausanneLausanneSwitzerland
| | - Kristina Schoonjans
- Laboratory of Metabolic Signaling, Institute of Bioengineering, École Polytechnique Fédérale de LausanneLausanneSwitzerland
| | - Maroun Bou Sleiman
- Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de LausanneLausanneSwitzerland
| | - Johan Auwerx
- Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de LausanneLausanneSwitzerland
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22
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Abstract
Numerous animal models of colitis have provided important insights into the pathogenesis of inflammatory bowel disease (IBD), contributing to a better understanding of the underlying mechanisms for IBD. As aberrant CD4+ T cell responses play a critical role in the pathogenesis and development of IBD, T cell adoptive transfer models of colitis have become a valuable tool in investigating the immunopathogenesis of intestinal inflammation. While the adoptive transfer of CD4+ CD45RBhi T cells into immunedeficient recipient mice was the first discovered and is currently the most widely used model, several variations of the T cell transfer model have also been developed with distinct features. Here, we describe the history, principle, and characteristics of adoptive transfer colitis models and discuss their strengths, limitations, and applications.
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Affiliation(s)
- Wenjing Yang
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
- Sealy Center for Microbiome Research, University of Texas Medical Branch, Galveston, TX, USA
| | - Yingzi Cong
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
- Sealy Center for Microbiome Research, University of Texas Medical Branch, Galveston, TX, USA
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23
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Yue NN, Xu HM, Xu J, Zhu MZ, Zhang Y, Tian CM, Nie YQ, Yao J, Liang YJ, Li DF, Wang LS. Therapeutic potential of gene therapy for gastrointestinal diseases: Advancements and future perspectives. Mol Ther Oncolytics 2023; 30:193-215. [PMID: 37663132 PMCID: PMC10471515 DOI: 10.1016/j.omto.2023.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/05/2023] Open
Abstract
Advancements in understanding the pathogenesis mechanisms underlying gastrointestinal diseases, encompassing inflammatory bowel disease, gastrointestinal cancer, and gastroesophageal reflux disease, have led to the identification of numerous novel therapeutic targets. These discoveries have opened up exciting possibilities for developing gene therapy strategies to treat gastrointestinal diseases. These strategies include gene replacement, gene enhancement, gene overexpression, gene function blocking, and transgenic somatic cell transplantation. In this review, we introduce the important gene therapy targets and targeted delivery systems within the field of gastroenterology. Furthermore, we provide a comprehensive overview of recent progress in gene therapy related to gastrointestinal disorders and shed light on the application of innovative gene-editing technologies in treating these conditions. These developments are fueling a revolution in the management of gastrointestinal diseases. Ultimately, we discuss the current challenges (particularly regarding safety, oral efficacy, and cost) and explore potential future directions for implementing gene therapy in the clinical settings for gastrointestinal diseases.
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Affiliation(s)
- Ning-ning Yue
- Department of Gastroenterology, Shenzhen People’s Hospital (the Second Clinical Medical College, Jinan University), Shenzhen 518000, China
| | - Hao-ming Xu
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou 510000, China
| | - Jing Xu
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou 510000, China
| | - Min-zheng Zhu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510000, China
| | - Yuan Zhang
- Department of Medical Administration, Huizhou Institute of Occupational Diseases Control and Prevention, Huizhou, Guangdong 516000, China
| | - Cheng-Mei Tian
- Department of Emergency, Shenzhen People’s Hospital (the Second Clinical Medical College, Jinan University, the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, China
| | - Yu-qiang Nie
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou 510000, China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People’s Hospital (the Second Clinical Medical College, Jinan University, the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, China
| | - Yu-jie Liang
- Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen 518000, China
| | - De-feng Li
- Department of Gastroenterology, Shenzhen People’s Hospital (the Second Clinical Medical College, Jinan University, the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, China
| | - Li-sheng Wang
- Department of Gastroenterology, Shenzhen People’s Hospital (the Second Clinical Medical College, Jinan University, the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518000, China
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24
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Yuan S, Wang KS, Meng H, Hou XT, Xue JC, Liu BH, Cheng WW, Li J, Zhang HM, Nan JX, Zhang QG. The gut microbes in inflammatory bowel disease: Future novel target option for pharmacotherapy. Biomed Pharmacother 2023; 165:114893. [PMID: 37352702 DOI: 10.1016/j.biopha.2023.114893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 05/09/2023] [Accepted: 05/13/2023] [Indexed: 06/25/2023] Open
Abstract
Gut microbes constitute the main microbiota in the human body, which can regulate biological processes such as immunity, cell proliferation, and differentiation, hence playing a specific function in intestinal diseases. In recent years, gut microbes have become a research hotspot in the pharmaceutical field. Because of their enormous number, diversity, and functional complexity, gut microbes have essential functions in the development of many digestive diseases. Inflammatory bowel disease (IBD) is a chronic non-specific inflammatory disease with a complex etiology, the exact cause and pathogenesis are unclear. There are no medicines that can cure IBD, and more research on therapeutic drugs is urgently needed. It has been reported that gut microbes play a critical role in pathogenesis, and there is a tight and complex association between gut microbes and IBD. The dysregulation of gut microbes may be a predisposing factor for IBD, and at the same time, IBD may exacerbate gut microbes' disorders, but the mechanism of interaction between the two is still not well defined. The study of the relationship between gut microbes and IBD is not only important to elucidate the pathogenesis but also has a positive effect on the treatment based on the regimen of regulating gut microbes. This review describes the latest research progress on the functions of gut microbes and their relationship with IBD, which can provide reference and assistance for further research. It may provide a theoretical basis for the application of probiotics, fecal microbiota transplantation, and other therapeutic methods to regulate gut microbes in IBD.
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Affiliation(s)
- Shuo Yuan
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Ke-Si Wang
- Chronic diseases research center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China
| | - Huan Meng
- Chronic diseases research center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China
| | - Xiao-Ting Hou
- Chronic diseases research center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China
| | - Jia-Chen Xue
- Chronic diseases research center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China; Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, 116001, China
| | - Bao-Hong Liu
- Chronic diseases research center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China
| | - Wen-Wen Cheng
- Chronic diseases research center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China
| | - Jiao Li
- Chronic diseases research center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China
| | - Hua-Min Zhang
- Chronic diseases research center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China
| | - Ji-Xing Nan
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
| | - Qing-Gao Zhang
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China; Chronic diseases research center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China.
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25
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Stummer N, Feichtinger RG, Weghuber D, Kofler B, Schneider AM. Role of Hydrogen Sulfide in Inflammatory Bowel Disease. Antioxidants (Basel) 2023; 12:1570. [PMID: 37627565 PMCID: PMC10452036 DOI: 10.3390/antiox12081570] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 07/28/2023] [Accepted: 08/04/2023] [Indexed: 08/27/2023] Open
Abstract
Hydrogen sulfide (H2S), originally known as toxic gas, has now attracted attention as one of the gasotransmitters involved in many reactions in the human body. H2S has been assumed to play a role in the pathogenesis of many chronic diseases, of which the exact pathogenesis remains unknown. One of them is inflammatory bowel disease (IBD), a chronic intestinal disease subclassified as Crohn's disease (CD) and ulcerative colitis (UC). Any change in the amount of H2S seems to be linked to inflammation in this illness. These changes can be brought about by alterations in the microbiota, in the endogenous metabolism of H2S and in the diet. As both too little and too much H2S drive inflammation, a balanced level is needed for intestinal health. The aim of this review is to summarize the available literature published until June 2023 in order to provide an overview of the current knowledge of the connection between H2S and IBD.
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Affiliation(s)
- Nathalie Stummer
- Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria; (N.S.); (R.G.F.); (D.W.); (B.K.)
| | - René G. Feichtinger
- Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria; (N.S.); (R.G.F.); (D.W.); (B.K.)
| | - Daniel Weghuber
- Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria; (N.S.); (R.G.F.); (D.W.); (B.K.)
| | - Barbara Kofler
- Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria; (N.S.); (R.G.F.); (D.W.); (B.K.)
- Research Program for Receptor Biochemistry and Tumor Metabolism, Paracelsus Medical University (PMU), 5020 Salzburg, Austria
| | - Anna M. Schneider
- Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria; (N.S.); (R.G.F.); (D.W.); (B.K.)
