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Wang S, Wang L, Lin J, Wang M, Li J, Guo Q, Jiao C, Tang N, Ma J, Zhang H, Zhao X. Inflammatory monocyte-derived amphiregulin mediates intestinal fibrosis in Crohn's disease by activating PI3K/AKT. Mucosal Immunol 2025:S1933-0219(25)00056-X. [PMID: 40480418 DOI: 10.1016/j.mucimm.2025.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 05/13/2025] [Accepted: 05/29/2025] [Indexed: 06/11/2025]
Abstract
Intestinal fibrosis is one of the most threatening complications of Crohn's disease (CD). Although our previous study identified the profibrotic role of amphiregulin (AREG) in intestinal fibrosis, the underlying molecular mechanisms remain poorly understood. This study aimed to elucidate the mechanisms by which AREG mediates intestinal fibrosis. Specimens from stenotic and non-stenotic lesions in CD patients were collected, alongside normal specimens from individuals with intestinal diverticula, for the assessment of AREG levels. A dextran sulfate sodium (DSS)-induced chronic colitis model was established in wild type (WT) and Areg-knockout (Areg-/-) mice. RNA-sequencing (RNA-seq) was performed on human intestinal fibroblasts (HIFs) to elucidate the underlying mechanisms. Additionally, the single-cell RNA-seq data of full-thickness CD, obtained from Prof. Rieder, was reanalyzed. Elevated levels of AREG were detected at stenotic sites in patients with CD. Areg-/- colitis mice exhibited decreased intestinal fibrosis. AREG enhanced the activation and proliferation of HIFs by activating the PI3K/AKT pathway. The inhibitor of the PI3K/AKT pathway effectively suppressed AREG-induced activation and proliferation of HIFs and attenuated colitis-associated fibrosis in mice. In stricturing CD, inflammatory monocytes exhibited higher AREG levels, contributing to the activation and proliferation of intestinal fibroblasts. Adoptive transfer of Ly6chi inflammatory monocytes from WT but not Areg-/- mice exacerbated intestinal fibrosis in DSS-induced colitis mice. These findings reveal that inflammatory monocytes derived-AREG promotes intestinal fibrosis in experimental colitis and CD patients by promoting intestinal fibroblasts activation and proliferation through the PI3K/AKT pathway. Inflammatory monocytes serve as the primary source of AREG in stricturing CD, critically mediating fibroblast-related fibrotic progression in an AREG-dependent manner. Therefore, AREG, the PI3K/AKT pathway and inflammatory monocytes may serve as potential therapeutic targets for intestinal fibrosis in CD.
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Affiliation(s)
- Shu Wang
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029 Jiangsu Province, China
| | - Lu Wang
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029 Jiangsu Province, China
| | - Junjie Lin
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029 Jiangsu Province, China
| | - Mingyuan Wang
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029 Jiangsu Province, China
| | - Jiajia Li
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029 Jiangsu Province, China
| | - Qiong Guo
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029 Jiangsu Province, China
| | - Chunhua Jiao
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029 Jiangsu Province, China
| | - Nana Tang
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029 Jiangsu Province, China
| | - Jingjing Ma
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029 Jiangsu Province, China
| | - Hongjie Zhang
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029 Jiangsu Province, China.
| | - Xiaojing Zhao
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029 Jiangsu Province, China.
