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Li Z, Chu T, Sun X, Zhuang S, Hou D, Zhang Z, Sun J, Liu Y, Li J, Bian Y. Polyphenols-rich Portulaca oleracea L. (purslane) alleviates ulcerative colitis through restiring the intestinal barrier, gut microbiota and metabolites. Food Chem 2025; 468:142391. [PMID: 39675274 DOI: 10.1016/j.foodchem.2024.142391] [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: 08/09/2024] [Revised: 11/03/2024] [Accepted: 12/04/2024] [Indexed: 12/17/2024]
Abstract
Ulcerative colitis (UC) is a recurrent intestinal disease caused by a complex of factors, and there are serious adverse effects and tolerance problems associated with the current long-term use of therapeutic drugs. The development of natural food sources and multi-targeted drugs for the treatment of UC is imminent. Portulaca oleracea L. (PO), as a vegetable, has been shown in studies to have an anti-UC effects. However, the relationship between the abundant active ingredients contained in Portulaca oleracea L. and the improvement of intestinal barrier, gut microbiota and metabolites is unclear. In the present study, Portulaca oleracea L. which was found to be rich in phenolic acid-based active ingredients, were effective in alleviating dextran sulfate sodium (DSS)-induced body weight loss, disease activity index (DAI) score and colon length in mice. It also decreased C-reactive protein (CRP) and myeloperoxidase (MPO) responses, reduced the permeation of fluorescein isothiocyanate (FITC)-dextran, lipopolysaccharide (LPS) and evans blue (EB), and improved histopathological scores. Meanwhile, in vitro and in vivo validation revealed the protective effects of purslane on the intestinal barrier indicators ZO-1, Occludin and Claudin-1, and inhibited the expression of inflammation-associated iNOS and NLRP3 proteins through the NF-κB signaling pathway. In addition, purslane increased the diversity of the intestinal flora, enhancing the proportion of the genera Butyricoccus, Dorea and Bifidobacterium and decreasing the percentage of Bacteroides, Turicibacter and Parabacteroides. Serum metabolomics analysis showed that the imbalance of 39 metabolites was significantly reversed after PO deployment. Enrichment analysis showed that Pentose phosphate pathway and Pyruvate metabolism pathway were the key pathways of PO against UC. Overall, purslane effectively improved the intestinal barrier disruption and intestinal inflammation by inhibiting the NF-κB signaling pathway, and adjusted the disorder of gut microbiota and metabolites to exert anti-UC effects.
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Affiliation(s)
- Zheng Li
- School of Pharmaceutical Sciences, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Tianjiao Chu
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Xin Sun
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Shen Zhuang
- College of Veterinary Medicine & Institute of Traditional Chinese Veterinary Medicine, Northwest A&F University, Yangling 712100, China
| | - Dianbo Hou
- School of Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Zhaohan Zhang
- College of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Jialu Sun
- School of Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Yuhong Liu
- School of Pharmaceutical Sciences, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
| | - Jing Li
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
| | - Yifei Bian
- School of Pharmaceutical Sciences, Shandong University of Traditional Chinese Medicine, Jinan 250355, China; Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
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Zheng H, Yu J, Gao L, Wang K, Xu Z, Zeng Z, Zheng K, Tang X, Tian X, Zhao Q, Zhao J, Wan H, Cao Z, Zhang K, Cheng J, Brosius J, Zhang H, Li W, Yan W, Shao Z, Luo F, Deng C. S1PR1-biased activation drives the resolution of endothelial dysfunction-associated inflammatory diseases by maintaining endothelial integrity. Nat Commun 2025; 16:1826. [PMID: 39979282 PMCID: PMC11842847 DOI: 10.1038/s41467-025-57124-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 02/10/2025] [Indexed: 02/22/2025] Open
Abstract
G protein-coupled sphingosine-1-phosphate receptor 1 (S1PR1), a drug target for inflammatory bowel disease (IBD), enables immune cells to egress from lymph nodes, but the treatment increases the risk of immunosuppression. The functional signaling pathway triggered by S1PR1 activation in endothelial cells and its therapeutic application remains unclear. Here, we showed that S1PR1 is highly expressed in endothelial cells of IBD patients and positively correlated with endothelial markers. Gi-biased agonist-SAR247799 activated S1PR1 and reversed pathology in male mouse and organoid IBD models by protecting the integrity of the endothelial barrier without affecting immune cell egress. Cryo-electron microscopy structure of S1PR1-Gi signaling complex bound to SAR247799 with a resolution of 3.47 Å revealed the recognition mode for the biased ligand. With the efficacy of SAR247799 in treating other endothelial dysfunction-associated inflammatory diseases, our study offers mechanistic insights into the Gi-biased S1PR1 agonist and represents a strategy for endothelial dysfunction-associated disease treatment.
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Affiliation(s)
- Huaping Zheng
- Department of Respiratory and Critical Care Medicine, Center for High Altitude Medicine, Institutes for Systems Genetics, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jingjing Yu
- Department of Respiratory and Critical Care Medicine, Center for High Altitude Medicine, Institutes for Systems Genetics, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- Division of Nephrology and Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Luhua Gao
- Department of Respiratory and Critical Care Medicine, Center for High Altitude Medicine, Institutes for Systems Genetics, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Kexin Wang
- Department of Respiratory and Critical Care Medicine, Center for High Altitude Medicine, Institutes for Systems Genetics, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- Division of Nephrology and Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Zheng Xu
- Department of Respiratory and Critical Care Medicine, Center for High Altitude Medicine, Institutes for Systems Genetics, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Zhen Zeng
- Department of Gastroenterology, Lab of Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Kun Zheng
- Department of Respiratory and Critical Care Medicine, Center for High Altitude Medicine, Institutes for Systems Genetics, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoju Tang
- Department of Respiratory and Critical Care Medicine, Center for High Altitude Medicine, Institutes for Systems Genetics, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaowen Tian
- Department of Respiratory and Critical Care Medicine, Center for High Altitude Medicine, Institutes for Systems Genetics, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- Division of Nephrology and Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Qing Zhao
- Department of Respiratory and Critical Care Medicine, Center for High Altitude Medicine, Institutes for Systems Genetics, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jie Zhao
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, China
| | - Huajing Wan
- Department of Respiratory and Critical Care Medicine, Center for High Altitude Medicine, Institutes for Systems Genetics, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Zhongwei Cao
- Department of Respiratory and Critical Care Medicine, Center for High Altitude Medicine, Institutes for Systems Genetics, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Kang Zhang
- Center for Biomedicine and Innovations, Faculty of Medicine, Macau University of Science and Technology and University Hospital, Macau, China
| | - Jingqiu Cheng
- Department of Respiratory and Critical Care Medicine, Center for High Altitude Medicine, Institutes for Systems Genetics, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jürgen Brosius
- Department of Respiratory and Critical Care Medicine, Center for High Altitude Medicine, Institutes for Systems Genetics, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Hu Zhang
- Department of Gastroenterology, Lab of Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Li
- Department of Dermatology, Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Yan
- Department of Respiratory and Critical Care Medicine, Center for High Altitude Medicine, Institutes for Systems Genetics, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, China.
| | - Zhenhua Shao
- Department of Respiratory and Critical Care Medicine, Center for High Altitude Medicine, Institutes for Systems Genetics, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
- Division of Nephrology and Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, China.
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, China.
| | - Fengming Luo
- Department of Respiratory and Critical Care Medicine, Center for High Altitude Medicine, Institutes for Systems Genetics, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
| | - Cheng Deng
- Department of Respiratory and Critical Care Medicine, Center for High Altitude Medicine, Institutes for Systems Genetics, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
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Wang S, Jiang Q, Liu Y, Zhang X, Huang Y, Zhang H. The Role of Immune Cells in Moyamoya Disease. Brain Sci 2025; 15:137. [PMID: 40002470 PMCID: PMC11852451 DOI: 10.3390/brainsci15020137] [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: 12/16/2024] [Revised: 01/23/2025] [Accepted: 01/29/2025] [Indexed: 02/27/2025] Open
Abstract
Moyamoya disease (MMD) is a rare progressive cerebrovascular disorder characterized by the stenosis or occlusion of the terminal segments of the internal carotid arteries, leading to the development of abnormal collateral vascular networks. These networks are a compensatory mechanism for reduced blood flow to the brain. Despite extensive research, the exact etiology of MMD remains unknown, although recent studies suggest that immune system dysfunction plays a critical role in its pathogenesis. In particular, the involvement of immune cells such as T cells, macrophages, and dendritic cells has been increasingly recognized. These immune cells contribute to the inflammatory process and vascular remodeling observed in MMD patients, further complicating the disease's progression. Inflammation and immune-mediated damage to the vessel walls may accelerate the narrowing and occlusion of arteries, exacerbating ischemic events in the brain. Additionally, studies have revealed that certain genetic and environmental factors can influence immune system activation in MMD, linking these pathways to disease development. This review aims to provide a comprehensive overview of the immune mechanisms at play in MMD, focusing on how immune cells participate in vascular injury and remodeling. Understanding these immunological processes may offer new therapeutic targets to halt or reverse disease progression, potentially leading to more effective treatment strategies for MMD.
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Affiliation(s)
- Sheng Wang
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan 430030, China; (S.W.); (Q.J.); (Y.L.); (X.Z.); (Y.H.)
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Qian Jiang
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan 430030, China; (S.W.); (Q.J.); (Y.L.); (X.Z.); (Y.H.)
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yuan Liu
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan 430030, China; (S.W.); (Q.J.); (Y.L.); (X.Z.); (Y.H.)
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xincheng Zhang
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan 430030, China; (S.W.); (Q.J.); (Y.L.); (X.Z.); (Y.H.)
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yimin Huang
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan 430030, China; (S.W.); (Q.J.); (Y.L.); (X.Z.); (Y.H.)
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Huaqiu Zhang
- Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan 430030, China; (S.W.); (Q.J.); (Y.L.); (X.Z.); (Y.H.)
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China
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Xu X, Ying H, Wang X, Hong W, Zhang M. Identification of Angiogenesis-Related Gene Signatures and Prediction of Potential Therapeutic Targets in Ulcerative Colitis Using Integrated Bioinformatics. J Inflamm Res 2024; 17:11699-11717. [PMID: 39741751 PMCID: PMC11687120 DOI: 10.2147/jir.s478880] [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: 07/20/2024] [Accepted: 12/10/2024] [Indexed: 01/03/2025] Open
Abstract
Objective This study aims to clarify angiogenesis mechanisms in ulcerative colitis and identify potential therapeutic targets. Methods The Gene Expression Omnibus (GEO) database was used to obtain expression profiles and clinical data for UC and healthy colon tissues. Angiogenesis-related gene sets were acquired from GeneCards. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) identified UC-associated hub genes. The CIBERSORT algorithm assessed immune cell infiltration. Analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to determine biological mechanisms. External datasets were utilized to validate and characterize the angiogenesis-related genes in relation to biological agents. Additionally, an ulcerative colitis mouse model was constructed to verify the key genes' expression using real-time quantitative PCR. To predict potential therapeutic agents, we used the DGIdb database. Molecular docking modeled small molecule binding conformations to key gene targets. Results This study identified 1,247 DEGs enriched in inflammatory/immune pathways from UC and healthy colon samples. WGCNA indicated the black and light cyan modules were most relevant. Intersecting these with 89 angiogenesis genes revealed 5 UC-associated hub genes (pdgfrb, vegfc, angpt2, tnc, hgf). Validation via ROC analysis, differential expression, and a mouse model confirmed upregulation, supporting their potential as UC diagnostic biomarkers. Bioinformatics approaches like protein-protein interaction, enrichment analysis, and GSEA revealed involvement in PDGFR and PI3K-Akt signaling pathways. CIBERSORT analysis of immune cell infiltration showed positive correlations between the key genes and various immune cells, especially neutrophils, highlighting angiogenesis-inflammation interplay in UC. A ceRNA network was constructed. Drug prediction and molecular docking revealed potential UC therapies like sunitinib and imatinib targeting angiogenesis. Conclusion This study identified and validated five angiogenesis-related genes (pdgfrb, vegfc, angpt2, tnc, hgf) that may serve as diagnostic biomarkers and drug targets for UC.
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Affiliation(s)
- Xijuan Xu
- Department of Anus & Intestine Surgery, Taizhou First People’s Hospital, Taizhou, Zhejiang, People’s Republic of China
| | - Hongan Ying
- Department of Geriatrics, Taizhou First People’s Hospital, Taizhou, People’s Republic of China
| | - Xiaozhi Wang
- Department of Anus & Intestine Surgery, Taizhou First People’s Hospital, Taizhou, Zhejiang, People’s Republic of China
| | - Weiwen Hong
- Department of Anus & Intestine Surgery, Taizhou First People’s Hospital, Taizhou, Zhejiang, People’s Republic of China
| | - Meng Zhang
- Department of General Surgery, Taizhou First People’s Hospital, Taizhou, Zhejiang, People’s Republic of China
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Zhao Y, Zhou R, Mu Z, Carbonetto P, Zhong X, Xie B, Luo K, Cham CM, Koval J, He X, Dahl AW, Liu X, Chang EB, Basu A, Pott S. Cell-type-resolved chromatin accessibility in the human intestine identifies complex regulatory programs and clarifies genetic associations in Crohn's disease. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.12.10.24318718. [PMID: 39711713 PMCID: PMC11661348 DOI: 10.1101/2024.12.10.24318718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
Crohn's disease (CD) is a complex inflammatory bowel disease resulting from an interplay of genetic, microbial, and environmental factors. Cell-type-specific contributions to CD etiology and genetic risk are incompletely understood. Here we built a comprehensive atlas of cell-type- resolved chromatin accessibility comprising 557,310 candidate cis-regulatory elements (cCREs) in terminal ileum and ascending colon from patients with active and inactive CD and healthy controls. Using this atlas, we identified cell-type-, anatomic location-, and context-specific cCREs and characterized the regulatory programs underlying inflammatory responses in the intestinal mucosa of CD patients. Genetic variants that disrupt binding motifs of cell-type-specific transcription factors significantly affected chromatin accessibility in specific mucosal cell types. We found that CD heritability is primarily enriched in immune cell types. However, using fine- mapped non-coding CD variants we identified 29 variants located within cCREs several of which were accessible in epithelial and stromal cells implicating cell types from additional lineages in mediating CD risk in some loci. Our atlas provides a comprehensive resource to study gene regulatory effects in CD and health, and highlights the cellular complexity underlying CD risk.
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Fang Z, Qu S, Ji X, Zheng C, Mo J, Xu J, Zhang J, Shen H. Correlation between PDGF-BB and M1-type macrophage in inflammatory bowel disease: a case-control study. BMC Gastroenterol 2024; 24:417. [PMID: 39567902 PMCID: PMC11580552 DOI: 10.1186/s12876-024-03518-y] [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: 08/16/2024] [Accepted: 11/14/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a chronic disease in which macrophages play an important role in its pathogenesis. Platelet-derived growth factor-BB (PDGF-BB) secreted by macrophages is involved in the repair of vascular endothelial injury during inflammatory reactions. METHODS The expression levels of M1 macrophages and PDGF-BB in serum and colonic mucosa of 30 patients with Crohn's disease (CD) and 30 patients with ulcerative colitis (UC) were measured using enzyme-linked immunosorbent assays and immunohistochemistry. Logistic regression was used for univariate and multivariate analyses, and receiver operating characteristic curves were used to evaluate diagnostic value. Associations were evaluated using Spearman correlation analysis. RESULTS The expression of serum PDGF-BB and M1 macrophages with positive CXCL9 expression in patients with active-stage IBD [206.55(160.41,262.90)and 337.30(217.73,472.28) pg/ml] was higher than that in patients with remission stage [153.42(107.02,219.68)and 218.37(144.49,347.33)pg/ml] and controls [156.19(91.16,216.08)and 191.20(121.42,311.76)pg/ml](P < 0.05). The expression of PDGF-BB, CD86, and CXCL9 in the colon of patients with active-stage IBD [0.380(0.266,0.542) 0.663(0.480,0.591) and 0.564(0.378,0.765) /µm2] was higher than that in the remission stage [0.308(0.214,0.420), 0.376(0.206,0.591) and 0.413(0.275,0.570) /µm2] and controls [0.265(0.185,0.384), 0.416(0.269,0.534) and 0.497(0.415,0.642) /µm2] (P < 0.05). A positive correlation was observed between CD86 and PDGF-BB, and CXCL9 and PDGF-BB levels in patients with IBD (P < 0.05). CD86 and PDGF-BB in the colonic mucosa were independent risk factors for active IBD, and the area under the curve for their combined diagnosis was 0.754 (95%CI: 0.654-0.852, P < 0.05). CONCLUSIONS PDGF-BB was associated with M1 macrophages and has a potential diagnostic value for active IBD. TRIAL REGISTRATION Not applicable.
