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Liu H, Liao X, Zhang Z, Min Q, Li Y, Xiong J, Lv Q, Xie X, Zhou J, Liao Z, Zhou H. HMGB1: key mediator in digestive system diseases. Inflamm Res 2025; 74:34. [PMID: 39903246 DOI: 10.1007/s00011-025-02002-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 01/21/2025] [Accepted: 01/21/2025] [Indexed: 02/06/2025] Open
Abstract
High Mobility Group Box 1 (HMGB1), a multifunctional non-histone protein, and its involvement in various physiological and pathological contexts has garnered significant attention. Given HMGB1's central function in modulating key biological activities, such as inflammatory responses and cellular death, its contribution to the pathogenesis of digestive system diseases has become a focus of growing interest. This review aims to comprehensively explore the mechanisms by which HMGB1 contributes to the progression of inflammatory bowel disease (IBD), liver disorders, and pancreatitis. Furthermore, we explore the prospective clinical applications and outline future research directions for HMGB1 in digestive diseases, providing fresh perspectives that highlight the necessity of ongoing studies to understand its role in these conditions.
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Affiliation(s)
- Hengqian Liu
- School of Medicine, Chongqing University Cancer Hospital, Chongqing University, No. 181 Hanyu Road, Shapingba District, Chongqing, China
- Clinical Medical Research Center, The Second Affiliated Hospital, Army Medical University, No. 83 Xinqiao Main Street, Shapingba District, Chongqing, China
| | - Xiping Liao
- Clinical Medical Research Center, The Second Affiliated Hospital, Army Medical University, No. 83 Xinqiao Main Street, Shapingba District, Chongqing, China
| | - Zuo Zhang
- Clinical Medical Research Center, The Second Affiliated Hospital, Army Medical University, No. 83 Xinqiao Main Street, Shapingba District, Chongqing, China
| | - Qian Min
- Clinical Medical Research Center, The Second Affiliated Hospital, Army Medical University, No. 83 Xinqiao Main Street, Shapingba District, Chongqing, China
| | - Yuanyuan Li
- Clinical Medical Research Center, The Second Affiliated Hospital, Army Medical University, No. 83 Xinqiao Main Street, Shapingba District, Chongqing, China
| | - Junzhi Xiong
- Clinical Medical Research Center, The Second Affiliated Hospital, Army Medical University, No. 83 Xinqiao Main Street, Shapingba District, Chongqing, China
| | - Qiao Lv
- Clinical Medical Research Center, The Second Affiliated Hospital, Army Medical University, No. 83 Xinqiao Main Street, Shapingba District, Chongqing, China
| | - Xia Xie
- Department of Gastroenterology, The Second Affiliated Hospital, Army Medical University, Chongqing, China
| | - Jianyun Zhou
- Clinical Medical Research Center, The Second Affiliated Hospital, Army Medical University, No. 83 Xinqiao Main Street, Shapingba District, Chongqing, China
| | - Zhongli Liao
- School of Medicine, Chongqing University Cancer Hospital, Chongqing University, No. 181 Hanyu Road, Shapingba District, Chongqing, China.
| | - Hongli Zhou
- Clinical Medical Research Center, The Second Affiliated Hospital, Army Medical University, No. 83 Xinqiao Main Street, Shapingba District, Chongqing, China.
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Vitali R, Novelli F, Palone F, Cucchiara S, Stronati L, Pioli C. PARP1 inactivation increases regulatory T / Th17 cell proportion in intestinal inflammation. Role of HMGB1. Immunol Lett 2024; 270:106912. [PMID: 39237041 DOI: 10.1016/j.imlet.2024.106912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 08/12/2024] [Accepted: 09/01/2024] [Indexed: 09/07/2024]
Abstract
Inflammatory bowel diseases (IBD) are chronic relapsing disorders with increasing prevalence. Knowledge gaps still limit the possibility to develop more specific and effective therapies. Using a dextran sodium sulfate colitis mouse model, we found that inflammation increased the total number and altered the frequencies of leukocytes within colon mesenteric lymph nodes (cMLNs). Although the inflammation reduced the frequency of regulatory T (Treg) cells, their absolute numbers were increased. Increased frequency of colitogenic Th17 cells was also observed. Noteworthy, untreated mice lacking Poly(ADP-ribose)-Polimerase-1 functional gene (PARP-1KO) displayed higher frequency of Treg cells and lower percentage of Th17 cells in cMLNs. In colitic PARP-1KO mice the inflammation driven expansion of the Foxp3 Treg population was more pronounced than in WT mice. Conversely, colitis increased Th17 cells to a lower extent in PARP-1KO mice compared with WT mice, resulting in a more protective Treg/Th17 cell ratio. Consequently PARP-1KO mice developed less severe colitis with reduced expression of inflammatory cytokines. In ex vivo experiments PARP-1KO and WT CD11c dendritic cells (DCs) promoted naïve CD4 T cell differentiation differently, the former sustaining more efficiently the generation of Treg cells, the latter that of Th17 cells. Addition of HMGB1 B box or of dipotassium glycyrrhizate, which sequesters extracellular HMGB1, revealed a role for this alarmin in the regulation exerted by PARP-1 on the stimulating vs. tolerogenic function of DCs during colitis. Moreover, a higher percentage of CD11c DC from PARP-1KO mice expressed CD103, a marker associated with the ability of DC to induce Treg cells, compared with WT DC. Conversely, PARP-1KO DC were including a reduced percentage of CX3CR1+ DC, described to induce Th17 cells. These findings were observed in both splenic and colon lamina propria DC.
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Affiliation(s)
| | | | | | - Salvatore Cucchiara
- Department of Maternal Infantile and Urological Sciences, Sapienza University, Rome, Italy
| | - Laura Stronati
- Department of Molecular Medicine, Sapienza University, Rome, Italy
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3
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Li Q, Liu Y, Li B, Zheng C, Yu B, Niu K, Qiao Y. Bioinformatics analysis of oxidative stress genes in the pathogenesis of ulcerative colitis based on a competing endogenous RNA regulatory network. PeerJ 2024; 12:e17213. [PMID: 39161963 PMCID: PMC11332386 DOI: 10.7717/peerj.17213] [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: 10/10/2023] [Accepted: 03/19/2024] [Indexed: 08/21/2024] Open
Abstract
Background Ulcerative colitis (UC) is a common chronic disease associated with inflammation and oxidative stress. This study aimed to construct a long noncoding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) network based on bioinformatics analysis and to explore oxidative stress-related genes underlying the pathogenesis of UC. Methods The GSE75214, GSE48959, and GSE114603 datasets were downloaded from the Gene Expression Omnibus database. Following differentially expressed (DE) analysis, the regulatory relationships among these DERNAs were identified through miRDB, miRTarBase, and TargetScan; then, the lncRNA-miRNA-mRNA network was established. The Molecular Signatures Database (MSigDB) was used to search oxidative stress-related genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed for functional annotation and enrichment analyses. Based on the drug gene interaction database DGIdb, drugs that interact with oxidative stress-associated genes were explored. A dextran sulfate sodium (DSS)-induced UC mouse model was used for experimental validation. Results A total of 30 DE-lncRNAs, 3 DE-miRNAs, and 19 DE-mRNAs were used to construct a lncRNA-miRNA-mRNA network. By comparing these 19 DE-mRNAs with oxidative stress-related genes in MSigDB, three oxidative stress-related genes (CAV1, SLC7A11, and SLC7A5) were found in the 19 DEM sets, which were all negatively associated with miR-194. GO and KEGG analyses showed that CAV1, SLC7A11, and SLC7A5 were associated with immune inflammation and steroid hormone synthesis. In animal experiments, the results showed that dexamethasone, a well-known glucocorticoid drug, could significantly decrease the expression of CAV1, SLC7A11, and SLC7A5 as well as improve UC histology, restore antioxidant activities, inhibit inflammation, and decrease myeloperoxidase activity. Conclusion SLC7A5 was identified as a representative gene associated with glucocorticoid therapy resistance and thus may be a new therapeutic target for the treatment of UC in the clinic.
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MESH Headings
- Animals
- Humans
- Mice
- Colitis, Ulcerative/genetics
- Colitis, Ulcerative/metabolism
- Colitis, Ulcerative/chemically induced
- Computational Biology
- Databases, Genetic
- Dextran Sulfate/toxicity
- Disease Models, Animal
- Gene Expression Profiling
- Gene Regulatory Networks/drug effects
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Oxidative Stress/genetics
- Oxidative Stress/drug effects
- RNA, Competitive Endogenous/genetics
- RNA, Competitive Endogenous/metabolism
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
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Affiliation(s)
- Qifang Li
- Department of Traditional Chinese Medicine, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Yuan Liu
- College of Integrated Chinese and Western Medicine, Jining Medical University, Jining, Shandong, China
| | - Bingbing Li
- College of Integrated Chinese and Western Medicine, Jining Medical University, Jining, Shandong, China
| | - Canlei Zheng
- College of Integrated Chinese and Western Medicine, Jining Medical University, Jining, Shandong, China
| | - Bin Yu
- College of Integrated Chinese and Western Medicine, Jining Medical University, Jining, Shandong, China
| | - Kai Niu
- College of Integrated Chinese and Western Medicine, Jining Medical University, Jining, Shandong, China
| | - Yi Qiao
- School of Public Health, Jining Medical University, Jining, Shandong, China
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Dovrolis N, Valatas V, Drygiannakis I, Filidou E, Spathakis M, Kandilogiannakis L, Tarapatzi G, Arvanitidis K, Bamias G, Vradelis S, Manolopoulos VG, Paspaliaris V, Kolios G. Landscape of Interactions between Stromal and Myeloid Cells in Ileal Crohn's Disease; Indications of an Important Role for Fibroblast-Derived CCL-2. Biomedicines 2024; 12:1674. [PMID: 39200138 PMCID: PMC11351973 DOI: 10.3390/biomedicines12081674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 07/20/2024] [Accepted: 07/25/2024] [Indexed: 09/01/2024] Open
Abstract
BACKGROUND AND AIMS Monocyte recruitment in the lamina propria and inflammatory phenotype driven by the mucosal microenvironment is critical for the pathogenesis of inflammatory bowel disease. However, the stimuli responsible remain largely unknown. Recent works have focused on stromal cells, the main steady-state cellular component in tissue, as they produce pro-inflammatory chemokines that contribute to the treatment-resistant nature of IBD. METHODS We studied the regulation of these processes by examining the communication patterns between stromal and myeloid cells in ileal Crohn's disease (CD) using a complete single-cell whole tissue sequencing analysis pipeline and in vitro experimentation in mesenchymal cells. RESULTS We report expansion of S4 stromal cells and monocyte-like inflammatory macrophages in the inflamed mucosa and describe interactions that may establish sustained local inflammation. These include expression of CCL2 by S1 fibroblasts to recruit and retain monocytes and macrophages in the mucosa, where they receive signals for proliferation, survival, and differentiation to inflammatory macrophages from S4 stromal cells through molecules such as MIF, IFNγ, and FN1. The overexpression of CCL2 in ileal CD and its stromal origin was further demonstrated in vitro by cultured mesenchymal cells and intestinal organoids in the context of an inflammatory milieu. CONCLUSIONS Our findings outline an extensive cross-talk between stromal and myeloid cells, which may contribute to the onset and progression of inflammation in ileal Crohn's disease. Understanding the mechanisms underlying monocyte recruitment and polarization, as well as the role of stromal cells in sustaining inflammation, can provide new avenues for developing targeted therapies to treat IBD.
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Affiliation(s)
- Nikolas Dovrolis
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.F.); (M.S.); (L.K.); (G.T.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Vassilis Valatas
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.F.); (M.S.); (L.K.); (G.T.); (K.A.); (V.G.M.); (G.K.)