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Schnell A, Schwarz B, Schmidt H, Allabauer I, Schuh W, Regensburger AP, Rauh M, Woelfle J, Hoerning A. Adenosine-generating CD39 + plasmablasts predispose to successful infliximab therapy in pediatric IBD. Life Sci Alliance 2025; 8:e202403055. [PMID: 40199584 PMCID: PMC11979362 DOI: 10.26508/lsa.202403055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 03/18/2025] [Accepted: 03/18/2025] [Indexed: 04/10/2025] Open
Abstract
B cells display several immunoregulatory mechanisms including the production of interleukin-10. Ectonucleotidases like CD39 and CD73 influence immune homeostasis by metabolizing eATP and generating immunosuppressive adenosine. The major objective was to examine the expression of those immunoregulatory molecules on B-cell subsets, and, more specifically, to determine their association with an infliximab (IFX) treatment in a pediatric inflammatory bowel disease (IBD) cohort. 42 IBD patients were assessed for IFX response after 12 mo of therapy and compared against 14 healthy controls (HC). Although IL10-producing plasmablasts were decreased in IFX nonresponders (NRS), we detected an up-regulation of CD39 on plasmablasts and increased fractions of CD39/CD73-co-expressing naïve and memory B cells in responding patients (RS). In addition, B cells of responders proved to have superior ATP degradation capacities and adenosine production before therapy initiation compared with NRS and HC. Moreover, IFX nonresponders had a marked deficiency of α4β7hi plasmablasts, whereas both cohorts had fewer CCR9-expressing plasmablasts. Consequently, CD39+ plasmablasts were decreased in biopsies of inflamed mucosal tissues, especially in IFX nonresponders. Our results highlight the regulatory potential of CD39/CD73-expressing B cells in pediatric IBD and suggest CD39+ plasmablasts as a potential determinant of a successful immunosuppressive therapy with IFX.
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Affiliation(s)
- Alexander Schnell
- Pediatric Gastroenterology and Hepatology, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Benedikt Schwarz
- Pediatric Gastroenterology and Hepatology, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Hannah Schmidt
- Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Ida Allabauer
- Pediatric Gastroenterology and Hepatology, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Wolfgang Schuh
- Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger Center, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Adrian P Regensburger
- Pediatric Gastroenterology and Hepatology, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Manfred Rauh
- Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Joachim Woelfle
- Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - André Hoerning
- Pediatric Gastroenterology and Hepatology, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
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Qayyum N, Seo H, Khan N, Manan A, Ramachandran R, Haseeb M, Kim E, Choi S. A hybrid protocol for peptide development: integrating deep generative models and physics simulations for biomolecular design targeting IL23R/IL23. Int J Biol Macromol 2025; 316:144652. [PMID: 40419055 DOI: 10.1016/j.ijbiomac.2025.144652] [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: 03/22/2025] [Revised: 05/13/2025] [Accepted: 05/23/2025] [Indexed: 05/28/2025]
Abstract
Recent advances in machine learning have revolutionized molecular design; however, a gap remains in integrating generative models with physics-based simulations to develop functional modulators, such as stable peptides, for challenging targets like the interleukin-23 receptor (IL23R) and its associated cytokine, interleukin-23 (IL23). The IL23R/IL23 axis plays a critical role in autoimmune diseases, and current therapies have largely been limited to antibody-based approaches. To address this gap, we employed a hybrid computational approach that combines Long Short-Term Memory (LSTM) networks for peptide generation, a Gated Recurrent Unit (GRU)-based classifier for anti-inflammatory property prediction, and molecular dynamics (MD) simulations to assess structural dynamics, binding interactions, as well as key properties such as binding affinity and stability. Using this hybrid framework, we identified novel inhibitory peptides, particularly P4, with an IC50 of 2 μM. Systematic experimental validation established its inhibitory activity, elucidated its binding mechanism, confirmed its specificity toward the IL23R, and demonstrated its ability to disrupt IL23R/IL23 interaction. This integrated approach highlights the significant potential of combining deep learning and simulations to accelerate the identification of peptide-based therapeutics targeting key protein targets.
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Affiliation(s)
- Naila Qayyum
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, South Korea.
| | - Hana Seo
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, South Korea
| | - Noman Khan
- Department of Computer Science, Yonsei University, Seoul 03722, South Korea
| | - Abdul Manan
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, South Korea
| | - Rajath Ramachandran
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, South Korea
| | - Muhammad Haseeb
- S&K Therapeutics, Ajou University Campus Plaza 418, Worldcup-ro 199, Yeongtong-gu, Suwon 16502, South Korea
| | - Eunha Kim
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, South Korea
| | - Sangdun Choi
- S&K Therapeutics, Ajou University Campus Plaza 418, Worldcup-ro 199, Yeongtong-gu, Suwon 16502, South Korea.