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Grants
- 2021KY1116 the Zhejiang Provincial Medicine and Health Technology Project
- 2021KY1116 the Zhejiang Provincial Medicine and Health Technology Project
- 2021KY1116 the Zhejiang Provincial Medicine and Health Technology Project
- 2021KY1116 the Zhejiang Provincial Medicine and Health Technology Project
- 2021KY1116 the Zhejiang Provincial Medicine and Health Technology Project
- 2021KY1116 the Zhejiang Provincial Medicine and Health Technology Project
- 2021KY1116 the Zhejiang Provincial Medicine and Health Technology Project
- 2021KY1116 the Zhejiang Provincial Medicine and Health Technology Project
- 2022AD30007 the Science and Technology Bureau of Jiaxing city, Zhejiang, China
- 2022AD30007 the Science and Technology Bureau of Jiaxing city, Zhejiang, China
- 2022AD30007 the Science and Technology Bureau of Jiaxing city, Zhejiang, China
- 2022AD30007 the Science and Technology Bureau of Jiaxing city, Zhejiang, China
- 2022AD30007 the Science and Technology Bureau of Jiaxing city, Zhejiang, China
- 2022AD30007 the Science and Technology Bureau of Jiaxing city, Zhejiang, China
- 2022AD30007 the Science and Technology Bureau of Jiaxing city, Zhejiang, China
- 2022AD30007 the Science and Technology Bureau of Jiaxing city, Zhejiang, China
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Affiliation(s)
- Zhiyun Fang
- The Second Hospital of Jiaxing, Jiaxing, 314000, China
| | - Siwen Qu
- The Second Hospital of Jiaxing, Jiaxing, 314000, China
| | - Xia Ji
- The Second Hospital of Jiaxing, Jiaxing, 314000, China
| | - Chuwei Zheng
- The Second Hospital of Jiaxing, Jiaxing, 314000, China
| | - Juanfen Mo
- The Second Hospital of Jiaxing, Jiaxing, 314000, China
| | - Jianqiu Xu
- The Second Hospital of Jiaxing, Jiaxing, 314000, China
| | - Jinming Zhang
- The Second Hospital of Jiaxing, Jiaxing, 314000, China.
| | - Haiyan Shen
- The Second Hospital of Jiaxing, Jiaxing, 314000, China.
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Qapaja T, Abu-Rumaileh M, Alsabbagh Alchirazi K, Gharaibeh A, Naser A, Hamid O, Alayan D, Regueiro M. Biologics and Oral Small Molecules Are Not Associated With Increased Major Adverse Cardiovascular Events or Venous Thromboembolism in Inflammatory Bowel Disease. Inflamm Bowel Dis 2024:izae267. [PMID: 39536156 DOI: 10.1093/ibd/izae267] [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: 06/02/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Biologics and oral small molecules (OSM) effectively treat inflammatory bowel disease (IBD), but some are linked to higher risks of major adverse cardiovascular events (MACE) and venous thromboembolism (VTE). This study evaluates the MACE and VTE risks in IBD patients treated with biologics or OSM. METHODS Using the TrinNetX multi-institutional database, we examined MACE and VTE in adult IBD patients on biologics and compared them to IBD patients not on biologics. We also compared IBD patients on OSM to those not on OSM. We performed 1:1 propensity score matching. MACE (myocardial infarction [MI], stroke, and all-cause mortality) and VTE were assessed from 30 days to 3 years after drug prescription. RESULTS After matching, IBD patients on biologics had reduced risk of MI, stroke, and all-cause mortality at 1 year, compared to those not on biologics (P < .05). No significant difference in VTE was observed (P = .5). At 3 years, biologic-treated patients had lower risks of MI, stroke, all-cause mortality, and VTE (P < .05). Inflammatory bowel disease patients on OSM showed no significant differences in MI, stroke, or VTE at 1 and 3 years, but had lower all-cause mortality (P < .05). In older IBD patients with at least 1 cardiovascular risk factor, OSM usage showed no significant difference in MI, stroke, or VTE risk compared to nonusers; however, all-cause mortality was decreased at 3 years (P < .05). CONCLUSIONS Inflammatory bowel disease patients treated with biologics or OSM were not at increased risk of MACE or VTE. Although further studies and longer follow-up periods are needed to confirm these findings, our results provide reassurance regarding the safety of these medications in IBD.
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Affiliation(s)
- Thabet Qapaja
- Division of Hospital Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | | | | | - Ahmad Gharaibeh
- Department of Internal Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Ahmad Naser
- Department of Internal Medicine, Jacobi Medical Center, New York, NY, USA
| | - Osama Hamid
- Department of Gastroenterology, University of Texas Southwestern, Dallas, TX, USA
| | - Dina Alayan
- Department of Pulmonary and Critical Care, MetroHealth Medical Center, Cleveland, OH, USA
| | - Miguel Regueiro
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA
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Larionov A, Hammer CM, Fiedler K, Filgueira L. Dynamics of Endothelial Cell Diversity and Plasticity in Health and Disease. Cells 2024; 13:1276. [PMID: 39120307 PMCID: PMC11312403 DOI: 10.3390/cells13151276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 07/19/2024] [Accepted: 07/19/2024] [Indexed: 08/10/2024] Open
Abstract
Endothelial cells (ECs) are vital structural units of the cardiovascular system possessing two principal distinctive properties: heterogeneity and plasticity. Endothelial heterogeneity is defined by differences in tissue-specific endothelial phenotypes and their high predisposition to modification along the length of the vascular bed. This aspect of heterogeneity is closely associated with plasticity, the ability of ECs to adapt to environmental cues through the mobilization of genetic, molecular, and structural alterations. The specific endothelial cytoarchitectonics facilitate a quick structural cell reorganization and, furthermore, easy adaptation to the extrinsic and intrinsic environmental stimuli, known as the epigenetic landscape. ECs, as universally distributed and ubiquitous cells of the human body, play a role that extends far beyond their structural function in the cardiovascular system. They play a crucial role in terms of barrier function, cell-to-cell communication, and a myriad of physiological and pathologic processes. These include development, ontogenesis, disease initiation, and progression, as well as growth, regeneration, and repair. Despite substantial progress in the understanding of endothelial cell biology, the role of ECs in healthy conditions and pathologies remains a fascinating area of exploration. This review aims to summarize knowledge and concepts in endothelial biology. It focuses on the development and functional characteristics of endothelial cells in health and pathological conditions, with a particular emphasis on endothelial phenotypic and functional heterogeneity.
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Affiliation(s)
- Alexey Larionov
- Faculty of Science and Medicine, Anatomy, University of Fribourg, Route Albert-Gockel 1, CH-1700 Fribourg, Switzerland; (C.M.H.); (L.F.)
| | - Christian Manfred Hammer
- Faculty of Science and Medicine, Anatomy, University of Fribourg, Route Albert-Gockel 1, CH-1700 Fribourg, Switzerland; (C.M.H.); (L.F.)
| | - Klaus Fiedler
- Independent Researcher, CH-1700 Fribourg, Switzerland;
| | - Luis Filgueira
- Faculty of Science and Medicine, Anatomy, University of Fribourg, Route Albert-Gockel 1, CH-1700 Fribourg, Switzerland; (C.M.H.); (L.F.)
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Di Nardo G, Di Pippo M, Zenzeri L, Mennini M, Piccirillo M, Furio S, Quatrale G, Evangelisti M, Parisi P, Lucchini L, Ferretti A, Villa MP, Scuderi G, Amadè DS, Abdolrahimzadeh S. Ocular endothelial dysfunction in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2024; 78:1297-1304. [PMID: 38587115 DOI: 10.1002/jpn3.12208] [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: 12/27/2023] [Revised: 02/28/2024] [Accepted: 03/25/2024] [Indexed: 04/09/2024]
Abstract
OBJECTIVES To assess ocular microvasculature changes using optical coherence tomography angiography (OCTA) in pediatric patients with inflammatory bowel disease (IBD). METHODS Patients (aged 6-18 years) with IBD were recruited between September 2021 and May 2023. All eligible participants underwent comprehensive clinical assessment and laboratory investigation. Patients with functional gastrointestinal disorders served as the controls. This study assessed specific IBD phenotypes, disease duration, clinical and endoscopic activity indices, laboratory markers, and medication histories. OCTA was utilized to evaluate ocular microvasculature changes in both groups. RESULTS A total of 63 children (mean age 12.9 ± 3.3 years) were enrolled, comprising 38 in the IBD group (16 ulcerative colitis, 22 Crohn's disease, and 25 in the control group). Most patients in the IBD group were in remission or had mild-to-moderate disease activity at enrollment. Analysis of the OCTA results revealed significant differences in the choroidal luminal area and total choroidal area between the IBD and control groups. CONCLUSIONS The study identified distinct ocular microvasculature changes in pediatric IBD patients through OCTA, suggestive of potential systemic endothelial dysfunction. These findings underscore the utility of OCTA in evaluating microvascular alterations associated with pediatric IBD, offering insights into potential systemic complications linked to inflammation in IBD patients.
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Affiliation(s)
- Giovanni Di Nardo
- Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Pediatric Unit, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Mariachiara Di Pippo
- Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Ophthalmology Unit, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Letizia Zenzeri
- Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Pediatric Unit, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
- Emergency Pediatric Department, Santobono-Pausilipon Children's Hospital, Naples, Italy
| | - Maurizio Mennini
- Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Pediatric Unit, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Marisa Piccirillo
- Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Pediatric Unit, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Silvia Furio
- Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Pediatric Unit, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Giovanna Quatrale
- Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Pediatric Unit, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Melania Evangelisti
- Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Pediatric Unit, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Pasquale Parisi
- Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Pediatric Unit, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Livia Lucchini
- Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Pediatric Unit, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Alessandro Ferretti
- Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Pediatric Unit, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Maria Pia Villa
- Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Pediatric Unit, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Gianluca Scuderi
- Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Ophthalmology Unit, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - David Sarzi Amadè
- Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Stomatology Unit, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Solmaz Abdolrahimzadeh
- Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Ophthalmology Unit, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
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Zhu F, Yang T, Ning M, Liu Y, Xia W, Fu Y, Wen T, Zheng M, Xia R, Qian R, Li Y, Sun M, Liu J, Tian L, Zhou Q, Yu X, Peng C. MiR-146a alleviates inflammatory bowel disease in mice through systematic regulation of multiple genetic networks. Front Immunol 2024; 15:1366319. [PMID: 38799464 PMCID: PMC11116640 DOI: 10.3389/fimmu.2024.1366319] [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: 01/06/2024] [Accepted: 04/08/2024] [Indexed: 05/29/2024] Open
Abstract
Introduction Inflammatory bowel disease (IBD) is a chronic disease involving multiple genes, and the current available targeted drugs for IBD only deliver moderate efficacy. Whether there is a single gene that systematically regulates IBD is not yet known. MiR-146a plays a pivotal role in repression of innate immunity, but its function in the intestinal inflammation is sort of controversy, and the genetic regulatory networks regulated by miR-146a in IBD has not been revealed. Methods RT-qPCR was employed to detect the expression of miR-146a in IBD patients and in a mouse IBD model induced by dextran sulfate sodium (DSS), and then we generated a miR-146a knock-out mouse line with C57/Bl6N background. The disease activity index was scored in DSS-treated miR-146a deficiency mice and their wild type (WT) littermates. Bulk RNA-sequencing, RT-qPCR and immunostaining were done to illustrate the downstream genetic regulatory networks of miR-146a in flamed colon. Finally, the modified miR-146a mimics were used to treat DSS-induced IBD in miR-146a knock-out and WT IBD mice. Results We showed that the expression of miR-146a in the colon was elevated in dextran sulfate sodium (DSS)-induced IBD mice and patients with IBD. DSS induced dramatic body weight loss and more significant rectal bleeding, shorter colon length, and colitis in miR-146a knock-out mice than WT mice. The miR-146a mimics alleviated DSS-induced symptoms in both miR-146a-/- and WT mice. Further RNA sequencing illustrated that the deficiency of miR-146a de-repressed majority of DSS-induced IBD-related genes that cover multiple genetic regulatory networks in IBD, and supplementation with miR-146a mimics inhibited the expression of many IBD-related genes. Quantitative RT-PCR or immunostaining confirmed that Ccl3, Saa3, Csf3, Lcn2, Serpine1, Serpine2, MMP3, MMP8, MMP10, IL1A, IL1B, IL6, CXCL2, CXCL3, S100A8, S100A9, TRAF6, P65, p-P65, and IRAK1 were regulated by miR-146a in DSS induced IBD. Among them, MMP3, MMP10, IL6, IL1B, S100A8, S100A9, SERPINE1, CSF3, and IL1A were involved in the active stage of IBD in humans. Discussion Our date demonstrated that miR-146a acts as a top regulator in C57/BL6N mice to systematically repress multiple genetic regulatory networks involved in immune response of intestine to environment factors, and combinatory treatment with miR-146a-5p and miR-146a-3p mimics attenuates DSS-induced IBD in mice through down-regulating multiple genetic regulatory networks which were increased in colon tissue from IBD patients. Our findings suggests that miR-146a is a top inhibitor of IBD, and that miR-146a-5p and miR-146a-3p mimics might be potential drug for IBD.