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Finnegan D, Tocmo R, Loscher C. Targeted Application of Functional Foods as Immune Fitness Boosters in the Defense against Viral Infection. Nutrients 2023; 15:3371. [PMID: 37571308 PMCID: PMC10421353 DOI: 10.3390/nu15153371] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 07/26/2023] [Accepted: 07/27/2023] [Indexed: 08/13/2023] Open
Abstract
In recent times, the emergence of viral infections, including the SARS-CoV-2 virus, the monkeypox virus, and, most recently, the Langya virus, has highlighted the devastating effects of viral infection on human life. There has been significant progress in the development of efficacious vaccines for the prevention and control of viruses; however, the high rates of viral mutation and transmission necessitate the need for novel methods of control, management, and prevention. In recent years, there has been a shift in public awareness on health and wellbeing, with consumers making significant dietary changes to improve their immunity and overall health. This rising health awareness is driving a global increase in the consumption of functional foods. This review delves into the benefits of functional foods as potential natural means to modulate the host immune system to enhance defense against viral infections. We provide an overview of the functional food market in Europe and discuss the benefits of enhancing immune fitness in high-risk groups, including the elderly, those with obesity, and people with underlying chronic conditions. We also discuss the immunomodulatory mechanisms of key functional foods, including dairy proteins and hydrolysates, plant-based functional foods, fermentates, and foods enriched with vitamin D, zinc, and selenium. Our findings reveal four key immunity boosting mechanisms by functional foods, including inhibition of viral proliferation and binding to host cells, modulation of the innate immune response in macrophages and dendritic cells, enhancement of specific immune responses in T cells and B cells, and promotion of the intestinal barrier function. Overall, this review demonstrates that diet-derived nutrients and functional foods show immense potential to boost viral immunity in high-risk individuals and can be an important approach to improving overall immune health.
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Affiliation(s)
| | | | - Christine Loscher
- School of Biotechnology, Dublin City University, D09 DX63 Dublin, Ireland; (D.F.); (R.T.)
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Zhang H, Ni Y, Ji H, Liu H, Liu S. Research trends of omics in ulcerative colitis: A bibliometric analysis. Front Med (Lausanne) 2023; 10:1115240. [PMID: 37051213 PMCID: PMC10083299 DOI: 10.3389/fmed.2023.1115240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Accepted: 02/20/2023] [Indexed: 03/28/2023] Open
Abstract
BackgroundOmics has emerged as a promising biological science to shed light on the etiology, pathogenesis, and treatment of ulcerative colitis (UC). At present, although research on the omics of UC has drawn global attention, there is still a lack of bibliometric analysis in this field. This study aimed to access the trends and hotspots of omics in UC research.MethodPublications related to omics in UC from 1 January 2000 to 15 October 2022 were retrieved from the Web of Science Core Collection database. VOSviewer, CiteSpace, and the online bibliometric analysis platform “Bibliometrix” were adopted to extract and visualize information.ResultsA total of 385 publications were finally included and the annual number of publications fluctuated. The trend in publications increased rapidly after 2019. The United States showed its dominant position in several publications, total citations, and international collaborations. The top five research organizations for publications on the research of omics in UC were Harvard Medical School, the Icahn School of Medicine at Mount Sinai, Karolinska Institutet, the Brigham and Women's Hospital, and the Massachusetts General Hospital. Ashwin Ananthakrishnan from the Massachusetts General Hospital was the most productive author, and Séverine Vermeire from the Catholic University of Leuven was co-cited most often. Inflammatory bowel disease was the most popular and co-cited journal in this field. The reference with citation bursts and trend topics showed that “ulcerative colitis,” “inflammatory bowel disease,” “microbiome,” “transcriptomics,” “genomics,” “metabolomics,” “proteomics,” “dysbiosis,” “biomarkers,” “loci,” and “therapy” are currently research hotspots.ConclusionOur study presents several important insights into the research trends and developments in the field of omics in UC, which will provide key information for further research.
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Affiliation(s)
- He Zhang
- Department of Gastroenterology, Guang' anmen Hospital, China Academy of Traditional Chinese Medical Sciences, Beijing, China
| | - Yuanyuan Ni
- Department of Gastroenterology, Guang' anmen Hospital, China Academy of Traditional Chinese Medical Sciences, Beijing, China
| | - Hangyu Ji
- Office of Good Clinical Practice, Guang' anmen Hospital, China Academy of Traditional Chinese Medical Sciences, Beijing, China
| | - Hongliang Liu
- Department of Gastroenterology, Guang' anmen Hospital, China Academy of Traditional Chinese Medical Sciences, Beijing, China
| | - Shaoneng Liu
- Department of Gastroenterology, Guang' anmen Hospital, China Academy of Traditional Chinese Medical Sciences, Beijing, China
- *Correspondence: Shaoneng Liu
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Peng Q, Pan T, He R, Yi M, Feng L, Cui Z, Gao R, Wang H, Feng X, Li H, Wang Y, Zhang C, Cheng D, Du Y, Wang C. BTNL2 promotes colitis-associated tumorigenesis in mice by regulating IL-22 production. EMBO Rep 2023; 24:e56034. [PMID: 36629012 PMCID: PMC9986825 DOI: 10.15252/embr.202256034] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 12/15/2022] [Accepted: 12/21/2022] [Indexed: 01/12/2023] Open
Abstract
Interleukin 22 (IL-22) has an important role in colorectal tumorigenesis and many colorectal diseases such as inflammatory bowel disease and certain infections. However, the regulation of IL-22 production in the intestinal system is still unclear. Here, we present evidence that butyrophilin-like protein 2 (BTNL2) is required for colorectal IL-22 production, and BTNL2 knockout mice show decreased colonic tumorigenesis and more severe colitis phenotypes than control mice due to defective production of IL-22. Mechanistically, BTNL2 acts on group 3 innate lymphoid cells (ILC3s), CD4+ T cells, and γδ T cells to promote the production of IL-22. Importantly, we find that a monoclonal antibody against BTNL2 attenuates colorectal tumorigenesis in mice and that the mBTNL2-Fc recombinant protein has a therapeutic effect in a dextran sulfate sodium (DSS)-induced colitis model. This study not only identifies a regulatory mechanism of IL-22 production in the colorectal system but also provides a potential therapeutic target for the treatment of human colorectal cancer and inflammatory bowel diseases.
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Affiliation(s)
- Qianwen Peng
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhanChina
| | - Ting Pan
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhanChina
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, Medical SchoolUniversity of Electronic Science and Technology of ChinaChengduChina
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026)Sichuan Academy of Medical Sciences and Sichuan Provincial People's HospitalChengduChina
| | - Ruirui He
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, Medical SchoolUniversity of Electronic Science and Technology of ChinaChengduChina
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026)Sichuan Academy of Medical Sciences and Sichuan Provincial People's HospitalChengduChina
| | - Ming Yi
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, Medical SchoolUniversity of Electronic Science and Technology of ChinaChengduChina
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026)Sichuan Academy of Medical Sciences and Sichuan Provincial People's HospitalChengduChina
| | - Lingyun Feng
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, Medical SchoolUniversity of Electronic Science and Technology of ChinaChengduChina
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026)Sichuan Academy of Medical Sciences and Sichuan Provincial People's HospitalChengduChina
| | - Zhihui Cui
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhanChina
| | - Ru Gao
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhanChina
| | - Heping Wang
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhanChina
| | - Xiong Feng
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhanChina
| | - Hui Li
- Shandong PolytechnicJinanChina
| | - Yuan Wang
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, Medical SchoolUniversity of Electronic Science and Technology of ChinaChengduChina
| | - Cun‐jin Zhang
- Department of Neurology of Nanjing Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical BiotechnologyNanjing UniversityNanjingChina
| | - Du Cheng
- Department of GastroenterologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Yanyun Du
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, Medical SchoolUniversity of Electronic Science and Technology of ChinaChengduChina
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026)Sichuan Academy of Medical Sciences and Sichuan Provincial People's HospitalChengduChina
| | - Chenhui Wang
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, Medical SchoolUniversity of Electronic Science and Technology of ChinaChengduChina
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026)Sichuan Academy of Medical Sciences and Sichuan Provincial People's HospitalChengduChina
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Hill AA, Kim M, Zegarra-Ruiz DF, Chang LC, Norwood K, Assié A, Wu WJH, Renfroe MC, Song HW, Major AM, Samuel BS, Hyser JM, Longman RS, Diehl GE. Acute high-fat diet impairs macrophage-supported intestinal damage resolution. JCI Insight 2023; 8:e164489. [PMID: 36538527 PMCID: PMC9977439 DOI: 10.1172/jci.insight.164489] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
Chronic exposure to high-fat diets (HFD) worsens intestinal disease pathology, but acute effects of HFD in tissue damage remain unclear. Here, we used short-term HFD feeding in a model of intestinal injury and found sustained damage with increased cecal dead neutrophil accumulation, along with dietary lipid accumulation. Neutrophil depletion rescued enhanced pathology. Macrophages from HFD-treated mice showed reduced capacity to engulf dead neutrophils. Macrophage clearance of dead neutrophils activates critical barrier repair and antiinflammatory pathways, including IL-10, which was lost after acute HFD feeding and intestinal injury. IL-10 overexpression restored intestinal repair after HFD feeding and intestinal injury. Macrophage exposure to lipids from the HFD prevented tethering and uptake of apoptotic cells and Il10 induction. Milk fat globule-EGF factor 8 (MFGE8) is a bridging molecule that facilitates macrophage uptake of dead cells. MFGE8 also facilitates lipid uptake, and we demonstrate that dietary lipids interfere with MFGE8-mediated macrophage apoptotic neutrophil uptake and subsequent Il10 production. Our findings demonstrate that HFD promotes intestinal pathology by interfering with macrophage clearance of dead neutrophils, leading to unresolved tissue damage.