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Takagi T, Uchiyama K, Asaeda K, Murakami E, Inoue K, Mizushima K, Hirai Y, Naito Y, Itoh Y. Association of Vascular Cell Adhesion Molecule-1 Expression in Colonic Mucosa With Mucosal Inflammation and Subsequent Relapse in Patients With Ulcerative Colitis. J Gastroenterol Hepatol 2025. [PMID: 40411296 DOI: 10.1111/jgh.17000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 04/04/2025] [Accepted: 04/26/2025] [Indexed: 05/26/2025]
Abstract
BACKGROUND AND AIM The association between vascular cell adhesion molecule-1 (VCAM-1) expression and intestinal mucosal inflammation and between VCAM-1 expression and the clinical course in patients with ulcerative colitis (UC) remains unclear. Therefore, we investigated not only the association between mucosal VCAM-1 expression and mucosal inflammation but also its association with subsequent relapse in UC patients with clinical remission. METHODS Fifty-eight patients with UC in clinical remission and 16 patients in clinical active who visited Kyoto Prefectural University of Medicine for a 2-year follow-up period were included. VCAM-1 expression was compared between patients who subsequently relapsed and those who remained in remission, and it was examined in relation to endoscopic findings, histological activity, and cytokine expression. We also investigated the expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1). RESULTS VCAM-1 was associated with clinical disease activity and endoscopic severity and was significantly elevated in histologically active mucosa compared with inactive mucosa. VCAM-1 expression co-localized with MAdCAM-1 in the mucosal and submucosal microvessels of the colon and was significantly higher in the relapse group than in the remission group. Similar results were observed for MAdCAM-1 expression. VCAM-1 expression levels were also closely correlated with those of several other cytokines. CONCLUSIONS VCAM-1 expression in the colonic mucosa of patients with UC is associated with mucosal inflammation and subsequent relapse. These results suggest that VCAM-1 may serve as a marker for relapse and therapeutic effectiveness in UC, and that treatment targeting α4 integrin is efficient and rational.
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Affiliation(s)
- Tomohisa Takagi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Department for Medical Innovation and Translational Medical Science, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kazuhiko Uchiyama
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kohei Asaeda
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Eiki Murakami
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Ken Inoue
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Katsura Mizushima
- Department of Human Immunology and Nutrition Science, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yasuko Hirai
- Department of Human Immunology and Nutrition Science, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yuji Naito
- Department of Human Immunology and Nutrition Science, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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D’Addio F, Amabile G, Assi E, Maestroni A, Petrazzuolo A, Loretelli C, Abdelasalam A, Ben Nasr M, Pastore I, Lunati ME, Usuelli V, Zocchi M, Seelam AJ, Corradi D, La Rosa S, Marin V, Zangarini M, Nardini M, Porzio S, Canducci F, Nardini C, El Essawy B, Nebuloni M, Yang J, Venturini M, Maconi G, Folli F, Danese S, Zuccotti G, Sampietro GM, Ardizzone S, Fiorina P. TMEM219 signaling promotes intestinal stem cell death and exacerbates colitis. J Clin Invest 2025; 135:e185783. [PMID: 40371646 PMCID: PMC12077909 DOI: 10.1172/jci185783] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 03/06/2025] [Indexed: 05/16/2025] Open
Abstract
Mechanisms by which mucosal regeneration is abrogated in inflammatory bowel disease (IBD) are still under investigation, and a role for an intestinal stem cell (ISC) defect is now emerging. Herein, we report an abnormal ISC death that occurs in Crohn's disease, which exacerbates colitis, limits ISC-dependent mucosal repair, and is controlled through the death factor Transmembrane protein 219 (TMEM219). Large alterations in TMEM219 expression were observed in patients with Crohn's disease, particularly in those with active disease and/or those who were nonresponders to conventional therapy, confirming that TMEM219 signaling is abnormally activated and leads to failure of the mucosal regenerative response. Mechanistic studies revealed a proapoptotic TMEM219-mediated molecular signature in Crohn's disease, which associates with Caspase-8 activation and ISC death. Pharmacological blockade of the IGFBP3/TMEM219 binding/signal with the recombinant protein ecto-TMEM219 restored the self-renewal abilities of miniguts generated from patients with Crohn's disease in vitro and ameliorated DSS-induced and T cell-mediated colitis in vivo, ultimately leading to mucosal healing. Genetic tissue-specific deletion of TMEM219 in ISCs in newly generated TMEM219fl/flLGR5cre mice revived their mucosal regenerative abilities both in vitro and in vivo. Our findings demonstrate that a TMEM219-dependent ISC death exacerbates colitis and that TMEM219 blockade reestablishes intestinal self-renewal properties in IBD.