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Affiliation(s)
- Fengting Zhu
- The First Rehabilitation Hospital of Shanghai, Clinic Center for Brain and Spinal Cord Research, School of Medicine and Advanced Institute of Translational Medicine, Tongji University, Shanghai, China
- Pre-clinical College, Dali University, Dali, Yunnan, China
| | - Taotan Yang
- The First Rehabilitation Hospital of Shanghai, Clinic Center for Brain and Spinal Cord Research, School of Medicine and Advanced Institute of Translational Medicine, Tongji University, Shanghai, China
- Xiang-Xing College, Hunan University of Traditional Chinese Medicine, Changsha, China
| | - Mengmeng Ning
- The First Rehabilitation Hospital of Shanghai, Clinic Center for Brain and Spinal Cord Research, School of Medicine and Advanced Institute of Translational Medicine, Tongji University, Shanghai, China
| | - Yang Liu
- The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wei Xia
- The First Rehabilitation Hospital of Shanghai, Clinic Center for Brain and Spinal Cord Research, School of Medicine and Advanced Institute of Translational Medicine, Tongji University, Shanghai, China
| | - Yan Fu
- The First Rehabilitation Hospital of Shanghai, Clinic Center for Brain and Spinal Cord Research, School of Medicine and Advanced Institute of Translational Medicine, Tongji University, Shanghai, China
| | - Ting Wen
- The First Rehabilitation Hospital of Shanghai, Clinic Center for Brain and Spinal Cord Research, School of Medicine and Advanced Institute of Translational Medicine, Tongji University, Shanghai, China
| | - Mei Zheng
- Department of Clinical Laboratory, Shanghai Songjiang District Central Hospital, Shanghai, China
| | - Ruilong Xia
- The First Rehabilitation Hospital of Shanghai, Clinic Center for Brain and Spinal Cord Research, School of Medicine and Advanced Institute of Translational Medicine, Tongji University, Shanghai, China
| | - Ran Qian
- The First Rehabilitation Hospital of Shanghai, Clinic Center for Brain and Spinal Cord Research, School of Medicine and Advanced Institute of Translational Medicine, Tongji University, Shanghai, China
| | - Yang Li
- The First Rehabilitation Hospital of Shanghai, Clinic Center for Brain and Spinal Cord Research, School of Medicine and Advanced Institute of Translational Medicine, Tongji University, Shanghai, China
| | - Minxuan Sun
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Jianping Liu
- Jiangxi Provincial Key Laboratory of Digestive Diseases, Department of Gastroenterology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Li Tian
- The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qian Zhou
- The First Rehabilitation Hospital of Shanghai, Clinic Center for Brain and Spinal Cord Research, School of Medicine and Advanced Institute of Translational Medicine, Tongji University, Shanghai, China
| | - Xin Yu
- Pre-clinical College, Dali University, Dali, Yunnan, China
| | - Changgeng Peng
- The First Rehabilitation Hospital of Shanghai, Clinic Center for Brain and Spinal Cord Research, School of Medicine and Advanced Institute of Translational Medicine, Tongji University, Shanghai, China
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Xiong Z, Fang Y, Lu S, Sun Q, Sun Y, Yang P, Huang J. Exploring the Relevance of Disulfidptosis to the Pathophysiology of Ulcerative Colitis by Bioinformatics Analysis. J Inflamm Res 2024; 17:2757-2774. [PMID: 38737111 PMCID: PMC11088416 DOI: 10.2147/jir.s454668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 04/25/2024] [Indexed: 05/14/2024] Open
Abstract
Background Ulcerative colitis (UC) is a nonspecific inflammatory disease confined to the intestinal mucosa and submucosa, and its prevalence significantly increases each year. Disulfidptosis is a recently discovered new form of cell death that has been suggested to be involved in multiple diseases. The aim of this study was to explore the relevance of disulfidptosis in UC. Methods First, the UC datasets were downloaded from the Gene Expression Omnibus (GEO) database, and UC samples were typed based on upregulated disulfidptosis-related genes (DRGs). Then, weighted gene co-expression network analysis (WGCNA) was performed on the datasets and molecular subtypes of UC, respectively, to obtain candidate signature genes. After validation of the validation set and qRT-PCR, we constructed a nomogram model by signature genes to predict the risk of UC. Finally, single-cell sequencing analysis was used to study the heterogeneity of UC and to demonstrate the expression of DRGs and signature genes at the single-cell level. Results A total of 7 DRGs were significantly upregulated in the expression profiles of UC, and 180 UC samples were divided into two subtypes based on these DRGs. Five candidate signature genes were obtained by intersecting two key gene modules selected by WGCNA. After evaluation, four signature genes with diagnostic relevance (COL4A1, PRRX1, NNMT, and PECAM1) were eventually identified. The nomogram model showed excellent prediction ability. Finally, in the single-cell analysis, there were eight cell types (including B cells, T cells, monocyte, smooth muscle cells, epithelial cells, neutrophil, endothelial cells and NK cells) were identified. The signature genes were significantly expressed mainly in endothelial cells and smooth muscle cells. Conclusion In this study, subtypes related to disulfidptosis were identified, and single-cell analysis was performed to understand the pathogenesis of UC from a new perspective. Four signature genes were screened and a prediction model with high accuracy was established. This provides novel insights for early diagnosis and therapeutic targets in UC.
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Affiliation(s)
- Zhe Xiong
- Department of Gastroenterology, The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, People’s Republic of China
- Graduate School of Dalian Medical University, Dalian, Liaoning Province, China
| | - Ying Fang
- Department of Gastroenterology, The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, People’s Republic of China
- Graduate School of Dalian Medical University, Dalian, Liaoning Province, China
| | - Shuangshuang Lu
- Department of Gastroenterology, The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, People’s Republic of China
| | - Qiuyue Sun
- Department of Gastroenterology, The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, People’s Republic of China
- Graduate School of Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
| | - Yuhui Sun
- Department of Gastroenterology, The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, People’s Republic of China
- Graduate School of Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
| | - Pengcheng Yang
- Department of Gastroenterology, Hengshanqiao People’s Hospital, Changzhou, Jiangsu Province, People’s Republic of China
| | - Jin Huang
- Department of Gastroenterology, The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, People’s Republic of China
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Kurumi H, Yokoyama Y, Hirano T, Akita K, Hayashi Y, Kazama T, Isomoto H, Nakase H. Cytokine Profile in Predicting the Effectiveness of Advanced Therapy for Ulcerative Colitis: A Narrative Review. Biomedicines 2024; 12:952. [PMID: 38790914 PMCID: PMC11117845 DOI: 10.3390/biomedicines12050952] [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: 03/31/2024] [Revised: 04/19/2024] [Accepted: 04/23/2024] [Indexed: 05/26/2024] Open
Abstract
Cytokine-targeted therapies have shown efficacy in treating patients with ulcerative colitis (UC), but responses to these advanced therapies can vary. This variability may be due to differences in cytokine profiles among patients with UC. While the etiology of UC is not fully understood, abnormalities of the cytokine profiles are deeply involved in its pathophysiology. Therefore, an approach focused on the cytokine profile of individual patients with UC is ideal. Recent studies have demonstrated that molecular analysis of cytokine profiles in UC can predict response to each advanced therapy. This narrative review summarizes the molecules involved in the efficacy of various advanced therapies for UC. Understanding these associations may be helpful in selecting optimal therapeutic agents.
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Affiliation(s)
- Hiroki Kurumi
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Hokkaido, Japan; (H.K.)
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Tottori University Faculty of Medicine, 36-1, Nishi-cho, Yonago 683-8504, Tottori, Japan
| | - Yoshihiro Yokoyama
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Hokkaido, Japan; (H.K.)
| | - Takehiro Hirano
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Hokkaido, Japan; (H.K.)
| | - Kotaro Akita
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Hokkaido, Japan; (H.K.)
| | - Yuki Hayashi
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Hokkaido, Japan; (H.K.)
| | - Tomoe Kazama
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Hokkaido, Japan; (H.K.)
| | - Hajime Isomoto
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Tottori University Faculty of Medicine, 36-1, Nishi-cho, Yonago 683-8504, Tottori, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Hokkaido, Japan; (H.K.)
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Park JS, Cresci GAM. Dysfunctional intestinal microvascular endothelial cells: Insights and therapeutic implications in gastrointestinal inflammation. IMMUNOMETABOLISM (COBHAM, SURREY) 2024; 6:e00043. [PMID: 38818514 PMCID: PMC11136270 DOI: 10.1097/in9.0000000000000043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 05/01/2024] [Indexed: 06/01/2024]
Abstract
The intestinal microvascular endothelium plays a crucial role in orchestrating host responses to inflammation within the gastrointestinal tract. This review delves into the unique aspects of intestinal microvascular endothelial cells, distinct from those of larger vessels, in mediating leukocyte recruitment, maintaining barrier integrity, and regulating angiogenesis during inflammation. Specifically, their role in the pathogenesis of inflammatory bowel diseases, where dysregulated endothelial functions contribute to the disease progression, is reviewed. Furthermore, this review discusses the isolation technique for these cells and commonly used adhesion molecules for in vitro and in vivo experiments. In addition, we reviewed the development and therapeutic implications of a biologic agent targeting the interaction between α4β7 integrin on T lymphocytes and mucosal addressin cellular adhesion molecule-1 on gut endothelium. Notably, vedolizumab, a humanized monoclonal antibody against α4β7 integrin, has shown promising outcomes in inflammatory bowel diseases and other gastrointestinal inflammatory conditions, including chronic pouchitis, immune checkpoint inhibitor-induced colitis, and acute cellular rejection post-intestinal transplantation.
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Affiliation(s)
- Ji Seok Park
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Gail A. M. Cresci
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Children’s Hospital, Cleveland, OH, USA
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14
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Kvedaraite E, Lourda M, Mouratidou N, Düking T, Padhi A, Moll K, Czarnewski P, Sinha I, Xagoraris I, Kokkinou E, Damdimopoulos A, Weigel W, Hartwig O, Santos TE, Soini T, Van Acker A, Rahkonen N, Flodström Tullberg M, Ringqvist E, Buggert M, Jorns C, Lindforss U, Nordenvall C, Stamper CT, Unnersjö-Jess D, Akber M, Nadisauskaite R, Jansson J, Vandamme N, Sorini C, Grundeken ME, Rolandsdotter H, Rassidakis G, Villablanca EJ, Ideström M, Eulitz S, Arnell H, Mjösberg J, Henter JI, Svensson M. Intestinal stroma guides monocyte differentiation to macrophages through GM-CSF. Nat Commun 2024; 15:1752. [PMID: 38409190 PMCID: PMC10897309 DOI: 10.1038/s41467-024-46076-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 02/09/2024] [Indexed: 02/28/2024] Open
Abstract
Stromal cells support epithelial cell and immune cell homeostasis and play an important role in inflammatory bowel disease (IBD) pathogenesis. Here, we quantify the stromal response to inflammation in pediatric IBD and reveal subset-specific inflammatory responses across colon segments and intestinal layers. Using data from a murine dynamic gut injury model and human ex vivo transcriptomic, protein and spatial analyses, we report that PDGFRA+CD142-/low fibroblasts and monocytes/macrophages co-localize in the intestine. In primary human fibroblast-monocyte co-cultures, intestinal PDGFRA+CD142-/low fibroblasts foster monocyte transition to CCR2+CD206+ macrophages through granulocyte-macrophage colony-stimulating factor (GM-CSF). Monocyte-derived CCR2+CD206+ cells from co-cultures have a phenotype similar to intestinal CCR2+CD206+ macrophages from newly diagnosed pediatric IBD patients, with high levels of PD-L1 and low levels of GM-CSF receptor. The study describes subset-specific changes in stromal responses to inflammation and suggests that the intestinal stroma guides intestinal macrophage differentiation.
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Affiliation(s)
- Egle Kvedaraite
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
- Department of Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden.
| | - Magda Lourda
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Natalia Mouratidou
- Pediatric Gastroenterology, Hepatology and Nutrition Unit, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Tim Düking
- Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany
| | - Avinash Padhi
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- Dermatology and Venereology Section, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Kirsten Moll
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Paulo Czarnewski
- Science for Life Laboratory, Department of Biochemistry and Biophysics and National Bioinformatics Infrastructure Sweden, Stockholm University, Solna, Sweden
| | - Indranil Sinha
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Ioanna Xagoraris
- Department of Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Efthymia Kokkinou
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Anastasios Damdimopoulos
- Bioinformatics and Expression Analysis Core Facility, Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
| | - Whitney Weigel
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Olga Hartwig
- Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany
| | - Telma E Santos
- Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany
| | - Tea Soini
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Aline Van Acker
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- Tech Watch, Flanders Institute for Biotechnology, Ghent, Belgium
| | - Nelly Rahkonen
- Integrated Cardio Metabolic Centre, Department of Medicine Huddinge, Karolinska Institutet, Huddinge, Sweden
| | - Malin Flodström Tullberg
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Emma Ringqvist
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Marcus Buggert
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Carl Jorns
- Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Ulrik Lindforss
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Pelvic Cancer, GI Oncology and Colorectal Surgery Unit, Karolinska University Hospital, Stockholm, Sweden
| | - Caroline Nordenvall
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Pelvic Cancer, GI Oncology and Colorectal Surgery Unit, Karolinska University Hospital, Stockholm, Sweden
| | - Christopher T Stamper
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - David Unnersjö-Jess
- Science for Life Laboratory, Dept. of Applied Physics, Royal Institute of Technology, Solna, Sweden
| | - Mira Akber
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Ruta Nadisauskaite
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Jessica Jansson
- Pediatric Gastroenterology, Hepatology and Nutrition Unit, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
| | - Niels Vandamme
- VIB Single Cell Core, VIB, Ghent, Belgium
- VIB-UGent Center for Inflammation Research, 9052, Ghent, Belgium
| | - Chiara Sorini
- Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institutet and University Hospital, Stockholm, Sweden
| | - Marijke Elise Grundeken
- Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Helena Rolandsdotter
- Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
- Sachs' Children and Youth Hospital, Department of Gastroenterology, Södersjukhuset, Stockholm, Sweden
| | - George Rassidakis
- Department of Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Eduardo J Villablanca
- Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institutet and University Hospital, Stockholm, Sweden
| | - Maja Ideström
- Pediatric Gastroenterology, Hepatology and Nutrition Unit, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Stefan Eulitz
- Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany
| | - Henrik Arnell
- Pediatric Gastroenterology, Hepatology and Nutrition Unit, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Jenny Mjösberg
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Jan-Inge Henter
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
- Theme of Children's Health, Karolinska University Hospital, Stockholm, Sweden
| | - Mattias Svensson
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
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15
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Bhardwaj A, Singh A, Midha V, Sood A, Wander GS, Mohan B, Batta A. Cardiovascular implications of inflammatory bowel disease: An updated review. World J Cardiol 2023; 15:553-570. [PMID: 38058397 PMCID: PMC10696203 DOI: 10.4330/wjc.v15.i11.553] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 10/22/2023] [Accepted: 11/08/2023] [Indexed: 11/23/2023] Open
Abstract
Emerging data highlights the heightened risk of atherosclerotic cardiovascular diseases (ASCVD) in patients with chronic inflammatory disorders, particularly those afflicted with inflammatory bowel disease (IBD). This review delves into the epidemiological connections between IBD and ASCVD, elucidating potential underlying mechanisms. Furthermore, it discusses the impact of current IBD treatments on cardiovascular risk. Additionally, the cardiovascular adverse effects of novel small molecule drugs used in moderate-to-severe IBD are investigated, drawing parallels with observations in patients with rheumatoid arthritis. This article aims to comprehensively evaluate the existing evidence supporting these associations. To achieve this, we conducted a meticulous search of PubMed, spanning from inception to August 2023, using a carefully selected set of keywords. The search encompassed topics related to IBD, such as Crohn's disease and ulcerative colitis, as well as ASCVD, including coronary artery disease, cardiovascular disease, atrial fibrillation, heart failure, conduction abnormalities, heart blocks, and premature coronary artery disease. This review encompasses various types of literature, including retrospective and prospective cohort studies, clinical trials, meta-analyses, and relevant guidelines, with the objective of providing a comprehensive overview of this critical intersection of inflammatory bowel disease and cardiovascular health.
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Affiliation(s)
- Arshia Bhardwaj
- Department of Gastroenterology, Dayanand Medical College and Hospital, Punjab, Ludhiana 141001, India
| | - Arshdeep Singh
- Department of Gastroenterology, Dayanand Medical College and Hospital, Punjab, Ludhiana 141001, India
| | - Vandana Midha
- Department of Internal Medicine, Dayanand Medical College and Hospital, Punjab, Ludhiana 141001, India
| | - Ajit Sood
- Department of Gastroenterology, Dayanand Medical College and Hospital, Punjab, Ludhiana 141001, India
| | - Gurpreet Singh Wander
- Department of Cardiology, Dayanand Medical College and Hospital, Punjab, Ludhiana 141001, India
| | - Bishav Mohan
- Department of Cardiology, Dayanand Medical College and Hospital, Punjab, Ludhiana 141001, India
| | - Akash Batta
- Department of Cardiology, Dayanand Medical College and Hospital, Punjab, Ludhiana 141001, India.
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16
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Pasternak G, Chrzanowski G, Aebisher D, Myśliwiec A, Dynarowicz K, Bartusik-Aebisher D, Sosna B, Cieślar G, Kawczyk-Krupka A, Filip R. Crohn's Disease: Basic Characteristics of the Disease, Diagnostic Methods, the Role of Biomarkers, and Analysis of Metalloproteinases: A Review. Life (Basel) 2023; 13:2062. [PMID: 37895443 PMCID: PMC10608618 DOI: 10.3390/life13102062] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 10/10/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
Crohn's disease is a chronic inflammatory bowel disease that affects the ileum and/or large intestine. At the same time, it can also affect any other part of the human body, i.e., from the mouth to the anus. In Crohn's disease, the physiology and functioning of the epithelial barrier are inhibited due to the correlation of various factors, such as the environment, genetic susceptibility or intestinal microbiota. The symptoms are very troublesome and cause a significant reduction in quality of life, sometimes occurring with paralyzing permanent damage to the digestive tract, requiring enteral or parenteral nutrition throughout life. In order to make a proper and accurate diagnosis, an appropriately selected diagnostic path in a given clinical entity is necessary. Standard diagnostic methods are: laboratory examination, histopathological examination, endoscopic examination, X-ray, computed tomography, ultrasound examination and magnetic resonance imaging. Medical biology and the analysis of metalloproteinases have also proved helpful in diagnosing changes occurring as a result of Crohn's disease. Here we provide a thorough review of the latest reports on Crohn's disease and its genetic conditions, symptoms, morphology, diagnosis (including the analysis of Crohn's disease biomarkers, i.e., metalloproteinases) and treatment.