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Affiliation(s)
| | - Myunghoo Kim
- Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - Daniel F. Zegarra-Ruiz
- Immunology Program of the Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Lin-Chun Chang
- Immunology Program of the Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Kendra Norwood
- Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - Adrien Assié
- Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - Wan-Jung H. Wu
- Immunology Program of the Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Michael C. Renfroe
- Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - Hyo Wong Song
- Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | | | - Buck S. Samuel
- Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - Joseph M. Hyser
- Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - Randy S. Longman
- Jill Roberts Institute for Research in IBD and Jill Roberts Center for IBD, Weill Cornell Medicine, New York, New York, USA
| | - Gretchen E. Diehl
- Alkek Center for Metagenomics and Microbiome Research and the Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
- Immunology Program of the Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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Ohkusa T, Nishikawa Y, Sato N. Gastrointestinal disorders and intestinal bacteria: Advances in research and applications in therapy. Front Med (Lausanne) 2023; 9:935676. [PMID: 36825261 PMCID: PMC9941163 DOI: 10.3389/fmed.2022.935676] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 12/27/2022] [Indexed: 02/09/2023] Open
Abstract
Intestinal bacteria coexist with humans and play a role in suppressing the invasion of pathogens, producing short-chain fatty acids, producing vitamins, and controlling the immune system. Studies have been carried out on culturable bacterial species using bacterial culture methods for many years. However, as metagenomic analysis of bacterial genes has been developed since the 1990s, it has recently revealed that many bacteria in the intestine cannot be cultured and that approximately 1,000 species and 40 trillion bacteria are present in the gut microbiota. Furthermore, the composition of the microbiota is different in each disease state compared with the healthy state, and dysbiosis has received much attention as a cause of various diseases. Regarding gastrointestinal diseases, dysbiosis has been reported to be involved in inflammatory bowel disease, irritable bowel syndrome, and non-alcoholic steatohepatitis. Recent findings have also suggested that dysbiosis is involved in colon cancer, liver cancer, pancreatic cancer, esophageal cancer, and so on. This review focuses on the relationship between the gut microbiota and gastrointestinal/hepatobiliary diseases and also discusses new therapies targeting the gut microbiota.
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Affiliation(s)
| | - Yuriko Nishikawa
- Department of Microbiota Research, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Nobuhiro Sato
- Department of Microbiota Research, Juntendo University Graduate School of Medicine, Tokyo, Japan
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Johnson TO, Akinsanmi AO, Ejembi SA, Adeyemi OE, Oche JR, Johnson GI, Adegboyega AE. Modern drug discovery for inflammatory bowel disease: The role of computational methods. World J Gastroenterol 2023; 29:310-331. [PMID: 36687123 PMCID: PMC9846937 DOI: 10.3748/wjg.v29.i2.310] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 11/02/2022] [Accepted: 12/21/2022] [Indexed: 01/06/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) comprising ulcerative colitis, Crohn’s disease and microscopic colitis are characterized by chronic inflammation of the gastrointestinal tract. IBD has spread around the world and is becoming more prevalent at an alarming rate in developing countries whose societies have become more westernized. Cell therapy, intestinal microecology, apheresis therapy, exosome therapy and small molecules are emerging therapeutic options for IBD. Currently, it is thought that low-molecular-mass substances with good oral bio-availability and the ability to permeate the cell membrane to regulate the action of elements of the inflammatory signaling pathway are effective therapeutic options for the treatment of IBD. Several small molecule inhibitors are being developed as a promising alternative for IBD therapy. The use of highly efficient and time-saving techniques, such as computational methods, is still a viable option for the development of these small molecule drugs. The computer-aided (in silico) discovery approach is one drug development technique that has mostly proven efficacy. Computational approaches when combined with traditional drug development methodology dramatically boost the likelihood of drug discovery in a sustainable and cost-effective manner. This review focuses on the modern drug discovery approaches for the design of novel IBD drugs with an emphasis on the role of computational methods. Some computational approaches to IBD genomic studies, target identification, and virtual screening for the discovery of new drugs and in the repurposing of existing drugs are discussed.
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Affiliation(s)
| | | | | | | | - Jane-Rose Oche
- Department of Biochemistry, University of Jos, Jos 930222, Plateau, Nigeria
| | - Grace Inioluwa Johnson
- Faculty of Clinical Sciences, College of Health Sciences, University of Jos, Jos 930222, Plateau, Nigeria
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Saez A, Herrero-Fernandez B, Gomez-Bris R, Sánchez-Martinez H, Gonzalez-Granado JM. Pathophysiology of Inflammatory Bowel Disease: Innate Immune System. Int J Mol Sci 2023; 24:ijms24021526. [PMID: 36675038 PMCID: PMC9863490 DOI: 10.3390/ijms24021526] [Citation(s) in RCA: 209] [Impact Index Per Article: 104.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 12/30/2022] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a heterogeneous state of chronic intestinal inflammation with no exact known cause. Intestinal innate immunity is enacted by neutrophils, monocytes, macrophages, and dendritic cells (DCs), and innate lymphoid cells and NK cells, characterized by their capacity to produce a rapid and nonspecific reaction as a first-line response. Innate immune cells (IIC) defend against pathogens and excessive entry of intestinal microorganisms, while preserving immune tolerance to resident intestinal microbiota. Changes to this equilibrium are linked to intestinal inflammation in the gut and IBD. IICs mediate host defense responses, inflammation, and tissue healing by producing cytokines and chemokines, activating the complement cascade and phagocytosis, or presenting antigens to activate the adaptive immune response. IICs exert important functions that promote or ameliorate the cellular and molecular mechanisms that underlie and sustain IBD. A comprehensive understanding of the mechanisms underlying these clinical manifestations will be important for developing therapies targeting the innate immune system in IBD patients. This review examines the complex roles of and interactions among IICs, and their interactions with other immune and non-immune cells in homeostasis and pathological conditions.
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Affiliation(s)
- Angela Saez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria (UFV), 28223 Pozuelo de Alarcón, Spain
| | - Beatriz Herrero-Fernandez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
| | - Raquel Gomez-Bris
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
| | - Hector Sánchez-Martinez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
| | - Jose M. Gonzalez-Granado
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-913908766
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Genetic and Epigenetic Etiology of Inflammatory Bowel Disease: An Update. Genes (Basel) 2022; 13:genes13122388. [PMID: 36553655 PMCID: PMC9778199 DOI: 10.3390/genes13122388] [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: 11/17/2022] [Revised: 12/06/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic disease with periods of exacerbation and remission of the disease. The etiology of IBD is not fully understood. Many studies point to the presence of genetic, immunological, environmental, and microbiological factors and the interactions between them in the occurrence of IBD. The review looks at genetic factors in the context of both IBD predisposition and pharmacogenetics.
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Najafi-Fard S, Petruccioli E, Farroni C, Petrone L, Vanini V, Cuzzi G, Salmi A, Altera AMG, Navarra A, Alonzi T, Nicastri E, Palmieri F, Gualano G, Carlini V, Noonan DM, Albini A, Goletti D. Evaluation of the immunomodulatory effects of interleukin-10 on peripheral blood immune cells of COVID-19 patients: Implication for COVID-19 therapy. Front Immunol 2022; 13:984098. [PMID: 36148228 PMCID: PMC9486547 DOI: 10.3389/fimmu.2022.984098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/11/2022] [Indexed: 12/03/2022] Open
Abstract
Objective Several therapies with immune-modulatory functions have been proposed to reduce the overwhelmed inflammation associated with COVID-19. Here we investigated the impact of IL-10 in COVID-19, through the ex-vivo assessment of the effects of exogenous IL-10 on SARS-CoV-2-specific-response using a whole-blood platform. Methods Two cohorts were evaluated: in “study population A”, plasma levels of 27 immune factors were measured by a multiplex (Luminex) assay in 39 hospitalized “COVID-19 patients” and 29 “NO COVID-19 controls” all unvaccinated. In “study population B”, 29 COVID-19 patients and 30 NO COVID-19-Vaccinated Controls (NO COVID-19-VCs) were prospectively enrolled for the IL-10 study. Whole-blood was stimulated overnight with SARS-COV-2 antigens and then treated with IL-10. Plasma was collected and used for ELISA and multiplex assay. In parallel, whole-blood was stimulated and used for flow cytometry analysis. Results Baseline levels of several immune factors, including IL-10, were significantly elevated in COVID-19 patients compared with NO COVID-19 subjects in “study population A”. Among them, IL-2, FGF, IFN-γ, and MCP-1 reached their highest levels within the second week of infection and then decreased. To note that, MCP-1 levels remained significantly elevated compared with controls. IL-10, GM-CSF, and IL-6 increased later and showed an increasing trend over time. Moreover, exogenous addition of IL-10 significantly downregulated IFN-γ response and several other immune factors in both COVID-19 patients and NO COVID-19-VCs evaluated by ELISA and a multiplex analysis (Luminex) in “study population B”. Importantly, IL-10 did not affect cell survival, but decreased the frequencies of T-cells producing IFN-γ, TNF-α, and IL-2 (p<0.05) and down-modulated HLA-DR expression on CD8+ and NK cells. Conclusion This study provides important insights into immune modulating effects of IL-10 in COVID-19 and may provide valuable information regarding the further in vivo investigations.