- Gastroenterology and Hepatology Research Laboratory, Medical School, University of Crete, 71003 Heraklion, Greece;
| | - Ioannis Drygiannakis
- Gastroenterology and Hepatology Research Laboratory, Medical School, University of Crete, 71003 Heraklion, Greece;
| | - Eirini Filidou
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.F.); (M.S.); (L.K.); (G.T.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Michail Spathakis
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.F.); (M.S.); (L.K.); (G.T.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Leonidas Kandilogiannakis
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.F.); (M.S.); (L.K.); (G.T.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Gesthimani Tarapatzi
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.F.); (M.S.); (L.K.); (G.T.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Konstantinos Arvanitidis
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.F.); (M.S.); (L.K.); (G.T.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | - Giorgos Bamias
- GI Unit, 3 Department of Internal Medicine, Sotiria Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Stergios Vradelis
- Second Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
| | - Vangelis G. Manolopoulos
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.F.); (M.S.); (L.K.); (G.T.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
| | | | - George Kolios
- Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.F.); (M.S.); (L.K.); (G.T.); (K.A.); (V.G.M.); (G.K.)
- Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece
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Xin R. Inflammatory Gene Panel Guiding the Study of Genetics in Inflammatory Bowel Disease. Mol Diagn Ther 2024; 28:389-401. [PMID: 38635139 DOI: 10.1007/s40291-024-00709-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2024] [Indexed: 04/19/2024]
Abstract
Inflammatory bowel disease (IBD) is a complex disease that develops through a sequence of molecular events that are still poorly defined. This process is driven by a multitude of context-dependent genes that play different roles based on their environment. The complexity and multi-faceted nature of these genes make it difficult to study the genetic basis of IBD. The goal of this article is to review the key genes in the pathophysiology of IBD and highlight new technology that can be used in further research. This paper examines Nanostring RNA probe technology, which uses tissue analyzed without the use of enzymes, transcription, or amplification. Nanostring offers several panels of genes to test, including an inflammation panel of 234 genes. This article analyzes this panel and reviews the literature for each gene's effect in IBD for use as a framework to review the pathophysiology of the disease. The panel was narrowed to 26 genes with significant evidence of mechanistic potential in IBD, which were then categorized into specific areas of pathogenesis. These include gut barrier breakdown, inappropriate recognition of commensal bacteria, immune cell activation, proinflammatory cytokine release, and subsequent impairment of the anti-inflammatory response. The eventual goal of this paper is the creation of a customized panel of IBD genes that can be used to better understand the genetic mechanism of IBD and aid in the development of future therapies in IBD.
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Affiliation(s)
- Ryan Xin
- Columbia University Irving Medical Center, 177 Fort Washington Avenue, New York, NY, 10032, USA.
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Edwards TS, Day AS. The role of fecal biomarkers in individuals with inflammatory bowel disease. Expert Rev Mol Diagn 2024; 24:497-508. [PMID: 38995110 DOI: 10.1080/14737159.2024.2375224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 06/28/2024] [Indexed: 07/13/2024]
Abstract
INTRODUCTION Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and Ulcerative Colitis (UC), is a relapsing and remitting condition. Noninvasive biomarkers have an increasingly important role in the diagnosis of IBD and in the prediction of future disease course in individuals with IBD. Strategies for the management of IBD increasingly rely upon close monitoring of gastrointestinal inflammation. AREAS COVERED This review provides an update on the current understanding of established and novel stool-based biomarkers in the diagnosis and management of IBD. It also highlights key gaps, identifies limitations, and advantages of current markers, and examines aspects that require further study and analysis. EXPERT OPINION Current noninvasive inflammatory markers play an important role in the diagnosis and management of IBD; however, limitations exist. Future work is required to further characterize and validate current and novel markers of inflammation. In addition, it is essential to better understand the roles and characteristics of noninvasive markers to enable the appropriate selection to accurately determine the condition of the intestinal mucosa.
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Affiliation(s)
- Teagan S Edwards
- Department of Paediatrics, University of Otago Christchurch, Christchurch, New Zealand
| | - Andrew S Day
- Department of Paediatrics, University of Otago Christchurch, Christchurch, New Zealand
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D’Incà R, Sturniolo G. Biomarkers in IBD: What to Utilize for the Diagnosis? Diagnostics (Basel) 2023; 13:2931. [PMID: 37761298 PMCID: PMC10527829 DOI: 10.3390/diagnostics13182931] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/05/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
The role of biomarkers in the diagnosis of inflammatory bowel disease is not fully characterized. C-reactive protein has a short half-life and elevates quickly after the onset of an inflammatory process; the performance is better in Crohn's disease than in ulcerative colitis. Erythrocyte sedimentation rate is easy to determine, widely available, and cheap, but the long half-life, the influence of age, anemia, smoking, and drugs limit its usefulness. Fecal markers have good specificity, but suboptimal accuracy. Microbial antibodies and novel immunological markers show promise but need further evidence before entering clinical practice. Proteomic methods could represent the dawn of a new era of stool protein/peptide biomarker panels able to select patients at risk of inflammatory bowel disease.
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Affiliation(s)
- Renata D’Incà
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, 35124 Padua, Italy
| | - Giulia Sturniolo
- Department of Women’s and Children’s Health, University of Padua, 35128 Padova, Italy
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Caliendo G, D'Elia G, Makker J, Passariello L, Albanese L, Molinari AM, Vietri MT. Biological, genetic and epigenetic markers in ulcerative colitis. Adv Med Sci 2023; 68:386-395. [PMID: 37813048 DOI: 10.1016/j.advms.2023.09.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 04/15/2023] [Accepted: 09/18/2023] [Indexed: 10/11/2023]
Abstract
In this review, we have summarized the existing knowledge of ulcerative colitis (UC) markers based on current literature, specifically, the roles of potential new biomarkers, such as circulating, fecal, genetic, and epigenetic alterations, in UC onset, disease activity, and in therapy response. UC is a complex multifactorial inflammatory disease. There are many invasive and non-invasive diagnostic methods in UC, including several laboratory markers which are employed in diagnosis and disease assessment; however, colonoscopy remains the most widely used method. Common laboratory abnormalities currently used in the clinical practice include inflammation-induced alterations, serum autoantibodies, and antibodies against bacterial antigens. Other new serum and fecal biomarkers are supportive in diagnosis and monitoring disease activity and therapy response; and potential salivary markers are currently being evaluated as well. Several UC-related genetic and epigenetic alterations are implied in its pathogenesis and therapeutic response. Moreover, the use of artificial intelligence in the integration of laboratory biomarkers and big data could potentially be useful in clinical translation and precision medicine in UC management.
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Affiliation(s)
- Gemma Caliendo
- Unity of Clinical and Molecular Pathology, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giovanna D'Elia
- Unity of Clinical and Molecular Pathology, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Jasmine Makker
- Department of GKT School of Medical Education, King's College London, London, UK
| | - Luana Passariello
- Unity of Clinical and Molecular Pathology, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Luisa Albanese
- Unity of Clinical and Molecular Pathology, AOU University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Anna Maria Molinari
- Unity of Clinical and Molecular Pathology, AOU University of Campania "Luigi Vanvitelli", Naples, Italy; Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Maria Teresa Vietri
- Unity of Clinical and Molecular Pathology, AOU University of Campania "Luigi Vanvitelli", Naples, Italy; Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
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Overstreet AMC, Anderson B, Burge M, Zhu X, Tao Y, Cham CM, Michaud B, Horam S, Sangwan N, Dwidar M, Liu X, Santos A, Finney C, Dai Z, Leone VA, Messer JS. HMGB1 acts as an agent of host defense at the gut mucosal barrier. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.30.542477. [PMID: 37398239 PMCID: PMC10312563 DOI: 10.1101/2023.05.30.542477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Mucosal barriers provide the first line of defense between internal body surfaces and microbial threats from the outside world. 1 In the colon, the barrier consists of two layers of mucus and a single layer of tightly interconnected epithelial cells supported by connective tissue and immune cells. 2 Microbes colonize the loose, outer layer of colonic mucus, but are essentially excluded from the tight, epithelial-associated layer by host defenses. 3 The amount and composition of the mucus is calibrated based on microbial signals and loss of even a single component of this mixture can destabilize microbial biogeography and increase the risk of disease. 4-7 However, the specific components of mucus, their molecular microbial targets, and how they work to contain the gut microbiota are still largely unknown. Here we show that high mobility group box 1 (HMGB1), the prototypical damage-associated molecular pattern molecule (DAMP), acts as an agent of host mucosal defense in the colon. HMGB1 in colonic mucus targets an evolutionarily conserved amino acid sequence found in bacterial adhesins, including the well-characterized Enterobacteriaceae adhesin FimH. HMGB1 aggregates bacteria and blocks adhesin-carbohydrate interactions, inhibiting invasion through colonic mucus and adhesion to host cells. Exposure to HMGB1 also suppresses bacterial expression of FimH. In ulcerative colitis, HMGB1 mucosal defense is compromised, leading to tissue-adherent bacteria expressing FimH. Our results demonstrate a new, physiologic role for extracellular HMGB1 that refines its functions as a DAMP to include direct, virulence limiting effects on bacteria. The amino acid sequence targeted by HMGB1 appears to be broadly utilized by bacterial adhesins, critical for virulence, and differentially expressed by bacteria in commensal versus pathogenic states. These characteristics suggest that this amino acid sequence is a novel microbial virulence determinant and could be used to develop new approaches to diagnosis and treatment of bacterial disease that precisely identify and target virulent microbes.
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10
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Vitali R, Mancuso AB, Palone F, Pioli C, Cesi V, Negroni A, Cucchiara S, Oliva S, Carissimi C, Laudadio I, Stronati L. PARP1 Activation Induces HMGB1 Secretion Promoting Intestinal Inflammation in Mice and Human Intestinal Organoids. Int J Mol Sci 2023; 24:ijms24087096. [PMID: 37108260 PMCID: PMC10138503 DOI: 10.3390/ijms24087096] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/23/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
Extracellular High-mobility group box 1 (HMGB1) contributes to the pathogenesis of inflammatory disorders, including inflammatory bowel diseases (IBD). Poly (ADP-ribose) polymerase 1 (PARP1) has been recently reported to promote HMGB1 acetylation and its secretion outside cells. In this study, the relationship between HMGB1 and PARP1 in controlling intestinal inflammation was explored. C57BL6/J wild type (WT) and PARP1-/- mice were treated with DSS to induce acute colitis, or with the DSS and PARP1 inhibitor, PJ34. Human intestinal organoids, which are originated from ulcerative colitis (UC) patients, were exposed to pro-inflammatory cytokines (INFγ + TNFα) to induce intestinal inflammation, or coexposed to cytokines and PJ34. Results show that PARP1-/- mice develop less severe colitis than WT mice, evidenced by a significant decrease in fecal and serum HMGB1, and, similarly, treating WT mice with PJ34 reduces the secreted HMGB1. The exposure of intestinal organoids to pro-inflammatory cytokines results in PARP1 activation and HMGB1 secretion; nevertheless, the co-exposure to PJ34, significantly reduces the release of HMGB1, improving inflammation and oxidative stress. Finally, HMGB1 release during inflammation is associated with its PARP1-induced PARylation in RAW264.7 cells. These findings offer novel evidence that PARP1 favors HMGB1 secretion in intestinal inflammation and suggest that impairing PARP1 might be a novel approach to manage IBD.