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Affiliation(s)
- Grzegorz Pasternak
- Department of General Surgery, Provincial Clinical Hospital No. 2 in Rzeszów, 35-301 Rzeszów, Poland;
| | - Grzegorz Chrzanowski
- Department of Biology, College of Natural Sciences, University of Rzeszów, 35-310 Rzeszów, Poland
| | - David Aebisher
- Department of Photomedicine and Physical Chemistry, Medical College, University of Rzeszów, 35-310 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, 35-310 Rzeszów, Poland;
| | - 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.); (G.C.); (A.K.-K.)
| | - 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.); (G.C.); (A.K.-K.)
| | - 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.); (G.C.); (A.K.-K.)
| | - Rafał Filip
- Department of Internal Medicine, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland;
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17
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Boccatonda A, Balletta M, Vicari S, Hoxha A, Simioni P, Campello E. The Journey Through the Pathogenesis and Treatment of Venous Thromboembolism in Inflammatory Bowel Diseases: A Narrative Review. Semin Thromb Hemost 2023; 49:744-755. [PMID: 36455617 DOI: 10.1055/s-0042-1758869] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the gastrointestinal tract including Crohn's disease and ulcerative colitis, which may result in several extraintestinal complications (∼20-30% of cases), such as increased risk of venous thromboembolism (VTE). The main pathophysiological mechanism of VTE is an inflammation-induced hypercoagulable state, and recent data have shown that endothelial dysregulation due to gut and systemic inflammation may also lead to a prothrombotic state. Several prothrombotic alterations have been described, such as the activation of the coagulation system, platelet abnormalities, and dysregulation of fibrinolysis. Furthermore, the dysregulation of the gut microbiome seems to play a vital role in increasing systemic inflammation and thus inducing a procoagulant state. Our review aims to examine the main correlations between IBD and VTE, the underlying pathophysiology, and current therapeutic options.
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Affiliation(s)
- Andrea Boccatonda
- Department of Internal Medicine, Bentivoglio Hospital, AUSL Bologna, Bologna, Italy
| | - Marco Balletta
- Department of Internal Medicine, Bologna University, Bologna, Italy
| | - Susanna Vicari
- Department of Internal Medicine, Bentivoglio Hospital, AUSL Bologna, Bologna, Italy
| | - Ariela Hoxha
- Hemorrhagic and Thrombotic Diseases Unit, Department of Medicine (DIMED), Padova University Hospital, Padova, Italy
| | - Paolo Simioni
- Hemorrhagic and Thrombotic Diseases Unit, Department of Medicine (DIMED), Padova University Hospital, Padova, Italy
| | - Elena Campello
- Hemorrhagic and Thrombotic Diseases Unit, Department of Medicine (DIMED), Padova University Hospital, Padova, Italy
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18
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Gordon H, Rodger B, Lindsay JO, Stagg AJ. Recruitment and Residence of Intestinal T Cells - Lessons for Therapy in Inflammatory Bowel Disease. J Crohns Colitis 2023; 17:1326-1341. [PMID: 36806613 DOI: 10.1093/ecco-jcc/jjad027] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Indexed: 02/23/2023]
Abstract
Targeting leukocyte trafficking in the management of inflammatory bowel disease [IBD] has been a significant therapeutic advance over the past 15 years. However, as with other advanced therapies, phase III clinical trials report response to trafficking inhibitors in only a proportion of patients, with fewer achieving clinical remission or mucosal healing. Additionally, there have been significant side effects, most notably progressive multifocal leukoencephalopathy in association with the α4 inhibitor natalizumab. This article reviews the mechanisms underpinning T cell recruitment and residence, to provide a background from which the strength and limitations of agents that disrupt leukocyte trafficking can be further explored. The therapeutic impact of trafficking inhibitors is underpinned by the complexity and plasticity of the intestinal immune response. Pathways essential for gut homing in health may be bypassed in the inflamed gut, thus providing alternative routes of entry when conventional homing molecules are targeted. Furthermore, there is conservation of trafficking architecture between proinflammatory and regulatory T cells. The persistence of resident memory cells within the gut gives rise to local established pro-inflammatory populations, uninfluenced by inhibition of trafficking. Finally, trafficking inhibitors may give rise to effects beyond the intended response, such as the impact of vedolizumab on innate immunity, as well as on target side effects. With significant research efforts into predictive biomarkers already underway, it is ultimately hoped that a better understanding of trafficking and residence will help us predict which patients are most likely to respond to inhibition of leukocyte trafficking, and how best to combine therapies.
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Affiliation(s)
- Hannah Gordon
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
- Department of Gastroenterology, Barts Health NHS Trust, London, UK
| | - Beverley Rodger
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
| | - James O Lindsay
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
- Department of Gastroenterology, Barts Health NHS Trust, London, UK
| | - Andrew J Stagg
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
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19
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Jingjie W, Jun S. Gut vascular barrier in the pathogenesis and resolution of Crohn's disease: A novel link from origination to therapy. Clin Immunol 2023; 253:109683. [PMID: 37406981 DOI: 10.1016/j.clim.2023.109683] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 06/07/2023] [Accepted: 06/12/2023] [Indexed: 07/07/2023]
Abstract
The gut vascular barrier (GVB) is the deepest layer of the gut barrier. It mainly comprised gut vascular endothelial cells, enteric glial cells, and pericytes. The GVB facilitates nutrient absorption and blocks bacterial translocation through its size-restricted permeability. Accumulating evidence suggests that dysfunction of this barrier correlates with several clinical pathologies including Crohn's disease (CD). Significant progress has been made to elucidate the mechanism of GVB dysfunction and to confirm the participation of disrupted GVB in the course of CD. However, further analyses are required to pinpoint the specific roles of GVB in CD pathogenesis. Many preclinical models and clinical trials have demonstrated that various agents are effective in protecting the GVB integrity and thus providing a potential CD treatment strategy. Through this review, we established a systemic understanding of the role of GVB in CD pathogenesis and provided novel insights for GVB-targeting strategies in CD treatment.
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Affiliation(s)
- Wang Jingjie
- Division of Gastroenterology and Hepatology, Baoshan Branch, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center; Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease; 160# Pu Jian Ave, Shanghai 200127, China
| | - Shen Jun
- Division of Gastroenterology and Hepatology, Baoshan Branch, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center; Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease; 160# Pu Jian Ave, Shanghai 200127, China.
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20
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Li Y, Xu M, Zhu Z, Xu F, Chen B. Transendothelial electrical resistance measurement by a microfluidic device for functional study of endothelial barriers in inflammatory bowel disease. Front Bioeng Biotechnol 2023; 11:1236610. [PMID: 37520295 PMCID: PMC10375910 DOI: 10.3389/fbioe.2023.1236610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 06/29/2023] [Indexed: 08/01/2023] Open
Abstract
Introduction: Inflammatory bowel disease (IBD) is a chronic relapsing and remitting disease with a rising incidence globally. Circulating exosomes play great roles in IBD pathogenesis through exosomal cargoes, especially impacting the function of endothelial barriers. Transendothelial electrical resistance (TEER) measurement is a widely used non-invasive and label-free strategy to monitor endothelial barrier function in vitro. This study established a well-designed microfluidic device to monitor the TEER changes of endothelial cellular barrier on-chip after treated with exosome derived from IBD serum. Methods: The chip comprised two layers of microfluidic chambers with top layer for the perfusion of medium to maintain the nutrition and pressure during cell culture, and bottom layer for the extracellular matrix mimic using hydrogel, which are separated by a semipermeable membrane that permitted the formation of endothelial cell barrier. Four electrodes independent from the outlets were integrated to the chip for TEER detection. In vivo mouse models mouse models and proteome profiling were performed to finding relevant regulators. Results: With this platform, significant decrease of TEER was detected, indicating that IBD serum exosome impact the endothelial cellular barrier on-chip. In vivo mouse models, IBD serum exosome treated group showed great higher DAI scores, shorter colons, more severe histological features, and higher levers of S100A8 expression, promoting the disease progress. Proteome profiling showed that TFRC and ANXA5 have great potentials as novel regulators in IBD. Discussion: This in-house customized microfluidic chip emulates the endothelial barrier microenvironment and enables the TEER monitoring, and can be used to investigate endothelial barrier function in vitro. IBD serum exosome promote the severity of disease.
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Affiliation(s)
- Ya Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Min Xu
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhu Zhu
- Department of Biological Sample Bank, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Feng Xu
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Bing Chen
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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21
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Sotra A, Jozani KA, Zhang B. A vascularized crypt-patterned colon model for high-throughput drug screening and disease modelling. LAB ON A CHIP 2023. [PMID: 37335565 DOI: 10.1039/d3lc00211j] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2023]
Abstract
The colon serves as a primary target for pharmaceutical compound screening and disease modelling. To better study colon diseases and develop treatments, engineered in vitro models with colon-specific physiological features are required. Existing colon models lack integration of colonic crypt structures with underlying perfusable vasculature, where vascular-epithelial crosstalk is affected by disease progression. We present a colon epithelium barrier model with vascularized crypts that recapitulates relevant cytokine gradients in both healthy and inflammatory conditions. Using our previously published IFlowPlate384 platform, we initially imprinted crypt topography and populated the patterned scaffold with colon cells. Proliferative colon cells spontaneously localized to the crypt niche and differentiated into epithelial barriers with a tight brush border. Toxicity of the colon cancer drug, capecitabine, was tested and showed a dose-dependent response and recovery from crypt-patterned colon epithelium exclusively. Perfusable microvasculature was then incorporated around the colon crypts followed by treatment with pro-inflammatory TNFα and IFNγ cytokines to simulate inflammatory bowel disease (IBD)-like conditions. We observed in vivo-like stromal basal-to-apical cytokine gradients in tissues with vascularized crypts and gradient reversals upon inflammation. Taken together, we demonstrated crypt topography integrated with underlying perfusable microvasculature has significant value for emulating colon physiology and in advanced disease modelling.
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Affiliation(s)
- Alexander Sotra
- School of Biomedical Engineering, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
| | - Kimia Asadi Jozani
- School of Biomedical Engineering, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
| | - Boyang Zhang
- School of Biomedical Engineering, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
- Department of Chemical Engineering, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
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22
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Frountzas M, Karanikki E, Toutouza O, Sotirakis D, Schizas D, Theofilis P, Tousoulis D, Toutouzas KG. Exploring the Impact of Cyanidin-3-Glucoside on Inflammatory Bowel Diseases: Investigating New Mechanisms for Emerging Interventions. Int J Mol Sci 2023; 24:9399. [PMID: 37298350 PMCID: PMC10254033 DOI: 10.3390/ijms24119399] [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: 04/11/2023] [Revised: 05/16/2023] [Accepted: 05/19/2023] [Indexed: 06/12/2023] Open
Abstract
Cyanidin-3-O-glucoside (C3G), the most widely distributed anthocyanin (ACN) in edible fruits, has been proposed for several bioactivities, including anti-inflammatory, neuro-protective, antimicrobial, anti-viral, anti-thrombotic and epigenetic actions. However, habitual intake of ACNs and C3G may vary widely among populations, regions, and seasons, among individuals with different education and financial status. The main point of C3G absorption occurs in the small and large bowel. Therefore, it has been supposed that the treating properties of C3G might affect inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD). IBDs develop through complex inflammatory pathways and sometimes may be resistant to conventional treatment strategies. C3G presents antioxidative, anti-inflammatory, cytoprotective, and antimicrobial effects useful for IBD management. In particular, different studies have demonstrated that C3G inhibits NF-κB pathway activation. In addition, C3G activates the Nrf2 pathway. On the other hand, it modulates the expression of antioxidant enzymes and cytoprotective proteins, such as NAD(P)H, superoxide dismutase, heme-oxygenase (HO-1), thioredoxin, quinone reductase-oxide 1 (NQO1), catalase, glutathione S-transferase and glutathione peroxidase. Interferon I and II pathways are downregulated by C3G inhibiting interferon-mediating inflammatory cascades. Moreover, C3G reduces reactive species and pro-inflammatory cytokines, such as C reactive protein, interferon-γ, tumor necrosis factor-α, interleukin (IL)-5, IL-9, IL-10, IL-12p70, and IL-17A in UC and CD patients. Finally, C3G modulates gut microbiota by inducing an increase in beneficial gut bacteria and increasing microbial abundances, thus mitigating dysbiosis. Thus, C3G presents activities that may have potential therapeutic and protective actions against IBD. Still, in the future, clinical trials should be designed to investigate the bioavailability of C3G in IBD patients and the proper therapeutic doses through different sources, aiming to the standardization of the exact clinical outcome and efficacy of C3G.
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Affiliation(s)
- Maximos Frountzas
- First Propaedeutic Department of Surgery, Hippocration General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Eva Karanikki
- Department of Clinical Nutrition, Hippocration General Hospital, 11527 Athens, Greece;
| | - Orsalia Toutouza
- School of Medicine, Imperial College of London, London SW7 2AZ, UK
| | - Demosthenis Sotirakis
- First Propaedeutic Department of Surgery, Hippocration General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Dimitrios Schizas
- First Department of Surgery, Laikon General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Panagiotis Theofilis
- First Cardiology Department, “Hippocration” General Hospital, University of Athens Medical School, 11527 Athens, Greece
| | - Dimitris Tousoulis
- First Cardiology Department, “Hippocration” General Hospital, University of Athens Medical School, 11527 Athens, Greece
| | - Konstantinos G. Toutouzas
- First Propaedeutic Department of Surgery, Hippocration General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
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23
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Lin M, Hartl K, Heuberger J, Beccaceci G, Berger H, Li H, Liu L, Müllerke S, Conrad T, Heymann F, Woehler A, Tacke F, Rajewsky N, Sigal M. Establishment of gastrointestinal assembloids to study the interplay between epithelial crypts and their mesenchymal niche. Nat Commun 2023; 14:3025. [PMID: 37230989 DOI: 10.1038/s41467-023-38780-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 05/15/2023] [Indexed: 05/27/2023] Open
Abstract
The cellular organization of gastrointestinal crypts is orchestrated by different cells of the stromal niche but available in vitro models fail to fully recapitulate the interplay between epithelium and stroma. Here, we establish a colon assembloid system comprising the epithelium and diverse stromal cell subtypes. These assembloids recapitulate the development of mature crypts resembling in vivo cellular diversity and organization, including maintenance of a stem/progenitor cell compartment in the base and their maturation into secretory/absorptive cell types. This process is supported by self-organizing stromal cells around the crypts that resemble in vivo organization, with cell types that support stem cell turnover adjacent to the stem cell compartment. Assembloids that lack BMP receptors either in epithelial or stromal cells fail to undergo proper crypt formation. Our data highlight the crucial role of bidirectional signaling between epithelium and stroma, with BMP as a central determinant of compartmentalization along the crypt axis.
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Affiliation(s)
- Manqiang Lin
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115, Berlin, Germany
| | - Kimberly Hartl
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115, Berlin, Germany
| | - Julian Heuberger
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115, Berlin, Germany
| | - Giulia Beccaceci
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115, Berlin, Germany
| | - Hilmar Berger
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
| | - Hao Li
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115, Berlin, Germany
| | - Lichao Liu
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
| | - Stefanie Müllerke
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115, Berlin, Germany
| | - Thomas Conrad
- Genomics Technology Platform, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125, Berlin, Germany
- Core Facility Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, 10178, Berlin, Germany
| | - Felix Heymann
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
| | - Andrew Woehler
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
| | - Nikolaus Rajewsky
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115, Berlin, Germany
| | - Michael Sigal
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany.
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115, Berlin, Germany.