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Affiliation(s)
- Saeid Najafi-Fard
- Translational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Elisa Petruccioli
- Translational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Chiara Farroni
- Translational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Linda Petrone
- Translational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Valentina Vanini
- Translational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
- Department of Epidemiology and Preclinical Research, UOS Professioni Sanitarie Tecniche National Institute for Infectious Diseases Lazzaro Spallanzani-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Gilda Cuzzi
- Translational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Andrea Salmi
- Translational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Anna Maria Gerarda Altera
- Translational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Assunta Navarra
- Clinical Epidemiology Unit, National Institute for Infectious Disease Lazzaro Spallanzani-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Tonino Alonzi
- Translational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Emanuele Nicastri
- Clinical Division of Infectious Diseases, National Institute for Infectious Diseases Lazzaro Spallanzani-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Fabrizio Palmieri
- Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases Lazzaro Spallanzani-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Gina Gualano
- Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases Lazzaro Spallanzani-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Valentina Carlini
- Unit of Molecular Pathology, Biochemistry and Immunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Douglas McClain Noonan
- Unit of Molecular Pathology, Biochemistry and Immunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Adriana Albini
- European Institute of Oncology IEO-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
- *Correspondence: Adriana Albini, ; Delia Goletti,
| | - Delia Goletti
- Translational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
- *Correspondence: Adriana Albini, ; Delia Goletti,
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Thanki KK, Johnson P, Higgins EJ, Maskey M, Phillips C, Dash S, Almenas FA, Govar AA, Tian B, Villéger R, Beswick E, Wang R, Szabo C, Chao C, Pinchuk IV, Hellmich MR, Módis K. Deletion of cystathionine-γ-lyase in bone marrow-derived cells promotes colitis-associated carcinogenesis. Redox Biol 2022; 55:102417. [PMID: 35933902 PMCID: PMC9357841 DOI: 10.1016/j.redox.2022.102417] [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: 05/09/2022] [Revised: 06/27/2022] [Accepted: 07/17/2022] [Indexed: 11/24/2022] Open
Abstract
Ulcerative colitis (UC) is characterized by widespread relapsing inflammation of the colonic mucosa. Colitis-associated cancer (CAC) is one of the most serious complications of a prolonged history of UC. Hydrogen sulfide (H2S) has emerged as an important physiological mediator of gastrointestinal homeostasis, limiting mucosal inflammation and promoting tissue healing in response to injury. Inhibition of cystathionine-γ-lyase (CSE)-dependent H2S production in animal models of UC has been shown to exacerbate colitis and delay tissue repair. It is unknown whether CSE plays a role in CAC, or the downregulation of CSE expression and/or activity promotes CAC development. In humans, we observed a significant decrease in CSE expression in colonic biopsies from patients with UC. Using the dextran sodium sulfate (DSS) model of epithelium injury-induced colitis and global CSE KO mouse strain, we demonstrated that CSE is critical in limiting mucosal inflammation and stimulating epithelial cell proliferation in response to injury. In vitro studies showed that CSE activity stimulates epithelial cell proliferation, basal and cytokine-stimulated cell migration, as well as cytokine regulation of transepithelial permeability. In the azoxymethane (AOM)/DSS model of CAC, the loss of CSE expression accelerated both the development and progression of CAC. The increased tumor multiplicity and severity of CAC observed in CSE-KO mice were associated with reduced levels of mucosal IL-10 expression and increased levels of IL-6. Restoring CSE expression in bone marrow (BM) cells of CSE-KO mice through reciprocal BM transplantation raised mucosal IL-10 expression, decreased IL-6 level, and reduced the number of aberrant crypt foci and tumors in AOM/DSS-treated mice. These studies demonstrate that CSE expression in BM cells plays a critical role in suppressing CAC in mice. Furthermore, the data suggest that the inhibitory effects of CSE on the development of CAC are due, in part, to the modulation of mucosal pro-and anti-inflammatory cytokine expression.
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Affiliation(s)
- Ketan K Thanki
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Paul Johnson
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Edward J Higgins
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Manjit Maskey
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Ches'Nique Phillips
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Swetaleena Dash
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | | | | | - Bing Tian
- Department of Internal Medicine, University of Texas Medical, Galveston, TX, USA.
| | - Romain Villéger
- Department of Internal Medicine, University of Texas Medical, Galveston, TX, USA.
| | - Ellen Beswick
- Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
| | - Rui Wang
- Department of Biology, York University, Toronto, ON, Canada.
| | - Csaba Szabo
- Chair of Pharmacology, Section of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
| | - Celia Chao
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Irina V Pinchuk
- Department of Internal Medicine, University of Texas Medical, Galveston, TX, USA.
| | - Mark R Hellmich
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Katalin Módis
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
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36
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Wang D, Jin H, Sheng J, Cheng L, Lin Q, Lazerev M, Jin P, Li X. A high salt diet protects interleukin 10-deficient mice against chronic colitis by improving the mucosal barrier function. Mol Immunol 2022; 150:39-46. [PMID: 35944464 DOI: 10.1016/j.molimm.2022.07.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 07/04/2022] [Accepted: 07/31/2022] [Indexed: 11/24/2022]
Abstract
A high salt diet (HSD) is often associated with a high risk for a variety of diseases, such as obesity and cardiovascular disease. Previous studies have demonstrated that an HSD enhances Th17 responses and increases the severity of autoimmune diseases. In this study, we investigated the effects of HSD (4% NaCl w/w) on colitis in IL-10-/- mice by comparing it with IL-10-/- mice on a normal salt diet (NSD, 1% NaCl w/w). The colonic epithelial barrier integrity in IL-10-/- mice, as well as differentiated Caco-2 cells exposed to high NaCl and proinflammatory cytokines, was also evaluated. Surprisingly, an HSD significantly ameliorated macroscopic colitis, improved the intestinal permeability of FITC-dextran, and decreased multiple proinflammatory cytokines in the colonic mucosa of IL-10-/- mice. While occludin and claudin-1, two major tight-junction proteins, were markedly down-regulated in IL-10-/- mice, HSD effectively restored their expressions. In Caco-2 cells, proinflammatory cytokines (TNF-α and IL-1β) potently decreased the expression of occludin and claudin-1 regardless of salt conditions [0.9% (standard), 1.2%, or 1.5% NaCl]. Under high salt conditions (1.5% NaCl), transepithelial electrical resistance (TEER) was elevated, while the addition of IL-10 further downregulated occludin and claudin-1 expressions by ~50% and lowered TEER. These findings suggest that, in the absence of IL-10, HSD promotes intestinal epithelial integrity and exerts an anti-inflammatory role as demonstrated by alleviated colitis in IL-10-/- mice. Moreover, Caco-2 data indicate that, in an inflammatory environment and under high NaCl conditions, IL-10 may play a proinflammatory role by disrupting colonic epithelial integrity and thus further promoting inflammation.
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Affiliation(s)
- Dezhi Wang
- Department of Gastroenterology, the Seventh Medical Center of PLA General Hospital, Beijing 100700, China; Department of Medicine/GI Division, School of Medicine, Johns Hopkins University, Baltimore 21205, United States
| | - Hua Jin
- Department of Pathology, the Seventh Medical Center of PLA General Hospital, Beijing 100700, China
| | - Jianqiu Sheng
- Department of Gastroenterology, the Seventh Medical Center of PLA General Hospital, Beijing 100700, China
| | - Leon Cheng
- Division of Pediatric Allergy and Immunology, Johns Hopkins University, Baltimore 21205, United States
| | - Qing Lin
- Department of Anesthesiology and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore 21205, United States
| | - Mark Lazerev
- Department of Medicine/GI Division, School of Medicine, Johns Hopkins University, Baltimore 21205, United States
| | - Peng Jin
- Department of Gastroenterology, the Seventh Medical Center of PLA General Hospital, Beijing 100700, China; Senior Department of Gastroenterology, the First Medical Center of PLA General Hospital, Beijing 100853, China.
| | - Xuhang Li
- Department of Medicine/GI Division, School of Medicine, Johns Hopkins University, Baltimore 21205, United States.