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Affiliation(s)
- Roberta Vitali
- Laboratory of Biomedical Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Anna Barbara Mancuso
- Department of Maternal Infantile and Urological Sciences, Sapienza University, 00161 Rome, Italy
| | - Francesca Palone
- Laboratory of Biomedical Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Claudio Pioli
- Laboratory of Biomedical Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Vincenzo Cesi
- Laboratory of Biomedical Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Anna Negroni
- Laboratory of Biomedical Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), 00123 Rome, Italy
| | - Salvatore Cucchiara
- Department of Maternal Infantile and Urological Sciences, Sapienza University, 00161 Rome, Italy
| | - Salvatore Oliva
- Department of Maternal Infantile and Urological Sciences, Sapienza University, 00161 Rome, Italy
| | - Claudia Carissimi
- Department of Molecular Medicine, Sapienza University, 00161 Rome, Italy
| | - Ilaria Laudadio
- Department of Molecular Medicine, Sapienza University, 00161 Rome, Italy
| | - Laura Stronati
- Department of Molecular Medicine, Sapienza University, 00161 Rome, Italy
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Sharma A, Junge O, Szymczak S, Rühlemann MC, Enderle J, Schreiber S, Laudes M, Franke A, Lieb W, Krawczak M, Dempfle A. Network-based quantitative trait linkage analysis of microbiome composition in inflammatory bowel disease families. Front Genet 2023; 14:1048312. [PMID: 36755569 PMCID: PMC9901208 DOI: 10.3389/fgene.2023.1048312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 01/09/2023] [Indexed: 01/24/2023] Open
Abstract
Introduction: Inflammatory bowel disease (IBD) is characterized by a dysbiosis of the gut microbiome that results from the interaction of the constituting taxa with one another, and with the host. At the same time, host genetic variation is associated with both IBD risk and microbiome composition. Methods: In the present study, we defined quantitative traits (QTs) from modules identified in microbial co-occurrence networks to measure the inter-individual consistency of microbial abundance and subjected these QTs to a genome-wide quantitative trait locus (QTL) linkage analysis. Results: Four microbial network modules were consistently identified in two cohorts of healthy individuals, but three of the corresponding QTs differed significantly between IBD patients and unaffected individuals. The QTL linkage analysis was performed in a sub-sample of the Kiel IBD family cohort (IBD-KC), an ongoing study of 256 German families comprising 455 IBD patients and 575 first- and second-degree, non-affected relatives. The analysis revealed five chromosomal regions linked to one of three microbial module QTs, namely on chromosomes 3 (spanning 10.79 cM) and 11 (6.69 cM) for the first module, chr9 (0.13 cM) and chr16 (1.20 cM) for the second module, and chr13 (19.98 cM) for the third module. None of these loci have been implicated in a microbial phenotype before. Discussion: Our study illustrates the benefit of combining network and family-based linkage analysis to identify novel genetic drivers of microbiome composition in a specific disease context.
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Affiliation(s)
- Arunabh Sharma
- Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany
| | - Olaf Junge
- Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany
| | - Silke Szymczak
- Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany
| | - Malte Christoph Rühlemann
- Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany,Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Janna Enderle
- Institute of Epidemiology, Kiel University, Kiel, Germany
| | - Stefan Schreiber
- Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany,Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Matthias Laudes
- Institute of Diabetology and Clinical Metabolic Research, Kiel University, Kiel, Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
| | - Wolfgang Lieb
- Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Michael Krawczak
- Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany
| | - Astrid Dempfle
- Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany,*Correspondence: Astrid Dempfle,
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Phuong-Nguyen K, McNeill BA, Aston-Mourney K, Rivera LR. Advanced Glycation End-Products and Their Effects on Gut Health. Nutrients 2023; 15:nu15020405. [PMID: 36678276 PMCID: PMC9867518 DOI: 10.3390/nu15020405] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/20/2022] [Accepted: 01/11/2023] [Indexed: 01/14/2023] Open
Abstract
Dietary advanced glycation end-products (AGEs) are a heterogeneous group of compounds formed when reducing sugars are heated with proteins, amino acids, or lipids at high temperatures for a prolonged period. The presence and accumulation of AGEs in numerous cell types and tissues are known to be prevalent in the pathology of many diseases. Modern diets, which contain a high proportion of processed foods and therefore a high level of AGE, cause deleterious effects leading to a multitude of unregulated intracellular and extracellular signalling and inflammatory pathways. Currently, many studies focus on investigating the chemical and structural aspects of AGEs and how they affect the metabolism and the cardiovascular and renal systems. Studies have also shown that AGEs affect the digestive system. However, there is no complete picture of the implication of AGEs in this area. The gastrointestinal tract is not only the first and principal site for the digestion and absorption of dietary AGEs but also one of the most susceptible organs to AGEs, which may exert many local and systemic effects. In this review, we summarise the current evidence of the association between a high-AGE diet and poor health outcomes, with a special focus on the relationship between dietary AGEs and alterations in the gastrointestinal structure, modifications in enteric neurons, and microbiota reshaping.
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Qian W, Huang L, Xu Y, Lu W, Wen W, Guo Z, Zhu W, Li Y. Hypoxic ASCs-derived Exosomes Attenuate Colitis by Regulating Macrophage Polarization via miR-216a-5p/HMGB1 Axis. Inflamm Bowel Dis 2022; 29:602-619. [PMID: 36287066 DOI: 10.1093/ibd/izac225] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND Exosomes derived from mesenchymal stem cells have shown therapeutic effects for colitis. As a more clinically accessible resource, the therapeutic potential of exosomes from adipose-derived stem cells (ASCs) has not been fully elucidated, and whether hypoxia precondition could improve the therapeutic effect of ASC-derived exosomes in colitis remains elusive. METHODS In this study, exosomes were derived from ASCs under normoxia (NExos) and hypoxia (HExos) and were identified by detecting their morphology, size distribution, and exosome surface markers. The concentration of inflammation-related cytokines was detected by ELISA, and macrophage phenotype-related genes were determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blot, and immunofluorescence. A miRNA microarray sequencing analysis was conducted to confirm the differentially expressed miRNAs. Dextran sulfate sodium-induced colitis was employed as an in vivo assay. RESULTS Administration of NExos alleviated inflammation by modulating the balance of macrophages both in cellular assays and in vivo experiments, and HExos showed higher therapeutic efficiency than NExos. The miR-216a-5p in HExos was significantly enriched and promoted macrophage M2 polarization through transfer to macrophages by exosomes. The miR-216a-5p was confirmed to target the 3'-UTR of HMGB1. Mechanistically, hypoxia-induced ASCs release miR-216a-5p in an exosomal way that induced macrophage M2 polarization by regulating the HMGB1/TLR4/NF-κB signaling pathway. CONCLUSIONS Exosomal miR-216a-5p released from hypoxia-prime ASCs showed higher therapeutic efficiency than NExos in experimental colitis by promoting the M2 macrophage phenotype, which indicated that hypoxia prime may represent a promising approach to optimizing the function of ASC-derived exosomes.
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Affiliation(s)
- Wenwei Qian
- Department of General Surgery, Jinling Hospital, Medical School of Southeast University, Nanjing, PR China
| | - Liangyu Huang
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China
| | - Yihan Xu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
| | - Wen Lu
- Department of Endocrinology and Metabolism, the First Affiliated Hospital of Soochow University, Suzhou, PR China
| | - Weiwei Wen
- Department of General Surgery, Jinling Hospital, Medical School of Southeast University, Nanjing, PR China
| | - Zhen Guo
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
| | - Weiming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Southeast University, Nanjing, PR China.,Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
| | - Yi Li
- Department of General Surgery, Jinling Hospital, Medical School of Southeast University, Nanjing, PR China.,Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
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14
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Chen H, Li P, Chen J, Wang Y, Yu Q, Wu Y, Chen Y, Cai J. Peripheral blood mononuclear cell microRNAs are novel biomarkers for diagnosing and monitoring Crohn's disease. FASEB J 2022; 36:e22549. [PMID: 36165177 DOI: 10.1096/fj.202200452r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 08/07/2022] [Accepted: 09/02/2022] [Indexed: 11/11/2022]
Abstract
Crohn's disease is a recurrent, progressive, immune-mediated inflammatory disease and merely manifests non-specific symptoms at early stage. In this study, we isolated peripheral blood mononuclear cells (PBMCs) to determine whether PBMC miRNAs are reliable biomarkers for Crohn's disease diagnosing and monitoring. 5 Crohn's disease patients and 5 healthy controls were recruited to find differentially expressed miRNAs by next generation sequencing. Candidate PBMC miRNAs were further validated by qRT-PCR in another cohort consisting of 86 Crohn's disease patients and 39 healthy controls. We found PBMC miR-582-5p could diagnose Crohn's disease with the area under receiver operating characteristic curve (AUROC) of 0.701(95%CI 0.606-0.796, p < .001). While PBMC miR-96-5p was significantly higher in active Crohn's disease and correlated with both clinical (ρ = 0.376, p < .001) and endoscopic activity (ρ = 0.512, p = .015). Furthermore, PBMC miR-96-5p had a better performance in recognizing active Crohn's disease with AUROC of 0.727 (95%CI 0.609-0.844, p = .001) than C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and fecal calprotectin. In conclusion, PBMC miR-582-5p may be further utilized as a diagnostic biomarker, while miR-96-5p may be a novel and valuable biomarker in monitoring disease activity.
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Affiliation(s)
- Hanwen Chen
- Center of Inflammatory Bowel Disease, Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, P. R. China
| | - Peiwei Li
- Center of Inflammatory Bowel Disease, Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, P. R. China
| | - Jiamin Chen
- Center of Inflammatory Bowel Disease, Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, P. R. China
| | - Yufang Wang
- Department of Gastroenterology, The Third People's Hospital of Hangzhou, Hangzhou, P. R. China
| | - Qiao Yu
- Center of Inflammatory Bowel Disease, Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, P. R. China
| | - Yihua Wu
- Department of Toxicology, Zhejiang University School of Public Health, Hangzhou, P. R. China
| | - Yan Chen
- Center of Inflammatory Bowel Disease, Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, P. R. China
| | - Jianting Cai
- Center of Inflammatory Bowel Disease, Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, P. R. China
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15
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Xu Y, Tang X, Fang A, Yan J, Kofi Wiredu Ocansey D, Zhang X, Mao F. HucMSC-Ex carrying miR-203a-3p.2 ameliorates colitis through the suppression of caspase11/4-induced macrophage pyroptosis. Int Immunopharmacol 2022; 110:108925. [PMID: 35724605 DOI: 10.1016/j.intimp.2022.108925] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 05/17/2022] [Accepted: 05/21/2022] [Indexed: 12/27/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a kind of chronic, idiopathic, and recurrent inflammation, associated with dysregulated intestinal mucosal immunity. Caspase (casp) 11/4-induced macrophage pyroptosis contributes to the development of inflammation, while human umbilical cord mesenchymal stem cell-secreted exosomes (hucMSC-Ex) play a reparative role in IBD. OBJECTIVE The present study focused on the treatment of IBD with hucMSC-Ex and its regulatory mechanism via the casp11/4 pathway. METHODS BALB/c mice were used to establish a dextran sulfate sodium (DSS)-induced colitis model, and hucMSC-Ex was administered intravenously to estimate its therapeutic effect. In vitro, RAW264.7 cells line, THP-1 cells line, and mouse peritoneal macrophages (MPMs) were stimulated with lipopolysaccharides (LPS) to activate an inflammatory environment of pyroptosis, followed by repairing with hucMSC-Ex. MicroRNA mimics and inhibitors were provided to verify the role of miR-203a-3p.2 from hucMSC-Ex in inflammation. The results were analyzed by Western blot, RT-qPCR、ELISA, and LDH secretion. RESULTS HucMSC-Ex inhibited the activation of casp11 and reduced the secretion of interleukin (IL)-1β, IL-6, and casp11, which relieved macrophage pyroptosis to alleviate murine colitis. A consistent outcome was revealed in the cell experiments, where hucMSC-Ex contributed to a decreased casp11/4 expression, and lactate dehydrogenase (LDH) release, as a marker of cell damage. Moreover, miR-203a-3p.2 from hucMSC-Ex functioned as an effective mediator in the interaction with casp4 in THP-1 macrophage pyroptosis. CONCLUSION HucMSC-Ex ameliorates colitis through the suppression of casp11/4-induced macrophage pyroptosis, and hucMSC-Ex carrying miR-203a-3p.2 inhibits casp4-induced macrophage pyroptosis in an inflammatory environment.
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Affiliation(s)
- Yuting Xu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China
| | - Xiaohua Tang
- The People's Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, Zhenjiang, Jiangsu, 212300, PR China
| | - Anning Fang
- Department of Basic Medicine, Anhui Medical College; Hefei, Anhui 230601, PR China
| | - Jialai Yan
- Medical Technology School, Anhui Medical Colleg, Hefei, Anhui 230061, PR China
| | - Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China; Directorate of University Health Services, University of Cape Coast, Cape Coast, Ghana
| | - Xu Zhang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China.
