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Li Z, Zeng L, Huang W, Zhang X, Zhang L, Xie Q. Angiogenic Factors and Inflammatory Bowel Diseases. Biomedicines 2025; 13:1154. [PMID: 40426981 PMCID: PMC12108873 DOI: 10.3390/biomedicines13051154] [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: 03/10/2025] [Revised: 04/29/2025] [Accepted: 05/07/2025] [Indexed: 05/29/2025] Open
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is characterized by chronic intestinal inflammation and impaired epithelial barrier function. Emerging evidence highlights the critical role of vascular remodeling and angiogenesis in IBD pathogenesis. This review explores the intricate relationship between blood vessels and the intestinal epithelial barrier, emphasizing how aberrant vascularization contributes to barrier dysfunction and disease progression. In IBD, excessive angiogenesis is driven by hypoxia, immune cell infiltration, and pro-inflammatory cytokines, further perpetuating inflammation and tissue damage. Key angiogenic factors, such as vascular endothelial growth factor (VEGF), angiopoietins, and platelet-derived growth factor (PDGF), are upregulated in IBD, promoting pathological vessel formation. These newly formed vessels are often immature and hyperpermeable, exacerbating leukocyte recruitment and inflammatory responses. Given the pivotal role of angiogenesis in IBD, anti-angiogenic therapies have emerged as a potential therapeutic strategy. Preclinical and clinical studies targeting VEGF and other angiogenic pathways have shown promise in reducing inflammation and promoting mucosal healing. This review summarizes current knowledge on vascular-epithelial interactions in IBD, the mechanisms driving pathological angiogenesis, and the therapeutic potential of anti-angiogenic approaches, providing insights for future research and treatment development.
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Affiliation(s)
- Zhiru Li
- Clinical Medical School, University of Electronic Science and Technology of China, Chengdu 610072, China;
| | - Li Zeng
- Department of Geriatric Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China; (L.Z.); (W.H.); (X.Z.); (L.Z.)
| | - Wei Huang
- Department of Geriatric Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China; (L.Z.); (W.H.); (X.Z.); (L.Z.)
| | - Xinxing Zhang
- Department of Geriatric Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China; (L.Z.); (W.H.); (X.Z.); (L.Z.)
| | - Li Zhang
- Department of Geriatric Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China; (L.Z.); (W.H.); (X.Z.); (L.Z.)
| | - Qin Xie
- Department of Geriatric Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China; (L.Z.); (W.H.); (X.Z.); (L.Z.)
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Pickett JR, Wu Y, Ta HT. VCAM-1 as a common biomarker in inflammatory bowel disease and colorectal cancer: unveiling the dual anti-inflammatory and anti-cancer capacities of anti-VCAM-1 therapies. Cancer Metastasis Rev 2025; 44:40. [PMID: 40095109 PMCID: PMC11913972 DOI: 10.1007/s10555-025-10258-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 03/04/2025] [Indexed: 03/19/2025]
Abstract
Vascular cell adhesion molecule (VCAM)-1 has garnered significant research attention due to its potential as a disease biomarker and drug target across several inflammatory pathologies-including atherosclerosis, asthma, rheumatoid arthritis, and inflammatory bowel disease (IBD). The VCAM-1 protein has also been noted for its functional involvement in cancer metastasis and drug resistance to conventional chemotherapeutics. Although the anti-inflammatory and anti-cancer facets of VCAM-1 antagonisation have been examined separately, there is yet to be a review that explicitly addresses the functional interrelationship between these mechanisms. Furthermore, the pleiotropic mechanisms of anti-VCAM-1 therapies may present a useful paradigm for designing drug candidates with synergistic anti-inflammatory and anti-tumorigenic effects. The pathological overlap between inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CRC) serves as the quintessential disease model to observe this therapeutic duality. This review thereby details the adhesive mechanisms of VCAM-1 in colorectal disease-specifically, driving immune cell infiltration during IBD and tumour cell metastasis in CRC-and posits the potential of this receptor as a common drug target for both diseases. To explore this hypothesis, the current progress of novel VCAM-1-directed drug candidates in experimental models of IBD and CRC is also discussed.
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Affiliation(s)
- Jessica R Pickett
- School of Environment and Science, Griffith University, Nathan Campus, Brisbane, 4111, QLD, Australia
| | - Yuao Wu
- School of Environment and Science, Griffith University, Nathan Campus, Brisbane, 4111, QLD, Australia
| | - Hang Thu Ta
- School of Environment and Science, Griffith University, Nathan Campus, Brisbane, 4111, QLD, Australia.
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Anakha J, Prasad YR, Pande AH. Endostatin in disease modulation: From cancer to beyond. Vascul Pharmacol 2025; 158:107459. [PMID: 39708990 DOI: 10.1016/j.vph.2024.107459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/04/2024] [Accepted: 12/16/2024] [Indexed: 12/23/2024]
Abstract
Angiogenesis plays a pivotal role in various pathological conditions, making it a key target in therapeutic development. Anti-angiogenic therapies are gaining traction for their potential in treating a range of angiogenesis-dependent diseases. Among these, endogenous angiogenesis inhibitors, particularly endostatin, have garnered significant attention for their therapeutic potential. While extensively studied for its anti-angiogenic effects in cancer, endostatin also exhibits anti-atherosclerotic and anti-fibrotic properties, broadening its therapeutic scope. Despite the successful clinical use of recombinant human endostatin in China for nearly two decades, its broader therapeutic potential remains underexplored. Thus, this review delves into the multifaceted applications of endostatin, examining its role in ocular diseases, inflammation, reproductive disorders, and tumor angiogenesis. Furthermore, it provides a comprehensive overview of its emerging roles beyond angiogenesis, particularly in the context of atherosclerosis and fibroproliferative conditions.
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Affiliation(s)
- J Anakha
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali 160062, Punjab, India.
| | - Yenisetti Rajendra Prasad
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali 160062, Punjab, India
| | - Abhay H Pande
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali 160062, Punjab, India.
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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: 1] [Impact Index Per Article: 1.0] [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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El Masri J, Fadlallah H, Al Sabsabi R, Afyouni A, Al-Sayegh M, Abou-Kheir W. Adipose-Derived Stem Cell Therapy in Spinal Cord Injury. Cells 2024; 13:1505. [PMID: 39273075 PMCID: PMC11394073 DOI: 10.3390/cells13171505] [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: 07/25/2024] [Revised: 09/04/2024] [Accepted: 09/05/2024] [Indexed: 09/15/2024] Open
Abstract
Spinal cord injury (SCI) is a serious condition accompanied by severe adverse events that affect several aspects of the patient's life, such as motor, sensory, and functional impairment. Despite its severe consequences, definitive treatment for these injuries is still missing. Therefore, researchers have focused on developing treatment strategies aimed at ensuring full recovery post-SCI. Accordingly, attention has been drawn toward cellular therapy using mesenchymal stem cells. Considering their wide availability, decreased immunogenicity, wide expansion capacity, and impressive effectiveness in many therapeutic approaches, adipose-derived stem cell (ADSC) injections in SCI cases have been investigated and showed promising results. In this review, SCI pathophysiology and ADSC transplantation benefits are discussed independently, together with SCI animal models and adipose stem cell preparation and application techniques. The mechanisms of healing in an SCI post-ADSC injection, the outcomes of this therapeutic approach, and current clinical trials are also deliberated, in addition to the challenges and future perspectives, aiming to encourage further research in this field.
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Affiliation(s)
- Jad El Masri
- Department of Anatomy, Cell Biology, and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon; (J.E.M.); (H.F.)
- Faculty of Medical Sciences, Lebanese University, Beirut 1533, Lebanon; (R.A.S.); (A.A.)
| | - Hiba Fadlallah
- Department of Anatomy, Cell Biology, and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon; (J.E.M.); (H.F.)
| | - Rahaf Al Sabsabi
- Faculty of Medical Sciences, Lebanese University, Beirut 1533, Lebanon; (R.A.S.); (A.A.)
| | - Ahmad Afyouni
- Faculty of Medical Sciences, Lebanese University, Beirut 1533, Lebanon; (R.A.S.); (A.A.)
| | - Mohamed Al-Sayegh
- Biology Division, New York University Abu Dhabi, Abu Dhabi 2460, United Arab Emirates
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology, and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon; (J.E.M.); (H.F.)
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Peter B, Rebeaud J, Vigne S, Bressoud V, Phillips N, Ruiz F, Petrova TV, Bernier-Latmani J, Pot C. Perivascular B cells link intestinal angiogenesis to immunity and to the gut-brain axis during neuroinflammation. J Autoimmun 2024; 148:103292. [PMID: 39067313 DOI: 10.1016/j.jaut.2024.103292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 06/28/2024] [Accepted: 07/15/2024] [Indexed: 07/30/2024]
Abstract
Disruption of gut barrier function and intestinal immune cell homeostasis are increasingly considered critical players in pathogenesis of extra-intestinal inflammatory diseases, including multiple sclerosis (MS) and its prototypical animal model, the experimental autoimmune encephalomyelitis (EAE). Breakdown of epithelial barriers increases intestinal permeability and systemic dissemination of microbiota-derived molecules. However, whether the gut-vascular barrier (GVB) is altered during EAE has not been reported. Here, we demonstrate that endothelial cell proliferation and vessel permeability increase before EAE clinical onset, leading to vascular remodeling and expansion of intestinal villi capillary bed during disease symptomatic phase in an antigen-independent manner. Concomitant to onset of angiogenesis observed prior to neurological symptoms, we identify an increase of intestinal perivascular immune cells characterized by the surface marker lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE-1). LYVE-1+ is expressed more frequently on B cells that show high levels of CD73 and have proangiogenic properties. B cell depletion was sufficient to mitigate enteric blood endothelial cell proliferation following immunization for EAE. In conclusion, we propose that altered intestinal vasculature driven by a specialized LYVE-1+ B cell subset promotes angiogenesis and that loss of GVB function is implicated in EAE development and autoimmunity.
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Affiliation(s)
- Benjamin Peter
- Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Epalinges, 1066, Switzerland
| | - Jessica Rebeaud
- Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Epalinges, 1066, Switzerland
| | - Solenne Vigne
- Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Epalinges, 1066, Switzerland
| | - Valentine Bressoud
- Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Epalinges, 1066, Switzerland
| | - Nicholas Phillips
- Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Epalinges, 1066, Switzerland
| | - Florian Ruiz
- Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Epalinges, 1066, Switzerland
| | - Tatiana V Petrova
- Department of Oncology, University of Lausanne and Ludwig Institute for Cancer Research, Epalinges, 1066, Switzerland
| | - Jeremiah Bernier-Latmani
- Department of Oncology, University of Lausanne and Ludwig Institute for Cancer Research, Epalinges, 1066, Switzerland
| | - Caroline Pot
- Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Epalinges, 1066, Switzerland.
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Van Remoortel S, Lambeets L, De Winter B, Dong X, Rodriguez Ruiz JP, Kumar-Singh S, Martinez SI, Timmermans JP. Mrgprb2-dependent Mast Cell Activation Plays a Crucial Role in Acute Colitis. Cell Mol Gastroenterol Hepatol 2024; 18:101391. [PMID: 39179175 PMCID: PMC11462171 DOI: 10.1016/j.jcmgh.2024.101391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 08/07/2024] [Accepted: 08/08/2024] [Indexed: 08/26/2024]
Abstract
BACKGROUND & AIMS Mast cells (MCs) are typically found at mucosal surfaces, where their immunoglobulin E (IgE)-dependent activation plays a central role in allergic diseases. Over the past years, signaling through Mas-related G protein-coupled receptor b2 (Mrgprb2) in mice and MRGPRX2 in humans has gained a lot of interest as an alternative MC activation pathway with high therapeutic potential. The aim of this study was to explore the relevance of such IgE-independent, Mrgprb2-mediated signaling in colonic MCs in the healthy and acutely inflamed mouse colon. METHODS Mrgprb2 expression and functionality was studied using a genetic labeling strategy combined with advanced microscopic imaging. Furthermore, Mrgprb2 knockout (Mrgprb2-/-) mice were used to determine the role of this pathway in a preclinical dextran sodium sulphate (DSS) colitis model. RESULTS We found that Mrgprb2 acts as a novel MC degranulation pathway in a large subset of connective tissue MCs in the mouse distal colon. Acute DSS colitis induced a pronounced increase of Mrgprb2-expressing MCs, which were found in close association with Substance P-positive nerve fibers. Loss of Mrgprb2-mediated signaling impaired DSS-induced neutrophil influx and significantly impacted on acute colitis progression. CONCLUSIONS Our findings uncover a novel, IgE-independent MC degranulation pathway in the mouse colon that plays a central role in acute colitis pathophysiology, mainly by safeguarding acute colitis progression and severity in mice. This pseudo allergic, Mrgprb2-induced signaling is part of a hitherto unconsidered colonic neuro-immune pathway and might have significant potential for the further development of effective therapeutic treatment strategies for gastrointestinal disorders, such as ulcerative colitis.