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Melcher C, Yu J, Duong VHH, Westphal K, Helmi Siasi Farimany N, Shaverskyi A, Zhao B, Strowig T, Glage S, Brand K, Chan AC, Föger N, Lee KH. B cell-mediated regulatory mechanisms control tumor-promoting intestinal inflammation. Cell Rep 2022; 40:111051. [PMID: 35830810 DOI: 10.1016/j.celrep.2022.111051] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 04/28/2022] [Accepted: 06/14/2022] [Indexed: 11/03/2022] Open
Abstract
Mechanisms underlying tumor-promoting inflammatory processes in colitis-associated colorectal cancer (CAC) remain largely elusive. Here, we provide genetic evidence for distinct B cell-mediated immunoregulatory mechanisms that protect from chronic colitis versus CAC. We demonstrate an inherent capacity of interleukin-10 (IL-10)-producing B cells to differentiate into immunoglobulin A (IgA) plasma cells (PCs) upon Toll-like receptor (TLR) activation. Our data show that B cell-derived IL-10 is essential to limit pathogenic T helper type 1 (Th1)/Th17 T cell responses during chronic colitis, while IgA PCs derived from IL-10+ B cells are being implicated in restraining tumorigenesis during CAC. Formation of a tumor-protective intestinal environment was associated with clonal expansion of specific types of colonic IgA PCs and development of an altered microbiota that attenuated CAC. We thus propose that regulatory B cell-mediated immunomodulation entails temporal release of IL-10, which is superseded by the generation of specific IgA affecting the microbial community, thereby controlling chronic inflammation and tumorigenesis in a distinctive but interrelated manner.
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Affiliation(s)
- Christian Melcher
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Jinbo Yu
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Vu Huy Hoang Duong
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Katrin Westphal
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Noushin Helmi Siasi Farimany
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Anton Shaverskyi
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Bei Zhao
- Department of Microbial Immune Regulation, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; Hannover Medical School, 30625 Hannover, Germany
| | - Till Strowig
- Department of Microbial Immune Regulation, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; Hannover Medical School, 30625 Hannover, Germany
| | - Silke Glage
- Experimental Pathology, Institute for Laboratory Animal Science, Hannover Medical School, 30625 Hannover, Germany
| | - Korbinian Brand
- Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Andrew C Chan
- Research, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
| | - Niko Föger
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Kyeong-Hee Lee
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany.
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Wong WY, Chan BD, Sham TT, Lee MML, Chan CO, Chau CT, Mok DKW, Kwan YW, Tai WCS. Lactobacillus casei Strain Shirota Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice by Increasing Taurine-Conjugated Bile Acids and Inhibiting NF-κB Signaling via Stabilization of Iκ Bα. Front Nutr 2022; 9:816836. [PMID: 35529468 PMCID: PMC9069136 DOI: 10.3389/fnut.2022.816836] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 03/28/2022] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic progressive intestinal inflammatory disease, characterized by an altered gut microbiota composition and accompanying alterations in circulatory bile acids. Increasing evidence supports the beneficial effect of probiotics intake on health. Introduction of probiotics to the intestines can modulate gut microbiota composition and in turn regulate the host immune system and modify the inflammatory response. Probiotics can also improve intestinal barrier function and exhibit a positive impact on host physiological and pathological conditions via gut microbiota-derived metabolites. Previous studies have demonstrated that Lactobacillus casei strain Shirota (LcS) treatment could inhibit clinical manifestation of colitis in dextran sulfate sodium (DSS)-induced mice, however, the underlying mechanisms remain unknown. In this study, we employed the DSS-induced acute colitis mouse model to investigate the anti-inflammatory effects of LcS and related mechanisms. Administration of LcS ameliorated the severity of DSS-induced colitis and enhanced intestinal integrity via induction of mucin-2 and occludin expression in colons. Fecal microbiota analysis showed that LcS increased the relative abundance of beneficial bacterial species in colitic mice, whereas the relative abundance of pathobionts was reduced. Additionally, LcS treatment modulated circulating bile acid profiles in colitic mice. In mice treated with LcS, we identified increased levels of primary taurine-conjugated bile acids, including taurocholic acid (TCA) and taurochenodeoxycholic acid (TCDCA). LcS treatment also increased the levels of secondary taurine-conjugated bile acids, including taurodeoxycholic acid (TDCA) and tauroursodeoxycholic acid (TUDCA). Moreover, LcS treatment exhibited a suppressive effect on the hydroxylated primary bile acids α-muricholic acid (α-MCA) and β-muricholic acid (β-MCA). We further demonstrated that LcS treatment suppressed the expression of pro-inflammatory mediators interferon-gamma (IFN-γ) and nitric oxide (NO), and increased the expression of the anti-inflammatory mediator interleukin-10 (IL-10) in colon tissues, potentially as a result of altered bile acid profiles. Mechanistically, we showed that LcS treatment suppressed the activation of nuclear factor-kappa B (NF-κB) signaling via stabilization of inhibitor of NF-κB alpha (IκBα). Altogether, we have demonstrated the therapeutic effects of LcS in DSS-induced colitis, providing new insights into its effect on bile acid metabolism and the related anti-inflammatory mechanisms. Our findings provide support for the application of LcS in the treatment of IBD.
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Affiliation(s)
- Wing-Yan Wong
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
- The Laboratory for Probiotic and Prebiotic Research in Human Health, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
| | - Brandon Dow Chan
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
- The Laboratory for Probiotic and Prebiotic Research in Human Health, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
| | - Tung-Ting Sham
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
| | - Magnolia Muk-Lan Lee
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
- The Laboratory for Probiotic and Prebiotic Research in Human Health, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
| | - Chi-On Chan
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen Research Institute, The Hong Kong Polytechnic University, Shenzhen, China
| | - Chung-Ting Chau
- School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, China
| | - Daniel Kam-Wah Mok
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen Research Institute, The Hong Kong Polytechnic University, Shenzhen, China
- Research Institute for Future Food, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
| | - Yiu-Wa Kwan
- School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, China
| | - William Chi-Shing Tai
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
- The Laboratory for Probiotic and Prebiotic Research in Human Health, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen Research Institute, The Hong Kong Polytechnic University, Shenzhen, China
- Research Institute for Future Food, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China
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39
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Zhou H, Beltrán JF, Brito IL. Host-microbiome protein-protein interactions capture disease-relevant pathways. Genome Biol 2022; 23:72. [PMID: 35246229 PMCID: PMC8895870 DOI: 10.1186/s13059-022-02643-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 02/22/2022] [Indexed: 01/02/2023] Open
Abstract
Background Host-microbe interactions are crucial for normal physiological and immune system development and are implicated in a variety of diseases, including inflammatory bowel disease (IBD), colorectal cancer (CRC), obesity, and type 2 diabetes (T2D). Despite large-scale case-control studies aimed at identifying microbial taxa or genes involved in pathogeneses, the mechanisms linking them to disease have thus far remained elusive. Results To identify potential pathways through which human-associated bacteria impact host health, we leverage publicly-available interspecies protein-protein interaction (PPI) data to find clusters of microbiome-derived proteins with high sequence identity to known human-protein interactors. We observe differential targeting of putative human-interacting bacterial genes in nine independent metagenomic studies, finding evidence that the microbiome broadly targets human proteins involved in immune, oncogenic, apoptotic, and endocrine signaling pathways in relation to IBD, CRC, obesity, and T2D diagnoses. Conclusions This host-centric analysis provides a mechanistic hypothesis-generating platform and extensively adds human functional annotation to commensal bacterial proteins. Supplementary Information The online version contains supplementary material available at 10.1186/s13059-022-02643-9.
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Affiliation(s)
- Hao Zhou
- Department of Microbiology, Cornell University, Ithaca, NY, USA
| | - Juan Felipe Beltrán
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
| | - Ilana Lauren Brito
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA.