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Affiliation(s)
- Francesca D’Addio
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milan, Italy
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | | | - Emma Assi
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Anna Maestroni
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Adriana Petrazzuolo
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Cristian Loretelli
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Ahmed Abdelasalam
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Moufida Ben Nasr
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milan, Italy
- Boston Children’s Hospital and Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ida Pastore
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milan, Italy
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | | | - Vera Usuelli
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Monica Zocchi
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Andy Joe Seelam
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Domenico Corradi
- Department of Medicine and Surgery, Unit of Pathology, University of Parma, Parma, Italy
| | - Stefano La Rosa
- Department of Medicine and Surgery, Università degli Studi dell’Insubria, Varese, Italy
| | | | | | | | | | | | | | - Basset El Essawy
- Nephrology Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MassachuseLs, USA
- Department of Medicine, Al-Azhar University, Cairo, Egypt
| | - Manuela Nebuloni
- Pathology Unit, ASST-Fatebenefratelli Sacco and Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Jun Yang
- Institute of Organ Transplantation, Tongji Hospital and Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Massimo Venturini
- Diagnostic and Interventional Radiology Department, Circolo Hospital, ASST Sette Laghi and School of Medicine and Surgery, Università degli Studi dell’Insubria, Varese, Italy
| | - Giovanni Maconi
- Gastrointestinal Unit, ASST-Fatebenefratelli Sacco and Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Franco Folli
- Endocrinology and Metabolism, Department of Health Science, Università di Milano, Diabetic and Metabolic Diseases Unit-ASST Santi Paolo e Carlo, Milan, Italy
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Medicine and Surgery Department, Vita-Salute San Raffaele University, Milan, Italy
| | - Gianvincenzo Zuccotti
- Pediatric Clinical Research Center Romeo ed Enrica Invernizzi-Università di Milano and Buzzi Children’s Hospital, Milan, Italy
| | - Gianluca M. Sampietro
- Division of General and HBP Surgery, Rho Memorial Hospital, ASST Rhodense, Milano, Italy
| | - Sandro Ardizzone
- Gastrointestinal Unit, ASST-Fatebenefratelli Sacco and Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Paolo Fiorina
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milan, Italy
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
- Boston Children’s Hospital and Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Adelfio M, Callen GE, He X, Paster BJ, Hasturk H, Ghezzi CE. Engineered Tissue Models to Decode Host-Microbiota Interactions. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2417687. [PMID: 40364768 DOI: 10.1002/advs.202417687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 04/13/2025] [Indexed: 05/15/2025]
Abstract
A mutualistic co-evolution exists between the host and its associated microbiota in the human body. Bacteria establish ecological niches in various tissues of the body, locally influencing their physiology and functions, but also contributing to the well-being of the whole organism through systemic communication with other distant niches (axis). Emerging evidence indicates that when the composition of the microbiota inhabiting the niche changes toward a pathogenic state (dysbiosis) and interactions with the host become unbalanced, diseases may present. In addition, imbalances within a single niche can cause dysbiosis in distant organs. Current research efforts are focused on elucidating the mechanisms leading to dysbiosis, with the goal of restoring tissue homeostasis. In vitro models can provide critical experimental platforms to address this need, by reproducing the niche cyto-architecture and physiology with high fidelity. This review surveys current in in vitro host-microbiota research strategies and provides a roadmap that can guide the field in further developing physiologically relevant in vitro models of ecological niches, thus enabling investigation of the role of the microbiota in human health and diseases. Lastly, given the Food and Drug Administration Modernization Act 2.0, this review highlights emerging in vitro strategies to support the development and validation of new therapies on the market.