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Affiliation(s)
- Samuel Van Remoortel
- Laboratory of Cell Biology and Histology and Member of the μNEURO Centre of Excellence, University of Antwerp, Wilrijk, Belgium.
| | - Lana Lambeets
- Laboratory of Cell Biology and Histology and Member of the μNEURO Centre of Excellence, University of Antwerp, Wilrijk, Belgium
| | - Benedicte De Winter
- Laboratory of Experimental Medicine and Pediatrics and Member of the Infla-Med Centre of Excellence, University of Antwerp, Wilrijk, Belgium
| | - Xinzhong Dong
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Juan Pablo Rodriguez Ruiz
- Laboratory of Medical Microbiology, University of Antwerp and Member of the VAXINFECTIO Centre of Excellence, Wilrijk, Belgium
| | - Samir Kumar-Singh
- Laboratory of Cell Biology and Histology and Member of the μNEURO Centre of Excellence, University of Antwerp, Wilrijk, Belgium; Laboratory of Medical Microbiology, University of Antwerp and Member of the VAXINFECTIO Centre of Excellence, Wilrijk, Belgium
| | - Sales Ibiza Martinez
- Laboratory of Cell Biology and Histology and Member of the μNEURO Centre of Excellence, University of Antwerp, Wilrijk, Belgium
| | - Jean-Pierre Timmermans
- Laboratory of Cell Biology and Histology and Member of the μNEURO Centre of Excellence, University of Antwerp, Wilrijk, Belgium
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Li B, Hu P, Liang H, Zhao X, Zhang A, Xu Y, Zhang B, Zhang J. Evaluating the causal effect of circulating proteome on the risk of inflammatory bowel disease-related traits using Mendelian randomization. Front Immunol 2024; 15:1434369. [PMID: 39144148 PMCID: PMC11321985 DOI: 10.3389/fimmu.2024.1434369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 07/17/2024] [Indexed: 08/16/2024] Open
Abstract
Objective This study sought to identify circulating proteins causally linked to Inflammatory Bowel Disease (IBD) traits through a Mendelian Randomization (MR) analytical framework. Methods Using a large-scale, two-sample MR approach, we estimated the genetic links of numerous plasma proteins with IBD and its subtypes, leveraging information from the Inflammatory Bowel Disease Genetics Consortium. To assess the robustness of MR findings, methods like Bayesian colocalization, and Steiger filtering analysis, evaluation of protein-altering variants. Further insights into IBD's underlying mechanisms and therapeutic targets were gleaned from single-cell sequencing analyses, protein-protein interaction assessments, pathway enrichment analyses, and evaluation of drug targets. Results By cis-only MR analysis, we identified 83 protein-phenotype associations involving 27 different proteins associated with at least one IBD subtype. Among these proteins, DAG1, IL10, IL12B, IL23R, MST1, STAT3 and TNFRSF6B showed overlapping positive or negative associations in all IBD phenotypes. Extending to cis + trans MR analysis, we further identified 117 protein-feature associations, including 44 unique proteins, most of which were not detected in the cis-only analysis. In addition, by performing co-localization analysis and Steiger filtering analysis on the prioritized associations, we further confirmed the causal relationship between these proteins and the IBD phenotype and verified the exact causal direction from the protein to the IBD-related feature. Conclusion MR analysis facilitated the identification of numerous circulating proteins associated with IBD traits, unveiling protein-mediated mechanisms and promising therapeutic targets.
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Affiliation(s)
- Beining Li
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
- The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Ping Hu
- Department of Orthopedic, Tianjin Medical University General Hospital, Tianjin, China
| | - Hongyan Liang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Xingliang Zhao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Aiting Zhang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Yingchong Xu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Bin Zhang
- Department of Orthopedic, Tianjin Medical University General Hospital, Tianjin, China
| | - Jie Zhang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
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Lin H, Cao B. Circulating VEGF and inflammatory bowel disease: a bidirectional mendelian randomization. Front Genet 2024; 15:1282471. [PMID: 38699232 PMCID: PMC11063361 DOI: 10.3389/fgene.2024.1282471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 03/18/2024] [Indexed: 05/05/2024] Open
Abstract
Introduction: Prior observational studies have suggested an association between circulating vascular endothelial growth factor (VEGF) levels and inflammatory bowel disease (IBD). This study sought to demonstrate the directionality of the association between circulating VEGF and particular forms of IBD as well as if there is a causal relationship between them. Methods: We collected summary data from relevant genome-wide association studies (GWASs) to assess the validity of causality, and a two-sample bidirectional Mendelian randomization (MR) study and sensitivity testing were performed to assess the causal relationship between circulating VEGF and IBD risk, including Crohn's disease and ulcerative colitis. Results: Our findings revealed a direct causal link between circulating VEGF and Crohn's disease (b 0.195, se 0.078, p < 0.013). However, neither circulating VEGF nor ulcerative colitis were shown to be causally linked (p > 0.025), nor was there proof of a reverse causal relationship from IBD to VEGF. Discussion: In conclusion, circulating VEGF shows a cause-and-effect relationship with Crohn's disease.
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Affiliation(s)
| | - Bangwei Cao
- Cancer Centre, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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10
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Aasmul-Olsen K, Akıllıoğlu HG, Christiansen LI, Engholm-Keller K, Brunse A, Stefanova DV, Bjørnshave A, Bechshøft MR, Skovgaard K, Thymann T, Sangild PT, Lund MN, Bering SB. A Gently Processed Skim Milk-Derived Whey Protein Concentrate for Infant Formula: Effects on Gut Development and Immunity in Preterm Pigs. Mol Nutr Food Res 2024; 68:e2300458. [PMID: 38389157 DOI: 10.1002/mnfr.202300458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 12/15/2023] [Indexed: 02/24/2024]
Abstract
SCOPE Processing of whey protein concentrate (WPC) for infant formulas may induce protein modifications with severe consequences for preterm newborn development. The study investigates how conventional WPC and a gently processed skim milk-derived WPC (SPC) affect gut and immune development after birth. METHODS AND RESULTS Newborn, preterm pigs used as a model of preterm infants were fed formula containing WPC, SPC, extra heat-treated SPC (HT-SPC), or stored HT-SPC (HTS-SPC) for 5 days. SPC contained no protein aggregates and more native lactoferrin, and despite higher Maillard reaction product (MRP) formation, the clinical response and most gut and immune parameters are similar to WPC pigs. SPC feeding negatively impacts intestinal MRP accumulation, mucosa, and bacterial diversity. In contrast, circulating T-cells are decreased and oxidative stress- and inflammation-related genes are upregulated in WPC pigs. Protein aggregation and MRP formation increase in HTS-SPC, leading to reduced antibacterial activity, lactase/maltase ratio, circulating neutrophils, and cytotoxic T-cells besides increased gut MRP accumulation and expression of TNFAIP3. CONCLUSION The gently processed SPC has more native protein, but higher MRP levels than WPC, resulting in similar tolerability but subclinical adverse gut effects in preterm pigs. Additional heat treatment and storage further induce MRP formation, gut inflammation, and intestinal mucosal damage.
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Affiliation(s)
- Karoline Aasmul-Olsen
- Section for Comparative Paediatrics and Nutrition, Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, 1870, Denmark
| | - Halise Gül Akıllıoğlu
- Section for Ingredient and Dairy Technology, Department of Food Science, University of Copenhagen, Frederiksberg, 1958, Denmark
| | - Line Iadsatian Christiansen
- Section for Comparative Paediatrics and Nutrition, Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, 1870, Denmark
| | - Kasper Engholm-Keller
- Section for Ingredient and Dairy Technology, Department of Food Science, University of Copenhagen, Frederiksberg, 1958, Denmark
| | - Anders Brunse
- Section for Comparative Paediatrics and Nutrition, Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, 1870, Denmark
| | - Denitsa Vladimirova Stefanova
- Section for Microbiology and Fermentation, Department of Food Science, University of Copenhagen, Frederiksberg, 1958, Denmark
| | | | | | - Kerstin Skovgaard
- Section for Protein Science and Biotherapeutics, Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, 2800, Denmark
| | - Thomas Thymann
- Section for Comparative Paediatrics and Nutrition, Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, 1870, Denmark
| | - Per Torp Sangild
- Section for Comparative Paediatrics and Nutrition, Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, 1870, Denmark
- Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, 2100, Denmark
- Hans Christian Andersen Children's Hospital, Odense, 5000, Denmark
| | - Marianne Nissen Lund
- Section for Ingredient and Dairy Technology, Department of Food Science, University of Copenhagen, Frederiksberg, 1958, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark
| | - Stine Brandt Bering
- Section for Comparative Paediatrics and Nutrition, Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, 1870, Denmark
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Kim G, Chen Z, Li J, Luo J, Castro-Martinez F, Wisniewski J, Cui K, Wang Y, Sun J, Ren X, Crawford SE, Becerra SP, Zhu J, Liu T, Wang S, Zhao K, Wu C. Gut-liver axis calibrates intestinal stem cell fitness. Cell 2024; 187:914-930.e20. [PMID: 38280375 PMCID: PMC10923069 DOI: 10.1016/j.cell.2024.01.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 10/25/2023] [Accepted: 01/02/2024] [Indexed: 01/29/2024]
Abstract
The gut and liver are recognized to mutually communicate through the biliary tract, portal vein, and systemic circulation. However, it remains unclear how this gut-liver axis regulates intestinal physiology. Through hepatectomy and transcriptomic and proteomic profiling, we identified pigment epithelium-derived factor (PEDF), a liver-derived soluble Wnt inhibitor, which restrains intestinal stem cell (ISC) hyperproliferation to maintain gut homeostasis by suppressing the Wnt/β-catenin signaling pathway. Furthermore, we found that microbial danger signals resulting from intestinal inflammation can be sensed by the liver, leading to the repression of PEDF production through peroxisome proliferator-activated receptor-α (PPARα). This repression liberates ISC proliferation to accelerate tissue repair in the gut. Additionally, treating mice with fenofibrate, a clinical PPARα agonist used for hypolipidemia, enhances colitis susceptibility due to PEDF activity. Therefore, we have identified a distinct role for PEDF in calibrating ISC expansion for intestinal homeostasis through reciprocal interactions between the gut and liver.
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Affiliation(s)
- Girak Kim
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Zuojia Chen
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jian Li
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jialie Luo
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Felipe Castro-Martinez
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jan Wisniewski
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Kairong Cui
- Laboratory of Epigenome Biology, Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Yan Wang
- Mass Spectrometry Facility, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jialei Sun
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xiaobai Ren
- Department of Ophthalmology, Mary M. and Sash A. Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Stanford, CA 94304, USA
| | - Susan E Crawford
- Department of Surgery, North Shore University Research Institute, University of Chicago Pritzker School of Medicine, Chicago, IL 60637, USA
| | - S Patricia Becerra
- Section of Protein Structure and Function, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jimin Zhu
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Taotao Liu
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Sui Wang
- Department of Ophthalmology, Mary M. and Sash A. Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Stanford, CA 94304, USA
| | - Keji Zhao
- Laboratory of Epigenome Biology, Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Chuan Wu
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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12
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Zong W, Friedman ES, Allu SR, Firrman J, Tu V, Daniel SG, Bittinger K, Liu L, Vinogradov SA, Wu GD. Disruption of intestinal oxygen balance in acute colitis alters the gut microbiome. Gut Microbes 2024; 16:2361493. [PMID: 38958039 PMCID: PMC11225921 DOI: 10.1080/19490976.2024.2361493] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 05/24/2024] [Indexed: 07/04/2024] Open
Abstract
The juxtaposition of well-oxygenated intestinal colonic tissue with an anerobic luminal environment supports a fundamentally important relationship that is altered in the setting of intestinal injury, a process likely to be relevant to diseases such as inflammatory bowel disease. Herein, using two-color phosphorometry to non-invasively quantify both intestinal tissue and luminal oxygenation in real time, we show that intestinal injury induced by DSS colitis reduces intestinal tissue oxygenation in a spatially defined manner and increases the flux of oxygen from the tissue into the gut lumen. By characterizing the composition of the microbiome in both DSS colitis-affected gut and in a bioreactor containing a stable human fecal community exposed to microaerobic conditions, we provide evidence that the increased flux of oxygen into the gut lumen augments glycan degrading bacterial taxa rich in glycoside hydrolases which are known to inhabit gut mucosal surface. Continued disruption of the intestinal mucus barrier through such a mechanism may play a role in the perpetuation of the intestinal inflammatory process.
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Affiliation(s)
- Wenjing Zong
- Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA ,USA
| | - Elliot S. Friedman
- Department of Gastroenterology & Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Srinivasa Rao Allu
- Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jenni Firrman
- Dairy and Functional Foods Research Unit, Eastern Regional Research Center, Agricultural Research Service, US Department of Agriculture, Wyndmoor, PA, USA
| | - Vincent Tu
- Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA ,USA
| | - Scott G. Daniel
- Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA ,USA
| | - Kyle Bittinger
- Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA ,USA
| | - LinShu Liu
- Dairy and Functional Foods Research Unit, Eastern Regional Research Center, Agricultural Research Service, US Department of Agriculture, Wyndmoor, PA, USA
| | - Sergei A. Vinogradov
- Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Gary D. Wu
- Department of Gastroenterology & Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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13
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Kurup S, Tan C, Kume T. Cardiac and intestinal tissue conduct developmental and reparative processes in response to lymphangiocrine signaling. Front Cell Dev Biol 2023; 11:1329770. [PMID: 38178871 PMCID: PMC10764504 DOI: 10.3389/fcell.2023.1329770] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 12/08/2023] [Indexed: 01/06/2024] Open
Abstract
Lymphatic vessels conduct a diverse range of activities to sustain the integrity of surrounding tissue. Besides facilitating the movement of lymph and its associated factors, lymphatic vessels are capable of producing tissue-specific responses to changes within their microenvironment. Lymphatic endothelial cells (LECs) secrete paracrine signals that bind to neighboring cell-receptors, commencing an intracellular signaling cascade that preludes modifications to the organ tissue's structure and function. While the lymphangiocrine factors and the molecular and cellular mechanisms themselves are specific to the organ tissue, the crosstalk action between LECs and adjacent cells has been highlighted as a commonality in augmenting tissue regeneration within animal models of cardiac and intestinal disease. Lymphangiocrine secretions have been owed for subsequent improvements in organ function by optimizing the clearance of excess tissue fluid and immune cells and stimulating favorable tissue growth, whereas perturbations in lymphatic performance bring about the opposite. Newly published landmark studies have filled gaps in our understanding of cardiac and intestinal maintenance by revealing key players for lymphangiocrine processes. Here, we will expand upon those findings and review the nature of lymphangiocrine factors in the heart and intestine, emphasizing its involvement within an interconnected network that supports daily homeostasis and self-renewal following injury.