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40
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Zhang Z, Yu PF, Gu GL, Zhang YH, Wang YM, Dong ZW, Yang HR. Diffuse invasive signet ring cell carcinoma in total colorectum caused by ulcerative colitis: A case report and review of literature. World J Clin Cases 2022; 10:1729-1737. [PMID: 35211616 PMCID: PMC8855258 DOI: 10.12998/wjcc.v10.i5.1729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 12/05/2021] [Accepted: 12/28/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diffuse invasive signet ring cell carcinoma of the colorectum is extremely rare clinically. This type of colorectal cancer has certain clinical, pathological and biological characteristics that are different from ordinary colorectal cancer. CASE SUMMARY A 31-year-old young woman was admitted to the hospital for nearly 1 wk due to recurrent symptoms of mucopurulent bloody stools and abdominal distension. Preoperative colonoscopy showed a ring-shaped intestinal wall mass 10 cm from the rectum to the anus. Three pieces of tumor tissue were removed for examination. The pathological results showed rectal mucinous adenocarcinoma. The patient underwent laparoscopic exploration under general anesthesia, and then laparoscopic total colorectal resection, ileal pouch-anal anastomosis and ileostomy were performed. The patient was switched to a FOLFOX + cetuximab regimen. After the fifth cycle, the patient was unable to tolerate further treatment due to tumor progression and multiple organ dysfunction, and died at the end of May 2020. Overall survival was 7 mo. CONCLUSION Carcinogenesis of ulcerative colitis is different from sporadic colon cancer, and the overall prognosis is extremely poor.
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Affiliation(s)
- Zhi Zhang
- Department of General Surgery, Air Force Medical Center, Chinese People's Liberation Army, Beijing 100142, China
| | - Peng-Fei Yu
- Department of General Surgery, Air Force Medical Center, Chinese People's Liberation Army, Beijing 100142, China
| | - Guo-Li Gu
- Department of General Surgery, Air Force Medical Center, Chinese People's Liberation Army, Beijing 100142, China
| | - Yu-Hui Zhang
- Department of General Surgery, Air Force Medical Center, Chinese People's Liberation Army, Beijing 100142, China
- Graduate School, Hebei North University, Zhangjiakou 075000, Hebei Province, China
| | - Yu-Ming Wang
- Health Team, 93656 Troop of Chinese People's Liberation Army, Beijing 101113, China
| | - Zhi-Wei Dong
- Department of General Surgery, Air Force Medical Center, Chinese People's Liberation Army, Beijing 100142, China
| | - Hai-Rui Yang
- Department of General Surgery, Air Force Medical Center, Chinese People's Liberation Army, Beijing 100142, China
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41
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Luu LDW, Popple G, Tsang SPW, Vinasco K, Hilmi I, Ng RT, Chew KS, Wong SY, Riordan S, Lee WS, Mitchell HM, Kaakoush NO, Castaño-Rodríguez N. Genetic variants involved in innate immunity modulate the risk of inflammatory bowel diseases in an understudied Malaysian population. J Gastroenterol Hepatol 2022; 37:342-351. [PMID: 34888949 DOI: 10.1111/jgh.15752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 11/18/2021] [Accepted: 12/01/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Inflammatory bowel diseases (IBD) are chronic gastrointestinal inflammatory conditions comprising two major subtypes: Crohn's disease (CD) and ulcerative colitis (UC). The incidence of IBD is increasing in Asian countries including Malaysia. The aim of this study was to determine whether 32 single nucleotide polymorphisms (SNPs) strongly associated with IBD from genome-wide association studies, performed mainly in Caucasian populations, are associated with IBD in a Malaysian population, correlating these findings with local and systemic inflammation. METHODS Selected SNPs were investigated in a Malaysian cohort comprising 36 IBD patients and 75 controls using customized matrix-assisted laser desorption ionization time-of-flight genotyping. Local mRNA and/or systemic protein levels of IL-10, IL-12, IL-22, IL-23, and TNF-α were measured in these same subjects. RESULTS ATG16L2 rs11235667 and LINC00824 rs6651252 was significantly associated with increased CD risk while IL12B rs56167332 was a significant protective factor. Three SNPs (SBNO2 rs2024092, CARD9 rs10781499, and rs17085007 between GPR12-USP12) were significantly associated with increased UC risk while NKX2-3 rs4409764 was a significant protective factor. After adjusting for age, gender, and ethnicity, SBNO2 rs2024092, ATG16L2 rs11235667, CARD9 rs10781499, and LINC00824 rs6651252 remained associated with IBD. Interestingly, the risk alleles of IL10 rs3024505, CARD9 rs1078149, and IL12 rs6556412 were associated with higher levels of IL-10, IL-22, and IL-23 in these same subjects, respectively. CONCLUSIONS This study identified eight SNPs associated with IBD and/or its subtypes in the Malaysia population, significantly advancing our understanding of the genetic contribution to IBD in this understudied population. Three of these SNPs modulated relevant cytokine levels and thus, may directly contribute to IBD pathogenesis.
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Affiliation(s)
- Laurence Don Wai Luu
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia
| | - Georgia Popple
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia
| | - Samuel Pok Wei Tsang
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia
| | - Karla Vinasco
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia
| | - Ida Hilmi
- Department of Medicine, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Ruey Terng Ng
- Department of Paediatrics, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Kee Seang Chew
- Department of Paediatrics, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Shin Yee Wong
- Department of Paediatrics, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Stephen Riordan
- Gastrointestinal and Liver Unit, Prince of Wales Hospital, University of New South Wales, Sydney, New South Wales, Australia
| | - Way Seah Lee
- Department of Paediatrics, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Hazel M Mitchell
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia
| | - Nadeem O Kaakoush
- School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Natalia Castaño-Rodríguez
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia
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42
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Juzenas S, Hübenthal M, Lindqvist CM, Kruse R, Steiert TA, Degenhardt F, Schulte D, Nikolaus S, Zeissig S, Bergemalm D, Almer S, Hjortswang H, Bresso F, SIC IBD Working Group, Strüning N, Kupcinskas J, Keller A, Lieb W, Rosenstiel P, Schreiber S, D’Amato M, Halfvarson J, Hemmrich-Stanisak G, Franke A. Detailed Transcriptional Landscape of Peripheral Blood Points to Increased Neutrophil Activation in Treatment-Naïve Inflammatory Bowel Disease. J Crohns Colitis 2022; 16:1097-1109. [PMID: 35022690 PMCID: PMC9351981 DOI: 10.1093/ecco-jcc/jjac003] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 12/13/2021] [Accepted: 01/08/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIMS Inflammatory bowel disease [IBD] is a chronic relapsing disorder of the gastrointestinal tract, which generally manifests as Crohn's disease [CD] or ulcerative colitis [UC]. These subtypes are heterogeneous in terms of disease location and histological features, while sharing common clinical presentation, genetic associations and, thus, common immune regulatory pathways. METHODS Using miRNA and mRNA coupled transcriptome profiling and systems biology approaches, we report a comprehensive analysis of blood transcriptomes from treatment-naïve [n = 110] and treatment-exposed [n = 177] IBD patients as well as symptomatic [n = 65] and healthy controls [n = 95]. RESULTS Broadly, the peripheral blood transcriptomes of CD and UC patients were similar. However, there was an extensive gene deregulation in the blood of IBD patients, while only a slight deregulation in symptomatic controls, when compared with healthy controls. The deregulated mRNAs and miRNAs are mainly involved in the innate immunity and are especially enriched in neutrophil activation-related pathways. Oxidative phosphorylation and neutrophil activation-related modules were found to be differentially co-expressed among treatment-naïve IBD as compared to healthy controls. In the deregulated neutrophil activation-related co-expression module, IL1B was identified as the central gene. Levels of co-expression among IL1B and chemosensing receptor [CXCR1/2 and FPR1/2] genes were reduced in the blood of IBD patients when compared with healthy controls. CONCLUSIONS Immune dysregulation seen in peripheral blood transcriptomes of treatment-naïve IBD patients is mainly driven by neutrophil activation.
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Affiliation(s)
- Simonas Juzenas
- Corresponding author: Simonas Juzenas, PhD, Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University of Kiel (CAU), Rosalind-Franklin-Str. 12, D-24105 Kiel, Germany.