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24
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Mendelson AA, Erickson D, Villar R. The role of the microcirculation and integrative cardiovascular physiology in the pathogenesis of ICU-acquired weakness. Front Physiol 2023; 14:1170429. [PMID: 37234410 PMCID: PMC10206327 DOI: 10.3389/fphys.2023.1170429] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 04/28/2023] [Indexed: 05/28/2023] Open
Abstract
Skeletal muscle dysfunction after critical illness, defined as ICU-acquired weakness (ICU-AW), is a complex and multifactorial syndrome that contributes significantly to long-term morbidity and reduced quality of life for ICU survivors and caregivers. Historically, research in this field has focused on pathological changes within the muscle itself, without much consideration for their in vivo physiological environment. Skeletal muscle has the widest range of oxygen metabolism of any organ, and regulation of oxygen supply with tissue demand is a fundamental requirement for locomotion and muscle function. During exercise, this process is exquisitely controlled and coordinated by the cardiovascular, respiratory, and autonomic systems, and also within the skeletal muscle microcirculation and mitochondria as the terminal site of oxygen exchange and utilization. This review highlights the potential contribution of the microcirculation and integrative cardiovascular physiology to the pathogenesis of ICU-AW. An overview of skeletal muscle microvascular structure and function is provided, as well as our understanding of microvascular dysfunction during the acute phase of critical illness; whether microvascular dysfunction persists after ICU discharge is currently not known. Molecular mechanisms that regulate crosstalk between endothelial cells and myocytes are discussed, including the role of the microcirculation in skeletal muscle atrophy, oxidative stress, and satellite cell biology. The concept of integrated control of oxygen delivery and utilization during exercise is introduced, with evidence of physiological dysfunction throughout the oxygen delivery pathway - from mouth to mitochondria - causing reduced exercise capacity in patients with chronic disease (e.g., heart failure, COPD). We suggest that objective and perceived weakness after critical illness represents a physiological failure of oxygen supply-demand matching - both globally throughout the body and locally within skeletal muscle. Lastly, we highlight the value of standardized cardiopulmonary exercise testing protocols for evaluating fitness in ICU survivors, and the application of near-infrared spectroscopy for directly measuring skeletal muscle oxygenation, representing potential advancements in ICU-AW research and rehabilitation.
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Affiliation(s)
- Asher A. Mendelson
- Section of Critical Care Medicine, Department of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Dustin Erickson
- Section of Critical Care Medicine, Department of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Rodrigo Villar
- Faculty of Kinesiology and Recreation Management, University of Manitoba, Winnipeg, MB, Canada
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25
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Zhang C, Cao X, Wang H, Li Z, Zhang Y. The ACE2 activator diminazene aceturate ameliorates colitis by repairing the gut-vascular barrier in mice. Microvasc Res 2023; 148:104544. [PMID: 37127063 DOI: 10.1016/j.mvr.2023.104544] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/21/2023] [Accepted: 04/25/2023] [Indexed: 05/03/2023]
Abstract
Alleviating vascular barrier injury improves colitis. Angiotensin converting enzyme 2/angiotensin 1-7/Mas receptor (ACE2/Ang1-7/MasR) axis-related drugs have various biological properties, such as inhibition of inflammation and fibrosis, but their role in improving the gut-vascular barrier (GVB) has rarely been reported. This study aims to investigate the effects of diminazene aceturate (DIZE), an ACE2 activator, on vascular barrier damage in colitis. Mice were randomly divided into three groups: control, dextran sulfate sodium salt (DSS), and DIZE+DSS. Mice in the DSS group drank DSS for 8 days starting on day 4. Mice in the DIZE+DSS group were pregavaged with DIZE for 3 days and then drank DSS for 8 days while continuing to be gavaged with DIZE for 4 days. Mice were euthanized and samples were collected on the last day. Injury to colonic structure and colonic microvasculature was assessed by visual observation and appropriate staining. DSS-induced colonic and microvascular pathological damage in mice was substantially reversed by DIZE treatment. Molecular pathways were investigated by Western blot, quantitative real-time polymerase chain reaction (qRT-PCR), and enzyme linked immunosorbent assay (ELISA). DSS treatment upregulated angiotensin converting enzyme (ACE), angiotensin type 1 receptor (AT1R) protein, pro-inflammatory cytokines and inhibited tight junction-related protein expression. DIZE treatment activated ACE2/MasR protein expression and reversed epithelial barrier damage and inflammatory infiltration during DSS injury. In addition, DIZE treatment inhibited vascular endothelial growth factor A/vascular endothelial growth factor receptor 2/proto-oncogene tyrosine-protein kinase Src (VEGFA/VEGFR2/Src) pathway activation and restored vascular adhesion-linker protein vascular endothelial cadherin (VE-cadherin) expression during DSS injury. In conclusion, DIZE treatment ameliorated colitis, which was associated with balancing the two axes of the renin-angiotensin system (RAS) and repairing the GVB injury.
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Affiliation(s)
- Chonghao Zhang
- Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Xiyue Cao
- Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Huanhuan Wang
- Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Zhiqiang Li
- Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Yuanshu Zhang
- Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
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26
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Britzen-Laurent N, Weidinger C, Stürzl M. Contribution of Blood Vessel Activation, Remodeling and Barrier Function to Inflammatory Bowel Diseases. Int J Mol Sci 2023; 24:ijms24065517. [PMID: 36982601 PMCID: PMC10051397 DOI: 10.3390/ijms24065517] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/09/2023] [Accepted: 03/10/2023] [Indexed: 03/17/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) consist of a group of chronic inflammatory disorders with a complex etiology, which represent a clinical challenge due to their often therapy-refractory nature. In IBD, inflammation of the intestinal mucosa is characterized by strong and sustained leukocyte infiltration, resulting in the loss of epithelial barrier function and subsequent tissue destruction. This is accompanied by the activation and the massive remodeling of mucosal micro-vessels. The role of the gut vasculature in the induction and perpetuation of mucosal inflammation is receiving increasing recognition. While the vascular barrier is considered to offer protection against bacterial translocation and sepsis after the breakdown of the epithelial barrier, endothelium activation and angiogenesis are thought to promote inflammation. The present review examines the respective pathological contributions of the different phenotypical changes observed in the microvascular endothelium during IBD, and provides an overview of potential vessel-specific targeted therapy options for the treatment of IBD.
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Affiliation(s)
- Nathalie Britzen-Laurent
- Division of Surgical Research, Department of Surgery, Translational Research Center, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany
- Correspondence:
| | - Carl Weidinger
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Michael Stürzl
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany
- Division of Molecular and Experimental Surgery, Translational Research Center, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
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27
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Di Tommaso N, Santopaolo F, Gasbarrini A, Ponziani FR. The Gut-Vascular Barrier as a New Protagonist in Intestinal and Extraintestinal Diseases. Int J Mol Sci 2023; 24:ijms24021470. [PMID: 36674986 PMCID: PMC9864173 DOI: 10.3390/ijms24021470] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/07/2023] [Accepted: 01/09/2023] [Indexed: 01/15/2023] Open
Abstract
The intestinal barrier, with its multiple layers, is the first line of defense between the outside world and the intestine. Its disruption, resulting in increased intestinal permeability, is a recognized pathogenic factor of intestinal and extra-intestinal diseases. The identification of a gut-vascular barrier (GVB), consisting of a structured endothelium below the epithelial layer, has led to new evidence on the etiology and management of diseases of the gut-liver axis and the gut-brain axis, with recent implications in oncology as well. The gut-brain axis is involved in several neuroinflammatory processes. In particular, the recent description of a choroid plexus vascular barrier regulating brain permeability under conditions of gut inflammation identifies the endothelium as a key regulator in maintaining tissue homeostasis and health.
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Affiliation(s)
- Natalia Di Tommaso
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Correspondence:
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28
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Cifarelli V, Peche VS, Abumrad NA. Vascular and lymphatic regulation of gastrointestinal function and disease risk. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159207. [PMID: 35882297 PMCID: PMC9642046 DOI: 10.1016/j.bbalip.2022.159207] [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: 01/17/2022] [Revised: 06/17/2022] [Accepted: 07/07/2022] [Indexed: 11/29/2022]
Abstract
The vascular and lymphatic systems in the gut regulate lipid transport while restricting transfer of commensal gut microbiota and directing immune cell trafficking. Increased permeability of the endothelial systems in the intestine associates with passage of antigens and microbiota from the gut into the bloodstream leading to tissue inflammation, the release of pro-inflammatory mediators and ultimately to abnormalities of systemic metabolism. Recent studies show that lipid metabolism maintains homeostasis and function of intestinal blood and lymphatic endothelial cells, BECs and LECs, respectively. This review highlights recent progress in this area, and information related to the contribution of the lipid transporter CD36, abundant in BECs and LECs, to gastrointestinal barrier integrity, inflammation, and to gut regulation of whole body metabolism. The potential role of endothelial lipid delivery in epithelial tissue renewal after injury and consequently in the risk of gastric and intestinal diseases is also discussed.
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Affiliation(s)
- Vincenza Cifarelli
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO, USA.
| | - Vivek S Peche
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Nada A Abumrad
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.
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29
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Identifying disease-critical cell types and cellular processes by integrating single-cell RNA-sequencing and human genetics. Nat Genet 2022; 54:1479-1492. [PMID: 36175791 PMCID: PMC9910198 DOI: 10.1038/s41588-022-01187-9] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 08/18/2022] [Indexed: 12/13/2022]
Abstract
Genome-wide association studies provide a powerful means of identifying loci and genes contributing to disease, but in many cases, the related cell types/states through which genes confer disease risk remain unknown. Deciphering such relationships is important for identifying pathogenic processes and developing therapeutics. In the present study, we introduce sc-linker, a framework for integrating single-cell RNA-sequencing, epigenomic SNP-to-gene maps and genome-wide association study summary statistics to infer the underlying cell types and processes by which genetic variants influence disease. The inferred disease enrichments recapitulated known biology and highlighted notable cell-disease relationships, including γ-aminobutyric acid-ergic neurons in major depressive disorder, a disease-dependent M-cell program in ulcerative colitis and a disease-specific complement cascade process in multiple sclerosis. In autoimmune disease, both healthy and disease-dependent immune cell-type programs were associated, whereas only disease-dependent epithelial cell programs were prominent, suggesting a role in disease response rather than initiation. Our framework provides a powerful approach for identifying the cell types and cellular processes by which genetic variants influence disease.
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30
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Vitali R, Prioreschi C, Lorenzo Rebenaque L, Colantoni E, Giovannini D, Frusciante S, Diretto G, Marco-Jiménez F, Mancuso M, Casciati A, Pazzaglia S. Gut–Brain Axis: Insights from Hippocampal Neurogenesis and Brain Tumor Development in a Mouse Model of Experimental Colitis Induced by Dextran Sodium Sulfate. Int J Mol Sci 2022; 23:ijms231911495. [PMID: 36232813 PMCID: PMC9569494 DOI: 10.3390/ijms231911495] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/23/2022] [Accepted: 09/26/2022] [Indexed: 11/28/2022] Open
Abstract
Chronic inflammatory bowel disorders (IBD) are idiopathic diseases associated with altered intestinal permeability, which in turn causes an exaggerated immune response to enteric antigens in a genetically susceptible host. A rise in psych cognitive disorders, such as anxiety and depression, has been observed in IBD patients. We here report investigations on a model of chemically induced experimental colitis by oral administration of sodium dextran sulfate (DSS) in C57BL/6 mice. We investigate, in vivo, the crosstalk between the intestine and the brain, evaluating the consequences of intestinal inflammation on neuroinflammation and hippocampal adult neurogenesis. By using different DSS administration strategies, we are able to induce acute or chronic colitis, simulating clinical characteristics observed in IBD patients. Body weight loss, colon shortening, alterations of the intestinal mucosa and fecal metabolic changes in amino acids-, lipid- and thiamine-related pathways are observed in colitis. The activation of inflammatory processes in the colon is confirmed by macrophage infiltration and increased expression of the proinflammatory cytokine and oxidative stress marker (Il-6 and iNOS). Interestingly, in the hippocampus of acutely DSS-treated mice, we report the upregulation of inflammatory-related genes (Il-6, Il-1β, S-100, Tgf-β and Smad-3), together with microgliosis. Chronic DSS treatment also resulted in neuroinflammation in the hippocampus, indicated by astrocyte activation. Evaluation of stage-specific neurogenesis markers reveals deficits in the dentate gyrus after acute and chronic DSS treatments, indicative of defective adult hippocampal neurogenesis. Finally, based on a possible causal relationship between gut-related inflammation and brain cancer, we investigate the impact of DSS-induced colitis on oncogenesis, using the Ptch1+/−/C57BL/6 mice, a well-established medulloblastoma (MB) mouse model, finding no differences in MB development between untreated and DSS-treated mice. In conclusion, in our experimental model, the intestinal inflammation associated with acute and chronic colitis markedly influences brain homeostasis, impairing hippocampal neurogenesis but not MB oncogenesis.
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Affiliation(s)
- Roberta Vitali
- Biomedical Technologies Laboratory, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Clara Prioreschi
- Biomedical Technologies Laboratory, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Laura Lorenzo Rebenaque
- Departamento Producción y Sanidad Animal, Salud Pública Veterinaria y Ciencia y Tecnología de los Alimentos, Universidad CEU-Cardenal Herrera, 46115 Valencia, Spain
| | - Eleonora Colantoni
- Biomedical Technologies Laboratory, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Daniela Giovannini
- Biomedical Technologies Laboratory, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Sarah Frusciante
- Biotechnology Laboratory, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Gianfranco Diretto
- Biotechnology Laboratory, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Francisco Marco-Jiménez
- Laboratory of Biotechnology of Reproduction, Institute for Animal Science and Technology (ICTA), Universitat Politècnica de València, 46022 Valencia, Spain
| | - Mariateresa Mancuso
- Biomedical Technologies Laboratory, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Arianna Casciati
- Biomedical Technologies Laboratory, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
- Correspondence: (A.C.); (S.P.)
| | - Simonetta Pazzaglia
- Biomedical Technologies Laboratory, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
- Correspondence: (A.C.); (S.P.)
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31
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Günther C, Winner B, Neurath MF, Stappenbeck TS. Organoids in gastrointestinal diseases: from experimental models to clinical translation. Gut 2022; 71:1892-1908. [PMID: 35636923 PMCID: PMC9380493 DOI: 10.1136/gutjnl-2021-326560] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 05/13/2022] [Indexed: 12/12/2022]
Abstract
We are entering an era of medicine where increasingly sophisticated data will be obtained from patients to determine proper diagnosis, predict outcomes and direct therapies. We predict that the most valuable data will be produced by systems that are highly dynamic in both time and space. Three-dimensional (3D) organoids are poised to be such a highly valuable system for a variety of gastrointestinal (GI) diseases. In the lab, organoids have emerged as powerful systems to model molecular and cellular processes orchestrating natural and pathophysiological human tissue formation in remarkable detail. Preclinical studies have impressively demonstrated that these organs-in-a-dish can be used to model immunological, neoplastic, metabolic or infectious GI disorders by taking advantage of patient-derived material. Technological breakthroughs now allow to study cellular communication and molecular mechanisms of interorgan cross-talk in health and disease including communication along for example, the gut-brain axis or gut-liver axis. Despite considerable success in culturing classical 3D organoids from various parts of the GI tract, some challenges remain to develop these systems to best help patients. Novel platforms such as organ-on-a-chip, engineered biomimetic systems including engineered organoids, micromanufacturing, bioprinting and enhanced rigour and reproducibility will open improved avenues for tissue engineering, as well as regenerative and personalised medicine. This review will highlight some of the established methods and also some exciting novel perspectives on organoids in the fields of gastroenterology. At present, this field is poised to move forward and impact many currently intractable GI diseases in the form of novel diagnostics and therapeutics.