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Affiliation(s)
- Shreya Kurup
- Department of Medicine, Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Honors College, University of Illinois at Chicago, Chicago, IL, United States
| | - Can Tan
- Department of Medicine, Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Tsutomu Kume
- Department of Medicine, Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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14
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Xie Z, Zhou G, Zhang M, Han J, Wang Y, Li X, Wu Q, Li M, Zhang S. Recent developments on BMPs and their antagonists in inflammatory bowel diseases. Cell Death Discov 2023; 9:210. [PMID: 37391444 DOI: 10.1038/s41420-023-01520-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/15/2023] [Accepted: 06/22/2023] [Indexed: 07/02/2023] Open
Abstract
Inflammatory bowel diseases (IBDs), including ulcerative colitis, and Crohn's disease, are intestinal disorders characterized by chronic relapsing inflammation. A large proportion of patients with IBD will progress to develop colitis-associated colorectal cancer due to the chronic intestinal inflammation. Biologic agents that target tumour necrosis factor-α, integrin α4β7, and interleukin (IL)12/23p40 have been more successful than conventional therapies in treating IBD. However, drug intolerance and loss of response are serious drawbacks of current biologics, necessitating the development of novel drugs that target specific pathways in IBD pathogenesis. One promising group of candidate molecules are bone morphogenetic proteins (BMPs), members of the TGF-β family involved in regulating morphogenesis, homeostasis, stemness, and inflammatory responses in the gastrointestinal tract. Also worth examining are BMP antagonists, major regulators of these proteins. Evidence has shown that BMPs (especially BMP4/6/7) and BMP antagonists (especially Gremlin1 and follistatin-like protein 1) play essential roles in IBD pathogenesis. In this review, we provide an updated overview on the involvement of BMPs and BMP antagonists in IBD pathogenesis and in regulating the fate of intestinal stem cells. We also described the expression patterns of BMPs and BMP antagonists along the intestinal crypt-villus axis. Lastly, we synthesized available research on negative regulators of BMP signalling. This review summarizes recent developments on BMPs and BMP antagonists in IBD pathogenesis, which provides novel insights into future therapeutic strategies.
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Affiliation(s)
- Zhuo Xie
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Gaoshi Zhou
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Mudan Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Jing Han
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Ying Wang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Xiaoling Li
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Qirui Wu
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Manying Li
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Shenghong Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.
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15
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Gunizi OC, Kol A, Gunizi H. Can montelukast sodium be an alternative treatment in the treatment of interstitial cystitis? Niger J Clin Pract 2023; 26:397-403. [PMID: 37203102 DOI: 10.4103/njcp.njcp_385_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
Background The leukotriene D4 receptors have been detected in human bladder detrusor myocytes, and they can play the role of interstitial cystitis etiology. Aim Our study aims to explain the role of mast cells histologically and immunohistochemically in the pathogenesis and the effectiveness of montelukast that leukotriene D4 receptor antagonist in the treatment of interstitial cystitis. Subjects and Methods Twenty-four Wistar albino adult female rats were used. Group 1 (n = 8): control (sham) group, Group 2 (n = 8): interstitial cystitis group, and Group 3 (n = 8): treatment group. Groups 2 and 3 rats were administered 75 mg/kg cyclophosphamide four times every three days intraperitoneally. The rats in the treatment group were started on montelukast sodium as 10 mg/kg, 1 × 1/day per orally after the last administration of cyclophosphamide and were given for 14 days. Mast cells in the bladder tissues were examined histologically, and the presence of IL-6, 8, VEGF, and TNF alpha was examined immunohistochemically. Results Thin transitional epithelium, loose connective tissue, weak smooth muscle bundles, and signs of chronic inflammation were observed in the interstitial cystitis group. Regenerated transitional epithelium, intact basement membrane, compact lamina propia, thick smooth muscle bundles, and rare inflammatory cells were observed after the treatment with the montelukast. Mast cells were decreased in bladder tissue after treatment. IL-6, IL-8, VEGF, and TNF alpha levels were significantly decreased after treatment. Conclusions We found that inflammatory mediators were significantly reduced after treatment with montelukast in the interstitial cystitis group. Montelukast can be used as an effective drug in the treatment of interstitial cystitis.
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Affiliation(s)
- O C Gunizi
- Department of Medical Pathology, Alanya Alaaddin Keykubat University, Faculty of Medicine, Antalya, Turkey
| | - A Kol
- Department of Urology, Aydin Adnan Menderes University, Faculty of Medicine, Aydin, Turkey
| | - H Gunizi
- Department of Otolaryngology, Alanya Alaaddin Keykubat University, Faculty of Medicine, Antalya, Turkey
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16
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Duan ZL, Wang YJ, Lu ZH, Tian L, Xia ZQ, Wang KL, Chen T, Wang R, Feng ZY, Shi GP, Xu XT, Bu F, Ding Y, Jiang F, Zhou JY, Wang Q, Chen YG. Wumei Wan attenuates angiogenesis and inflammation by modulating RAGE signaling pathway in IBD: Network pharmacology analysis and experimental evidence. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 111:154658. [PMID: 36706698 DOI: 10.1016/j.phymed.2023.154658] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 12/28/2022] [Accepted: 01/09/2023] [Indexed: 06/18/2023]
Abstract
BACKGROUND Wumei Wan (WMW) has been used to address digestive disorder for centuries in traditional Chinese medicine. Previous studies have demonstrated its anti-colitis efficacy, but the underlying mechanism of its action remains to be further clarified. PURPOSE To investigate the underlying mechanisms of WMW in the treatment of chronic ulcerative colitis (UC) through network pharmacology and experimental validation. METHODS Traditional Chinese Medicine Systems Pharmacology (TCMSP) platform were used to identify the ingredients and potential targets of WMW. The microarray gene data GSE75214 datasets from GEO database was used to define UC-associated targets. Cytoscape3.7.2 was employed to construct the protein-protein interaction (PPI) network and compounds-disease targets network. GO enrichment analysis and KEGG pathway analysis were performed by R software for functional annotation. UPLC-TOF-MS/MS method was used to quantitatively analyze the active ingredients of WMW. For experimental validation, three cycles of 2% dextran sulfate sodium salt (DSS) were used to construct chronic colitis model. The hub targets and signal pathway were detected by qPCR, ELISA, western blotting , immunohistochemical and immunofluorescence. RESULTS Through network analysis, 104 active ingredients were obtained from WMW, and 47 of these ingredients had potential targets for UC. A total of 41 potential targets of WMW and 13 hub targets were identified. KEGG analysis showed that WMW involved in advanced glycation end products-receptor of advanced glycation end products (AGE-RAGE) signaling pathway. Taxifolin, rutaecarpine, kaempferol, quercetin, and luteolin of WMW were the more highly predictive components related to the AGE-RAGE signaling pathway. In vivo validation, WMW improved DSS-induced colitis, reduced the expression of inflammatory cytokines and chemokines. Notably, it significantly decreased the mRNA expression of Spp1, Serpine1, Mmp2, Mmp9, Ptgs2, Nos2, Kdr and Icam1, which were associated with angiogenesis. In addition, we confirmed WMW inhibited RAGE expression and diminished DSS-induced epithelial barrier alterations CONCLUSION: Our results initially demonstrated the effective components and the strong anti-angiogenic activity of WMW in experimental chronic colitis. Sufficient evidence of the satisfactory anti-colitis action of WMW was verified in this study, suggesting its potential as a quite prospective agent for the therapy of UC.
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Affiliation(s)
- Zheng-Lan Duan
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Yu-Ji Wang
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Zhi-Hua Lu
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Lin Tian
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Zi-Qian Xia
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Kui-Ling Wang
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Tuo Chen
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Rong Wang
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Ze-Yu Feng
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Guo-Ping Shi
- Collaborative Innovation Center for Cancer Medicine, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, PR China
| | - Xin-Tian Xu
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Fan Bu
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Yang Ding
- No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Feng Jiang
- Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, PR China; Department of Colorectal Surgery, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, PR China
| | - Jin-Yong Zhou
- Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, PR China; Central Laboratory, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, PR China
| | - Qiong Wang
- Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, PR China.
| | - Yu-Gen Chen
- Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, PR China; Collaborative Innovation Center for Cancer Medicine, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, PR China.
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17
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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: 11] [Impact Index Per Article: 3.7] [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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18
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Mia MM, Singh MK. Emerging roles of the Hippo signaling pathway in modulating immune response and inflammation-driven tissue repair and remodeling. FEBS J 2022; 289:4061-4081. [PMID: 35363945 DOI: 10.1111/febs.16449] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 01/17/2022] [Accepted: 03/30/2022] [Indexed: 02/06/2023]
Abstract
Inflammation is an evolutionarily conserved process and part of the body's defense mechanism. Inflammation leads to the activation of immune and non-immune cells that protect the host tissue/organs from injury or intruding pathogens. The Hippo pathway is an evolutionarily conserved kinase cascade with an established role in regulating cell proliferation, survival, and differentiation. It is involved in diverse biological processes, including organ size control and tissue homeostasis. Recent clinical and pre-clinical studies have shown that the Hippo signaling pathway is also associated with injury- and pathogen-induced tissue inflammation and associated immunopathology. In this review, we have summarized the recent findings related to the involvement of the Hippo signaling pathway in modulating the immune response in different acute and chronic inflammatory diseases and its impact on tissue repair and remodeling.
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Affiliation(s)
- Masum M Mia
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore
| | - Manvendra K Singh
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore.,National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore
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19
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The Role of Urinary VEGF in Observational Studies of BPS/IC Patients: A Systematic Review. Diagnostics (Basel) 2022; 12:diagnostics12051037. [PMID: 35626193 PMCID: PMC9139518 DOI: 10.3390/diagnostics12051037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/06/2022] [Accepted: 04/19/2022] [Indexed: 02/04/2023] Open
Abstract
Background: Bladder pain syndrome/interstitial cystitis (BPS/IC) is a chronic pain condition, often underdiagnosed, with an important impact on patient quality of life. More recently, an association between VEGF and its receptors has been suggested in BPS/IC pathophysiology, due to their role in promoting angiogenesis and inflammation, which can enhance bladder pain. Eventually, VEGF may be used as a biomarker for the diagnosis and prognostication of BPS/IC. To further clarify this issue, this review aims to critically summarize the available information, giving rise to a solid starting point for future studies. Methods: We systematically searched PubMed and Embase, using the queries “urinary VEGF”, “urinary VEGF” AND “pain”, “urinary VEGF” AND “lower urinary tract symptoms” and “urinary VEGF” AND “LUTS” from January 2016 to February 2022. Results: A total of 1026 papers were identified from which 7 articles were included in this study, which assessed 1036 participants. Regarding VEGF levels, overactive bladder (OAB) and healthy patients were used for comparison with BPS/IC patients. VEGF concentration seems to be higher when compared to healthy patients and overactive bladder (OAB) patients. Higher levels of VEGF were associated with pain severity, while a decrease in VEGF concentration was associated with pain and symptom improvement in women. However, these findings were not constant in all studies. Conclusions: There is a trend toward a relevant association between increased VEGF levels and pain or symptom severity in BPS/IC patients. Although there are some discrepancies among the studies and the number of patients included is small, VEGF and its receptors should be considered for future studies regarding its use in BPS/IC pathophysiology, diagnosis and prognostication.
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20
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Grape Pomace Extract Attenuates Inflammatory Response in Intestinal Epithelial and Endothelial Cells: Potential Health-Promoting Properties in Bowel Inflammation. Nutrients 2022; 14:nu14061175. [PMID: 35334833 PMCID: PMC8953566 DOI: 10.3390/nu14061175] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel disease (IBD) implies the chronic inflammation of the gastrointestinal tract, combined with systemic vascular manifestations. In IBD, the incidence of cardiovascular disease appears to be related to an increase of oxidative stress and endothelial dysfunction. Grape pomace contains high levels of anti-oxidant polyphenols that are able to counteract chronic inflammatory symptoms. The aim of this study was to determine whether grape pomace polyphenolic extract (GPE) was able to mitigate the overwhelming inflammatory response in enterocyte-like cells and to improve vascular function. Intestinal epithelial Caco-2 cells, grown in monolayers or in co-culture with endothelial cells (Caco-2/HMEC-1), were treated with different concentrations of GPE (1, 5, 10 µg/mL gallic acid equivalents) for 2 h and then stimulated with lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-α for 16 h. Through multiple assays, the expression of intestinal and endothelial inflammatory mediators, intracellular reactive oxygen species (ROS) levels and NF-κB activation, as well as endothelial-leukocyte adhesion, were evaluated. The results showed that GPE supplementation prevented, in a concentration-dependent manner, the intestinal expression and release of interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, and matrix metalloproteinases (MMP)-9 and MMP-2. In Caco-2 cells, GPE also suppressed the gene expression of several pro-inflammatory markers, such as IL-1β, TNF-α, macrophage colony-stimulating factor (M-CSF), C-X-C motif ligand (CXCL)-10, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and cyclooxygenase (COX)-2. The GPE anti-inflammatory effect was mediated by the inhibition of NF-κB activity and reduced intracellular ROS levels. Furthermore, transepithelial GPE suppressed the endothelial expression of IL-6, MCP-1, VCAM-1, and ICAM-1 and the subsequent adhesion of leukocytes to the endothelial cells under pro-inflammatory conditions. In conclusion, our findings suggest grape pomace as a natural source of polyphenols with multiple health-promoting properties that could contribute to the mitigation of gut chronic inflammatory diseases and improve vascular endothelial function.
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21
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Ding H, Chang J, He F, Gai S, Yang P. Hydrogen Sulfide: An Emerging Precision Strategy for Gas Therapy. Adv Healthc Mater 2022; 11:e2101984. [PMID: 34788499 DOI: 10.1002/adhm.202101984] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 11/06/2021] [Indexed: 12/13/2022]
Abstract
Advances in nanotechnology have enabled the rapid development of stimuli-responsive therapeutic nanomaterials for precision gas therapy. Hydrogen sulfide (H2 S) is a significant gaseous signaling molecule with intrinsic biochemical properties, which exerts its various physiological effects under both normal and pathological conditions. Various nanomaterials with H2 S-responsive properties, as new-generation therapeutic agents, are explored to guide therapeutic behaviors in biological milieu. The cross disciplinary of H2 S is an emerging scientific hotspot that studies the chemical properties, biological mechanisms, and therapeutic effects of H2 S. This review summarizes the state-of-art research on H2 S-related nanomedicines. In particular, recent advances in H2 S therapeutics for cancer, such as H2 S-mediated gas therapy and H2 S-related synergistic therapies (combined with chemotherapy, photodynamic therapy, photothermal therapy, and chemodynamic therapy) are highlighted. Versatile imaging techniques for real-time monitoring H2 S during biological diagnosis are reviewed. Finally, the biosafety issues, current challenges, and potential possibilities in the evolution of H2 S-based therapy that facilitate clinical translation to patients are discussed.