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Hone Lopez S, Jalving M, Fehrmann RS, Nagengast WB, de Vries EG, de Haan JJ. The gut wall’s potential as a partner for precision oncology in immune checkpoint treatment. Cancer Treat Rev 2022; 107:102406. [DOI: 10.1016/j.ctrv.2022.102406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/29/2022] [Accepted: 05/01/2022] [Indexed: 11/02/2022]
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17
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Caravaca AS, Levine YA, Drake A, Eberhardson M, Olofsson PS. Vagus Nerve Stimulation Reduces Indomethacin-Induced Small Bowel Inflammation. Front Neurosci 2022; 15:730407. [PMID: 35095387 PMCID: PMC8789651 DOI: 10.3389/fnins.2021.730407] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 12/16/2021] [Indexed: 12/11/2022] Open
Abstract
Crohn's disease is a chronic, idiopathic condition characterized by intestinal inflammation and debilitating gastrointestinal symptomatology. Previous studies of inflammatory bowel disease (IBD), primarily in colitis, have shown reduced inflammation after electrical or pharmacological activation of the vagus nerve, but the scope and kinetics of this effect are incompletely understood. To investigate this, we studied the effect of electrical vagus nerve stimulation (VNS) in a rat model of indomethacin-induced small intestinal inflammation. 1 min of VNS significantly reduced small bowel total inflammatory lesion area [(mean ± SEM) sham: 124 ± 14 mm2, VNS: 62 ± 14 mm2, p = 0.002], intestinal peroxidation and chlorination rates, and intestinal and systemic pro-inflammatory cytokine levels as compared with sham-treated animals after 24 h following indomethacin administration. It was not known whether this observed reduction of inflammation after VNS in intestinal inflammation was mediated by direct innervation of the gut or if the signals are relayed through the spleen. To investigate this, we studied the VNS effect on the small bowel lesions of splenectomized rats and splenic nerve stimulation (SNS) in intact rats. We observed that VNS reduced small bowel inflammation also in splenectomized rats but SNS alone failed to significantly reduce small bowel lesion area. Interestingly, VNS significantly reduced small bowel lesion area for 48 h when indomethacin administration was delayed. Thus, 1 min of electrical activation of the vagus nerve reduced indomethacin-induced intestinal lesion area by a spleen-independent mechanism. The surprisingly long-lasting and spleen-independent effect of VNS on the intestinal response to indomethacin challenge has important implications on our understanding of neural control of intestinal inflammation and its potential translation to improved therapies for IBD.
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Affiliation(s)
- April S. Caravaca
- Laboratory of Immunobiology, Department of Medicine, Karolinska University Hospital, Solna, Sweden
- MedTechLabs, BioClinicum, Stockholm Center for Bioelectronic Medicine, Karolinska University Hospital, Solna, Sweden
- SetPoint Medical, Inc., Valencia, CA, United States
| | - Yaakov A. Levine
- Laboratory of Immunobiology, Department of Medicine, Karolinska University Hospital, Solna, Sweden
- MedTechLabs, BioClinicum, Stockholm Center for Bioelectronic Medicine, Karolinska University Hospital, Solna, Sweden
- SetPoint Medical, Inc., Valencia, CA, United States
- Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, New York, NY, United States
| | - Anna Drake
- SetPoint Medical, Inc., Valencia, CA, United States
| | - Michael Eberhardson
- Laboratory of Immunobiology, Department of Medicine, Karolinska University Hospital, Solna, Sweden
- MedTechLabs, BioClinicum, Stockholm Center for Bioelectronic Medicine, Karolinska University Hospital, Solna, Sweden
- Department of Gastroenterology and Hepatology, University Hospital of Linköping, Linköping, Sweden
- Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Peder S. Olofsson
- Laboratory of Immunobiology, Department of Medicine, Karolinska University Hospital, Solna, Sweden
- MedTechLabs, BioClinicum, Stockholm Center for Bioelectronic Medicine, Karolinska University Hospital, Solna, Sweden
- Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, New York, NY, United States
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18
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Mitselos IV, Fousekis FS, Lamouri C, Katsanos KH, Christodoulou DK. Current noninvasive modalities in Crohn's disease monitoring. Ann Gastroenterol 2021; 34:770-780. [PMID: 34815642 PMCID: PMC8596218 DOI: 10.20524/aog.2021.0648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 04/16/2021] [Indexed: 12/01/2022] Open
Abstract
Crohn’s disease (CD) is characterized by a remitting and relapsing course. Longstanding active CD may result in accumulating intestinal damage and disease-related complications. In contrast, mucosal healing is associated with significant improvement in the health-related quality of life, longer periods of disease remission and lower risk of disease progression, complications, hospitalizations, intestinal surgeries, as well as a lower risk of developing colorectal cancer. Mucosal healing, the new treatment endpoint in CD, made necessary the development of noninvasive, accurate, objective and reliable tools for the evaluation of CD activity. Ileocolonoscopy with biopsies remains the reference standard method for the evaluation of the colonic and terminal ileal mucosa. However, it is an invasive procedure with a low risk of complications, allowing the investigation of only a small part of the small bowel mucosa without being able to assess transmural inflammation. These disadvantages limit its role in the frequent follow up of CD patients. In this review, we present the currently available biomarkers and imaging modalities for the noninvasive assessment of CD activity.
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Affiliation(s)
- Ioannis V Mitselos
- Department of Gastroenterology, General Hospital of Ioannina (Ioannis V. Mitselos)
| | - Fotios S Fousekis
- Department of Gastroenterology, School of Health Sciences, University Hospital of Ioannina, Faculty of Medicine, University of Ioannina (Fotios S. Fousekis, Charikleia Lamouri, Konstantinos H. Katsanos, Dimitrios K. Christodoulou), Greece
| | - Charikleia Lamouri
- Department of Gastroenterology, School of Health Sciences, University Hospital of Ioannina, Faculty of Medicine, University of Ioannina (Fotios S. Fousekis, Charikleia Lamouri, Konstantinos H. Katsanos, Dimitrios K. Christodoulou), Greece
| | - Konstantinos H Katsanos
- Department of Gastroenterology, School of Health Sciences, University Hospital of Ioannina, Faculty of Medicine, University of Ioannina (Fotios S. Fousekis, Charikleia Lamouri, Konstantinos H. Katsanos, Dimitrios K. Christodoulou), Greece
| | - Dimitrios K Christodoulou
- Department of Gastroenterology, School of Health Sciences, University Hospital of Ioannina, Faculty of Medicine, University of Ioannina (Fotios S. Fousekis, Charikleia Lamouri, Konstantinos H. Katsanos, Dimitrios K. Christodoulou), Greece
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Vernia F, Viscido A, Di Ruscio M, Stefanelli G, Valvano M, Latella G. Fecal Lactoferrin and Other Putative Fecal Biomarkers in Crohn's Disease: Do They Still Have a Potential Clinical Role? Digestion 2021; 102:833-844. [PMID: 34518458 DOI: 10.1159/000518419] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 07/11/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION The need for noninvasive markers of disease activity is mandatory in the assessment of Crohn's disease (CD). The most widely fecal biomarker in CD, despite several limits, is fecal calprotectin. This review aims to elucidate the role, if any, of all other fecal biomarkers, as alternative tools for assessing clinical and endoscopic disease activity, and predict capsule endoscopy findings, response to therapy, disease relapse, and postoperative recurrence. These fecal biomarkers included lactoferrin, S100A12, high mobility group box 1, neopterin, polymorphonuclear neutrophil elastase, fecal hemoglobin, alpha1-antitrypsin, lysozyme, human beta-defensin-2, neutrophil gelatinase-associated lipocalin, matrix metalloproteinase-9, chitinase 3-like-1, M2-pyruvate kinase, myeloperoxidase, and eosinophil proteins. METHODS A systematic electronic search in the medical literature was performed up to April 2020. Seventy eligible studies were identified out of 859 citations. Data were grouped according to the assessment of clinical and endoscopic disease activity, capsule endoscopy findings, response to therapy, prediction of relapse, and postoperative recurrence. RESULTS The overall correlation between lactoferrin and clinical indexes is poor, while performance is good with endoscopic scores. Lactoferrin seems to represent a reasonably good surrogate marker of response to therapy and to be potentially useful in identifying patients at high risk for endoscopic relapse or postoperative recurrence. The evaluation of the performance of all other fecal markers is limited by the lack of adequate data. CONCLUSIONS None of the fecal markers so far represents an acceptable alternative to calprotectin in clinical practice. Fecal lactoferrin is the only possible exception, but a more extensive investigation is still required.
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Affiliation(s)
- Filippo Vernia
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, Piazza S. Tommasi, L'Aquila, Italy
| | - Angelo Viscido
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, Piazza S. Tommasi, L'Aquila, Italy
| | - Mirko Di Ruscio
- IBD Unit of IRCCS Ospedale Sacro Cuore - Don Calabria, Verona, Italy
| | - Gianpiero Stefanelli
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, Piazza S. Tommasi, L'Aquila, Italy
| | - Marco Valvano
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, Piazza S. Tommasi, L'Aquila, Italy
| | - Giovanni Latella
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, Piazza S. Tommasi, L'Aquila, Italy
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20
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Huo R, Liu H, Chen J, Sheng H, Miao L. Serum HMGB1 level is correlated with serum I-FABP level in neonatal patients with necrotizing enterocolitis. BMC Pediatr 2021; 21:355. [PMID: 34418984 PMCID: PMC8379747 DOI: 10.1186/s12887-021-02818-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 07/21/2021] [Indexed: 11/12/2022] Open
Abstract
Background This study aims to investigate clinical significance of HMGB1 in neonatal patients with necrotizing enterocolitis (NEC). Methods This observational study enrolled a total of 106 stage II-III NEC neonatal patients, who were admitted in our hospital from March 2014 to March 2019. In addition, 99 suspected NEC patients and 200 healthy controls were included. The serum levels of HMGB1, I-FABP, and inflammatory factors CRP, IL-1β, IL-6 and TNF-α were determined by enzyme-linked immunosorbent assay (ELISA). Then, the demographic data and clinical characteristics of all patients were collected. Statistical analysis was conducted to determine the correlation between HMGB1 and the clinical characteristics. Results No significant difference was found in the basic characteristics of NEC patients and healthy controls, except for birth weight and gestational age. The expression levels of HMGB1, I-FABP, and inflammatory factors IL-1β, IL-6 and TNF-α were significantly higher in NEC patients, when compared to healthy controls. The serum levels of HMGB1, I-FABP, IL-1β and IL-6 markedly increased in stage II-III NEC patients, when compared to stage I NEC patients. The Pearson’s analysis revealed a positive correlation between HMGB1 and I-FABP, HMGB1 and IL-1β, and HMGB1 and IL-6. The ROC curve revealed that both HMGB1 and I-FABP can potentially be used as diagnostic factors for NEC. The logistic multivariate regression revealed that I-FABP, IL-1β and IL-6 are independent risk factors for mortality in neonatal NEC patients. Conclusions Serum HMGB1 levels are upregulated in neonatal NEC patients, and these are correlated with the patient’s prognosis.
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Affiliation(s)
- Ruyahan Huo
- Department of Neonatology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, 222000, Lianyungang, China
| | - Heng Liu
- Department of Neonatology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, 222000, Lianyungang, China
| | - Jing Chen
- Department of Neonatology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, 222000, Lianyungang, China
| | - Hong Sheng
- Department of Neonatology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, 222000, Lianyungang, China
| | - Li Miao
- Department of Pediatrics, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, No. 182 Tongguan North Road, 222000, Lianyungang, China.
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21
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Kvivik I, Grimstad T, Jonsson G, Kvaløy JT, Omdal R. Anti-HMGB1 auto-Abs influence fatigue in patients with Crohn's disease. Innate Immun 2021; 27:286-293. [PMID: 33940970 PMCID: PMC8186155 DOI: 10.1177/17534259211014252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Fatigue is common in all chronic inflammatory and autoimmune diseases. A conceptual model for understanding the biological basis of fatigue describes it as being a part of the sickness behaviour response generated by pro-inflammatory cytokines and other mediators. We hypothesised that the pro-inflammatory high mobility group box 1 (HMGB1) protein is a fatigue-inducing molecule and that auto-Abs against HMGB1 reduce fatigue. We measured Abs against disulphide (ds) HMGB1 and fully reduced (fr) HMGB1 in plasma from 57 patients with Crohn’s disease. Fatigue was rated using the fatigue visual analogue scale (fVAS) and disease activity with faecal calprotectin, C-reactive protein and the Simple Endoscopic Score for Crohn’s disease. Multivariable regression models identified anti-dsHMGB1 and anti-frHMGB1 Abs as the strongest contributing factors for fVAS scores (B = −29.10 (P = 0.01), R2 = 0.17, and B = −17.77 (P = 0.01), R2 = 0.17, respectively). Results indicate that anti-HMGB1 auto-Abs alleviate fatigue possibly by down-regulating HMGB1-induced sickness behaviour.