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Affiliation(s)
- Claudia Günther
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Beate Winner
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Department of Stem Cell Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
- Center of Rare Diseases Erlangen (ZSEER), University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Thaddeus S Stappenbeck
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
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32
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Sazonovs A, Stevens CR, Venkataraman GR, Yuan K, Avila B, Abreu MT, Ahmad T, Allez M, Ananthakrishnan AN, Atzmon G, Baras A, Barrett JC, Barzilai N, Beaugerie L, Beecham A, Bernstein CN, Bitton A, Bokemeyer B, Chan A, Chung D, Cleynen I, Cosnes J, Cutler DJ, Daly A, Damas OM, Datta LW, Dawany N, Devoto M, Dodge S, Ellinghaus E, Fachal L, Farkkila M, Faubion W, Ferreira M, Franchimont D, Gabriel SB, Ge T, Georges M, Gettler K, Giri M, Glaser B, Goerg S, Goyette P, Graham D, Hämäläinen E, Haritunians T, Heap GA, Hiltunen M, Hoeppner M, Horowitz JE, Irving P, Iyer V, Jalas C, Kelsen J, Khalili H, Kirschner BS, Kontula K, Koskela JT, Kugathasan S, Kupcinskas J, Lamb CA, Laudes M, Lévesque C, Levine AP, Lewis JD, Liefferinckx C, Loescher BS, Louis E, Mansfield J, May S, McCauley JL, Mengesha E, Mni M, Moayyedi P, Moran CJ, Newberry RD, O'Charoen S, Okou DT, Oldenburg B, Ostrer H, Palotie A, Paquette J, Pekow J, Peter I, Pierik MJ, Ponsioen CY, Pontikos N, Prescott N, Pulver AE, Rahmouni S, Rice DL, Saavalainen P, Sands B, Sartor RB, Schiff ER, Schreiber S, Schumm LP, Segal AW, Seksik P, Shawky R, et alSazonovs A, Stevens CR, Venkataraman GR, Yuan K, Avila B, Abreu MT, Ahmad T, Allez M, Ananthakrishnan AN, Atzmon G, Baras A, Barrett JC, Barzilai N, Beaugerie L, Beecham A, Bernstein CN, Bitton A, Bokemeyer B, Chan A, Chung D, Cleynen I, Cosnes J, Cutler DJ, Daly A, Damas OM, Datta LW, Dawany N, Devoto M, Dodge S, Ellinghaus E, Fachal L, Farkkila M, Faubion W, Ferreira M, Franchimont D, Gabriel SB, Ge T, Georges M, Gettler K, Giri M, Glaser B, Goerg S, Goyette P, Graham D, Hämäläinen E, Haritunians T, Heap GA, Hiltunen M, Hoeppner M, Horowitz JE, Irving P, Iyer V, Jalas C, Kelsen J, Khalili H, Kirschner BS, Kontula K, Koskela JT, Kugathasan S, Kupcinskas J, Lamb CA, Laudes M, Lévesque C, Levine AP, Lewis JD, Liefferinckx C, Loescher BS, Louis E, Mansfield J, May S, McCauley JL, Mengesha E, Mni M, Moayyedi P, Moran CJ, Newberry RD, O'Charoen S, Okou DT, Oldenburg B, Ostrer H, Palotie A, Paquette J, Pekow J, Peter I, Pierik MJ, Ponsioen CY, Pontikos N, Prescott N, Pulver AE, Rahmouni S, Rice DL, Saavalainen P, Sands B, Sartor RB, Schiff ER, Schreiber S, Schumm LP, Segal AW, Seksik P, Shawky R, Sheikh SZ, Silverberg MS, Simmons A, Skeiceviciene J, Sokol H, Solomonson M, Somineni H, Sun D, Targan S, Turner D, Uhlig HH, van der Meulen AE, Vermeire S, Verstockt S, Voskuil MD, Winter HS, Young J, Duerr RH, Franke A, Brant SR, Cho J, Weersma RK, Parkes M, Xavier RJ, Rivas MA, Rioux JD, McGovern DPB, Huang H, Anderson CA, Daly MJ. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility. Nat Genet 2022; 54:1275-1283. [PMID: 36038634 PMCID: PMC9700438 DOI: 10.1038/s41588-022-01156-2] [Show More Authors] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 07/12/2022] [Indexed: 01/18/2023]
Abstract
Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.
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Affiliation(s)
- Aleksejs Sazonovs
- Genomics of Inflammation and Immunity Group, Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Christine R Stevens
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | | | - Kai Yuan
- Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Brandon Avila
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Maria T Abreu
- Crohn's and Colitis Center, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | | | - Matthieu Allez
- Hopital Saint-Louis, APHP, Universite de Paris, INSERM U1160, Paris, France
| | - Ashwin N Ananthakrishnan
- Division of Gastroenterology, Crohn's and Colitis Center, Massachusetts General Hospital, Boston, MA, USA
| | - Gil Atzmon
- Department for Human Biology, University of Haifa, Haifa, Israel
- Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Aris Baras
- Regeneron Genetics Center, Tarrytown, NY, USA
| | - Jeffrey C Barrett
- Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Nir Barzilai
- Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
- The Institute for Aging Research, The Nathan Shock Center of Excellence in the Basic Biology of Aging and the Paul F. Glenn Center for the Biology of Human Aging Research at Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, USA
| | - Laurent Beaugerie
- Gastroenterology Department, Sorbonne Universite, Saint Antoine Hospital, Paris, France
| | - Ashley Beecham
- John P. Hussman Institute for Human Genomics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
- The Dr. John T. Macdonald Foundation Department of Human Genetics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | | | - Alain Bitton
- McGill University and McGill University Health Centre, Montreal, Quebec, Canada
| | - Bernd Bokemeyer
- Department of Internal Medicine, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Andrew Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Womens Hospital, Boston, MA, USA
| | | | | | - Jacques Cosnes
- Professeur Chef de Service chez APHP and Universite Paris-6, Paris, France
| | - David J Cutler
- Department of Human Genetics, Emory University, Atlanta, GA, USA
- Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Allan Daly
- Human Genetics Informatics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | | | - Lisa W Datta
- Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Noor Dawany
- Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA
| | - Marcella Devoto
- Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA
- University of Rome Sapienza, Rome, Italy
- IRGB - CNR, Cagliari, Italy
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
| | - Sheila Dodge
- Genomics Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Eva Ellinghaus
- Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Laura Fachal
- Genomics of Inflammation and Immunity Group, Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | | | | | | | | | - Stacey B Gabriel
- Genomics Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Tian Ge
- Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA, USA
| | | | - Kyle Gettler
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Mamta Giri
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Benjamin Glaser
- Department of Endocrinology and Metabolism, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | | | - Philippe Goyette
- Research Center Montreal Heart Institute, Montreal, Quebec, Canada
| | - Daniel Graham
- Infectious Disease and Microbiome Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
| | - Eija Hämäläinen
- Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Talin Haritunians
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | | | - Mikko Hiltunen
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
| | - Marc Hoeppner
- Christian-Albrechts-University of Kiel, Kiel, Germany
| | | | - Peter Irving
- Department of Gastroenterology, Guys and Saint Thomas Hospital, London, UK
- School of Immunology and Microbial Sciences, Kings College London, London, UK
| | - Vivek Iyer
- Human Genetics Informatics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Chaim Jalas
- Director of Genetic Resources and Services, Center for Rare Jewish Genetic Disorders, Bonei Olam, Brooklyn, NY, USA
| | - Judith Kelsen
- Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA
| | - Hamed Khalili
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Barbara S Kirschner
- Department of Gastroenterology, University of Chicago Medicine, Chicago, IL, USA
| | - Kimmo Kontula
- Department of Medicine, Helsinki University Hospital, and Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland
| | - Jukka T Koskela
- Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Subra Kugathasan
- Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Juozas Kupcinskas
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Christopher A Lamb
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
- Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | | | - Chloé Lévesque
- Research Center Montreal Heart Institute, Montreal, Quebec, Canada
| | | | - James D Lewis
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
- Crohn's and Colitis Foundation, New York, NY, USA
| | | | - Britt-Sabina Loescher
- Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | | | - John Mansfield
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
- Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Sandra May
- Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Jacob L McCauley
- John P. Hussman Institute for Human Genomics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
- The Dr. John T. Macdonald Foundation Department of Human Genetics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Emebet Mengesha
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Myriam Mni
- University of Liège, ULG, Liège, Belgium
| | | | | | | | | | - David T Okou
- Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA
- Institut National de Sante Publique (INSP), Abidjan, Côte d'Ivoire
| | - Bas Oldenburg
- Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Harry Ostrer
- Albert Einstein College of Medicine, Bronx, NY, USA
| | - Aarno Palotie
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland
- Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
- Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
| | - Jean Paquette
- Research Center Montreal Heart Institute, Montreal, Quebec, Canada
| | - Joel Pekow
- Department of Gastroenterology, University of Chicago Medicine, Chicago, IL, USA
| | - Inga Peter
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Marieke J Pierik
- Department of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | | | - Natalie Prescott
- Department of Medical and Molecular Genetics, Kings College London, London, UK
| | - Ann E Pulver
- School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | | | - Daniel L Rice
- Genomics of Inflammation and Immunity Group, Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Päivi Saavalainen
- Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
| | - Bruce Sands
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - R Balfour Sartor
- Center for Gastrointestinal Biology and Disease, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | | | - Stefan Schreiber
- Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - L Philip Schumm
- Department of Public Health Sciences, University of Chicago, Chicago, IL, USA
| | | | - Philippe Seksik
- Gastroenterology Department, Sorbonne Universite, Saint Antoine Hospital, Paris, France
| | - Rasha Shawky
- IBD BioResource, NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Shehzad Z Sheikh
- Center for Gastrointestinal Biology and Disease, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | | | - Alison Simmons
- MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Jurgita Skeiceviciene
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Harry Sokol
- Gastroenterology Department, Sorbonne Universite, Saint Antoine Hospital, Paris, France
| | - Matthew Solomonson
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Hari Somineni
- Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Dylan Sun
- Regeneron Genetics Center, Tarrytown, NY, USA
| | - Stephan Targan
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Dan Turner
- Shaare Zedek Medical Center, Jerusalem, Israel
| | - Holm H Uhlig
- Translational Gastroenterology Unit and Biomedical Research Centre, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford, Oxford, UK
- Department of Pediatrics, John Radcliffe Hospital, Oxford, UK
| | - Andrea E van der Meulen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Séverine Vermeire
- University Hospitals Leuven, Leuven, Belgium
- Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Sare Verstockt
- Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Michiel D Voskuil
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | | | | | | | - Andre Franke
- Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Steven R Brant
- Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Crohn's Colitis Center of New Jersey, Department of Medicine, Rutgers Robert Wood Johnson Medical School and Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers University, New Brunswick and Piscataway, NJ, USA
| | - Judy Cho
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Miles Parkes
- Department of Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Ramnik J Xavier
- Infectious Disease and Microbiome Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Kurt Isselbacher Professor of Medicine at Harvard Medical School, Cambridge, MA, USA
- Core Institute Member, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Klarman Cell Observatory, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Immunology Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Microbiome Informatics and Therapeutics at MIT, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Manuel A Rivas
- Department of Biomedical Data Science, Stanford University, Stanford, CA, USA
| | - John D Rioux
- Research Center Montreal Heart Institute, Montreal, Quebec, Canada
- Faculty of Medicine, Université de Montréal, Montreal, Canada
| | - Dermot P B McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Hailiang Huang
- Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
| | - Carl A Anderson
- Genomics of Inflammation and Immunity Group, Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
| | - Mark J Daly
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
- Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.
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Proteomic analyses do not reveal subclinical inflammation in fatigued patients with clinically quiescent inflammatory bowel disease. Sci Rep 2022; 12:14581. [PMID: 36028644 PMCID: PMC9418325 DOI: 10.1038/s41598-022-17504-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 07/26/2022] [Indexed: 11/08/2022] Open
Abstract
Fatigue is a common and clinically challenging symptom in patients with inflammatory bowel diseases (IBD), occurring in ~ 50% of patients with quiescent disease. In this study, we aimed to investigate whether fatigue in patients with clinically quiescent IBD is reflected by circulating inflammatory proteins, which might reflect ongoing subclinical inflammation. Ninety-two (92) different inflammation-related proteins were measured in plasma of 350 patients with clinically quiescent IBD. Quiescent IBD was defined as clinical (Harvey-Bradshaw Index < 5 or Simple Clinical Colitis Activity Index < 2.5) and biochemical remission (C-reactive protein < 5 mg/L and absence of anemia) at time of fatigue assessment. Leukemia inhibitory factor receptor (LIF-R) concentrations were inversely associated with severe fatigue, also after adjustment for confounding factors (nominal P < 0.05). Although solely LIF-R showed weak ability to discriminate between mild and severe fatigue (area under the curve [AUC] = 0.61, 95%CI: 0.53–0.69, P < 0.05), a combined set of the top seven (7) fatigue-associated proteins (all P < 0.10) was observed to have reasonable discriminative performance (AUC = 0.82 [95%CI: 0.74–0.91], P < 0.01). Fatigue in patients with IBD is not clearly reflected by distinct protein signatures, suggesting there is no subclinical inflammation defined by the studied inflammatory proteins. Future studies are warranted to investigate other proteomic markers that may reflect fatigue in clinically quiescent IBD.
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Rana T. Influence and Implications of the Molecular Paradigm of Nitric Oxide Underlying Inflammatory Reactions of the Gastrointestinal Tract of Dog: A Major Hallmark of Inflammatory Bowel Disease. Inflamm Bowel Dis 2022; 28:1280-1288. [PMID: 35312776 DOI: 10.1093/ibd/izac017] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Indexed: 12/09/2022]
Abstract
Nitric oxide (NO), a pleiotropic free radical messenger molecule, is responsible for the various cellular function of the gastrointestinal mucosa. It plays a major role in the maintenance of perfusion, regulation of microvascular, epithelial permeability, and immune functions. Nitric oxide exerts its beneficial effect on the initiation and maintenance of inflammation in human inflammatory bowel disease (IBD). But the accelerated production of NO triggers activation of the inducible form of the NO synthase enzyme (iNOS) that leads to damages of the intestinal membrane. Nitric oxide synthase enzyme is responsible for the higher production of NO from l-arginine and causes an inflammatory condition in the intestinal epithelium. Nitric oxide induces nitrative DNA damage and oxidative DNA damage in the cellular system. Accelerated production of NO enhances iNOS activity that is associated with cytotoxicity and apoptosis of gastrointestinal epithelial cells in the dog. Chronic inflammation leads to angiogenesis that is modulated by the immune system in IBD. Chronic inflammation is a major risk factor for the development of gastrointestinal malignancies. Nitric oxide participates in mucosal inflammation in the intestine through invigoration of NO synthase enzyme. The intrinsic complex mechanism is correlated with the inflammation in the gastrointestinal tract and is also correlated with the expression of iNOS, enzymatic activity and NO production. Nitric oxide employs a significant role in modulating epithelial permeability with accelerated immune response in acute colitis. But the enormous generation of NO causes adverse effects on the mucosal cell during the inflammatory process in IBD. In this review, a complex episode of NO generation with altered biochemical pathways was assessed for the regulation of mucosal inflammation in inflammatory bowel disease of dogs. This review is a unique compilation of the role of NO in the pathogenesis of inflammatory bowel disease of dogs. Nitric oxide plays a key role in modulating cancer in the gastrointestinal tract. This review seeks to explore the characteristics of NO as a major hallmark of canine inflammatory bowel diseases.
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Affiliation(s)
- Tanmoy Rana
- Department of Veterinary Clinical Complex (VMEJ), West Bengal University of Animal & Fishery Science, Kolkata, India
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35
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Behl T, Gupta A, Sehgal A, Singh S, Sharma N, Garg M, Bhatia S, Al-Harrasi A, Aleya L, Bungau S. Exploring the multifaceted role of TGF-β signaling in diabetic complications. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:35643-35656. [PMID: 35247177 DOI: 10.1007/s11356-022-19499-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 02/24/2022] [Indexed: 06/14/2023]
Abstract
Diabetes is one of the most comprehensive metabolic disorders and is spread across the globe. The data from IDF Diabetes Atlas and National Diabetes Statistics mentions that the number of patients with diabetes is increasing at an exponential rate which is challenging the current therapeutics used for the management of diabetes. However, current therapies used for the treatment may provide symptomatic relief but lack in preventing the progression of the disease and thereby limiting the treatment of diabetes-associated complications. A thorough review and analysis were conducted using various databases including EMBASE, MEDLINE, and Google Scholar to extract the available information on challenges faced by current therapies which have triggered the development of novel molecules or drugs. From the analysis, it was analyzed that transforming growth factor βs (TGF-βs) have been shown to exhibit pleiotropic activity and are responsible for maintaining homeostasis and its overexpression is convoluted in the pathogenesis of various disorders. Therefore, developing drugs that block TGF-β signaling may provide therapeutic benefits. This extensive review concluded that drugs targeting TGF-β signaling pathway and its subsequent blockade have shown promising results and hold the potential to become drugs of choice in the management of diabetes and associated complications.