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Affiliation(s)
- He Ding
- Key Laboratory of Superlight Materials and Surface Technology Ministry of Education College of Materials Science and Chemical Engineering Harbin Engineering University Harbin 150001 P. R. China
| | - Jinhu Chang
- Key Laboratory of Superlight Materials and Surface Technology Ministry of Education College of Materials Science and Chemical Engineering Harbin Engineering University Harbin 150001 P. R. China
| | - Fei He
- Key Laboratory of Superlight Materials and Surface Technology Ministry of Education College of Materials Science and Chemical Engineering Harbin Engineering University Harbin 150001 P. R. China
| | - Shili Gai
- Key Laboratory of Superlight Materials and Surface Technology Ministry of Education College of Materials Science and Chemical Engineering Harbin Engineering University Harbin 150001 P. R. China
| | - Piaoping Yang
- Key Laboratory of Superlight Materials and Surface Technology Ministry of Education College of Materials Science and Chemical Engineering Harbin Engineering University Harbin 150001 P. R. China
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22
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Ueda T, Hanno PM, Saito R, Meijlink JM, Yoshimura N. Current Understanding and Future Perspectives of Interstitial Cystitis/Bladder Pain Syndrome. Int Neurourol J 2021; 25:99-110. [PMID: 34218637 PMCID: PMC8255826 DOI: 10.5213/inj.2142084.042] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 04/13/2021] [Indexed: 01/06/2023] Open
Abstract
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic disease characterized by suprapubic pain and lower urinary tract symptoms. Perhaps because of the heterogeneous nature of this disease and its multifactorial etiology, clinical trials in allinclusive populations of IC/BPS patients without phenotyping in the last decade have mainly failed to discover new therapeutic modalities of IC/BPS. Thus, phenotyping IC/BPS, aimed at identifying bladder-centric and/or bladder-beyond pathologies, including cystoscopic observation of Hunner or non-Hunner lesions of the bladder mucosa, is particularly important for the future of IC/BPS management. Based on recent discussions at international conferences, including the International Consultation on IC, Japan, it has been proposed that Hunner-lesion IC should be separated from other non-Hunner IC/BPS because of its distinct inflammatory profiles and epithelial denudation compared with non-Hunner IC/BPS. However, there are still no standard criteria for the diagnosis of Hunner lesions other than typical lesions, while conventional cystoscopic observations may miss atypical or small Hunner lesions. Furthermore, diagnosis of the bladder-centric phenotype of IC/BPS requires confirmation that identified mucosal lesions are truly a cause of bladder pain in IC/BPS patients. This review article discusses the current status of IC/BPS pathophysiology and diagnosis, as well as future directions of the proper diagnosis of bladder-centric IC/BPS, in which pathophysiological mechanisms other than those in inflammatory pathways, such as angiogenic and immunogenic abnormalities, could also be involved in both Hunner-lesion IC and non-Hunner IC/BPS. It is hoped that this new paradigm in the pathophysiological evaluation and diagnosis of IC/BPS could lead to pathology-based phenotyping and new treatments for this heterogeneous disease.
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Affiliation(s)
- Tomohiro Ueda
- Department of Urology, Ueda Clinic & Comfortable Urology Network, Kyoto, Japan
| | - Philip M. Hanno
- Department of Urology, Stanford University School of Medicine, Stanford, CA, USA
| | - Ryoichi Saito
- Department of Urology, Ueda Clinic & Comfortable Urology Network, Kyoto, Japan
- Department of Urology and Andrology, Kansai Medical University, Osaka, Japan
| | - Jane M. Meijlink
- International Painful Bladder Foundation, Naarden, The Netherlands
| | - Naoki Yoshimura
- Department of Urology, Ueda Clinic & Comfortable Urology Network, Kyoto, Japan
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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23
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Ruskovska T, Massaro M, Carluccio MA, Arola-Arnal A, Muguerza B, Vanden Berghe W, Declerck K, Bravo FI, Calabriso N, Combet E, Gibney ER, Gomes A, Gonthier MP, Kistanova E, Krga I, Mena P, Morand C, Nunes Dos Santos C, de Pascual-Teresa S, Rodriguez-Mateos A, Scoditti E, Suárez M, Milenkovic D. Systematic bioinformatic analysis of nutrigenomic data of flavanols in cell models of cardiometabolic disease. Food Funct 2021; 11:5040-5064. [PMID: 32537624 DOI: 10.1039/d0fo00701c] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Flavanol intake positively influences several cardiometabolic risk factors in humans. However, the specific molecular mechanisms of action of flavanols, in terms of gene regulation, in the cell types relevant to cardiometabolic disease have never been systematically addressed. On this basis, we conducted a systematic literature review and a comprehensive bioinformatic analysis of genes whose expression is affected by flavanols in cells defining cardiometabolic health: hepatocytes, adipocytes, endothelial cells, smooth muscle cells and immune cells. A systematic literature search was performed using the following pre-defined criteria: treatment with pure compounds and metabolites (no extracts) at low concentrations that are close to their plasma concentrations. Differentially expressed genes were analyzed using bioinformatics tools to identify gene ontologies, networks, cellular pathways and interactions, as well as transcriptional and post-transcriptional regulators. The systematic literature search identified 54 differentially expressed genes at the mRNA level in in vitro models of cardiometabolic disease exposed to flavanols and their metabolites. Global bioinformatic analysis revealed that these genes are predominantly involved in inflammation, leukocyte adhesion and transendothelial migration, and lipid metabolism. We observed that, although the investigated cells responded differentially to flavanol exposure, the involvement of anti-inflammatory responses is a common mechanism of flavanol action. We also identified potential transcriptional regulators of gene expression: transcriptional factors, such as GATA2, NFKB1, FOXC1 or PPARG, and post-transcriptional regulators: miRNAs, such as mir-335-5p, let-7b-5p, mir-26b-5p or mir-16-5p. In parallel, we analyzed the nutrigenomic effects of flavanols in intestinal cells and demonstrated their predominant involvement in the metabolism of circulating lipoproteins. In conclusion, the results of this systematic analysis of the nutrigenomic effects of flavanols provide a more comprehensive picture of their molecular mechanisms of action and will support the future setup of genetic studies to pave the way for individualized dietary recommendations.
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Affiliation(s)
- Tatjana Ruskovska
- Faculty of Medical Sciences, Goce Delcev University, Stip, North Macedonia
| | - Marika Massaro
- National Research Council (CNR) Institute of Clinical Physiology (IFC), 73100 Lecce, Italy
| | | | - Anna Arola-Arnal
- Universitat Rovira i Virgili, Departament de Bioquímica i Biotecnologia, Nutrigenomics Research Group, 43007, Tarragona, Spain
| | - Begoña Muguerza
- Universitat Rovira i Virgili, Departament de Bioquímica i Biotecnologia, Nutrigenomics Research Group, 43007, Tarragona, Spain
| | - Wim Vanden Berghe
- Laboratory of Protein Chemistry, Proteomics and Epigenetic Signaling (PPES), Department of Biomedical Sciences, University of Antwerp, Wilrijk, Belgium
| | - Ken Declerck
- Laboratory of Protein Chemistry, Proteomics and Epigenetic Signaling (PPES), Department of Biomedical Sciences, University of Antwerp, Wilrijk, Belgium
| | - Francisca Isabel Bravo
- Universitat Rovira i Virgili, Departament de Bioquímica i Biotecnologia, Nutrigenomics Research Group, 43007, Tarragona, Spain
| | - Nadia Calabriso
- National Research Council (CNR) Institute of Clinical Physiology (IFC), 73100 Lecce, Italy
| | - Emilie Combet
- Human Nutrition, School of Medicine, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Eileen R Gibney
- UCD Institute of Food and Health, School of Agriculture and Food Science, University College Dublin, Ireland
| | - Andreia Gomes
- iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2780-901, Oeiras, Portugal and Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, 2780-157, Oeiras, Portugal
| | - Marie-Paule Gonthier
- Université de La Réunion, INSERM, UMR 1188 Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), Saint-Denis de La Réunion, France
| | - Elena Kistanova
- Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Irena Krga
- Centre of Research Excellence in Nutrition and Metabolism, Institute for Medical Research, University of Belgrade, Belgrade, Serbia and Université Clermont Auvergne, INRAe, UNH, F-63000 Clermont-Ferrand, France.
| | - Pedro Mena
- The Laboratory of Phytochemicals in Physiology, Human Nutrition Unit, Department of Food and Drug, University of Parma, Via Volturno 39, 43125 Parma, Italy
| | - Christine Morand
- Université Clermont Auvergne, INRAe, UNH, F-63000 Clermont-Ferrand, France.
| | - Claudia Nunes Dos Santos
- iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2780-901, Oeiras, Portugal and Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, 2780-157, Oeiras, Portugal and CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056 Lisboa, Portugal
| | - Sonia de Pascual-Teresa
- Department of Metabolism and Nutrition, Institute of Food Science, Technology and Nutrition (ICTAN-CSIC), Jose Antonio Novais 10, 28040 Madrid, Spain
| | - Ana Rodriguez-Mateos
- Department of Nutritional Sciences, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Egeria Scoditti
- National Research Council (CNR) Institute of Clinical Physiology (IFC), 73100 Lecce, Italy
| | - Manuel Suárez
- Universitat Rovira i Virgili, Departament de Bioquímica i Biotecnologia, Nutrigenomics Research Group, 43007, Tarragona, Spain
| | - Dragan Milenkovic
- Université Clermont Auvergne, INRAe, UNH, F-63000 Clermont-Ferrand, France. and Department of Internal Medicine, Division of Cardiovascular Medicine, School of Medicine, University of California Davis, Davis, California 95616, USA
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24
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Text Mining-Based Drug Discovery in Osteoarthritis. JOURNAL OF HEALTHCARE ENGINEERING 2021; 2021:6674744. [PMID: 33953899 PMCID: PMC8060081 DOI: 10.1155/2021/6674744] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 03/08/2021] [Accepted: 04/01/2021] [Indexed: 02/06/2023]
Abstract
Background Osteoarthritis (OA) is a chronic and degenerative joint disease, which causes stiffness, pain, and decreased function. At the early stage of OA, nonsteroidal anti-inflammatory drugs (NSAIDs) are considered the first-line treatment. However, the efficacy and utility of available drug therapies are limited. We aim to use bioinformatics to identify potential genes and drugs associated with OA. Methods The genes related to OA and NSAIDs therapy were determined by text mining. Then, the common genes were performed for GO, KEGG pathway analysis, and protein-protein interaction (PPI) network analysis. Using the MCODE plugin-obtained hub genes, the expression levels of hub genes were verified using quantitative real-time polymerase chain reaction (qRT-PCR). The confirmed genes were queried in the Drug Gene Interaction Database to determine potential genes and drugs. Results The qRT-PCR result showed that the expression level of 15 genes was significantly increased in OA samples. Finally, eight potential genes were targetable to a total of 53 drugs, twenty-one of which have been employed to treat OA and 32 drugs have not yet been used in OA. Conclusions The 15 genes (including PTGS2, NLRP3, MMP9, IL1RN, CCL2, TNF, IL10, CD40, IL6, NGF, TP53, RELA, BCL2L1, VEGFA, and NOTCH1) and 32 drugs, which have not been used in OA but approved by the FDA for other diseases, could be potential genes and drugs, respectively, to improve OA treatment. Additionally, those methods provided tremendous opportunities to facilitate drug repositioning efforts and study novel target pharmacology in the pharmaceutical industry.
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25
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Tolomeo AM, Castagliuolo I, Piccoli M, Grassi M, Magarotto F, De Lazzari G, Malvicini R, Caicci F, Franzin C, Scarpa M, Macchi V, De Caro R, Angriman I, Viola A, Porzionato A, Pozzobon M, Muraca M. Extracellular Vesicles Secreted by Mesenchymal Stromal Cells Exert Opposite Effects to Their Cells of Origin in Murine Sodium Dextran Sulfate-Induced Colitis. Front Immunol 2021; 12:627605. [PMID: 33927713 PMCID: PMC8076641 DOI: 10.3389/fimmu.2021.627605] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 03/17/2021] [Indexed: 12/15/2022] Open
Abstract
Several reports have described a beneficial effect of Mesenchymal Stromal Cells (MSCs) and of their secreted extracellular vesicles (EVs) in mice with experimental colitis. However, the effects of the two treatments have not been thoroughly compared in this model. Here, we compared the effects of MSCs and of MSC-EV administration in mice with colitis induced by dextran sulfate sodium (DSS). Since cytokine conditioning was reported to enhance the immune modulatory activity of MSCs, the cells were kept either under standard culture conditions (naïve, nMSCs) or primed with a cocktail of pro-inflammatory cytokines, including IL1β, IL6 and TNFα (induced, iMSCs). In our experimental conditions, nMSCs and iMSCs administration resulted in both clinical and histological worsening and was associated with pro-inflammatory polarization of intestinal macrophages. However, mice treated with iEVs showed clinico-pathological improvement, decreased intestinal fibrosis and angiogenesis and a striking increase in intestinal expression of Mucin 5ac, suggesting improved epithelial function. Moreover, treatment with iEVs resulted in the polarization of intestinal macrophages towards and anti-inflammatory phenotype and in an increased Treg/Teff ratio at the level of the intestinal lymph node. Collectively, these data confirm that MSCs can behave either as anti- or as pro-inflammatory agents depending on the host environment. In contrast, EVs showed a beneficial effect, suggesting a more predictable behavior, a safer therapeutic profile and a higher therapeutic efficacy with respect to their cells of origin.