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Affiliation(s)
| | - Tore Grimstad
- Unit of Gastroenterology, Department of Internal Medicine, Stavanger University Hospital, Norway.,Department of Clinical Science, Faculty of Medicine, University of Bergen, Norway
| | - Grete Jonsson
- Department of Medical Biochemistry, Stavanger University Hospital, Norway.,Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Norway
| | - Jan T Kvaløy
- Research Department, Stavanger University Hospital, Norway.,Department of Mathematics and Physics, University of Stavanger, Norway
| | - Roald Omdal
- Department of Clinical Science, Faculty of Medicine, University of Bergen, Norway.,Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Norway
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22
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Eberhardson M, Levine YA, Tarnawski L, Olofsson PS. The brain-gut axis, inflammatory bowel disease and bioelectronic medicine. Int Immunol 2021; 33:349-356. [PMID: 33912906 DOI: 10.1093/intimm/dxab018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 04/26/2021] [Indexed: 12/21/2022] Open
Abstract
The hallmark of inflammatory bowel diseases (IBD) is chronic intestinal inflammation with typical onset in adolescents and young adults. An abundance of neutrophils is seen in the inflammatory lesions, but adaptive immunity is also an important player in the chronicity of the disease. There is an unmet need for new treatment options since modern medicines such as biological therapy with anti-cytokine antibodies still leave a substantial number of patients with persisting disease activity. The role of the central nervous system and its interaction with the gut in the pathophysiology of IBD have been brought to attention both in animal models and in humans after the discovery of the inflammatory reflex. The suggested control of gut immunity by the brain-gut axis represents a novel therapeutic target suitable for bioelectronic intervention. In this review, we discuss the role of the inflammatory reflex in gut inflammation and the recent advances in the treatment of IBD by intervening with the brain-gut axis through bioelectronic devices.
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Affiliation(s)
- Michael Eberhardson
- Department of Gastroenterology and Hepatology, University Hospital of Linköping, 581 91 Linköping, Sweden.,Department of Medicine, Center for Bioelectronic Medicine, Bioclinicum, Karolinska Institutet, 171 64 Stockholm, Sweden.,Department of Health, Medicine and Caring Sciences, Linköping University, 581 83 Linköping, Sweden
| | - Yaakov A Levine
- Department of Medicine, Center for Bioelectronic Medicine, Bioclinicum, Karolinska Institutet, 171 64 Stockholm, Sweden.,SetPoint Medical, Valencia, CA 91355, USA
| | - Laura Tarnawski
- Department of Medicine, Center for Bioelectronic Medicine, Bioclinicum, Karolinska Institutet, 171 64 Stockholm, Sweden
| | - Peder S Olofsson
- Department of Medicine, Center for Bioelectronic Medicine, Bioclinicum, Karolinska Institutet, 171 64 Stockholm, Sweden.,Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
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23
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Vitali R, Terrin G, Palone F, Laudadio I, Cucchiara S, Boscarino G, Di Chiara M, Stronati L. Fecal High-Mobility Group Box 1 as a Marker of Early Stage of Necrotizing Enterocolitis in Preterm Neonates. Front Pediatr 2021; 9:672131. [PMID: 34178888 PMCID: PMC8222523 DOI: 10.3389/fped.2021.672131] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 04/22/2021] [Indexed: 12/28/2022] Open
Abstract
Introduction: An early diagnosis of necrotizing enterocolitis (NEC), a major gastrointestinal emergency in preterm newborns, is crucial to improve diagnostic approach and prognosis. We evaluated whether fecal high-mobility group box protein 1 (HMGB1) may early identify preterms at risk of developing NEC. Materials and Methods: A case-control study including neonates admitted at the Neonatal Intensive Care Unit (NICU) of the Sapienza University Hospital "Umberto I" in Rome, from July 2015 to December 2016. Stool samples obtained from cases (preterm newborns with NEC) and controls (newborns without NEC) were collected at the enrolment (T0) and within 7-14 days after the first sample collection (T1). HMGB1, extracted and measured with western blot, was reported as densitometry units (DUS). Results: HMGB1 levels in 30 cases (n = 28-Bell stage 1, n = 2 Bell stage 2) were higher [T0: 21,462 DUS (95% CI, 16,370-26,553 DUS)-T1: 17,533 DUS (95% CI, 13,052-22,014 DUS)] than in 30 preterm controls [T0: 9,446 DUS (95% CI, 6,147-12,746 DUS)-T1: 9,261 DUS (95% CI, 5,126-13,396 DUS), p < 0.001). Preterm newborns showed significant higher levels of HMGB1 (15,690 DUS (95% CI, 11,929-19,451 DUS)] in comparison with 30 full-term neonates with birth weight >2,500 g [6,599 DUS (95% CI, 3,141-10,058 DUS), p = 0.003]. Multivariate analysis showed that the risk of NEC was significantly (p = 0.012) related to the HMGB1 fecal levels at T0. Conclusions: We suggest fecal HMGB1 as a reliable marker of early NEC in preterm neonates. This study supports further investigation on the role of fecal HMGB1 assessment in managing preterm newborns at risk of NEC. Further studies are advocated to evaluate diagnostic accuracy of this marker in more severe forms of the disease.
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Affiliation(s)
- Roberta Vitali
- Division of Health Protection Technologies, Territorial and Production Systems Sustainability Department, Agenzia nazionale per le nuove tecnologie, l'energia e lo sviluppo economico sostenibile (ENEA), Rome, Italy
| | - Gianluca Terrin
- Department of Maternal and Child Health, University of Roma La Sapienza, Rome, Italy
| | - Francesca Palone
- Division of Health Protection Technologies, Territorial and Production Systems Sustainability Department, Agenzia nazionale per le nuove tecnologie, l'energia e lo sviluppo economico sostenibile (ENEA), Rome, Italy
| | - Ilaria Laudadio
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Salvatore Cucchiara
- Department of Maternal and Child Health, University of Roma La Sapienza, Rome, Italy
| | - Giovanni Boscarino
- Department of Maternal and Child Health, University of Roma La Sapienza, Rome, Italy
| | - Maria Di Chiara
- Department of Maternal and Child Health, University of Roma La Sapienza, Rome, Italy
| | - Laura Stronati
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
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24
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Li B, Peng X, Li H, Chen F, Chen Y, Zhang Y, Le K. The performance of the alarmin HMGB1 in pediatric diseases: From lab to clinic. IMMUNITY INFLAMMATION AND DISEASE 2020; 9:8-30. [PMID: 33140586 PMCID: PMC7860603 DOI: 10.1002/iid3.370] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/10/2020] [Accepted: 10/21/2020] [Indexed: 12/13/2022]
Abstract
INTRODUCTION The ubiquitously expressed nonhistone nuclear protein high-mobility group box protein 1 (HMGB1) has different functions related to posttranslational modifications and cellular localization. In the nucleus, HMGB1 modulates gene transcription, replication and DNA repair as well as determines chromosomal architecture. When the post-transcriptional modified HMGB1 is released into the extracellular space, it triggers several physiological and pathological responses and initiates innate immunity through interacting with its reciprocal receptors (i.e., TLR4/2 and RAGE). The effect of HMGB1-mediated inflammatory activation on different systems has received increasing attention. HMGB1 is now considered to be an alarmin and participates in multiple inflammation-related diseases. In addition, HMGB1 also affects the occurrence and progression of tumors. However, most studies involving HMGB1 have been focused on adults or mature animals. Due to differences in disease characteristics between children and adults, it is necessary to clarify the role of HMGB1 in pediatric diseases. METHODS AND RESULTS Through systematic database retrieval, this review aimed to first elaborate the characteristics of HMGB1 under physiological and pathological conditions and then discuss the clinical significance of HMGB1 in the pediatric diseases according to different systems. CONCLUSIONS HMGB1 plays an important role in a variety of pediatric diseases and may be used as a diagnostic biomarker and therapeutic target for new strategies for the prevention and treatment of pediatric diseases.
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Affiliation(s)
- Bo Li
- Department of Cardiology, Children's Hospital of Hebei Province Affiliated to Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xin Peng
- Department of Otolaryngology, The Affiliated Children's Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - He Li
- Department of Urology Surgery, Qilu Children's Hospital of Shandong University, Jinan, Shandong, China
| | - Fei Chen
- Department of Child Health Care, Qilu Children's Hospital of Shandong University, Jinan, Shandong, China
| | - Yuxia Chen
- Ministry of Education Key Laboratory of Child Development and Disorders, and Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, and Rehabilitation Centre, Children's Hospital, Chongqing Medical University, Chongqing, Yuzhong, China
| | - Yingqian Zhang
- Department of Cardiology, Children's Hospital of Hebei Province Affiliated to Hebei Medical University, Shijiazhuang, Hebei, China
| | - Kai Le
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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25
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Leucine-rich alpha-2 glycoprotein 1, high mobility group box 1, matrix metalloproteinase 3 and annexin A1 as biomarkers of ulcerative colitis endoscopic and histological activity. Eur J Gastroenterol Hepatol 2020; 32:1106-1115. [PMID: 32483088 DOI: 10.1097/meg.0000000000001783] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE The LRG, HMGB1, MMP3 and ANXA1 proteins have been implicated in different inflammatory pathways in ulcerative colitis (UC), but their role as specific biomarkers of both endoscopic and histological activity has yet to be elucidated. In the present study, we aimed to evaluate the LRG1, HMGB1, MMP3 and ANXA1 as potential serum biomarkers for UC endoscopic and histological activity. METHODS This cross-sectional study included UC patients under 5-ASA, and healthy controls (HC) undergoing colonoscopy. Blood and biopsy samples were obtained and endoscopic Mayo sub-score (Ms) was recorded for the UC patients. Intramucosal calprotectin as a marker of histologic activity was evaluated in all biopsy samples and serum LRG1, HMGB1, MMP3 and ANXA1 levels were measured in the blood samples. RESULTS The HCs ANXA1 level was lower compared to that of the UC group [P = 0.00, area under the curve (AUC) = 0.881] and so was the HCs MMP3 level compared to that of patients (P = 0.00, AUC = 0.835). The HCs ANXA1 levels were also lower compared to these of the independent Ms groups, even to the Ms = 0 (P = 0.00, AUC = 0.913). UC endoscopic activity was associated with MMP3 levels (r = 0.54, P = 0.000) but not with ANXA1, LRG1 and HMGB1 levels CONCLUSION: Serum ANXA1 is a potential diagnostic biomarker of UC and serum MMP3 is a potential biomarker of UC endoscopic and histological activity.
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Liu C, Hu T, Cai Z, Xie Q, Yuan Y, Li N, Xie S, Yao Q, Zhao J, Wu QQ, Tang Q. Nucleotide-Binding Oligomerization Domain-Like Receptor 3 Deficiency Attenuated Isoproterenol-Induced Cardiac Fibrosis via Reactive Oxygen Species/High Mobility Group Box 1 Protein Axis. Front Cell Dev Biol 2020; 8:713. [PMID: 32850832 PMCID: PMC7431462 DOI: 10.3389/fcell.2020.00713] [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: 03/01/2020] [Accepted: 07/13/2020] [Indexed: 01/05/2023] Open
Abstract
Nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) is involved in fibrosis of multiple organs, such as kidney, liver, lung, and the like. However, the role of NLRP3 in cardiac fibrosis is still controversial and remains unclear. The study aims to investigate the role of NLRP3 on cardiac fibrosis induced by isoproterenol (ISO). In vivo, NLRP3 knockout and wild-type mice were subcutaneously injected with ISO to induce the cardiac fibrosis model. The results showed that NLRP3 deficiency alleviated the cardiac fibrosis and inflammation induced by ISO. In vitro, neonatal rat ventricular myocytes (NRVMs) and primary adult mouse cardiac fibroblasts of NLRP3 knockout and wild-type mice were isolated and challenged with ISO. Adenovirus (Ad-) NLRP3 and small interfering RNAs targeting NLRP3 were used to transfect NRVMs to overexpress or knockdown NLRP3. We found that NLRP3 could regulate high-mobility group box 1 protein (HMGB1) secretion via reactive oxygen species production in NRVMs and the HMGB1 secreted by NRVMs promoted the activation and proliferation of cardiac fibroblasts. Thus, we concluded that the NLRP3/reactive oxygen species/HMGB1 pathway could be the underlying mechanism of ISO-induced cardiac fibrosis.