| | - Matthias Hübenthal
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany,Department of Dermatology, Quincke Research Center, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Carl Mårten Lindqvist
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany,School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Robert Kruse
- Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden,iRiSC – Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Tim Alexander Steiert
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Frauke Degenhardt
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Dominik Schulte
- Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine I, University Hospital of Schleswig-Holstein, Kiel, Germany,Institute of Diabetes and Clinical Metabolic Research, Kiel University, Kiel, Germany
| | - Susanna Nikolaus
- Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Sebastian Zeissig
- Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany,Center for Regenerative Therapies Dresden (CRTD), Technische Universität (TU) Dresden, Dresden, Germany
| | - Daniel Bergemalm
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Sven Almer
- Department of Medicine, Karolinska Institutet, Solna, and Division of Gastroenterology, Karolinska University Hospital, Stockholm, Sweden
| | - Henrik Hjortswang
- Department of Gastroenterology and Hepatology, Linköping University, Linköping, and Department of Health, Medicine, and Caring Sciences, Linköping University, Linköping, Sweden
| | - Francesca Bresso
- Department of Medicine, Karolinska Institutet, Solna, and Division of Gastroenterology, Karolinska University Hospital, Stockholm, Sweden
| | | | - Nina Strüning
- Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Juozas Kupcinskas
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Andreas Keller
- Chair for Clinical Bioinformatics, Saarland University, Saarbrücken, Germany,Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Wolfgang Lieb
- Institute of Epidemiology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Stefan Schreiber
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany,Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Mauro D’Amato
- Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden,Gastrointestinal Genetics Lab, CIC bioGUNE – BRTA, Derio, Spain,Ikerbasque, Basque Foundation for Science, Bilbao, Spain
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Cancer cell-expressed BTNL2 facilitates tumour immune escape via engagement with IL-17A-producing γδ T cells. Nat Commun 2022; 13:231. [PMID: 35017553 PMCID: PMC8752682 DOI: 10.1038/s41467-021-27936-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 12/21/2021] [Indexed: 12/21/2022] Open
Abstract
Therapeutic blockade of the immune checkpoint proteins programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA4) has transformed cancer treatment. However, the overall response rate to these treatments is low, suggesting that immune checkpoint activation is not the only mechanism leading to dysfunctional anti-tumour immunity. Here we show that butyrophilin-like protein 2 (BTNL2) is a potent suppressor of the anti-tumour immune response. Antibody-mediated blockade of BTNL2 attenuates tumour progression in multiple in vivo murine tumour models, resulting in prolonged survival of tumour-bearing mice. Mechanistically, BTNL2 interacts with local γδ T cell populations to promote IL-17A production in the tumour microenvironment. Inhibition of BTNL2 reduces the number of tumour-infiltrating IL-17A-producing γδ T cells and myeloid-derived suppressor cells, while facilitating cytotoxic CD8+ T cell accumulation. Furthermore, we find high BTNL2 expression in several human tumour samples from highly prevalent cancer types, which negatively correlates with overall patient survival. Thus, our results suggest that BTNL2 is a negative regulator of anti-tumour immunity and a potential target for cancer immunotherapy. Cancer cells producing ligands for the immune checkpoint molecules PD-1 and CTLA-4 is an important mechanism of tumour immune resistance. Here authors show that BTNL2 expression on cancer cells generates a dysfunctional tumour immune microenvironment via promoting IL-17A-producing γδ T cells.
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Yang W, Liu H, Xu L, Yu T, Zhao X, Yao S, Zhao Q, Barnes S, Cohn SM, Dann SM, Zhang H, Zuo X, Li Y, Cong Y. GPR120 Inhibits Colitis Through Regulation of CD4 + T Cell Interleukin 10 Production. Gastroenterology 2022; 162:150-165. [PMID: 34536451 PMCID: PMC8678294 DOI: 10.1053/j.gastro.2021.09.018] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 09/01/2021] [Accepted: 09/02/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND & AIMS G protein-coupled receptor (GPR) 120 has been implicated in regulating metabolic syndromes with anti-inflammatory function. However, the role of GPR120 in intestinal inflammation is unknown. Here, we investigated whether and how GPR120 regulates CD4+ T cell function to inhibit colitis development. METHODS Dextran sodium sulfate (DSS)-induced colitis model, Citrobacter rodentium infection model, and CD4+ T cell adoptive transfer model were used to analyze the role of GPR120 in regulating colitis development. The effect of GPR120 on CD4+ T cell functions was analyzed by RNA sequencing, flow cytometry, and Seahorse metabolic assays. Mice were administered GPR120 agonist for investigating the potential of GPR120 agonist in preventing and treating colitis. RESULTS Deficiency of GPR120 in CD4+ T cells resulted in more severe colitis in mice upon dextran sodium sulfate insult and enteric infection. Transfer of GPR120-deficient CD4+CD45Rbhi T cells induced more severe colitis in Rag-/- mice with lower intestinal interleukin (IL) 10+CD4+ T cells. Treatment with the GPR120 agonist CpdA promoted CD4+ T cell production of IL10 by up-regulating Blimp1 and enhancing glycolysis, which was regulated by mTOR. GPR120 agonist-treated wild-type, but not IL10-deficient and Blimp1-deficient, T helper 1 cells induced less severe colitis. Furthermore, oral administration of GPR120 agonist protected mice from intestinal inflammation in both prevention and treatment schemes. Gpr120 expression was positively correlated with Il10 expression in the human colonic mucosa, including patients with inflammatory bowel diseases. CONCLUSIONS Our findings show the role of GPR120 in regulating intestinal CD4+ T cell production of IL10 to inhibit colitis development, which identifies GPR120 as a potential therapeutic target for treating inflammatory bowel diseases.
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Affiliation(s)
- Wenjing Yang
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas
| | - Han Liu
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas; Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
| | - Leiqi Xu
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas; Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
| | - Tianming Yu
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas
| | - Xiaojing Zhao
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas; Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Suxia Yao
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas
| | | | - Sean Barnes
- Department of Gastroenterology and Hepatology, University of Texas Medical Branch at Galveston, Galveston, Texas
| | - Steven M Cohn
- Department of Gastroenterology and Hepatology, University of Texas Medical Branch at Galveston, Galveston, Texas
| | - Sara M Dann
- Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas
| | - Hongjie Zhang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiuli Zuo
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
| | - Yanqing Li
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
| | - Yingzi Cong
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas; Department of Pathology, The University of Texas Medical Branch, Galveston, Texas.
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Li QQ, Zhang HH, Dai SX. New Insights and Advances in Pathogenesis and Treatment of Very Early Onset Inflammatory Bowel Disease. Front Pediatr 2022; 10:714054. [PMID: 35299671 PMCID: PMC8921506 DOI: 10.3389/fped.2022.714054] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 01/25/2022] [Indexed: 12/26/2022] Open
Abstract
Very early onset inflammatory bowel disease (VEO-IBD) is characterized by multifactorial chronic recurrent intestinal inflammation. Compared with elderly patients, those with VEO-IBD have a more serious condition, not responsive to conventional treatments, with a poor prognosis. Recent studies found that genetic and immunologic abnormalities are closely related to VEO-IBD. Intestinal immune homeostasis monogenic defects (IIHMDs) are changed through various mechanisms. Recent studies have also revealed that abnormalities in genes and immune molecular mechanisms are closely related to VEO-IBD. IIHMDs change through various mechanisms. Epigenetic factors can mediate the interaction between the environment and genome, and genetic factors and immune molecules may be involved in the pathogenesis of the environment and gut microbiota. These discoveries will provide new directions and ideas for the treatment of VEO-IBD.
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Affiliation(s)
- Qi-Qi Li
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Hui-Hong Zhang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Shi-Xue Dai
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Department of Gastroenterology, Guangdong Provincial Geriatrics Institute, National Key Clinical Specialty, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, South China University of Technology, Guangzhou, China
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46
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An Update of Research Animal Models of Inflammatory Bowel Disease. ScientificWorldJournal 2021; 2021:7479540. [PMID: 34938152 PMCID: PMC8687830 DOI: 10.1155/2021/7479540] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 11/28/2021] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a group of chronic disorders that includes two main disease forms, Crohn's disease, and ulcerative colitis. The understanding of the intestinal inflammation occurring in IBD has been immeasurably advanced by the development of the now numerous murine models of intestinal inflammation. The usefulness of this research tool in IBD arises from a convergence of underlying genetic susceptibility, immune system dysfunction, environmental factors, and shifts in gut microbiota. Due to the multifactorial feature of these diseases, different animal models have been used to investigate the underlying mechanisms and develop potential therapeutic strategies. The results of preclinical efficacy studies often inform the progression of therapeutic strategies. This review describes the distinct feature and limitations of each murine IBD model and discusses the previous and current lessons from the IBD models.
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47
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Zhang B, Kuipers F, de Boer JF, Kuivenhoven JA. Modulation of Bile Acid Metabolism to Improve Plasma Lipid and Lipoprotein Profiles. J Clin Med 2021; 11:jcm11010004. [PMID: 35011746 PMCID: PMC8745251 DOI: 10.3390/jcm11010004] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/15/2021] [Accepted: 12/16/2021] [Indexed: 02/06/2023] Open
Abstract
New drugs targeting bile acid metabolism are currently being evaluated in clinical studies for their potential to treat cholestatic liver diseases, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Changes in bile acid metabolism, however, translate into an alteration of plasma cholesterol and triglyceride concentrations, which may also affect cardiovascular outcomes in such patients. This review attempts to gain insight into this matter and improve our understanding of the interactions between bile acid and lipid metabolism. Bile acid sequestrants (BAS), which bind bile acids in the intestine and promote their faecal excretion, have long been used in the clinic to reduce LDL cholesterol and, thereby, atherosclerotic cardiovascular disease (ASCVD) risk. However, BAS modestly but consistently increase plasma triglycerides, which is considered a causal risk factor for ASCVD. Like BAS, inhibitors of the apical sodium-dependent bile acid transporter (ASBTi’s) reduce intestinal bile acid absorption. ASBTi’s show effects that are quite similar to those obtained with BAS, which is anticipated when considering that accelerated faecal loss of bile acids is compensated by an increased hepatic synthesis of bile acids from cholesterol. Oppositely, treatment with farnesoid X receptor agonists, resulting in inhibition of bile acid synthesis, appears to be associated with increased LDL cholesterol. In conclusion, the increasing efforts to employ drugs that intervene in bile acid metabolism and signalling pathways for the treatment of metabolic diseases such as NAFLD warrants reinforcing interactions between the bile acid and lipid and lipoprotein research fields. This review may be considered as the first step in this process.