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Affiliation(s)
- Anna Maria Tolomeo
- Department of Women’s and Children’s Health, University of Padova, Padua, Italy
- Laboratory of Extracellular Vesicles as Therapeutic Tools, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padua, Italy
- L.i.f.e.L.a.b. Program, Consorzio per la Ricerca Sanitaria (CORIS), Padua, Italy
| | | | - Martina Piccoli
- Laboratory of Tissue Engineering, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padua, Italy
| | - Michele Grassi
- Department of Women’s and Children’s Health, University of Padova, Padua, Italy
| | - Fabio Magarotto
- Department of Women’s and Children’s Health, University of Padova, Padua, Italy
- Laboratory of Stem Cells and Regenerative Medicine, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padua, Italy
| | - Giada De Lazzari
- Department of Women’s and Children’s Health, University of Padova, Padua, Italy
- Laboratory of Extracellular Vesicles as Therapeutic Tools, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padua, Italy
- L.i.f.e.L.a.b. Program, Consorzio per la Ricerca Sanitaria (CORIS), Padua, Italy
| | - Ricardo Malvicini
- Laboratory of Extracellular Vesicles as Therapeutic Tools, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padua, Italy
- L.i.f.e.L.a.b. Program, Consorzio per la Ricerca Sanitaria (CORIS), Padua, Italy
- Instituto de medicina traslacional, trasplante y bioingenieria (IMeTTyB-CONICET), Buenos Aires, Argentina
| | | | - Chiara Franzin
- Laboratory of Tissue Engineering, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padua, Italy
| | - Melania Scarpa
- Laboratory of Advanced Translational Research, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy
| | - Veronica Macchi
- Department of Neurosciences, University of Padova, Padua, Italy
| | - Raffaele De Caro
- L.i.f.e.L.a.b. Program, Consorzio per la Ricerca Sanitaria (CORIS), Padua, Italy
- Department of Neurosciences, University of Padova, Padua, Italy
| | - Imerio Angriman
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy
| | - Antonella Viola
- Department of Biomedical Sciences, University of Padova, Padua, Italy
| | - Andrea Porzionato
- L.i.f.e.L.a.b. Program, Consorzio per la Ricerca Sanitaria (CORIS), Padua, Italy
- Department of Neurosciences, University of Padova, Padua, Italy
| | - Michela Pozzobon
- Department of Women’s and Children’s Health, University of Padova, Padua, Italy
- Laboratory of Stem Cells and Regenerative Medicine, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padua, Italy
| | - Maurizio Muraca
- Department of Women’s and Children’s Health, University of Padova, Padua, Italy
- Laboratory of Extracellular Vesicles as Therapeutic Tools, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padua, Italy
- L.i.f.e.L.a.b. Program, Consorzio per la Ricerca Sanitaria (CORIS), Padua, Italy
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Lagatuz M, Vyas RJ, Predovic M, Lim S, Jacobs N, Martinho M, Valizadegan H, Kao D, Oza N, Theriot CA, Zanello SB, Taibbi G, Vizzeri G, Dupont M, Grant MB, Lindner DJ, Reinecker HC, Pinhas A, Chui TY, Rosen RB, Moldovan N, Vickerman MB, Radhakrishnan K, Parsons-Wingerter P. Vascular Patterning as Integrative Readout of Complex Molecular and Physiological Signaling by VESsel GENeration Analysis. J Vasc Res 2021; 58:207-230. [PMID: 33839725 PMCID: PMC9903340 DOI: 10.1159/000514211] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 12/23/2020] [Indexed: 11/19/2022] Open
Abstract
The molecular signaling cascades that regulate angiogenesis and microvascular remodeling are fundamental to normal development, healthy physiology, and pathologies such as inflammation and cancer. Yet quantifying such complex, fractally branching vascular patterns remains difficult. We review application of NASA's globally available, freely downloadable VESsel GENeration (VESGEN) Analysis software to numerous examples of 2D vascular trees, networks, and tree-network composites. Upon input of a binary vascular image, automated output includes informative vascular maps and quantification of parameters such as tortuosity, fractal dimension, vessel diameter, area, length, number, and branch point. Previous research has demonstrated that cytokines and therapeutics such as vascular endothelial growth factor, basic fibroblast growth factor (fibroblast growth factor-2), transforming growth factor-beta-1, and steroid triamcinolone acetonide specify unique "fingerprint" or "biomarker" vascular patterns that integrate dominant signaling with physiological response. In vivo experimental examples described here include vascular response to keratinocyte growth factor, a novel vessel tortuosity factor; angiogenic inhibition in humanized tumor xenografts by the anti-angiogenesis drug leronlimab; intestinal vascular inflammation with probiotic protection by Saccharomyces boulardii, and a workflow programming of vascular architecture for 3D bioprinting of regenerative tissues from 2D images. Microvascular remodeling in the human retina is described for astronaut risks in microgravity, vessel tortuosity in diabetic retinopathy, and venous occlusive disease.
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Affiliation(s)
- Mark Lagatuz
- Redline Performance Solutions, Ames Research Center, National Aeronautics and Space Administration, Moffett Field CA, USA
| | - Ruchi J. Vyas
- Mori Associates, Space Biology Division, Ames Research Center, National Aeronautics and Space Administration, Moffett Field CA, USA
| | - Marina Predovic
- Blue Marble Space Institute of Science, Space Biology Division, Ames Research Center, National Aeronautics and Space Administration, Moffett Field CA, USA
| | - Shiyin Lim
- Blue Marble Space Institute of Science, Space Biology Division, Ames Research Center, National Aeronautics and Space Administration, Moffett Field CA, USA
| | - Nicole Jacobs
- Blue Marble Space Institute of Science, Space Biology Division, Ames Research Center, National Aeronautics and Space Administration, Moffett Field CA, USA
| | - Miguel Martinho
- Universities Space Research Association, Intelligent Systems Division, Exploration Technology Directorate, Ames Research Center, National Aeronautics and Space Administration, Moffett Field CA, USA
| | - Hamed Valizadegan
- Universities Space Research Association, Intelligent Systems Division, Exploration Technology Directorate, Ames Research Center, National Aeronautics and Space Administration, Moffett Field CA, USA
| | - David Kao
- Advanced Supercomputing & Intelligent Systems Divisions, Exploration Technology Directorate, Ames Research Center, National Aeronautics and Space Administration, Moffett Field CA, USA
| | - Nikunj Oza
- Advanced Supercomputing & Intelligent Systems Divisions, Exploration Technology Directorate, Ames Research Center, National Aeronautics and Space Administration, Moffett Field CA, USA
| | - Corey A. Theriot
- Department of Preventive Medicine and Community Health, The University of Texas Medical Branch at Galveston, Galveston, TX, USA
- KBRWyle, Johnson Space Center, National Aeronautics and Space Administration, Houston, TX, USA
| | - Susana B. Zanello
- KBRWyle, Johnson Space Center, National Aeronautics and Space Administration, Houston, TX, USA
| | - Giovanni Taibbi
- Department of Ophthalmology and Visual Sciences, The University of Texas Medical Branch at Galveston, Galveston, TX, USA
| | - Gianmarco Vizzeri
- Department of Ophthalmology and Visual Sciences, The University of Texas Medical Branch at Galveston, Galveston, TX, USA
| | - Mariana Dupont
- Department of Ophthalmology and Visual Sciences, School of Medicine, University of Alabama, Birmingham AL, USA
| | - Maria B. Grant
- Department of Ophthalmology and Visual Sciences, School of Medicine, University of Alabama, Birmingham AL, USA
| | - Daniel J. Lindner
- Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland OH, USA
| | - Hans-Christian Reinecker
- Departments of Medicine and Immunology, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Alexander Pinhas
- Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, New York, NY, USA
| | - Toco Y. Chui
- Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, New York, NY, USA
| | - Richard B. Rosen
- Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, New York, NY, USA
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Nicanor Moldovan
- Department of Ophthalmology, Indiana University School of Medicine and Indiana University Purdue University at Indianapolis IN, USA
- Richard L. Roudebush VA Medical Center, Veteran’s Administration, Indianapolis IN, USA
| | - Mary B. Vickerman
- Data Systems Branch, John Glenn Research Center, National Aeronautics and Space Administration, Cleveland, OH, USA (retired)
| | - Krishnan Radhakrishnan
- Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration, U.S. Department of Health and Human Services, Rockville, MD, USA
- College of Medicine, University of Kentucky, Lexington, KY, USA
| | - Patricia Parsons-Wingerter
- Space Biology Division, Space Technology Mission Directorate, Ames Research Center, National Aeronautics and Space Administration, Moffett Field, CA, USA
- Low Gravity Exploration Technology, Research and Engineering Directorate, John Glenn Research Center, National Aeronautics and Space Administration, Cleveland, OH, USA
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Xie Z, Wang Y, Yang G, Han J, Zhu L, Li L, Zhang S. The role of the Hippo pathway in the pathogenesis of inflammatory bowel disease. Cell Death Dis 2021; 12:79. [PMID: 33436549 PMCID: PMC7804279 DOI: 10.1038/s41419-021-03395-3] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 12/24/2020] [Accepted: 12/28/2020] [Indexed: 01/29/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic and recurrent inflammatory disorder that primarily comprises Crohn's disease (CD) and ulcerative colitis (UC). Owing to its increasing prevalence in Eastern countries and the intractable challenges faced during IBD treatment, extensive research on IBD has been carried out over the last few years. Although the precise aetiology of IBD is undefined, the currently accepted hypothesis for IBD pathogenesis considers it to be a combination of environment, genetic predisposition, gut microbiota, and abnormal immunity. A recently emerged signalling pathway, the Hippo pathway, acts as a key regulator of cell growth, tissue homoeostasis, organ size, and has been implicated in several human cancers. In the past few years, studies have revealed the importance of the Hippo pathway in gastrointestinal tract physiology and gastrointestinal diseases, such as colorectal cancer and IBD. However, the role of the Hippo pathway and its exact impact in IBD remains to be elucidated. This review summarises the latest scientific literature on the involvement of this pathway in IBD from the following perspectives that account for the IBD pathogenesis: intestinal epithelial cell regeneration, immune regulation, gut microbiota, and angiogenesis. A comprehensive understanding of the specific role of the Hippo pathway in IBD will provide novel insights into future research directions and clinical implications of the Hippo pathway.
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Affiliation(s)
- Zhuo Xie
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Ying Wang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Guang Yang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Jing Han
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Liguo Zhu
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Li Li
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Shenghong Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.
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Wang L, Wang S, Xue A, Shi J, Zheng C, Huang Y. Thalidomide Inhibits Angiogenesis via Downregulation of VEGF and Angiopoietin-2 in Crohn's Disease. Inflammation 2020; 44:795-807. [PMID: 33206273 DOI: 10.1007/s10753-020-01378-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/20/2020] [Accepted: 10/25/2020] [Indexed: 12/14/2022]
Abstract
Immune-mediated angiogenesis is important in the pathogenesis of inflammatory bowel disease and targeted treatment could alleviate the disease. Thalidomide is an effective drug in inflammatory bowel disease, which might be related to its multiple role in anti-inflammatory, immunoregulatory, and anti-angiogenesis. This study is to investigate the effect of thalidomide on angiogenesis in tissues from patients and in vitro cells. Angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), VEGF, and CD31 expressions in intestinal mucosa from pediatric CD patients before and after thalidomide treatment were measured by immunohistochemistry. Western blotting and polymerase chain reaction were performed to characterize the change of angiogenic factors before and after treatment in remission. Human umbilical vein endothelial cells (HUVECs) treated by thalidomide were used to examine its effect on endothelial cell proliferation and migration and capillary-like structures. Results showed that VEGF and Ang-2 levels were significantly greater in CD patients over controls. Thalidomide produced a significant reduction in protein expression of Ang-2 and VEGF, along with a decrease in mRNA expression of Ang-2. While, Ang-1 level did not show a statistically significant change. Thalidomide significantly inhibited cell proliferation in a dose-dependent manner. It also suppressed VEGF- and Ang-2-induced cell migration and capillary-like tube formation in HUVECs. Therefore, our study suggests that VEGF and Ang-2 levels are up-regulated in pediatric CD patients. It also indicated that thalidomide can be able to deactivate endothelium by the downregulation effect on angiogenic factors by targeting VEGF and Ang-2.
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Affiliation(s)
- Lin Wang
- Department of Gastroenterology, Children's Hospital of Fudan University/National Children's Medical Center, Shanghai, China
| | - Shengnan Wang
- Department of Gastroenterology, Children's Hospital of Fudan University/National Children's Medical Center, Shanghai, China
| | - Aijuan Xue
- Department of Gastroenterology, Children's Hospital of Fudan University/National Children's Medical Center, Shanghai, China
| | - Jieru Shi
- Department of Gastroenterology, Children's Hospital of Fudan University/National Children's Medical Center, Shanghai, China
| | - Cuifang Zheng
- Department of Gastroenterology, Children's Hospital of Fudan University/National Children's Medical Center, Shanghai, China
| | - Ying Huang
- Department of Gastroenterology, Children's Hospital of Fudan University/National Children's Medical Center, Shanghai, China.