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Affiliation(s)
- Chen Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, China
| | - Tongtong Hu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, China
| | - Zhulan Cai
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, China
| | - Qingwen Xie
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, China
| | - Yuan Yuan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, China
| | - Ning Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, China
| | - Saiyang Xie
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, China
| | - Qi Yao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, China
| | - Jinhua Zhao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, China
| | - Qing Qing Wu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, China
| | - Qizhu Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, China
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27
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Langhorst J, Kairey L, Oberle A, Boone J, Dobos G, Juette H, Tannapfel A, Rueffer A. Assessing Histological Inflammatory Activity in Patients With Ulcerative Colitis: A Diagnostic Accuracy Study Testing Fecal Biomarkers Lactoferrin and Calprotectin. CROHN'S & COLITIS 360 2020; 2:otaa053. [PMID: 36776494 PMCID: PMC9802191 DOI: 10.1093/crocol/otaa053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Indexed: 11/13/2022] Open
Abstract
Background and Aims Histological remission has arisen as the optimal treatment outcome in ulcerative colitis (UC). The aim of this retrospective study was to explore the diagnostic performance of the noninvasive fecal biomarkers calprotectin (FC) and lactoferrin (FL) compared to the histological indices Nancy Index (NI) and Riley Index (RI). Methods This study is a retrospective diagnostic accuracy study based on secondary analysis of patient data from 2002 to 2017 extracted from medical registries of our clinics in Essen-Mitte, Germany. Patients with UC underwent a colonoscopy, with biopsies taken from the rectum and the sigmoid scored by 2 experienced pathologists according to NI and RI and provided a stool sample within 7 days pre- or post-colonoscopy. Diagnostic accuracy of recommended cutoffs for FC (>50 μg/g) and FL (≥7.25 μg/g) were tested against our reference standard (NI ≥2) in terms of specificity, sensitivity, positive predictive value, negative predictive value, and accuracy (effectiveness). Results The number of patients with UC recruited was n = 226, aged 45.2 (SD 13.3). Histological indices were highly correlated (r = 0.980, P < 0.001). Fecal biomarkers correlated moderately with NI (FC: r = 0.383, P < 0.001; FL: r = 0.420, P < 0.001) and RI (FC: r = 0.395, P < 0.001; FL: r = 0.424, P < 0.001). Fecal biomarker concentrations were increased in patients with active histological disease (NI ≥2), median [IQR], FC 69.72 [20.07-254.38], FL 18.59 [6.06-44.42], compared to those with inactive disease (NI ≤1), FC 12.35 [3.89 - 32.16], FL 3.14 [0.75-11.05], z = -6.60, P < 0.001. Fecal biomarker concentrations differed significantly across NI grades 0-4 (FC: H4 = 45.2; FL: H4 = 47.5, both P < 0.001). Patients with grade 0 had significantly lower concentrations of fecal biomarkers than those with grade 3 (median; FC 10.94 vs 72.22; FL 2.30 vs 29.10; both P < 0.001) or grade 4 (FC 10.94 vs 67.00; FL 2.30 vs 27.64; both P < 0.001), as well as grade 2 for FC only (10.94 vs 56.22, P = 0.001). Concentrations were also lower in patients with grade 1 compared to those with grade 3 (FC 17.49 vs 72.22; FL 4.24 vs. 29.10; both P ≤ 0.001) or grade 4 (FC 17.49 vs 67.00; FL 4.24 vs 27.64; both P < 0.001).Receiver operating characteristics area under the curve showed moderate diagnostic accuracy for both FC 0.76 (95% confidence interval [CI] 0.70-0.83) and FL 0.73 (95% CI 0.66-0.80). Optimized cutoffs for both FC (≥34.29) and FL (≥5.85 μg/g) had slightly improved accuracy, compared with the manufacturer's cutoffs (FC: 69.9% vs 65.9%; FL: 71.7% vs 69.0%). Conclusions Fecal biomarkers calprotectin and lactoferrin correlate with histological disease activity and differentiate between patients in histological remission from those with evidence of moderate to severe disease activity. Their noninvasiveness, in addition to being inexpensive, supports their use in the clinical monitoring of patients with UC.
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Affiliation(s)
- Jost Langhorst
- Department of Internal and Integrative Medicine, Klinikum Bamberg, Bamberg, Germany,Chair for Integrative Medicine, University of Duisburg, Essen, Germany,Address correspondence to: Jost Langhorst, MD, Buger Str. 80, 96049 Bamberg, Germany ()
| | - Lana Kairey
- Department of Internal and Integrative Medicine, Klinikum Bamberg, Bamberg, Germany
| | - Angela Oberle
- Department of Internal and Integrative Medicine, Kliniken Essen-Mitte, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany
| | | | - Gustav Dobos
- Department of Internal and Integrative Medicine, Kliniken Essen-Mitte, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany
| | - Hendrik Juette
- Institute for Pathology, Ruhr University Bochum, Bochum, Germany
| | - Andrea Tannapfel
- Institute for Pathology, Ruhr University Bochum, Bochum, Germany
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Almási N, Török S, Dvorácskó S, Tömböly C, Csonka Á, Baráth Z, Murlasits Z, Valkusz Z, Pósa A, Varga C, Kupai K. Lessons on the Sigma-1 Receptor in TNBS-Induced Rat Colitis: Modulation of the UCHL-1, IL-6 Pathway. Int J Mol Sci 2020; 21:E4046. [PMID: 32516975 PMCID: PMC7312485 DOI: 10.3390/ijms21114046] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/27/2020] [Accepted: 06/03/2020] [Indexed: 12/17/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) is an autoimmune ailment of the gastrointestinal (GI) tract, which is characterized by enhanced activation of proinflammatory cytokines. It is suggested that the sigma-1 receptor (σ1R) confers anti-inflammatory effects. As the exact pathogenesis of IBD is still unknown and treatment options are limited, we aimed to investigate the effects of σ1R in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced experimental colitis. To this end, male Wistar-Harlan rats were used to model colitic inflammation through the administration of TNBS. To investigate the effects of σ1R, Fluvoxamine (FLV, σ1R agonist) and BD1063 (σ1R antagonist) were applied via intracolonic administration to the animals once a day for three days. Our radioligand binding studies indicated the existence of σ1Rs as [3H](+)-pentazocine binding sites, and FLV treatment increased the reduced σ1R maximum binding capacity in TNBS-induced colitis. Furthermore, FLV significantly attenuated the colonic damage, the effect of which was abolished by the administration of BD1063. Additionally, FLV potentially increased the expression of ubiquitin C-terminal hydrolase ligase-1 (UCHL-1) and the levels of endothelial nitric oxide synthase (eNOS), and decreased the levels of interleukin-6 (IL-6) and inducible NOS (iNOS) expression. In summary, our study offers evidence for the anti-inflammatory potential of FLV and σ1R in experimental colitis, and our results present a promising approach to the development of new σ1R-targeted treatment options against IBD.
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Affiliation(s)
- Nikoletta Almási
- Department of Physiology, Anatomy and Neuroscience, University of Szeged, H-6726 Szeged, Hungary; (N.A.); (S.T.); (A.P.); (C.V.)
| | - Szilvia Török
- Department of Physiology, Anatomy and Neuroscience, University of Szeged, H-6726 Szeged, Hungary; (N.A.); (S.T.); (A.P.); (C.V.)
| | - Szabolcs Dvorácskó
- Laboratory of Chemical Biology, Institute of Biochemistry, Biological Research Centre, H-6726 Szeged, Hungary; (S.D.); (C.T.)
- Department of Medical Chemistry, University of Szeged, H-6725 Szeged, Hungary
| | - Csaba Tömböly
- Laboratory of Chemical Biology, Institute of Biochemistry, Biological Research Centre, H-6726 Szeged, Hungary; (S.D.); (C.T.)
| | - Ákos Csonka
- Department of Traumatology, University of Szeged, H-6725 Szeged, Hungary;
| | - Zoltán Baráth
- Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, University of Szeged, H-6720 Szeged, Hungary;
| | - Zsolt Murlasits
- Laboratory Animals Research Center, Qatar University, Doha 2713, Qatar;
| | - Zsuzsanna Valkusz
- 1st Department of Medicine, Medical Faculty, Albert Szent-Györgyi Clinical Center, University of Szeged, H-6720 Szeged, Hungary;
| | - Anikó Pósa
- Department of Physiology, Anatomy and Neuroscience, University of Szeged, H-6726 Szeged, Hungary; (N.A.); (S.T.); (A.P.); (C.V.)
| | - Csaba Varga
- Department of Physiology, Anatomy and Neuroscience, University of Szeged, H-6726 Szeged, Hungary; (N.A.); (S.T.); (A.P.); (C.V.)
| | - Krisztina Kupai
- Department of Physiology, Anatomy and Neuroscience, University of Szeged, H-6726 Szeged, Hungary; (N.A.); (S.T.); (A.P.); (C.V.)
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29
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Chen Y, Wu D, Sun L. Clinical Significance of High-Mobility Group Box 1 Protein (HMGB1) and Nod-Like Receptor Protein 3 (NLRP3) in Patients with Ulcerative Colitis. Med Sci Monit 2020; 26:e919530. [PMID: 31901930 PMCID: PMC6977607 DOI: 10.12659/msm.919530] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background The aim of this study was to investigate the clinical significance of NLRP3 and HMGB1 in patients with active ulcerative colitis. Material/Methods This was a prospective observational study which included a total of 62 cases with active ulcerative colitis during January 2017 to December 2018. The patients were divided into a mild/moderate group or a severe group according to Sutherland Disease Activity Index (DAI) score. Clinical activity index and endoscopic index were used to determine the severity of UC. Serum levels of NLRP3, HMGB1, endothelin-1, IL-1β, and TNF-α were determined by enzyme-linked immunosorbent assay (ELISA). Results Sutherland DAI score, clinical activity index, and endoscopic index were all significantly higher in severe patients than in the mild/moderate group. NLRP3, HMGB1, endothelin-1, IL-1β, and TNF-α were significantly higher in severe UC patients. NLRP3 level was positively correlated with HMGB1, ET-1, IL-1β, and TNF-α levels. Both NLRP3 and HMGB1 were positively correlated with Sutherland DAI score, clinical activity index, and endoscopic index. Conclusions Both serum NLRP3 and HMGB1 were elevated in UC patients, and the serum levels of NLRP3 were positively correlated with serum levels of HMGB1, ET-1, IL-1β, and TNF-α, as well as severity of UC patients.
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Affiliation(s)
- YanMin Chen
- Department of Gastroenterology, HwaMei Hospital, University of Chinese Academy of Sciences (Ningbo No. 2 Hospital), Ningbo, Zhejiang, China (mainland)
| | - Dong Wu
- Department of Gastroenterology, HwaMei Hospital, University of Chinese Academy of Sciences (Ningbo No. 2 Hospital), Ningbo, Zhejiang, China (mainland)
| | - LingJia Sun
- Department of Gastroenterology, HwaMei Hospital, University of Chinese Academy of Sciences (Ningbo No. 2 Hospital), Ningbo, Zhejiang, China (mainland)
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30
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Kimono D, Sarkar S, Albadrani M, Seth R, Bose D, Mondal A, Li Y, Kar AN, Nagarkatti M, Nagarkatti P, Sullivan K, Janulewicz P, Lasley S, Horner R, Klimas N, Chatterjee S. Dysbiosis-Associated Enteric Glial Cell Immune-Activation and Redox Imbalance Modulate Tight Junction Protein Expression in Gulf War Illness Pathology. Front Physiol 2019; 10:1229. [PMID: 31680990 PMCID: PMC6802578 DOI: 10.3389/fphys.2019.01229] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 09/09/2019] [Indexed: 12/19/2022] Open
Abstract
About 14% of veterans who suffer from Gulf war illness (GWI) complain of some form of gastrointestinal disorder but with no significant markers of clinical pathology. Our previous studies have shown that exposure to GW chemicals resulted in altered microbiome which was associated with damage associated molecular pattern (DAMP) release followed by neuro and gastrointestinal inflammation with loss of gut barrier integrity. Enteric glial cells (EGC) are emerging as important regulators of the gastrointestinal tract and have been observed to change to a reactive phenotype in several functional gastrointestinal disorders such as IBS and IBD. This study is aimed at investigating the role of dysbiosis associated EGC immune-activation and redox instability in contributing to observed gastrointestinal barrier integrity loss in GWI via altered tight junction protein expression. Using a mouse model of GWI and in vitro studies with cultured EGC and use of antibiotics to ensure gut decontamination we show that exposure to GW chemicals caused dysbiosis associated change in EGCs. EGCs changed to a reactive phenotype characterized by activation of TLR4-S100β/RAGE-iNOS pathway causing release of nitric oxide and activation of NOX2 since gut sterility with antibiotics prevented this change. The resulting peroxynitrite generation led to increased oxidative stress that triggered inflammation as shown by increased NLRP-3 inflammasome activation and increased cell death. Activated EGCs in vivo and in vitro were associated with decrease in tight junction protein occludin and selective water channel aquaporin-3 with a concomitant increase in Claudin-2. The tight junction protein levels were restored following a parallel treatment of GWI mice with a TLR4 inhibitor SsnB and butyric acid that are known to decrease the immunoactivation of EGCs. Our study demonstrates that immune-redox mechanisms in EGC are important players in the pathology in GWI and may be possible therapeutic targets for improving outcomes in GWI symptom persistence.