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Affiliation(s)
- Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Amit Gupta
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Madhukar Garg
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Saurabh Bhatia
- Natural & Medical Sciences Research Centre, University of Nizwa, Nizwa, Oman
- Adjunct Professor, Amity Institute of Pharmacy, Amity University, Haryana, India
| | - Ahmed Al-Harrasi
- Natural & Medical Sciences Research Centre, University of Nizwa, Nizwa, Oman
| | - Lotfi Aleya
- Chrono-Environment Laboratory, UMR CNRS 6249, Bourgogne Franche-Comté University, Bourgogne Franche-Comté, France
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
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36
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Principi M, Scicchitano P, Carparelli S, Nitti R, Ruggieri R, Bellino MC, Cecere A, Manca F, DI Leo A, Ciccone MM. Influence of systemic manifestations of inflammatory bowel diseases on endothelial function and cardiovascular risk. Minerva Med 2022; 113:291-299. [PMID: 33913656 DOI: 10.23736/s0026-4806.21.06970-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Inflammatory bowel diseases (IBD) may be complicated by extraintestinal manifestations (EIM). Both conditions may be implicated in the overall increase of cardiovascular (CV) risk profile of the patients. The study aimed to assess CV risk in IBD patients with EIMs in relation to the stages of both diseases. METHODS A total of 70 (38 men, mean age 51.7±12.4 years) patients with IBD and 22 controls (12 men, mean age 49.2±13.6 years) were enrolled. All patients and controls were screened for extraintestinal manifestations and underwent physical and anthropometric examinations, standard laboratory investigations, ultrasound evaluation of carotid arteries and flow-mediated vasodilatation (FMD). Patients were divided into four groups in relation to their active or remission stage of disease: 1) IBD+ EIM+; 2) IBD+ EIM-; 3) IBD- EIM+; and 4) IBD- EIM-. RESULTS The groups were homogenous according to their clinical characteristics. Patients with both IBD and EIM in active phase showed significantly lower values in FMD than controls (P=0.024). Carotid intima-media thickness values (cIMT) were similar among groups. Patients with active phases of IBD and/or EIM showed statistically significant lower values in FMD measurements (P=0.0008 and P=0.0011, respectively). Multivariate regression did not reveal any independent predictors for FMD values. CONCLUSIONS The active phase of IBD or EIM or both may promote endothelial dysfunction in patients, thus increasing their CV risk profile. Patients in remission phase showed endothelial function similar at controls.
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Affiliation(s)
- Mariabeatrice Principi
- Unit of Gastroenterology, Department of Emergency and Organ Transplantation - DETO, University of Bari, Bari, Italy
| | - Pietro Scicchitano
- Section of Cardiovascular Diseases, Ospedale della Murgia Fabio Perinei, Altamura, Bari, Italy -
- Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation - DETO, University of Bari, Bari, Italy
| | - Sonia Carparelli
- Unit of Gastroenterology, Department of Emergency and Organ Transplantation - DETO, University of Bari, Bari, Italy
| | - Rosa Nitti
- Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation - DETO, University of Bari, Bari, Italy
| | - Roberta Ruggieri
- Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation - DETO, University of Bari, Bari, Italy
| | - Maria C Bellino
- Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation - DETO, University of Bari, Bari, Italy
| | - Annagrazia Cecere
- Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation - DETO, University of Bari, Bari, Italy
| | - Fabio Manca
- Department of Science of Educational, Psychology, and Communication, University of Bari, Bari, Italy
| | - Alfredo DI Leo
- Unit of Gastroenterology, Department of Emergency and Organ Transplantation - DETO, University of Bari, Bari, Italy
| | - Marco M Ciccone
- Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation - DETO, University of Bari, Bari, Italy
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37
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Craig CF, Filippone RT, Stavely R, Bornstein JC, Apostolopoulos V, Nurgali K. Neuroinflammation as an etiological trigger for depression comorbid with inflammatory bowel disease. J Neuroinflammation 2022; 19:4. [PMID: 34983592 PMCID: PMC8729103 DOI: 10.1186/s12974-021-02354-1] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 12/14/2021] [Indexed: 02/06/2023] Open
Abstract
Patients with inflammatory bowel disease (IBD) suffer from depression at higher rates than the general population. An etiological trigger of depressive symptoms is theorised to be inflammation within the central nervous system. It is believed that heightened intestinal inflammation and dysfunction of the enteric nervous system (ENS) contribute to impaired intestinal permeability, which facilitates the translocation of intestinal enterotoxins into the blood circulation. Consequently, these may compromise the immunological and physiological functioning of distant non-intestinal tissues such as the brain. In vivo models of colitis provide evidence of increased blood–brain barrier permeability and enhanced central nervous system (CNS) immune activity triggered by intestinal enterotoxins and blood-borne inflammatory mediators. Understanding the immunological, physiological, and structural changes associated with IBD and neuroinflammation may aid in the development of more tailored and suitable pharmaceutical treatment for IBD-associated depression.
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Affiliation(s)
- Colin F Craig
- Institute for Heath and Sport, Victoria University, Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia
| | - Rhiannon T Filippone
- Institute for Heath and Sport, Victoria University, Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia
| | - Rhian Stavely
- Institute for Heath and Sport, Victoria University, Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia.,Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Joel C Bornstein
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Australia
| | - Vasso Apostolopoulos
- Institute for Heath and Sport, Victoria University, Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia.,Immunology Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC, Australia
| | - Kulmira Nurgali
- Institute for Heath and Sport, Victoria University, Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia. .,Department of Medicine Western Health, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia. .,Regenerative Medicine and Stem Cells Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC, Australia. .,Institute for Health and Sport, Victoria University, Level 4 Research Labs, Western Centre for Health Research and Education, Sunshine Hospital, 176 Furlong Road, St Albans, VIC, 3021, Australia.
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38
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Carloni S, Rescigno M. Unveiling the gut-brain axis: structural and functional analogies between the gut and the choroid plexus vascular and immune barriers. Semin Immunopathol 2022; 44:869-882. [PMID: 35861857 PMCID: PMC9301898 DOI: 10.1007/s00281-022-00955-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 06/14/2022] [Indexed: 02/07/2023]
Abstract
The vasculature plays an essential role in the development and maintenance of blood-tissue interface homeostasis. Knowledge on the morphological and functional nature of the blood vessels in every single tissue is, however, very poor, but it is becoming clear that each organ is characterized by the presence of endothelial barriers with different properties fundamental for the maintenance of tissue resident immune homeostasis and for the recruitment of blood-trafficking immune cells. The tissue specificity of the vascular unit is dependent on the presence of differentiated endothelial cells that form continues, fenestrated, or sinusoidal vessels with different grades of permeability and different immune receptors, according to how that particular tissue needs to be protected. The gut-brain axis highlights the prominent role that the vasculature plays in allowing a direct and prompt exchange of molecules between the gut, across the gut vascular barrier (GVB), and the brain. Recently, we identified a new choroid plexus vascular barrier (PVB) which receives and integrates information coming from the gut and is fundamental in the modulation of the gut-brain axis. Several pathologies are linked to functional dysregulation of either the gut or the choroid plexus vascular barriers. In this review, we unveil the structural and functional analogies between the GVB and PVB, comparing their peculiar features and highlighting the functional role of pitcher and catcher of the gut-brain axis, including their role in the establishment of immune homeostasis and response upon systemic stimuli. We propose that when the gut vascular barrier-the main protecting system of the body from the external world-is compromised, the choroid plexus gatekeeper becomes a second barrier that protects the central nervous system from systemic inflammation.
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Affiliation(s)
- Sara Carloni
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini, 20072, Pieve Emanuele, MI, Italy.
- IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, MI, Italy.
| | - Maria Rescigno
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini, 20072, Pieve Emanuele, MI, Italy.
- IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, MI, Italy.
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39
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Jagadeesh KA, Dey KK, Montoro DT, Mohan R, Gazal S, Engreitz JM, Xavier RJ, Price AL, Regev A. Identifying disease-critical cell types and cellular processes across the human body by integration of single-cell profiles and human genetics. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2021:2021.03.19.436212. [PMID: 34845454 PMCID: PMC8629197 DOI: 10.1101/2021.03.19.436212] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Genome-wide association studies (GWAS) provide a powerful means to identify loci and genes contributing to disease, but in many cases the related cell types/states through which genes confer disease risk remain unknown. Deciphering such relationships is important for identifying pathogenic processes and developing therapeutics. Here, we introduce sc-linker, a framework for integrating single-cell RNA-seq (scRNA-seq), epigenomic maps and GWAS summary statistics to infer the underlying cell types and processes by which genetic variants influence disease. We analyzed 1.6 million scRNA-seq profiles from 209 individuals spanning 11 tissue types and 6 disease conditions, and constructed gene programs capturing cell types, disease progression, and cellular processes both within and across cell types. We evaluated these gene programs for disease enrichment by transforming them to SNP annotations with tissue-specific epigenomic maps and computing enrichment scores across 60 diseases and complex traits (average N= 297K). Cell type, disease progression, and cellular process programs captured distinct heritability signals even within the same cell type, as we show in multiple complex diseases that affect the brain (Alzheimer’s disease, multiple sclerosis), colon (ulcerative colitis) and lung (asthma, idiopathic pulmonary fibrosis, severe COVID-19). The inferred disease enrichments recapitulated known biology and highlighted novel cell-disease relationships, including GABAergic neurons in major depressive disorder (MDD), a disease progression M cell program in ulcerative colitis, and a disease-specific complement cascade process in multiple sclerosis. In autoimmune disease, both healthy and disease progression immune cell type programs were associated, whereas for epithelial cells, disease progression programs were most prominent, perhaps suggesting a role in disease progression over initiation. Our framework provides a powerful approach for identifying the cell types and cellular processes by which genetic variants influence disease.
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40
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Carloni S, Bertocchi A, Mancinelli S, Bellini M, Erreni M, Borreca A, Braga D, Giugliano S, Mozzarelli AM, Manganaro D, Fernandez Perez D, Colombo F, Di Sabatino A, Pasini D, Penna G, Matteoli M, Lodato S, Rescigno M. Identification of a choroid plexus vascular barrier closing during intestinal inflammation. Science 2021; 374:439-448. [PMID: 34672740 DOI: 10.1126/science.abc6108] [Citation(s) in RCA: 160] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Sara Carloni
- Humanitas University, Department of Biomedical Sciences, 20072 Pieve Emanuele (Milan), Italy.,IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
| | - Alice Bertocchi
- IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
| | - Sara Mancinelli
- Humanitas University, Department of Biomedical Sciences, 20072 Pieve Emanuele (Milan), Italy.,IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
| | - Martina Bellini
- Humanitas University, Department of Biomedical Sciences, 20072 Pieve Emanuele (Milan), Italy.,IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
| | - Marco Erreni
- Humanitas University, Department of Biomedical Sciences, 20072 Pieve Emanuele (Milan), Italy.,IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
| | - Antonella Borreca
- IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy.,Institute of Neuroscience, National Research Council, c/o Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
| | - Daniele Braga
- IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
| | | | - Alessandro M Mozzarelli
- Humanitas University, Department of Biomedical Sciences, 20072 Pieve Emanuele (Milan), Italy.,IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
| | - Daria Manganaro
- Department of Experimental Oncology, European Institute of Oncology (IEO), IRCCS, 20139 Milan, Italy
| | - Daniel Fernandez Perez
- Department of Experimental Oncology, European Institute of Oncology (IEO), IRCCS, 20139 Milan, Italy
| | | | - Antonio Di Sabatino
- Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, 27100 Pavia, Italy
| | - Diego Pasini
- Department of Experimental Oncology, European Institute of Oncology (IEO), IRCCS, 20139 Milan, Italy.,Department of Health Sciences, University of Milan, 20142 Milan, Italy
| | - Giuseppe Penna
- IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
| | - Michela Matteoli
- IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy.,Institute of Neuroscience, National Research Council, c/o Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
| | - Simona Lodato
- Humanitas University, Department of Biomedical Sciences, 20072 Pieve Emanuele (Milan), Italy.,IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
| | - Maria Rescigno
- Humanitas University, Department of Biomedical Sciences, 20072 Pieve Emanuele (Milan), Italy.,IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
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41
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Stürzl M, Kunz M, Krug SM, Naschberger E. Angiocrine Regulation of Epithelial Barrier Integrity in Inflammatory Bowel Disease. Front Med (Lausanne) 2021; 8:643607. [PMID: 34409045 PMCID: PMC8365087 DOI: 10.3389/fmed.2021.643607] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 07/07/2021] [Indexed: 12/16/2022] Open
Abstract
Inflammatory bowel disease describes chronic inflammatory disorders. The incidence of the disease is rising. A major step in disease development is the breakdown of the epithelial cell barrier. Numerous blood vessels are directly located underneath this barrier. Diseased tissues are heavily vascularized and blood vessels significantly contribute to disease progression. The gut-vascular barrier (GVB) is an additional barrier controlling the entry of substances into the portal circulation and to the liver after passing the first epithelial barrier. The presence of the GVB rises the question, whether the vascular and endothelial barriers may communicate bi-directionally in the regulation of selective barrier permeability. Communication from epithelial to endothelial cells is well-accepted. In contrast, little is known on the respective backwards communication. Only recently, perfusion-independent angiocrine functions of endothelial cells were recognized in a way that endothelial cells release specific soluble factors that may directly act on the epithelial barrier. This review discusses the putative involvement of angiocrine inter-barrier communication in the pathogenesis of IBD.
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Affiliation(s)
- Michael Stürzl
- Division of Molecular and Experimental Surgery, Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander University (FAU) of Erlangen-Nürnberg, Erlangen, Germany
| | - Meik Kunz
- Chair of Medical Informatics, Friedrich-Alexander-University (FAU) of Erlangen-Nürnberg, Erlangen, and Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany
| | - Susanne M. Krug
- Clinical Physiology/Nutritional Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Elisabeth Naschberger
- Division of Molecular and Experimental Surgery, Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander University (FAU) of Erlangen-Nürnberg, Erlangen, Germany
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42
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Martin P, Gurevich DB. Macrophage regulation of angiogenesis in health and disease. Semin Cell Dev Biol 2021; 119:101-110. [PMID: 34330619 DOI: 10.1016/j.semcdb.2021.06.010] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 05/24/2021] [Accepted: 06/18/2021] [Indexed: 12/15/2022]
Abstract
Macrophages are primarily known as phagocytic innate immune cells, but are, in fact, highly dynamic multi-taskers that interact with many different tissue types and have regulatory roles in development, homeostasis, tissue repair, and disease. In all of these scenarios angiogenesis is pivotal and macrophages appear to play a key role in guiding both blood vessel sprouting and remodelling wherever that occurs. Recent studies have explored these processes in a diverse range of models utilising the complementary strengths of rodent, fish and tissue culture studies to unravel the mechanisms underlying these interactions and regulatory functions. Here we discuss how macrophages regulate angiogenesis and its resolution as embryonic tissues grow, as well as their parallel and different functions in repairing wounds and in pathologies, with a focus on chronic wounds and cancer.
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Affiliation(s)
- Paul Martin
- School of Biochemistry, Biomedical Sciences, University of Bristol, Bristol BS8 1TD, UK; School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, Bristol BS8 1TD, UK
| | - David Baruch Gurevich
- Department of Biology & Biochemistry, Faculty of Science, University of Bath, Claverton Down, Bath BA2 7AY, UK.