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Kim YS, Zhang H, Lee S, Park S, Noh M, Kim YM, Kwon YG. CU06-1004 Alleviates Experimental Colitis by Modulating Colonic Vessel Dysfunction. Front Pharmacol 2020; 11:571266. [PMID: 33041812 PMCID: PMC7523507 DOI: 10.3389/fphar.2020.571266] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 08/25/2020] [Indexed: 01/08/2023] Open
Abstract
Inflammatory bowel disease is an autoimmune disease that causes chronic inflammation of the gastrointestinal tract. Endothelial dysfunction, defined by a reduced endothelial barrier and an increase in the expression of adhesion molecules, is part of the pathology of inflammatory bowel disease. In this study, we assessed the therapeutic effect of CU06-1004, an endothelial dysfunction blocker that reduces vascular hyperpermeability and inflammation in a mouse model of colitis. Acute colitis was induced in mice using 3% (w/v) dextran sodium sulfate added to their drinking water for 7 days. Twenty-four hours after the addition of dextran sodium sulfate, either mesalazine or CU06-1004 was administered orally each day. Administration of CU06-1004 significantly reduced the clinical manifestations (weight loss, diarrhea, and bloody stool) and histological changes (epithelium loss, inflammatory cell infiltration, and crypt destruction) induced by dextran sodium sulfate. Proinflammatory cytokines were also reduced, indicating that inflammation was ameliorated. From a vascular perspective, CU06-1004 reduced interrupted and tortuous vessels, enhanced junction protein expression, and reduced inflammatory adhesion molecules, indicating a broad improvement of endothelial dysfunction. Endothelial protection induced epithelial barrier restoration and decreased epithelial inflammation. Blocking endothelial dysfunction with CU06-1004 significantly ameliorated the progression of inflammatory bowel disease. Therefore, CU06-1004 may represent a potential therapeutic agent for the treatment of inflammatory bowel disease as well as other inflammatory diseases.
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Affiliation(s)
- Ye-Seul Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
| | - Haiying Zhang
- R&D Department, Curacle Co. Ltd, Seongnam-si, South Korea
| | - Sunghye Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
| | - Songyi Park
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
| | - Minyoung Noh
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
| | - Young-Myeong Kim
- Vascular System Research Center, Kangwon National University, Chuncheon, South Korea
| | - Young-Guen Kwon
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
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Enriquez J, Mims BMD, Trasti S, Furr KL, Grisham MB. Genomic, microbial and environmental standardization in animal experimentation limiting immunological discovery. BMC Immunol 2020; 21:50. [PMID: 32878597 PMCID: PMC7464063 DOI: 10.1186/s12865-020-00380-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 08/25/2020] [Indexed: 02/07/2023] Open
Abstract
Background The use of inbred mice housed under standardized environmental conditions has been critical in identifying immuno-pathological mechanisms in different infectious and inflammatory diseases as well as revealing new therapeutic targets for clinical trials. Unfortunately, only a small percentage of preclinical intervention studies using well-defined mouse models of disease have progressed to clinically-effective treatments in patients. The reasons for this lack of bench-to-bedside transition are not completely understood; however, emerging data suggest that genetic diversity and housing environment may greatly influence muring immunity and inflammation. Results Accumulating evidence suggests that certain immune responses and/or disease phenotypes observed in inbred mice may be quite different than those observed in their outbred counterparts. These differences have been thought to contribute to differing immune responses to foreign and/or auto-antigens in mice vs. humans. There is also a growing literature demonstrating that mice housed under specific pathogen free conditions possess an immature immune system that remarkably affects their ability to respond to pathogens and/or inflammation when compared with mice exposed to a more diverse spectrum of microorganisms. Furthermore, recent studies demonstrate that mice develop chronic cold stress when housed at standard animal care facility temperatures (i.e. 22–24 °C). These temperatures have been shown alter immune responses to foreign and auto-antigens when compared with mice housed at their thermo-neutral body temperature of 30–32 °C. Conclusions Exposure of genetically diverse mice to a spectrum of environmentally-relevant microorganisms at housing temperatures that approximate their thermo-neutral zone may improve the chances of identifying new and more potent therapeutics to treat infectious and inflammatory diseases.
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Affiliation(s)
- Josue Enriquez
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, 3601 4th Street STOP 6591, Lubbock, TX, 79430-6591, USA
| | - Brianyell Mc Daniel Mims
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, 3601 4th Street STOP 6591, Lubbock, TX, 79430-6591, USA
| | - Scott Trasti
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, 3601 4th Street STOP 6591, Lubbock, TX, 79430-6591, USA.,Laboratory Animal Research Center, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA
| | - Kathryn L Furr
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, 3601 4th Street STOP 6591, Lubbock, TX, 79430-6591, USA
| | - Matthew B Grisham
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, 3601 4th Street STOP 6591, Lubbock, TX, 79430-6591, USA.
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Chaudhary CL, Chaudhary P, Dahal S, Bae D, Nam TG, Kim JA, Jeong BS. Inhibition of colitis by ring-modified analogues of 6-acetamido-2,4,5-trimethylpyridin-3-ol. Bioorg Chem 2020; 103:104130. [PMID: 32745758 DOI: 10.1016/j.bioorg.2020.104130] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 07/02/2020] [Accepted: 07/20/2020] [Indexed: 12/16/2022]
Abstract
6-Aminopyridin-3-ol scaffold has shown an excellent anti-inflammatory bowel disease activity. Various analogues with the scaffold were synthesized in pursuit of the diversity of side chains tethering on the C(6)-position. Structure-activity relationship among the analogues was investigated to understand the effects of the side chains and their linkers on their anti-inflammatory activities. In this study, structural modification moved beyond side chains on the C(6)-position and reached to pyridine ring itself. It expedited us to synthesize diverse ring-modified analogues of a representative pyridine-3-ol, 6-acetamido-2,4,5-trimethylpyridin-3-ol (9). In the evaluation of compounds on their inhibitory actions against TNF-α-induced adhesion of monocytic cells to colonic epithelial cells, an in vitro model mimicking colon inflammation, the effects of compounds 9, 17, and 19 were greater than tofacitinib, an orally available anti-colitis drug, and compound 17 showed the greatest activity. In addition, TNF-α-induced angiogenesis, which permits more inflammatory cell migration into inflamed tissues, was significantly blocked by compounds 17 and 19 in a concentration-dependent manner. In the comparison of in vivo therapeutic effects of compounds 9, 17, and 19 on dextran sulfate sodium (DSS)-induced colitis in mice, compound 17 was the most potent and efficacious, and compound 19 was better than compound 9 which showed a similar degree of inhibitory effect to tofacitinib. Taken together, it seems that either the trimethyl system or the hydroxyl group on the pyridinol ring is essential to the activity. This finding might become a new milestone in the development of pyridinol-based anti-inflammatory bowel disease agents.
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Affiliation(s)
- Chhabi Lal Chaudhary
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Prakash Chaudhary
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Sadan Dahal
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Dawon Bae
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Tae-Gyu Nam
- Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do 15588, Republic of Korea.
| | - Jung-Ae Kim
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea.
| | - Byeong-Seon Jeong
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea.
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Furuta A, Suzuki Y, Igarashi T, Koike Y, Kimura T, Egawa S, Yoshimura N. Angiogenesis in bladder tissues is strongly correlated with urinary frequency and bladder pain in patients with interstitial cystitis/bladder pain syndrome. Int J Urol 2020; 26 Suppl 1:35-40. [PMID: 31144750 DOI: 10.1111/iju.13972] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 03/18/2019] [Indexed: 12/20/2022]
Abstract
OBJECTIVES To examine the correlation among bladder inflammation, angiogenesis, fibrosis and urothelial denudation in biopsied bladder specimens, and O'Leary-Sant symptom indexes, O'Leary-Sant problem indexes and visual analog scale pain scores in interstitial cystitis/bladder pain syndrome patients with or without Hunner lesions (Hunner type interstitial cystitis or non-Hunner type interstitial cystitis). METHODS Bladder biopsied tissues were collected from 12 Hunner type interstitial cystitis female patients, 12 non-Hunner type interstitial cystitis female patients and 12 age-matched non-interstitial cystitis female patients (controls). Immunohistochemical stainings of tissue necrotic factor-α, mast cell tryptase, vascular endothelial growth factor, CD31, transforming growth factor-β, SLUG associated with epithelial mesenchymal transition and E-cadherin as well as Masson trichrome staining were evaluated. The significant correlation between the expression of tissue necrotic factor-α, mast cell tryptase, vascular endothelial growth factor, CD31, transforming growth factor-β, collagen, SLUG or E-cadherin, and O'Leary-Sant symptom indexes, O'Leary-Sant problem indexes or visual analog scale pain scores was then examined. RESULTS The expression of tissue necrotic factor-α, vascular endothelial growth factor, CD31, transforming growth factor-β and SLUG was significantly increased in non-Hunner type interstitial cystitis and Hunner type interstitial cystitis patients compared with controls whereas the significant increases in the expression of mast cell tryptase and collagen were observed in Hunner type interstitial cystitis patients compared with controls and non-Hunner type interstitial cystitis patients. On the other hand, the expression of E-cadherin was significantly decreased in Hunner type interstitial cystitis patients compared with controls and non-Hunner type interstitial cystitis patients. In addition, the increased expression of CD31 in bladder tissues was strongly correlated with O'Leary-Sant symptom indexes, O'Leary-Sant problem indexes and visual analog scale pain scores. CONCLUSIONS These results suggest that bladder angiogenesis evident as the increased expression of CD31 is strongly correlated with urinary frequency and bladder pain in patients with non-Hunner type interstitial cystitis and Hunner type interstitial cystitis.
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Affiliation(s)
- Akira Furuta
- Department of Urology, Jikei University School of Medicine, Tokyo, Japan
| | - Yasuyuki Suzuki
- Department of Urology, Tokyo Metropolitan Rehabilitation Hospital, Tokyo, Japan
| | - Taro Igarashi
- Department of Urology, Jikei University School of Medicine, Tokyo, Japan
| | - Yusuke Koike
- Department of Urology, Jikei University School of Medicine, Tokyo, Japan
| | - Takahiro Kimura
- Department of Urology, Jikei University School of Medicine, Tokyo, Japan
| | - Shin Egawa
- Department of Urology, Jikei University School of Medicine, Tokyo, Japan
| | - Naoki Yoshimura
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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Deletion of SOCS2 Reduces Post-Colitis Fibrosis via Alteration of the TGFβ Pathway. Int J Mol Sci 2020; 21:ijms21093073. [PMID: 32349250 PMCID: PMC7246483 DOI: 10.3390/ijms21093073] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 03/31/2020] [Accepted: 04/05/2020] [Indexed: 12/31/2022] Open
Abstract
Inflammatory bowel disease (IBD) is an immunologically mediated chronic intestinal disorder. Growth hormone (GH) administration enhances mucosal repair and decreases intestinal fibrosis in patients with IBD. In the present study, we investigated the effect of cellular sensitivity to GH via suppressor of cytokine signaling 2 (SOCS2) deletion on colitis and recovery. To induce colitis, wild type and SOCS2 knockout (SOCS2−/−) mice were treated with 3% dextran sodium sulphate (DSS), followed by a recovery period. SOCS2−/− mice showed higher disease activity during colitis with increased mRNA expression of the pro-inflammatory cytokines nitric oxide synthase 2 (NOS2) and interleukin 1 β (IL1-β). At recovery time point, SOCS2−/− showed better recovery with less fibrosis measured by levels of α-SMA and collagen deposition. Protein and mRNA expressions of transforming growth factor beta β1 (TGF-β1) receptors were significantly lower in SOCS2−/− mice compared to wild-type littermates. Using an in vivo bromodeoxyuridine (BrdU) proliferation assay, SOCS2−/− mice showed higher intestinal epithelial proliferation compared to wild-type mice. Our results demonstrated that deletion of the SOCS2 protein results in higher growth hormone sensitivity associated with higher pro-inflammatory signaling; however, it resulted in less tissue damage with less fibrotic lesions and higher epithelial proliferation, which are markers of GH-protective effects in IBD. This suggests a pleiotropic effect of SOCS2 and multiple cellular targets. Further study is required to study role of SOCS2 in regulation of TGFβ-mothers against the decapentaplegic homolog (Smad) pathway.
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Gastrointestinal disorders-induced pain. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2019.100580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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35
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Henderson AR, Choi H, Lee E. Blood and Lymphatic Vasculatures On-Chip Platforms and Their Applications for Organ-Specific In Vitro Modeling. MICROMACHINES 2020; 11:E147. [PMID: 32013154 PMCID: PMC7074693 DOI: 10.3390/mi11020147] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 01/23/2020] [Accepted: 01/28/2020] [Indexed: 02/07/2023]
Abstract
The human circulatory system is divided into two complementary and different systems, the cardiovascular and the lymphatic system. The cardiovascular system is mainly concerned with providing nutrients to the body via blood and transporting wastes away from the tissues to be released from the body. The lymphatic system focuses on the transport of fluid, cells, and lipid from interstitial tissue spaces to lymph nodes and, ultimately, to the cardiovascular system, as well as helps coordinate interstitial fluid and lipid homeostasis and immune responses. In addition to having distinct structures from each other, each system also has organ-specific variations throughout the body and both systems play important roles in maintaining homeostasis. Dysfunction of either system leads to devastating and potentially fatal diseases, warranting accurate models of both blood and lymphatic vessels for better studies. As these models also require physiological flow (luminal and interstitial), extracellular matrix conditions, dimensionality, chemotactic biochemical gradient, and stiffness, to better reflect in vivo, three dimensional (3D) microfluidic (on-a-chip) devices are promising platforms to model human physiology and pathology. In this review, we discuss the heterogeneity of both blood and lymphatic vessels, as well as current in vitro models. We, then, explore the organ-specific features of each system with examples in the gut and the brain and the implications of dysfunction of either vasculature in these organs. We close the review with discussions on current in vitro models for specific diseases with an emphasis on on-chip techniques.