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Affiliation(s)
- Diana Kimono
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, SC, United States
| | - Sutapa Sarkar
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, SC, United States
| | - Muayad Albadrani
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, SC, United States
| | - Ratanesh Seth
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, SC, United States
| | - Dipro Bose
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, SC, United States
| | - Ayan Mondal
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, SC, United States
| | - Yuxi Li
- Department of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Amar N. Kar
- Department of Biological Sciences, University of South Carolina, Columbia, SC, United States
| | - Mitzi Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, United States
| | - Prakash Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, United States
| | - Kimberly Sullivan
- Department of Environmental Health Sciences, Boston University School of Public Health, Boston, MA, United States
| | - Patricia Janulewicz
- Department of Environmental Health Sciences, Boston University School of Public Health, Boston, MA, United States
| | - Stephen Lasley
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, United States
| | - Ronnie Horner
- Department of Health Services Policy and Management, University of South Carolina, Columbia, SC, United States
| | - Nancy Klimas
- Department of Clinical Immunology, Nova Southeastern University, Fort Lauderdale, FL, United States
| | - Saurabh Chatterjee
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, SC, United States
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Carissimi C, Laudadio I, Palone F, Fulci V, Cesi V, Cardona F, Alfonsi C, Cucchiara S, Isoldi S, Stronati L. Functional analysis of gut microbiota and immunoinflammation in children with autism spectrum disorders. Dig Liver Dis 2019; 51:1366-1374. [PMID: 31320306 DOI: 10.1016/j.dld.2019.06.006] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 05/21/2019] [Accepted: 06/09/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Recent evidence implicates gut microbiota (GM) and immune alterations in autism spectrum disorders (ASD). We assess GM profile and peripheral levels of immunological, neuronal and bacterial molecules in ASD children and controls. Alarmin HMGB1 was explored as a non-invasive biomarker to monitor gastrointestinal (GI) symptoms. METHODS Thirty ASD children and 14 controls entered into the study. GM metagenomic analysis was performed for 16 ASD patients and 7 controls. GM functional profile was assessed by GO term analysis. Blood levels of IL-1β, TNFα, TGFβ, IL-10, INFγ, IL-8, lipopolysaccharide, Neurotensin, Sortilin1 and GSSG/GSH ratio were analyzed in all subjects by ELISA. Fecal HMGB1 was analyzed by Western blot. RESULTS We observed a significant decrease in bacterial diversity. Furthermore, 82 GO terms underrepresented in ASD. Four of them pointed at 3,3 phenylpropionate catabolism and were imputable to Escherichia coli (E. coli) group. Serum levels of TNFα, TGFβ, NT, and SORT-1 increased in ASD patients. Fecal levels of HMGB1 correlated with GI sign severity in ASD children. CONCLUSIONS We suggest that a decrease of E. coli might affect the propionate catabolism in ASD. We report occurrence of peripheral inflammation in ASD children. We propose fecal HMGB1 as a non-invasive biomarker to detect GI symptoms.
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Affiliation(s)
- Claudia Carissimi
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Ilaria Laudadio
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Francesca Palone
- Department of Pediatrics, Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy
| | - Valerio Fulci
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Vincenzo Cesi
- Division of Health Protection Technologies, Territorial and Production Systems Sustainability Department, ENEA, Santa Maria di Galeria, Rome, Italy
| | - Francesco Cardona
- Division of Child Neurology and Psychiatry, Department of Human Neurosciences, Sapienza University of Rome, Policlinico Umberto I Hospital, Rome, Italy
| | - Chiara Alfonsi
- Division of Child Neurology and Psychiatry, Department of Human Neurosciences, Sapienza University of Rome, Policlinico Umberto I Hospital, Rome, Italy
| | - Salvatore Cucchiara
- Department of Pediatrics, Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy
| | - Sara Isoldi
- Department of Pediatrics, Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy
| | - Laura Stronati
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
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Liu XW, Wang CD. Melatonin alleviates circadian rhythm disruption exacerbating DSS-induced colitis by inhibiting the distribution of HMGB1 in intestinal tissues. Int Immunopharmacol 2019; 73:108-117. [DOI: 10.1016/j.intimp.2019.05.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 05/03/2019] [Accepted: 05/05/2019] [Indexed: 02/07/2023]
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Abstract
OBJECTIVES In 2015, the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program proposed shifting the therapeutic focus on ulcerative colitis (UC) toward altering the natural history of the disease course by regularly monitoring objective measurements of disease activity and tailoring treatment accordingly. The therapeutic paradigm shift was well received in the research community and is often cited. However, new evidence on optimal UC treatment targets continues to accumulate since the time of the STRIDE guidelines. This systematic review summarizes the evidence accrued since the STRIDE UC recommendations, discusses the barriers for adoption of treat-to-target approaches in clinical practice in UC, and suggests directions for future research. METHODS We systematically reviewed MEDLINE for studies from the time of the STRIDE systematic review up to March 31, 2018, that assessed the potential treatment targets identified by the STRIDE recommendations. RESULTS Each potential treatment target literature search returned > 200 articles, which were then reviewed by 2 independent investigators for relevant studies. Selected studies of clinical factors, patient-reported outcomes, endoscopy, histology, imaging, and biomarkers and implications on treatment targets are summarized. CONCLUSIONS It appears that the relative weight given to different therapeutic targets in the development and improvement of UC treatments could be optimized, with an increased emphasis on endoscopic and histological targets over clinical or symptomatic targets. For this evolution to occur, however, new research has to demonstrate that the treat-to-target approach will deliver on the promise of better long-term outcomes compared with current approaches.
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Stronati L, Palone F, Negroni A, Colantoni E, Mancuso AB, Cucchiara S, Cesi V, Isoldi S, Vitali R. Dipotassium Glycyrrhizate Improves Intestinal Mucosal Healing by Modulating Extracellular Matrix Remodeling Genes and Restoring Epithelial Barrier Functions. Front Immunol 2019; 10:939. [PMID: 31105713 PMCID: PMC6498413 DOI: 10.3389/fimmu.2019.00939] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 04/11/2019] [Indexed: 12/16/2022] Open
Abstract
Gut mucosal healing (MH) is considered a key therapeutic target and prognostic parameter in the management of inflammatory bowel disease (IBD). The dipotassium glycyrrhizate (DPG), a salt of the glycoconjugated triterpene glycyrrhizin, has been shown to inhibit the High Mobility Group Box 1 (HMGB1) protein, an allarmin strongly implicated in the pathogenesis of most inflammatory and auto-immune disorders. Here we discuss new insights on how DPG acts on MH comparing the acute phase and the recovery phase from experimental colitis in mice. We found that DPG strongly accelerates MH by differently regulating pro-inflammatory (CXCL1, CXCL3, CXCL5, PTGS2, IL-1β, IL-6, CCL12, CCL7) and wound healing (COL3A1, MMP9, VTN, PLAUR, SERPINE, CSF3, FGF2, FGF7, PLAT, TIMP1) genes as observed only during the recovery phase of colitis. Relevant issue is the identification of extracellular matrix (ECM) remodeling genes, VTN, and PLAUR, as crucial genes to achieve MH during DPG treatment. Furthermore, a noticeable recovery of intestinal epithelial barrier structural organization, wound repair ability, and functionality is observed in two human colorectal adenocarcinoma cell lines exposed to DPG during inflammation. Thus, our study identifies DPG as a potent tool for controlling intestinal inflammation and improving MH.
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Affiliation(s)
- Laura Stronati
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Francesca Palone
- Pediatric Gastroenterology and Liver Unit, Department of Pediatrics, Sapienza University of Rome, Rome, Italy
| | - Anna Negroni
- Division of Health Protection Technologies, Territorial and Production Systems Sustainability Department, ENEA, Rome, Italy
| | - Eleonora Colantoni
- Pediatric Gastroenterology and Liver Unit, Department of Pediatrics, Sapienza University of Rome, Rome, Italy
| | - Anna Barbara Mancuso
- Pediatric Gastroenterology and Liver Unit, Department of Pediatrics, Sapienza University of Rome, Rome, Italy
| | - Salvatore Cucchiara
- Pediatric Gastroenterology and Liver Unit, Department of Pediatrics, Sapienza University of Rome, Rome, Italy
| | - Vincenzo Cesi
- Division of Health Protection Technologies, Territorial and Production Systems Sustainability Department, ENEA, Rome, Italy
| | - Sara Isoldi
- Pediatric Gastroenterology and Liver Unit, Department of Pediatrics, Sapienza University of Rome, Rome, Italy
| | - Roberta Vitali
- Division of Health Protection Technologies, Territorial and Production Systems Sustainability Department, ENEA, Rome, Italy
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Abstract
High-mobility group box 1 (HMGB1) is one of the most abundant proteins in eukaryotes and the best characterized damage-associated molecular pattern (DAMP). The biological activities of HMGB1 depend on its subcellular location, context and post-translational modifications. Inside the nucleus, HMGB1 is engaged in many DNA events such as DNA repair, transcription regulation and genome stability; in the cytoplasm, its main function is to regulate the autophagic flux while in the extracellular environment, it possesses more complicated functions and it is involved in a large variety of different processes such as inflammation, migration, invasion, proliferation, differentiation and tissue regeneration. Due to this pleiotropy, the role of HMGB1 has been vastly investigated in various pathological diseases and a large number of studies have explored its function in cardiovascular pathologies. However, in this contest, the precise mechanism of action of HMGB1 and its therapeutic potential are still very controversial since is debated whether HMGB1 is involved in tissue damage or plays a role in tissue repair and regeneration. The main focus of this review is to provide an overview of the effects of HMGB1 in different ischemic heart diseases and to discuss its functions in these pathological conditions.
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Nanini HF, Bernardazzi C, Castro F, de Souza HSP. Damage-associated molecular patterns in inflammatory bowel disease: From biomarkers to therapeutic targets. World J Gastroenterol 2018; 24:4622-4634. [PMID: 30416310 PMCID: PMC6224468 DOI: 10.3748/wjg.v24.i41.4622] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 10/08/2018] [Accepted: 10/15/2018] [Indexed: 02/06/2023] Open
Abstract
The chronic inflammatory process underlying inflammatory bowel disease (IBD), comprising Crohn’s disease and ulcerative colitis, derives from the interplay of several components in a genetically susceptible host. These components include environmental elements and gut microbiota a dysbiosis. For decades, immune abnormalities have been investigated as critically important in IBD pathogenesis, and attempts to develop effective therapies have predominantly targeted the immune system. Nevertheless, immune events represent only one of the constituents contributing to IBD pathogenesis within the context of the complex cellular and molecular network underlying chronic intestinal inflammation. These factors need to be appreciated within the milieu of non-immune components. Damage-associated molecular patterns (DAMPs), which are essentially endogenous stress proteins expressed or released as a result of cell or tissue damage, have been shown to act as direct pro-inflammatory mediators. Excessive or persistent signalling mediated by such molecules can underlie several chronic inflammatory disorders, including IBD. The release of endogenous DAMPs amplifies the inflammatory response driven by immune and non-immune cells and promotes epigenetic reprogramming in IBD. The effects determine pathologic changes, which may sustain chronic intestinal inflammation and also underlie specific disease phenotypes. In addition to highlighting the potential use of DAMPs such as calprotectin as biomarkers, research on DAMPs may reveal novel mechanistic associations in IBD pathogenesis and is expected to uncover putative therapeutic targets.