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43
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Triantafyllou C, Nikolaou M, Ikonomidis I, Bamias G, Kouretas D, Andreadou I, Tsoumani M, Thymis J, Papaconstantinou I. Effects of Anti-Inflammatory Treatment and Surgical Intervention on Endothelial Glycocalyx, Peripheral and Coronary Microcirculatory Function and Myocardial Deformation in Inflammatory Bowel Disease Patients: A Two-Arms Two-Stage Clinical Trial. Diagnostics (Basel) 2021; 11:993. [PMID: 34070768 PMCID: PMC8227308 DOI: 10.3390/diagnostics11060993] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 02/06/2023] Open
Abstract
Sixty inflammatory bowel disease (IBD) patients (45 Crohn disease and 15 ulcerative colitis, 40 ± 13 years, 53% male) were examined at baseline and 4 months after intervention (surgical (35 patients) or anti-TNFa treatment (25 patients)). IBD severity, using Mayo score, Harvey-Bradshaw Index (HBI) and biomarkers, was correlated with cardiovascular markers. At baseline, the disease severity, the white blood cells (WBC) values and the reducing power (RP) were significantly correlated with the aortic pulse wave velocity (PWV) (r = 0.4, r = 0.44 and r = 0.48, p < 0.05) and the lateral mitral E' velocity (r = 0.35, p < 0.05 and r = 0.3, p < 0.05). Four months after intervention, there was a reduction of WBC (1962.8/mm3 ± 0.425/mm3, p < 0.001), C-reactive protein (CRP) (8.1 mg/L ± 1.7 mg/L, p < 0.001), malondialdehyde (MDA) (0.81 nmol/mg ± 0.37, p < 0.05) and glycocalyx perfused boundary region (PBR 5-25) (0.24 μm ± 0.05 μm, p < 0.01). Moreover, the brachial flow mediated dilatation (FMD), the coronary flow reserve (CFR) and the left ventricle global longitudinal strain (LV GLS) were significantly improved for both groups (4.5% ± 0.9%, 0.55 ± 0.08, 1.4% ± 0.35%, p < 0.01), while a more significant improvement of PWV/GLS was noticed in the anti-TNFa group. IBD severity is associated with vascular endothelial, cardiac diastolic, and coronary microcirculatory dysfunction. The systemic inflammatory inhibition and the local surgical intervention lead to significant improvement in endothelial function, coronary microcirculation and myocardial deformation.
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Affiliation(s)
- Charilaos Triantafyllou
- 2nd Academic Department of Cardiology, Attikon Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece; (I.I.); (J.T.)
| | - Maria Nikolaou
- Department of Cardiology, Amalia Fleming General Hospital of Athens, 15127 Athens, Greece;
| | - Ignatios Ikonomidis
- 2nd Academic Department of Cardiology, Attikon Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece; (I.I.); (J.T.)
| | - Giorgos Bamias
- GI-Unit, 3rd Academic Department of Internal Medicine, Sotiria Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Dimitrios Kouretas
- Department of Biochemistry and Biotechnology, University of Thessaly, 41500 Larissa, Greece;
| | - Ioanna Andreadou
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15741 Athens, Greece; (I.A.); (M.T.)
| | - Maria Tsoumani
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15741 Athens, Greece; (I.A.); (M.T.)
| | - John Thymis
- 2nd Academic Department of Cardiology, Attikon Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece; (I.I.); (J.T.)
| | - Ioannis Papaconstantinou
- 2nd Academic Department of Surgery, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece;
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44
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Haque M, Siegel RJ, Fox DA, Ahmed S. Interferon-stimulated GTPases in autoimmune and inflammatory diseases: promising role for the guanylate-binding protein (GBP) family. Rheumatology (Oxford) 2021; 60:494-506. [PMID: 33159795 DOI: 10.1093/rheumatology/keaa609] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 08/16/2020] [Accepted: 08/23/2020] [Indexed: 12/14/2022] Open
Abstract
Human IFNs are secreted cytokines shown to stimulate the expression of over one thousand genes. These IFN-inducible genes primarily encode four major protein families, known as IFN-stimulated GTPases (ISGs), namely myxovirus-resistance proteins, guanylate-binding proteins (GBPs), p47 immunity-related GTPases and very large inducible guanosine triphosphate hydrolases (GTPases). These families respond specifically to type I or II IFNs and are well reported in coordinating immunity against some well known as well as newly discovered viral, bacterial and parasitic infections. A growing body of evidence highlights the potential contributory and regulatory roles of ISGs in dysregulated inflammation and autoimmune diseases. Our focus was to draw attention to studies that demonstrate increased expression of ISGs in the serum and affected tissues of patients with RA, SS, lupus, IBD and psoriasis. In this review, we analysed emerging literature describing the potential roles of ISGs, particularly the GBP family, in the context of autoimmunity. We also highlighted the promise and implications for therapeutically targeting IFNs and GBPs in the treatment of rheumatic diseases.
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Affiliation(s)
- Mahamudul Haque
- Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA, USA
| | - Ruby J Siegel
- Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA, USA
| | - David A Fox
- Division of Rheumatology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Salahuddin Ahmed
- Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA, USA.,Division of Rheumatology, University of Washington School of Medicine, Seattle, WA, USA
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45
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Pompili S, Latella G, Gaudio E, Sferra R, Vetuschi A. The Charming World of the Extracellular Matrix: A Dynamic and Protective Network of the Intestinal Wall. Front Med (Lausanne) 2021; 8:610189. [PMID: 33937276 PMCID: PMC8085262 DOI: 10.3389/fmed.2021.610189] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 03/22/2021] [Indexed: 02/06/2023] Open
Abstract
The intestinal extracellular matrix (ECM) represents a complex network of proteins that not only forms a support structure for resident cells but also interacts closely with them by modulating their phenotypes and functions. More than 300 molecules have been identified, each of them with unique biochemical properties and exclusive biological functions. ECM components not only provide a scaffold for the tissue but also afford tensile strength and limit overstretch of the organ. The ECM holds water, ensures suitable hydration of the tissue, and participates in a selective barrier to the external environment. ECM-to-cells interaction is crucial for morphogenesis and cell differentiation, proliferation, and apoptosis. The ECM is a dynamic and multifunctional structure. The ECM is constantly renewed and remodeled by coordinated action among ECM-producing cells, degrading enzymes, and their specific inhibitors. During this process, several growth factors are released in the ECM, and they, in turn, modulate the deposition of new ECM. In this review, we describe the main components and functions of intestinal ECM and we discuss their role in maintaining the structure and function of the intestinal barrier. Achieving complete knowledge of the ECM world is an important goal to understand the mechanisms leading to the onset and the progression of several intestinal diseases related to alterations in ECM remodeling.
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Affiliation(s)
- Simona Pompili
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Giovanni Latella
- Department of Life, Health and Environmental Sciences, Gastroenterology Unit, University of L'Aquila, L'Aquila, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine, and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Roberta Sferra
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Antonella Vetuschi
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
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46
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Zhong J, Yu R, Zhou Q, Liu P, Liu Z, Bian Y. Naringenin prevents TNF-α-induced gut-vascular barrier disruption associated with inhibiting the NF-κB-mediated MLCK/p-MLC and NLRP3 pathways. Food Funct 2021; 12:2715-2725. [PMID: 33667286 DOI: 10.1039/d1fo00155h] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The microvasculature endothelium accurately regulates the passage of molecules across the gut-vascular barrier (GVB), which plays an essential role in intestinal immunity. Naringenin is reported to have therapeutic potential against several intestinal disorders. However, the effect of naringenin on GVB disruption has been rarely studied. This study aims to investigate the effect of naringenin on GVB function and the potential mechanism. In the present study, the in vitro GVB disruption of rat intestinal microvascular endothelial cells (RIMVEC) was induced by 50 ng mL-1 of tumor necrosis factor-α (TNF-α). The integrity of the in vitro GVB was determined by Evans blue (EB)-albumin efflux assay and trans-endothelial electrical resistance (TER). Meanwhile, the expression of tight junction proteins and the related NF-κB, MLCK/p-MLC and NLRP3 pathways were determined using enzyme-linked immunosorbent assay (ELISA), real-time quantitative polymerase chain reaction (RT-qPCR), western blot analysis and immunofluorescence. The results show that naringenin (100 μM) inhibits TNF-α-induced interleukin (IL)-6 hypersecretion, alleviates GVB disruption and mitigates the change in the tight junction protein expression pattern. Naringenin inhibits the GVB-disruption-associated activation of the MLCK/p-MLC system and TLR4/NF-κB/NLRP3 pathways. Furthermore, naringenin shows a similar effect to that of NF-κB inhibitor Bay 11-7082 in reducing the TNF-α-induced activation of NLRP3, p-MLC and secondary GVB disruption. The results suggest that naringenin evidently alleviates TNF-α-induced in vitro GVB disruption via the maintenance of a tight junction protein pattern, partly with the inhibition of the NF-κB-mediated MLCK/p-MLC and NLRP3 pathway activation.
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Affiliation(s)
- Jia Zhong
- Division of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China.
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47
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Lohning A, Kidachi Y, Kamiie K, Sasaki K, Ryoyama K, Yamaguchi H. 6-(methylsulfinyl)hexyl isothiocyanate (6-MITC) from Wasabia japonica alleviates inflammatory bowel disease (IBD) by potential inhibition of glycogen synthase kinase 3 beta (GSK-3β). Eur J Med Chem 2021; 216:113250. [PMID: 33691258 DOI: 10.1016/j.ejmech.2021.113250] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/08/2020] [Accepted: 01/25/2021] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel disease (IBD) describes a set of disorders involving alterations to gastrointestinal physiology and mucosal immunity. Unravelling its complex pathophysiology is important since many IBD patients are refractory to or suffer adverse side effects from current treatments. Isothiocyanates (ITCs), such as 6-(methylsulfinyl)hexyl ITC (6-MITC) in Wasabia japonica, have potential anti-inflammatory activity. We aimed to elucidate the pathways through which 6-MITC alleviates inflammation by examining its role in the nuclear factor-kappa B (NF-κB) pathway through inhibition of glycogen synthase kinase 3 beta (GSK-3β) using a chemically induced murine model of IBD, cell-based and in silico techniques. The effects of 6-MITC and two NF-κB inhibitors, sulfasalazine (SS), pyrrolidine dithiolcarbamate (PDTC) were investigated on a dextran sulfate sodium (DSS)-induced murine mouse model of acute and chronic colitis using macroscopic measurements and pro-inflammatory markers. The effect of 6-MITC on NF-κB induction was assessed using a murine macrophage cell line. Complexes of GSK-3β-6-MITC and GSK-3β-ATP were generated in silico to elucidate the mechanism of 6-MITC's direct inhibition of GSK-3β. Changes in pro-inflammatory markers, inducible nitric oxide synthase (iNOS) (increased) and interleukin-6 (IL-6) (decreased) demonstrated that iNOS regulation occurred at the translational level. Intraperitoneal (ip) injection of 6-MITC to the colitis-induced mice ameliorated weight loss whereas oral administration had negligible effect. Fecal blood and colon weight/length ratio parameters improved on treatment with 6-MITC and the other NF-κB inhibitors. Levels of NF-κB decreased upon addition of 6-MITC in vitro while structural studies showed 6-MITC acts competitively to inhibit GSK-3β at the ATP binding site. In this study we demonstrated that 6-MITC inhibits NF-κB signaling via GSK-3β inhibition ameliorating fecal blood, colonic alterations and DSS-induced weight loss indirectly indicating reduced intestinal stress. Taken together these results suggest a role for 6-MITC in the treatment of IBD acting to alleviate inflammation through the GSK-3β/NF-κB pathway. Furthermore, the GSK-3β-6-MITC model can be utilized as a basis for development of novel therapeutics targeting GSK-3β for use in other disorders including cancer.
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Affiliation(s)
- Anna Lohning
- Faculty of Health Sciences & Medicine, Bond University, Gold Coast, Australia.
| | - Yumi Kidachi
- Department of Pharmacy, Aomori University, 2-3-1 Kobata, Aomori, 030-0943, Japan
| | - Katsuyoshi Kamiie
- Department of Pharmacy, Aomori University, 2-3-1 Kobata, Aomori, 030-0943, Japan
| | - Kazuo Sasaki
- Department of Food and Life Sciences, Toyo University, 1-1-1 Izumino, Itakura, Gunma, 374-0193, Japan
| | - Kazuo Ryoyama
- Department of Pharmacy, Aomori University, 2-3-1 Kobata, Aomori, 030-0943, Japan
| | - Hideaki Yamaguchi
- Department of Applied Biological Chemistry, Meijo University, 1-501 Shiogamaguchi, Tempaku, Nagoya, 468-8502, Japan
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48
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Kondreddy V, Keshava S, Esmon CT, Pendurthi UR, Rao LVM. A critical role of endothelial cell protein C receptor in the intestinal homeostasis in experimental colitis. Sci Rep 2020; 10:20569. [PMID: 33239717 PMCID: PMC7689504 DOI: 10.1038/s41598-020-77502-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 11/11/2020] [Indexed: 12/28/2022] Open
Abstract
Crohn’s disease and ulcerative colitis are the two forms of disorders of the human inflammatory bowel disease with unknown etiologies. Endothelial cell protein C receptor (EPCR) is a multifunctional and multiligand receptor, which is expressed on the endothelium and other cell types, including epithelial cells. Here, we report that EPCR is expressed in the colon epithelial cells, CD11c+, and CD21+/CD35+ myeloid cells surrounding the crypts in the colon mucosa. EPCR expression was markedly decreased in the colon mucosa during colitis. The loss of EPCR appeared to associate with increased disease index of the experimental colitis in mice. EPCR−/− mice were more susceptible to dextran sulfate sodium (DSS)-induced colitis, manifested by increased weight loss, macrophage infiltration, and inflammatory cytokines in the colon tissue. DSS treatment of EPCR−/− mice resulted in increased bleeding, bodyweight loss, anemia, fibrin deposition, and loss of colon epithelial and goblet cells. Administration of coagulant factor VIIa significantly attenuated the DSS-induced colon length shortening, rectal bleeding, bodyweight loss, and disease activity index in the wild-type mice but not EPCR−/− mice. In summary, our data provide direct evidence that EPCR plays a crucial role in regulating the inflammation in the colon during colitis.
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Affiliation(s)
- Vijay Kondreddy
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center At Tyler, 11937 US Highway 271, Tyler, TX, 75708-3154, USA
| | - Shiva Keshava
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center At Tyler, 11937 US Highway 271, Tyler, TX, 75708-3154, USA
| | - Charles T Esmon
- Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Usha R Pendurthi
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center At Tyler, 11937 US Highway 271, Tyler, TX, 75708-3154, USA
| | - L Vijaya Mohan Rao
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center At Tyler, 11937 US Highway 271, Tyler, TX, 75708-3154, USA.
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49
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Liu S, Song P, Sun F, Ai S, Hu Q, Guan W, Wang M. The concept revolution of gut barrier: from epithelium to endothelium. Int Rev Immunol 2020; 40:401-408. [PMID: 33140982 DOI: 10.1080/08830185.2020.1841185] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Gut barrier controls the food tolerance as well as host defense against potential hazards. The gut epithelium has been extensively studied for its importance in the structure and function of gut barrier. Recently, a new concept of barrier, named gut vascular barrier (GVB) has been discovered in both mice and human. Subsequent studies identified the morphological characteristics of GVB, the involved signaling events and its association with clinical diseases. In current study, we will summarize recent breakthroughs of GVB, with particular attentions to the molecular basis of GVB dysfunction. We will perform bioinformatics analysis to compare the transcriptional profiles of endothelium between blood and lymphatic vessels, healthy and inflammatory bowel diseases (IBD), healthy and colorectal cancer in the absence or presence of liver metastasis. We will further discuss the significance of impaired GVB in associated diseases, including vascular diseases, IBD and cancer metastasis. Our study will provide insights into the new concept of gut barrier, and promote the development of new strategies toward the vascular endothelium in the management of various diseases.
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Affiliation(s)
- Song Liu
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Peng Song
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Feng Sun
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Shichao Ai
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Qiongyuan Hu
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Wenxian Guan
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Meng Wang
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
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50
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Song Y, Xie F, Ma S, Deng G, Li Y, Nie Y, Wang F, Yu G, Gao Z, Chen K, Han L, Gao L. Caveolin-1 protects against DSS-induced colitis through inhibiting intestinal nitrosative stress and mucosal barrier damage in mice. Biochem Pharmacol 2020; 180:114153. [PMID: 32679126 DOI: 10.1016/j.bcp.2020.114153] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 07/07/2020] [Accepted: 07/10/2020] [Indexed: 01/12/2023]
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