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Affiliation(s)
- Aria R. Henderson
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA;
| | - Hyoann Choi
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA;
| | - Esak Lee
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA;
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Lee Y, Lee J, Ju J. Perilla frutescens Britton var. frutescens leaves attenuate dextran sulfate sodium-induced acute colitis in mice and lipopolysaccharide-stimulated angiogenic processes in human umbilical vein endothelial cells. Food Sci Biotechnol 2019; 29:131-140. [PMID: 31976135 DOI: 10.1007/s10068-019-00711-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 10/31/2019] [Accepted: 11/04/2019] [Indexed: 02/08/2023] Open
Abstract
The aim of the current study was to investigate whether the leaves of Perilla frutescens Britton var. frutescens (PL), a frequently consumed vegetable in Korea, attenuate dextran sulfate sodium (DSS)-induced acute colitis in mice and lipopolysaccharide (LPS)-stimulated angiogenic processes in human umbilical vein endothelial cells (HUVEC). In DSS-treated mice, dietary supplementation with PL mitigated DAI and colon shortening. The dietary PL also reduced colonic levels of inflammatory and angiogenic mediators, such as interleukin-1β, interleukin-6, monocyte chemoattractant protein-1, macrophage inflammatory protein-2, leukotriene B4, inducible nitric oxide synthase, cyclooxygenase-2, basic fibroblast growth factor, and intercellular adhesion molecule-1 (ICAM-1). Treatment of HUVEC with ethanol extract of PL attenuated LPS-stimulated increases in ICAM-1 levels, monocyte adhesion, invasion, and tube formation. This study suggests that dietary PL effectively inhibited DSS-induced acute colitis in mice, and its anti-angiogenic activities may partially contribute to the inhibition.
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Affiliation(s)
- Yuna Lee
- Department of Food and Nutrition, Chungbuk National University, 1 Chungdae-ro, Seowon-gu, Cheongju, 362-763 Korea
| | - Jungjae Lee
- Department of Food and Nutrition, Chungbuk National University, 1 Chungdae-ro, Seowon-gu, Cheongju, 362-763 Korea
| | - Jihyeung Ju
- Department of Food and Nutrition, Chungbuk National University, 1 Chungdae-ro, Seowon-gu, Cheongju, 362-763 Korea
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Adipose Stem Cell-Based Clinical Strategy for Neural Regeneration: A Review of Current Opinion. Stem Cells Int 2019; 2019:8502370. [PMID: 31827536 PMCID: PMC6885831 DOI: 10.1155/2019/8502370] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 11/02/2019] [Accepted: 11/11/2019] [Indexed: 02/05/2023] Open
Abstract
Nerve injury is a critical problem in the clinic. Nerve injury causes serious clinic issues including pain and dysfunctions for patients. The disconnection between damaged neural fibers and muscles will result in muscle atrophy in a few weeks if no treatment is applied. Moreover, scientists have discovered that nerve injury can affect the osteogenic differentiation of skeletal stem cells (SSCs) and the fracture repairing. In plastic surgery, muscle atrophy and bone fracture after nerve injury have plagued clinicians for many years. How to promote neural regeneration is the core issue of research in the recent years. Without obvious effects of traditional neurosurgical treatments, research on stem cells in the past 10 years has provided a new therapeutic strategy for us to address this problem. Adipose stem cells (ASCs) are a kind of mesenchymal stem cells that have differentiation potential in adipose tissue. In the recent years, ASCs have become the focus of regenerative medicine. They play a pivotal role in tissue regeneration engineering. As a type of stem cell, ASCs are becoming popular for neuroregenerative medicine due to their advantages and characteristics. In the various diseases of the nervous system, ASCs are gradually applied to treat the related diseases. This review article focuses on the mechanism and clinical application of ASCs in nerve regeneration as well as the related research on ASCs over the past decades.
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Kamio Y, Miyamoto T, Kimura T, Mitsui K, Furukawa H, Zhang D, Yokosuka K, Korai M, Kudo D, Lukas RJ, Lawton MT, Hashimoto T. Roles of Nicotine in the Development of Intracranial Aneurysm Rupture. Stroke 2019; 49:2445-2452. [PMID: 30355112 DOI: 10.1161/strokeaha.118.021706] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Background and Purpose- Tobacco cigarette smoking is considered to be a strong risk factor for intracranial aneurysmal rupture. Nicotine is a major biologically active constituent of tobacco products. Nicotine's interactions with vascular cell nicotinic acetylcholine receptors containing α7 subunits (α7*-nAChR) are thought to promote local inflammation and sustained angiogenesis. In this study, using a mouse intracranial aneurysm model, we assessed potential contributions of nicotine exposure and activation of α7*-nAChR to the development of aneurysmal rupture. Methods- Intracranial aneurysms were induced by a combination of deoxycorticosterone-salt induced hypertension and a single-dose elastase injection into cerebrospinal fluid in mice. Results- Exposure to nicotine or an α7*-nAChR-selective agonist significantly increased aneurysm rupture rate. Coexposure to an α7*-nAChR antagonist abolished nicotine's deleterious effect. In addition, nicotine's promotion of aneurysm rupture was absent in smooth muscle cell-specific α7*-nAChR subunit knockout mice but not in mice lacking α7*-nAChR on endothelial cells or macrophages. Nicotine treatment increased the mRNA levels of vascular endothelial growth factor, platelet-derived growth factor-B, and inflammatory cytokines. α7*-nAChR antagonist reversed nicotine-induced upregulation of these growth factors and cytokines. Conclusions- Our findings indicate that nicotine exposure promotes aneurysmal rupture through actions on vascular smooth muscle cell α7*-nAChR.
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Affiliation(s)
- Yoshinobu Kamio
- From the Departments of Neurosurgery (Y.K., T.M., T.K., D.K., M.T.L., T.H.), Barrow Neurological Institute, Phoenix, AZ.,Barrow Aneurysm and AVM Research Center (Y.K., T.M., T.K., D.K., M.T.L., T.H.), Barrow Neurological Institute, Phoenix, AZ
| | - Takeshi Miyamoto
- From the Departments of Neurosurgery (Y.K., T.M., T.K., D.K., M.T.L., T.H.), Barrow Neurological Institute, Phoenix, AZ.,Neurobiology (T.M., T.K., D.K., R.J.L., T.H.), Barrow Neurological Institute, Phoenix, AZ.,Barrow Aneurysm and AVM Research Center (Y.K., T.M., T.K., D.K., M.T.L., T.H.), Barrow Neurological Institute, Phoenix, AZ
| | - Tetsuro Kimura
- From the Departments of Neurosurgery (Y.K., T.M., T.K., D.K., M.T.L., T.H.), Barrow Neurological Institute, Phoenix, AZ.,Neurobiology (T.M., T.K., D.K., R.J.L., T.H.), Barrow Neurological Institute, Phoenix, AZ.,Barrow Aneurysm and AVM Research Center (Y.K., T.M., T.K., D.K., M.T.L., T.H.), Barrow Neurological Institute, Phoenix, AZ
| | - Kazuha Mitsui
- Department of Anesthesia and Perioperative Care, University of California, San Francisco (K.M., H.F., D.Z., K.Y., M.K.)
| | - Hajime Furukawa
- Department of Anesthesia and Perioperative Care, University of California, San Francisco (K.M., H.F., D.Z., K.Y., M.K.)
| | - Dingding Zhang
- Department of Anesthesia and Perioperative Care, University of California, San Francisco (K.M., H.F., D.Z., K.Y., M.K.)
| | - Kimihiko Yokosuka
- Department of Anesthesia and Perioperative Care, University of California, San Francisco (K.M., H.F., D.Z., K.Y., M.K.)
| | - Masaaki Korai
- Department of Anesthesia and Perioperative Care, University of California, San Francisco (K.M., H.F., D.Z., K.Y., M.K.)
| | - Daisuke Kudo
- From the Departments of Neurosurgery (Y.K., T.M., T.K., D.K., M.T.L., T.H.), Barrow Neurological Institute, Phoenix, AZ.,Neurobiology (T.M., T.K., D.K., R.J.L., T.H.), Barrow Neurological Institute, Phoenix, AZ.,Barrow Aneurysm and AVM Research Center (Y.K., T.M., T.K., D.K., M.T.L., T.H.), Barrow Neurological Institute, Phoenix, AZ
| | - Ronald J Lukas
- Neurobiology (T.M., T.K., D.K., R.J.L., T.H.), Barrow Neurological Institute, Phoenix, AZ
| | - Michael T Lawton
- From the Departments of Neurosurgery (Y.K., T.M., T.K., D.K., M.T.L., T.H.), Barrow Neurological Institute, Phoenix, AZ.,Barrow Aneurysm and AVM Research Center (Y.K., T.M., T.K., D.K., M.T.L., T.H.), Barrow Neurological Institute, Phoenix, AZ
| | - Tomoki Hashimoto
- From the Departments of Neurosurgery (Y.K., T.M., T.K., D.K., M.T.L., T.H.), Barrow Neurological Institute, Phoenix, AZ.,Neurobiology (T.M., T.K., D.K., R.J.L., T.H.), Barrow Neurological Institute, Phoenix, AZ.,Barrow Aneurysm and AVM Research Center (Y.K., T.M., T.K., D.K., M.T.L., T.H.), Barrow Neurological Institute, Phoenix, AZ
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Rajendran S, Shen X, Glawe J, Kolluru GK, Kevil CG. Nitric Oxide and Hydrogen Sulfide Regulation of Ischemic Vascular Growth and Remodeling. Compr Physiol 2019; 9:1213-1247. [PMID: 31187898 DOI: 10.1002/cphy.c180026] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ischemic vascular remodeling occurs in response to stenosis or arterial occlusion leading to a change in blood flow and tissue perfusion. Altered blood flow elicits a cascade of molecular and cellular physiological responses leading to vascular remodeling of the macro- and micro-circulation. Although cellular mechanisms of vascular remodeling such as arteriogenesis and angiogenesis have been studied, therapeutic approaches in these areas have had limited success due to the complexity and heterogeneous constellation of molecular signaling events regulating these processes. Understanding central molecular players of vascular remodeling should lead to a deeper understanding of this response and aid in the development of novel therapeutic strategies. Hydrogen sulfide (H2 S) and nitric oxide (NO) are gaseous signaling molecules that are critically involved in regulating fundamental biochemical and molecular responses necessary for vascular growth and remodeling. This review examines how NO and H2 S regulate pathophysiological mechanisms of angiogenesis and arteriogenesis, along with important chemical and experimental considerations revealed thus far. The importance of NO and H2 S bioavailability, their synthesis enzymes and cofactors, and genetic variations associated with cardiovascular risk factors suggest that they serve as pivotal regulators of vascular remodeling responses. © 2019 American Physiological Society. Compr Physiol 9:1213-1247, 2019.
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Affiliation(s)
| | - Xinggui Shen
- Departments of Pathology, LSU Health Sciences Center, Shreveport
| | - John Glawe
- Departments of Pathology, LSU Health Sciences Center, Shreveport
| | - Gopi K Kolluru
- Departments of Pathology, LSU Health Sciences Center, Shreveport
| | - Christopher G Kevil
- Departments of Pathology, LSU Health Sciences Center, Shreveport.,Departments of Cellular Biology and Anatomy, LSU Health Sciences Center, Shreveport.,Departments of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport
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40
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The RAGE signaling pathway is involved in intestinal inflammation and represents a promising therapeutic target for Inflammatory Bowel Diseases. Mucosal Immunol 2019; 12:468-478. [PMID: 30542111 DOI: 10.1038/s41385-018-0119-z] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 10/25/2018] [Accepted: 10/30/2018] [Indexed: 02/07/2023]
Abstract
Inflammatory Bowel Diseases (IBD) are chronic inflammatory conditions of the intestinal tract. IBD are believed to result from an inappropriate immune response against the intestinal flora in genetically predisposed patients. The precise etiology of these diseases is not fully understood, therefore treatments rely on the dampening of symptoms, essentially inflammation, rather than on the cure of the disease. Despite the availability of biologics, such as anti-TNF antibodies, some patients remain in therapeutic failure and new treatments are thus needed. The multiligand receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor implicated in inflammatory reactions and immune system activation. Here, we investigated the role of RAGE in intestinal inflammation and its potential as a therapeutic target in IBD. We showed that RAGE was upregulated in inflamed tissues from IBD patients compared to controls. Rage-/- mice were less susceptible to intestinal and colonic inflammation development than WT mice. WT mice treated with the RAGE-specific inhibitor FPS-ZM1 experienced less severe enteritis and colitis. We demonstrated that RAGE could induce intestinal inflammation by promoting oxidative stress and endothelial activation which were diminished by FPS-ZM1 treatment. Our results revealed the RAGE signaling pathway as a promising therapeutic target for IBD patients.
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Narrow-Band Imaging Colonoscopy to Assess Mucosal Angiogenesis in Ulcerative Colitis. Gastroenterol Res Pract 2019; 2019:8312624. [PMID: 30918516 PMCID: PMC6409060 DOI: 10.1155/2019/8312624] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 12/15/2018] [Accepted: 01/30/2019] [Indexed: 01/17/2023] Open
Abstract
Background and Aim It has been documented that angiogenesis is a largely unstudied component of the pathogenesis of ulcerative colitis (UC). Under narrow-band imaging (NBI) colonoscopy, the mucosal vascular pattern (MVP) can be visualized without the use of dyes. The aim of this study was to assess the grade of mucosal angiogenesis based on the MVP in UC. Methods A total of 119 colorectal segments taken from 42 patients with UC were observed using NBI colonoscopy. The MVP was classified as follows: clear, obscure, or absent. Quantification of the degree of inflammation was performed using histological colitis scoring. Potent angiogenic activity was assessed by immunohistochemical staining for vascular endothelial growth factor (VEGF). Microvascular density was assessed using vessel counts as revealed by CD31 staining. The correlation between the MVP and histological grades of inflammation and angiogenesis was evaluated. Results The MVP correlated well with the histological severity of inflammation. We also demonstrated an increasing level of microvascular density and VEGF staining along with the ordered types of MVPs. In addition, a statistically strong association existed between microvascular density and VEGF staining. Conclusions NBI colonoscopy might be a useful tool for the in vivo assessment of the grade of mucosal angiogenesis in UC.