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Affiliation(s)
- Boyan Zhang
- Department of Pediatrics, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; (B.Z.); (F.K.)
| | - Folkert Kuipers
- Department of Pediatrics, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; (B.Z.); (F.K.)
- Department of Laboratory Medicine, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands
| | - Jan Freark de Boer
- Department of Pediatrics, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; (B.Z.); (F.K.)
- Department of Laboratory Medicine, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands
- Correspondence: (J.F.d.B.); (J.A.K.)
| | - Jan Albert Kuivenhoven
- Department of Pediatrics, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; (B.Z.); (F.K.)
- Correspondence: (J.F.d.B.); (J.A.K.)
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Moriichi K, Fujiya M, Okumura T. The endoscopic diagnosis of mucosal healing and deep remission in inflammatory bowel disease. Dig Endosc 2021; 33:1008-1023. [PMID: 33020947 DOI: 10.1111/den.13863] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 09/24/2020] [Accepted: 09/28/2020] [Indexed: 12/13/2022]
Abstract
The therapeutic goal in inflammatory bowel disease (IBD) patients has shifted from controlling the clinical activity alone to managing other associated problems. The concept of mucosal healing (MH) and deep remission (DR) are advocated and regarded as new therapeutic goals in IBD. However, the definition of MH still remains controversial. It is unclear whether or not the histological structures or functional factors should be included in the definition of DR in addition to clinical remission and MH. The classifications of white-light imaging (e.g. Mayo endoscopic subscore, UCEIS, CD Endoscopic Index of Severity, simple Endoscopic Score-CD) have been proposed and are now widely used to assess the severity as well as the MH of inflammation in IBD. In ulcerative colitis, magnifying chromoendoscopy has been shown to be useful to assess the MH of inflammation while other types of image-enhanced endoscopy, such as narrow-band imaging, have not. Endocytoscopy and confocal laser endomicroscopy (CLE) are also applied to assess the activity in IBD. These endoscopic procedures can estimate MH with more precision through observing the details of superficial structures, such as crypt openings. In addition, CLE can partially assess the mucosal function by detecting fluorescence leakage. Molecular imaging can possibly detect the molecules associated with inflammation, intestinal regeneration and differentiation, and various functions including the intestinal barrier and mucus secretion. These novel procedures may improve the diagnosis strategy of DR through the assessment of DR-associated factors such as the histological structures and functional factors in the near future.
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Affiliation(s)
- Kentaro Moriichi
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Hokkaido, Japan
| | - Mikihiro Fujiya
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Hokkaido, Japan
| | - Toshikatsu Okumura
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Hokkaido, Japan
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Noda M, Danshiitsoodol N, Kanno K, Uchida T, Sugiyama M. The Exopolysaccharide Produced by Lactobacillus paracasei IJH-SONE68 Prevents and Ameliorates Inflammatory Responses in DSS-Induced Ulcerative Colitis. Microorganisms 2021; 9:microorganisms9112243. [PMID: 34835369 PMCID: PMC8621803 DOI: 10.3390/microorganisms9112243] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 10/20/2021] [Accepted: 10/26/2021] [Indexed: 12/17/2022] Open
Abstract
Inflammatory bowel disease (IBD) is an autoimmune disease characterized by chronic inflammation of the gastrointestinal tract. IBD includes Crohn’s disease (CD) and ulcerative colitis (UC). CD can occur in any part of the gastrointestinal tract, whereas UC mainly occurs in the colon and rectum. We previously demonstrated that a novel exopolysaccharide (EPS) produced by a plant-derived bacterium, Lactobacillus paracasei IJH-SONE68, prevents and improves the inflammation in contact dermatitis model mice via oral administration. To evaluate the preventive effect of the EPS against other inflammatory diseases, in the present study, we employed dextran sulfate sodium (DSS)-induced UC model mice. The stool consistency, hematochezia, and colonic atrophy of the mice were improved by the orally administered EPS. We also evaluated the cytokine transcription. Overexpression of the mouse macrophage inflammatory protein 2 mRNA in the colon as a functional homolog of human interleukin-8 was decreased by the orally administered EPS. However, the expression of interleukin-10, which is known as an anti-inflammatory cytokine, was stimulated in the EPS-administrated group. Based on these results, we conclude that the IJH-SONE68-derived EPS is a promising lead material for the development of drugs useful in treating inflammatory diseases such as UC.
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Affiliation(s)
- Masafumi Noda
- Department of Probiotic Science for Preventive Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (M.N.); (N.D.)
| | - Narandalai Danshiitsoodol
- Department of Probiotic Science for Preventive Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (M.N.); (N.D.)
| | - Keishi Kanno
- Department of General Internal Medicine, Hiroshima University Hospital, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan;
- Department of Clinical Pharmaceutical and Therapeutics, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan;
| | - Tomoyuki Uchida
- Department of Clinical Pharmaceutical and Therapeutics, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan;
- Sone Farm Co., Ltd., Shinjuku, Shinjuku-ku, Tokyo 160-0022, Japan
| | - Masanori Sugiyama
- Department of Probiotic Science for Preventive Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (M.N.); (N.D.)
- Correspondence: ; Tel.: +81-82-257-5280
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50
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Liu M, Yuan W, Park S. Association between IL-10 rs3024505 and susceptibility to inflammatory bowel disease: A systematic review and meta-analysis. Cytokine 2021; 149:155721. [PMID: 34628128 DOI: 10.1016/j.cyto.2021.155721] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/03/2021] [Accepted: 09/20/2021] [Indexed: 02/08/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease that affects the small intestine, colon, and rectum. We evaluated associations between the interleukin 10 (IL-10) rs3024505 polymorphism and IBD, ulcerative colitis (UC), and Crohn's disease (CD) by meta-analysis. All peer-reviewed manuscripts concerning the relationship between IL-10_rs3024505 and IBD identified by searing the PubMed, Cochrane Library, EMBASE, and Chinese Medical Database were examined. The association between IL-10_rs3024505 and IBD was evaluated in allele (AG), recessive (RG), dominant (DG), homozygous (HMG), and heterozygous (HTG) genetic models. Associations were also conducted on IBD subtypes, CD and UC, and ethnicity (Non-Europeans and Europeans) subgroups. The meta-analysis included 13 studies, 8552 cases (IBD patients), and 12,830 healthy controls. Subgroup analysis of IBD (UC and CD) revealed heterogeneity in AG, DG, and HTG but no heterogeneity in RG or HMG. Moreover, AG, DG, and HTG did not show publication bias in IBD, CD, or UC, but RG and HMG exhibited publication bias. No heterogeneity and no publication bias were found among the five genetic models by a subgroup analysis of Non-Europeans and European ethnicities. The minor allele(T) of rs3024505 was significantly related to IBD: 1.37 (1.30-1.45) for AG, 2.06 (1.74-2.45) for RG, 1.39 (1.27-1.52) for DG, 2.25 (1.89-2.67) for HMG, and 1.32 (1.23-1.40) for HTG (all P < 0.00001). In the subgroup analysis of ethnicity, there was a significant effect of rs3024505 on IBD in Europeans but not non-Europeans: 1.38 (1.31-1.46) for AG, 2.07 (1.73-2.48) for RG, 1.39 (1.31-1.49) for DG, 2.26 (1.89-2.71) for HMG, and 1.33 (1.24-1.42) for HTG in Europeans (all P < 0.00001). Sensitivity analysis showed no dominant study in Europeans, but one study had a dominant impact in Non-Europeans. In conclusion, IL-10_rs3024505 polymorphism confers susceptibility to CD and UC in Europeans, but its impact should have conducted more studies in Non-Europeans.
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Affiliation(s)
- Meiling Liu
- Dept. of Food and Nutrition, Obesity/Diabetes Research Center, Hoseo University, Asan, Chungnam 31499, Republic of Korea
| | - Wang Yuan
- Dept. of Bio-Convergence System, Hoseo University, Asan, 31499, Republic of Korea
| | - Sunmin Park
- Dept. of Food and Nutrition, Obesity/Diabetes Research Center, Hoseo University, Asan, Chungnam 31499, Republic of Korea; Dept. of Bio-Convergence System, Hoseo University, Asan, 31499, Republic of Korea.
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