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Affiliation(s)
- Hayandra Ferreira Nanini
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
| | - Claudio Bernardazzi
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
| | - Fernando Castro
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
| | - Heitor Siffert Pereira de Souza
- Serviço de Gastroenterologia e Laboratório Multidisciplinar de Pesquisa, Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
- D’Or Institute for Research and Education (IDOR), Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro, RJ 22281-100, Brazil
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Palone F, Vitali R, Trovato CM, Montuori M, Negroni A, Mallardo S, Stronati L. Faecal high mobility group box 1 in children with celiac disease: A pilot study. Dig Liver Dis 2018; 50:916-919. [PMID: 29709462 DOI: 10.1016/j.dld.2018.04.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 03/28/2018] [Accepted: 04/03/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Celiac disease (CD) is a gluten-related immunological disorder resulting in inflammatory enteropathy. AIMS We assessed a stool marker of intestinal inflammation, the HMGB1 protein, in children with CD on a gluten free diet (GFD) at baseline and at follow up (FU). METHODS Thirty-nine children were investigated at diagnosis and at FU. Traditional serum markers of CD (anti-transglutaminase and anti-endomysial antibodies) and faecal HMGB1 (by enzyme-linked immunosorbent assay and immunoblotting) were tested. RESULTS There was a marked increase at baseline in both serum anti-transglutaminase IgA (anti-tTGAs) and faecal HMGB1; the latter being undetectable in controls. A strong correlation occurred between the two markers. At 12-month FU in 24 patients on GFD, HMGB1 decreased in all subjects, yet still being detectable in six children: high anti-tTGAs where evident in three, while the three with normal anti-tTGAs were complaining of intestinal symptoms and reported a low GFD adherence. CONCLUSIONS Faecal HMGB1 is a valuable marker of intestinal inflammation and may have a role in complementing serology in the management of CD children. Future studies including larger patient cohorts and small bowel mucosa histology will be designed to assess the relationship between faecal HMGB1 levels and duodeno-jejunal histopathology.
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Affiliation(s)
| | - Roberta Vitali
- Department of Radiation Biology and Human Health, ENEA, Rome, Italy
| | | | - Monica Montuori
- Department of Paediatrics, Sapienza University of Rome, Italy
| | - Anna Negroni
- Department of Radiation Biology and Human Health, ENEA, Rome, Italy
| | | | - Laura Stronati
- Department of Cellular Biotechnology and Haematology, Sapienza University of Rome, Italy.
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Splichalova A, Slavikova V, Splichalova Z, Splichal I. Preterm Life in Sterile Conditions: A Study on Preterm, Germ-Free Piglets. Front Immunol 2018; 9:220. [PMID: 29491864 PMCID: PMC5817058 DOI: 10.3389/fimmu.2018.00220] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 01/25/2018] [Indexed: 12/21/2022] Open
Abstract
Preterm infants born with immature organ systems, which can impede normal development, can also be highly sensitive to different biological and/or environmental factors. Animal models could aid in investigating and understanding the effects of different conditions on the health of these immunocompromised infants. The epitheliochorial placentation of the pig prevents the prenatal transfer of protective colostral immunoglobulins. Surgical colostrum-deprived piglets are free of maternal immunoglobulins, and the cells that are normally provided via colostrum. We bred preterm germ-free piglets in sterile conditions and compared them with their term counterparts. Enterocyte development and intestinal morphology, tight junction proteins claudin-1 and occludin, pattern-recognizing receptors, adaptor molecules and coreceptors (RAGE, TLR2, TLR4, TLR9, MyD88, TRIF, MD2, and CD14), and inflammasome NLRP3 transcription were all evaluated. The production of inflammatory mediators IFN-α, IL-4, IL-6, IL-8, IL-10, IL-12/23 p40, TNF-α, IFN-γ, and high mobility group box 1 (HMGB1) in the intestine of germ-free piglets was also assessed. In the preterm germ-free piglets, the ileum showed decreased lamina propria cellularity, reduced villous height, and thinner and less distinct stratification - especially muscle layer, in comparison with their term counterparts. Claudin-1 transcription increased in the intestine of the preterm piglets. The transcription levels of pattern-recognizing receptors and adaptor molecules showed ambiguous trends between the groups. The levels of IL-6, IL-8, IL-10, and TNF-α were increased in the preterm ileum numerically (though not significantly), with statistically significant increases in the colon. Additionally, IL-12/23 p40 and IFN-γ were statistically significantly higher in the preterm colon. Both blood plasma and intestinal HMGB1 levels were nonsignificantly higher in the preterm group. We propose that the intestine of the preterm germ-free piglets showed "mild inflammation in sterile conditions." This model, which establishes preterm, hysterectomy-derived germ-free piglets, without protective maternal immunoglobulins, can be used to study influences of microbiota, nutrition, and therapeutic interventions on the development and health of vulnerable immunocompromised preterm infants.
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Affiliation(s)
- Alla Splichalova
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, Novy Hradek, Czechia
| | - Vera Slavikova
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, Novy Hradek, Czechia
| | - Zdislava Splichalova
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, Novy Hradek, Czechia
| | - Igor Splichal
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, Novy Hradek, Czechia
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Di Ruscio M, Vernia F, Ciccone A, Frieri G, Latella G. Surrogate Fecal Biomarkers in Inflammatory Bowel Disease: Rivals or Complementary Tools of Fecal Calprotectin? Inflamm Bowel Dis 2017; 24:78-92. [PMID: 29272479 DOI: 10.1093/ibd/izx011] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Current noninvasive methods for assessing intestinal inflammation in inflammatory bowel disease (IBD) remain unsatisfactory. Along with C-reactive protein and erythrocyte sedimentation rate, fecal calprotectin (FC) is the standard test for assessing IBD activity, even though its specificity and accuracy are not optimal and it lacks a validated cutoff. Over the past few decades, several fecal markers released from intestinal inflammatory cells have been investigated in IBD; they are the subject of this systematic review. METHODS A systematic electronic search of the English literature up to April 2017 was performed using Medline and the Cochrane Library. Only papers written in English that analyzed fecal biomarkers in IBD were included. In vitro studies, animal studies, studies on blood/serum samples, and studies analyzing FC or fecal lactoferrin alone were excluded. RESULTS Out of 1023 citations, 125 eligible studies were identified. Data were grouped according to each fecal marker including S100A12, high-mobility group box 1, neopterin, polymorphonuclear neutrophil elastase, fecal hemoglobin, alpha1-antitrypsin, human neutrophil peptides, neutrophil gelatinase-associated lipocalin, chitinase 3-like-1, matrix metalloproteinase 9, lysozyme, M2-pyruvate kinase, myeloperoxidase, fecal eosinophil proteins, human beta-defensin-2, and beta-glucuronidase. Some of these markers showed a high sensitivity and specificity and correlated with disease activity, response to therapy, and mucosal healing. Furthermore, they showed a potential utility in the prediction of clinical relapse. CONCLUSIONS Several fecal biomarkers have the potential to become useful tools complementing FC in IBD diagnosis and monitoring. However, wide variability in their accuracy in assessment of intestinal inflammation suggests the need for further studies.
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Affiliation(s)
- Mirko Di Ruscio
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, Piazza S. Tommasi, Coppito, L'Aquila, Italy
| | - Filippo Vernia
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, Piazza S. Tommasi, Coppito, L'Aquila, Italy
| | - Antonio Ciccone
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, Piazza S. Tommasi, Coppito, L'Aquila, Italy
| | - Giuseppe Frieri
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, Piazza S. Tommasi, Coppito, L'Aquila, Italy
| | - Giovanni Latella
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, Piazza S. Tommasi, Coppito, L'Aquila, Italy
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Galgut BJ, Lemberg DA, Day AS, Leach ST. The Value of Fecal Markers in Predicting Relapse in Inflammatory Bowel Diseases. Front Pediatr 2017; 5:292. [PMID: 29404311 PMCID: PMC5780398 DOI: 10.3389/fped.2017.00292] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 12/20/2017] [Indexed: 12/12/2022] Open
Abstract
The inflammatory bowel diseases (IBDs) are lifelong chronic illnesses that place an immense burden on patients. The primary aim of therapy is to reduce disease burden and prevent relapse. However, the occurrence of relapses is often unpredictable. Current disease monitoring is primarily by way of clinical indices, with relapses often only recognized once the inflammatory episode is established with subsequent symptoms and gut damage. The window between initial upregulation of the inflammatory response and the recognition of symptoms may provide an opportunity to prevent the relapse and associated morbidity. This review will describe the existing literature surrounding predictive indicators of relapse of IBD with a specific focus on fecal biomarkers. Fecal biomarkers offer promise as a convenient, non-invasive, low cost option for disease monitoring that is predictive of subsequent relapse. To exploit the potential of fecal biomarkers in this role, further research is now required. This research needs to assess multiple fecal markers in context with demographics, disease phenotype, genetics, and intestinal microbiome composition, to build disease behavior models that can provide the clinician with sufficient confidence to intervene and change the long-term disease course.
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Affiliation(s)
- Bianca J Galgut
- School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia
| | - Daniel A Lemberg
- School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia.,Department of Gastroenterology, Sydney Children's Hospital Randwick, Sydney, NSW, Australia
| | - Andrew S Day
- Department of Paediatrics, University of Otago, Christchurch, New Zealand
| | - Steven T Leach
- School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia
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Manti S, Cuppari C, Tardino L, Parisi G, Spina M, Salpietro C, Leonardi S. HMGB1 as a new biomarker of celiac disease in children: A multicenter study. Nutrition 2016; 37:18-21. [PMID: 28359357 DOI: 10.1016/j.nut.2016.12.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 12/03/2016] [Accepted: 12/17/2016] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Despite the availability of specific sierology and point-of-care tests, the phenotypic heterogeneity and the symptoms fluctuation as well as the "open-window" existing among the late and silent forms cause often a delayed celiac disease (CD) diagnosis. Recently, it has been reported that high mobility group box 1 (HMGB1) mediates inflammation and gastrointestinal barrier failure. The aim of this study was to detect serum HMGB1 levels at CD diagnosis and to evaluate the relationship between serum HMGB1 levels and clinical and histologic phenotypes. METHODS 49 CD children and 44 healthy children were enrolled. Specific antitissue transglutaminase type 2, antideaminated form of gliadin antibodies, serum HMGB1 levels, and typical histopathological changes in duodenal mucosa were performed in all patients. Mucosal lesions were classified according to Marsh classification. In relation to clinical presentation, we classified patients into: typical, atypical and silent forms. RESULTS Serum HMGB1 levels were significantly higher in those with CD than those in the healthy control group (P < 0.001). Significant differences in serum HMGB1 levels were detected in children with typical CD form compared to both children with atypical CD form (P < 0.001) and children with silent CD form (P < 0.001). By using the Marsh classification, significant differences were found between subjects with grade 3 B-B1 and 3 C-B2 and villous atrophy, respectively (P < 0.05). On the contrary, no significant differences in serum HMGB1 levels in subgroups of children with grade 3 A compared to grade 3 B-B1 were detected. CONCLUSIONS HMGB1 is upregulated at diagnosis in all CD children, especially in typical form, and reflecting the histologic severity of disease.
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Affiliation(s)
- Sara Manti
- Department of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Messina, Italy
| | - Caterina Cuppari
- Department of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Messina, Italy
| | - Lucia Tardino
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Giuseppe Parisi
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Massimo Spina
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Carmelo Salpietro
- Department of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Messina, Italy
| | - Salvatore Leonardi
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
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Routine testing of folate levels in geriatric assessment for dementia. J Am Geriatr Soc 1988; 497:141-146. [PMID: 3136199 DOI: 10.1016/j.cca.2019.07.033] [Citation(s) in RCA: 29] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 07/26/2019] [Accepted: 07/26/2019] [Indexed: 12/16/2022]
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