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Aksoy EK, Çetinkaya H, Savaş B, Ensari A, Torgutalp M, Efe C. Vascular endothelial growth factor, endostatin levels and clinical features among patients with ulcerative colitis and irritable bowel syndrome and among healthy controls: a cross-sectional analytical study. SAO PAULO MED J 2018; 136:543-550. [PMID: 30892485 PMCID: PMC9897133 DOI: 10.1590/1516-3180.2018.0274161118] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 06/26/2018] [Accepted: 11/16/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Increased angiogenetic activity in inflammatory bowel disease (IBD) has been shown in previous studies. The aim of this study was to evaluate the relationship of serum vascular endothelial growth factor (VEGF) and endostatin levels with clinical features and mucosal expression in patients with ulcerative colitis (UC). DESIGN AND SETTING Cross-sectional analytical study conducted in a tertiary-level public hospital. METHODS Serum VEGF and endostatin levels were determined in 82 individuals: 39 with UC, 28 with irritable bowel syndrome (IBS) and 15 healthy controls (HCs), using enzyme-linked immunosorbent assays (ELISA). VEGF and endostatin expressions were studied using immunohistochemistry (IHC). RESULTS Mean serum VEGF and endostatin levels were significantly higher in patients with UC than in patients with IBS and in HCs (511.9 ± 377.5 pg/ml, 305.0 ± 121.42 pg/ml and 36.1 ± 40.6 pg/ml; P = 0.001 for VEGF; and 155.50 ± 59.8 ng/ml, 116.9 ± 23.8 ng/ml and 102.2 ± 22.4 ng/ml; P < 0.001 for endostatin, respectively). There was a positive correlation between serum VEGF and endostatin levels (r = 0.422; P < 0.01). Mean H-scores for VEGF expression were higher in the active UC group than in the inactive UC and IBS groups, in the stroma, endothelium and epithelium. Mean H-scores for endostatin expression were higher in the active UC group than in the inactive UC and IBS groups, in the stroma and endothelium. There was no endostatin expression in the epithelium. CONCLUSION Increased endostatin appears to be a defensive reaction to increased VEGF in patients with UC.
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Affiliation(s)
- Evrim Kahramanoğlu Aksoy
- MD. Physician, Department of Gastroenterology, Keçiören Training and Research Hospital, Ankara, Turkey.
| | - Hülya Çetinkaya
- MD. Professor, Department of Gastroenterology, Ankara University Faculty of Medicine, Ankara, Turkey.
| | - Berna Savaş
- MD. Professor, Department of Pathology, Ankara University Faculty of Medicine, Ankara, Turkey
| | - Arzu Ensari
- MD. Professor, Department of Pathology, Ankara University Faculty of Medicine, Ankara, Turkey.
| | - Murat Torgutalp
- MD. Physician, Department of Rheumatology, Ankara University Faculty of Medicine, Ankara, Turkey.
| | - Cumali Efe
- MD. Associate Professor, Department of Gastroenterology, Gazi Yaşargil Training And Research Hospital, Diyarbakır, Turkey.
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Sun B, Yuan J, Wang S, Lin J, Zhang W, Shao J, Wang R, Shi B, Hu H. Qingchang Suppository Ameliorates Colonic Vascular Permeability in Dextran-Sulfate-Sodium-Induced Colitis. Front Pharmacol 2018; 9:1235. [PMID: 30429788 PMCID: PMC6220057 DOI: 10.3389/fphar.2018.01235] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 10/11/2018] [Indexed: 12/13/2022] Open
Abstract
Ulcerative colitis (UC), with a long course and repeated attack, severely affects patient's life quality and increases economic burden all over the world. However, the concrete causes and mechanisms of UC are still unclear, but it is generally considered that many factors participate in this process. Qingchang Suppository (QCS) has been used in treating rectitis and colitis for about 30 years in Shanghai, China. Its satisfactory clinical effects have been proved. The aim of this study is to investigate the effect and mechanisms of QCS on colonic vascular endothelial barrier in dextran sulfate sodium (DSS)-induced colitis. The results indicated that increased vascular permeability (VP) appeared earlier than increased intestinal epithelial permeability (EP) in the process of DSS-induced colitis. QCS attenuated colonic tissue edema, vascular congestion and inflammatory cell infiltration. QCS inhibited the elevation of MPO, TNF-α, and IL-6 levels in colon tissues and alleviated the microvascular damage induced by DSS. QCS also improved colonic hypoxia and decreased the expression of VEGF, HIF-1α, and iNOS. These results revealed that QCS can reduce colonic VP and can improve vascular endothelial barrier function maybe by regulating the VEGF/HIF-1α signaling pathway.
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Affiliation(s)
- Boyun Sun
- Department of Gastroenterology, China-Canada Center of Research for Digestive Diseases, Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jianye Yuan
- Department of Gastroenterology, China-Canada Center of Research for Digestive Diseases, Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shiying Wang
- Department of Gastroenterology, China-Canada Center of Research for Digestive Diseases, Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiang Lin
- Department of Gastroenterology, China-Canada Center of Research for Digestive Diseases, Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wanjun Zhang
- Department of Gastroenterology, China-Canada Center of Research for Digestive Diseases, Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiadong Shao
- Department of Gastroenterology, China-Canada Center of Research for Digestive Diseases, Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ruiqing Wang
- Department of Gastroenterology, China-Canada Center of Research for Digestive Diseases, Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Bei Shi
- Department of Gastroenterology, China-Canada Center of Research for Digestive Diseases, Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hongyi Hu
- Department of Gastroenterology, China-Canada Center of Research for Digestive Diseases, Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Iwazawa R, Kozakai S, Kitahashi T, Nakamura K, Hata KI. The Therapeutic Effects of Adipose-Derived Stem Cells and Recombinant Peptide Pieces on Mouse Model of DSS Colitis. Cell Transplant 2018; 27:1390-1400. [PMID: 29978718 PMCID: PMC6168991 DOI: 10.1177/0963689718782442] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Cell therapies using adipose-derived stem cells (ADSCs) have been used to treat inflammatory bowel disease (IBD) in human and dog. We previously reported the CellSaic technique, which uses a recombinant scaffold to enhance the efficacy of cell therapy. To examine whether this technique can be applied to cell therapy for colitis, we evaluated the efficacy of CellSaic in colitis mouse models. Colitis mouse models were developed by administering dextran sulfate sodium (DSS) to C57BL/6 mice for 7 days. Then CellSaic comprising human/canine ADSCs (1.2 × 106 cells) or human/canine ADSCs only (1.2 × 106 cells) were administered to the mice. The body weights were measured, and the colon length measurements and histological evaluations were conducted at 7 days after administration. After in vitro culture of human ADSC (hADSC) CellSaic and hADSC spheroids in medium containing TNFα, the levels of the anti-inflammatory protein TSG-6 in each supernatant were measured. Furthermore, we conducted tumorigenicity and general toxicity tests of canine ADSC (cADSC) CellSaic in NOG mice for 8 weeks. In the colitis mouse models, the ADSC CellSaic group presented recovery of body weight and colon length compared with the ADSC-only group. Histological analysis showed that ADSC CellSaic decreased the number of inflammatory cells and repaired ulceration. In vitro, hADSC CellSaic secreted 3.1-fold more TSG-6 than the hADSCs. In addition, tumorigenicity and general toxicity of cADSC CellSaic were not observed. This study suggests that human and canine ADSC CellSaic has a therapeutic effect of colitis in human and dogs.
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Affiliation(s)
- Reiko Iwazawa
- 1 Regenerative Medicine Research Laboratories, FUJIFILM Corporation, Kanagawa, Japan
| | - Sayako Kozakai
- 1 Regenerative Medicine Research Laboratories, FUJIFILM Corporation, Kanagawa, Japan
| | - Tsukasa Kitahashi
- 1 Regenerative Medicine Research Laboratories, FUJIFILM Corporation, Kanagawa, Japan
| | - Kentaro Nakamura
- 1 Regenerative Medicine Research Laboratories, FUJIFILM Corporation, Kanagawa, Japan
| | - Ken-Ichiro Hata
- 1 Regenerative Medicine Research Laboratories, FUJIFILM Corporation, Kanagawa, Japan
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Banskota S, Ghia JE, Khan WI. Serotonin in the gut: Blessing or a curse. Biochimie 2018; 161:56-64. [PMID: 29909048 DOI: 10.1016/j.biochi.2018.06.008] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Accepted: 06/12/2018] [Indexed: 12/25/2022]
Abstract
Serotonin (5-hydroxytryptamine or 5-HT) once most extensively studied as a neurotransmitter of the central nervous system, is seen to be predominantly secreted in the gut. About 95% of 5-HT is estimated to be found in gut mainly within the enterochromaffin cells whereas about 5% is found in the brain. 5-HT is an important enteric signaling molecule and is well known for playing a key role in sensory-motor and secretory functions in the gut. In recent times, studies uncovering various new functions of gut-derived 5-HT indicate that many more are yet to be discovered in coming days. Recent studies revealed that 5-HT plays a pivotal role in immune cell activation and generation/perpetuation of inflammation in the gut. In addition to its various roles in the gut, there are now emerging evidences that suggest an important role of gut-derived 5-HT in other biological processes beyond the gut, such as bone remodeling and metabolic homeostasis. This review focuses to briefly summarize the accumulated and newly updated role of 5-HT in the maintenance of normal gut physiology and in the pathogenesis of inflammation in the gut. The collected information about this multifaceted signaling molecule may aid in distinguishing its good and bad effects which may lead to the development of novel strategies to overcome the unwanted effect, such as in inflammatory bowel disease.
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Affiliation(s)
- Suhrid Banskota
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Jean-Eric Ghia
- Department of Immunology and Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Waliul I Khan
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
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Abstract
The primary β-globin gene mutation that causes sickle cell disease (SCD) has significant pathophysiological consequences that result in hemolytic events and the induction of the inflammatory processes that ultimately lead to vaso-occlusion. In addition to their role in the initiation of the acute painful vaso-occlusive episodes that are characteristic of SCD, inflammatory processes are also key components of many of the complications of the disease including autosplenectomy, acute chest syndrome, pulmonary hypertension, leg ulcers, nephropathy and stroke. We, herein, discuss the events that trigger inflammation in the disease, as well as the mechanisms, inflammatory molecules and cells that propagate these inflammatory processes. Given the central role that inflammation plays in SCD pathophysiology, many of the therapeutic approaches currently under pre-clinical and clinical development for the treatment of SCD endeavor to counter aspects or specific molecules of these inflammatory processes and it is possible that, in the future, we will see anti-inflammatory drugs being used either together with, or in place of, hydroxyurea in those SCD patients for whom hematopoietic stem cell transplants and evolving gene therapies are not a viable option.
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Affiliation(s)
- Nicola Conran
- Hematology Center, University of Campinas - UNICAMP, Cidade Universitária, Campinas-SP, Brazil
| | - John D Belcher
- Department of Medicine, Division of Hematology, Oncology and Transplantation, Vascular Biology Center, University of Minnesota, Minneapolis, MN, USA
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Sivananthan K, Petersen AM. Review ofSaccharomyces boulardiias a treatment option in IBD. Immunopharmacol Immunotoxicol 2018; 40:465-475. [DOI: 10.1080/08923973.2018.1469143] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Kavitha Sivananthan
- Department of Gastroenterology, Copenhagen University Hospital, Hvidovre, Denmark
- Department of Microbiology, Copenhagen University Hospital, Hvidovre, Denmark
| | - Andreas Munk Petersen
- Department of Gastroenterology, Copenhagen University Hospital, Hvidovre, Denmark
- Department of Microbiology, Copenhagen University Hospital, Hvidovre, Denmark
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Microbial interactions with the intestinal epithelium and beyond: Focusing on immune cell maturation and homeostasis. CURRENT PATHOBIOLOGY REPORTS 2018; 6:47-54. [PMID: 30294506 DOI: 10.1007/s40139-018-0165-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Microbial metabolites influence the function of epithelial, endothelial and immune cells in the intestinal mucosa. Microbial metabolites like SCFAs and B complex vitamins direct macrophage polarization whereas microbial derived biogenic amines modulate intestinal epithelium and immune response. Aberrant bacterial lipopolysaccharide-mediated signaling may be involved in the pathogenesis of chronic intestinal inflammation and colorectal carcinogenesis. Our perception of human microbes has changed from that of opportunistic pathogens to active participants maintaining intestinal and whole body homeostasis. This review attempts to explain the dynamic and enriched interactions between the intestinal epithelial mucosa and commensal bacteria in homeostasis maintenance.
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Comparison of inflammatory urine markers in patients with interstitial cystitis and overactive bladder. Int Urogynecol J 2018; 29:961-966. [DOI: 10.1007/s00192-017-3547-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 12/14/2017] [Indexed: 01/26/2023]
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Law IKM, Padua DM, Iliopoulos D, Pothoulakis C. Role of G protein-coupled receptors-microRNA interactions in gastrointestinal pathophysiology. Am J Physiol Gastrointest Liver Physiol 2017; 313:G361-G372. [PMID: 28774868 PMCID: PMC5792214 DOI: 10.1152/ajpgi.00144.2017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 07/13/2017] [Accepted: 07/24/2017] [Indexed: 01/31/2023]
Abstract
G protein-coupled receptors (GPCRs) make up the largest transmembrane receptor superfamily in the human genome and are expressed in nearly all gastrointestinal cell types. Coupling of GPCRs and their respective ligands activates various phosphotransferases in the cytoplasm, and, thus, activation of GPCR signaling in intestine regulates many cellular and physiological processes. Studies in microRNAs (miRNAs) demonstrate that they represent critical epigenetic regulators of different pathophysiological responses in different organs and cell types in humans and animals. Here, we reviewed recent research on GPCR-miRNA interactions related to gastrointestinal pathophysiology, such as inflammatory bowel diseases, irritable bowel syndrome, and gastrointestinal cancers. Given that the presence of different types of cells in the gastrointestinal tract suggests the importance of cell-cell interactions in maintaining gastrointestinal homeostasis, we also discuss how GPCR-miRNA interactions regulate gene expression at the cellular level and subsequently modulate gastrointestinal pathophysiology through molecular regulatory circuits and cell-cell interactions. These studies helped identify novel molecular pathways leading to the discovery of potential biomarkers for gastrointestinal diseases.
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Affiliation(s)
- Ivy Ka Man Law
- 1Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and
| | - David Miguel Padua
- 1Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and
| | - Dimitrios Iliopoulos
- 1Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and ,2Center for Systems Biomedicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Charalabos Pothoulakis
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and
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