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Affiliation(s)
- Miryam Adelfio
- Department of Biomedical Engineering, University of Massachusetts-Lowell, Lowell, MA, 01854, USA
| | - Grace E Callen
- Department of Biomedical Engineering, University of Massachusetts-Lowell, Lowell, MA, 01854, USA
| | - Xuesong He
- ADA Forsyth Institute, 245 First St, Cambridge, MA, 02142, USA
| | - Bruce J Paster
- ADA Forsyth Institute, 245 First St, Cambridge, MA, 02142, USA
| | - Hatice Hasturk
- ADA Forsyth Institute, 245 First St, Cambridge, MA, 02142, USA
| | - Chiara E Ghezzi
- Department of Biomedical Engineering, University of Massachusetts-Lowell, Lowell, MA, 01854, USA
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7
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Li H, Zhang Y, Du S, Shen J, Liu X, Jing J. "Remodeling the intestinal immune microenvironment": immune regulation and tissue regeneration by mesenchymal stem/stromal cells in the repair microenvironment of inflammatory bowel disease. Front Immunol 2025; 16:1543702. [PMID: 40433382 PMCID: PMC12106535 DOI: 10.3389/fimmu.2025.1543702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 04/21/2025] [Indexed: 05/29/2025] Open
Abstract
The global prevalence of inflammatory bowel disease (IBD) has significantly increased in recent decades. IBD is a long-term, recurring, gastrointestinal inflammatory condition that mainly comprises two primary clinical types: ulcerative colitis and Crohn's disease. The current treatment paradigm for IBD primarily focuses on symptom management. However, this approach does not support mucosal epithelial repair, maintenance of barrier homeostasis, or regulation of biological functions in the gut. Conventional therapies rely on the frequent use of high-dose medications, including antibiotics, nonsteroidal anti-inflammatory drugs, biological agents, and immunomodulators. Recently, mesenchymal stem/stromal cells (MSCs) have gained interest in tissue regeneration owing to their unique ability to differentiate and secrete regulatory factors, including extracellular vesicles (EVs), which play crucial roles in abnormal organization. Various routes of administration have been explored in preclinical and clinical studies to deliver MSCs from diverse tissue sources. The routes include intraperitoneal, intravenous, and local (intracolonic or rectal) delivery. The MSCs employed were obtained from various tissues, including bone marrow, umbilical cord, and adipose tissue. This article reviews the research framework for the application of MSCs and EVs secretion in the treatment of IBD, emphasizing key immunological effects, such as immune microenvironment regulation, intestinal barrier stabilization, and therapeutic approaches targeting intestinal barrier disorders. The discussion primarily focuses on the advantages of MSCs over other biologics, impairment of gut mucosal tissue-resident mesenchymal stem cells in IBD development, immune targets (at the cellular and molecular levels) within the framework of IBD, and the reparative effects of MSCs in the microenvironment of IBD. We aimed to present an overview of the current trends in MSC research and therapy, as well as to identify the challenges and future directions that must be addressed to advance research on MSC-mediated therapeutic strategies for IBD.
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Affiliation(s)
| | | | | | | | | | - Jie Jing
- School and Hospital of Stomatology, Zunyi Medical University, Zunyi, Guizhou, China
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8
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Pugliese D, Privitera G, Cersullo N, Bordekar H, Crispino F, Mezzina N, Pellegrini L, Allocca M, Laterza L, Viola A, Bertani L, Soru P, Scrivo B, Barberio B, Ricci C, Balestrieri P, Daperno M, Pluchino D, Rizzello F, Scribano ML, Sablich R, Pastorelli L, Manguso F, Variola A, Di Sario A, Grossi L, Ribaldone DG, Biscaglia G, Buda A, Mocci G, Viscido A, Di Paolo MC, Onali S, Rodino' S, Coletta M, Principi M, Miranda A, Amato A, Bezzio C, Petruzzellis C, Mazzuoli S, Festa S, Sartini A, Checchin D, Fanigliulo L, Gallina S, Cesarini M, Bodini G, Stradella D, Spagnuolo R, Guidi L, Savarino E, Cappello M, Caprioli F, Costa F, Fries W, Scaldaferri F, Fiorino G, Castiglione F, Massari A, Orlando A, Armuzzi A. Vedolizumab in inflammatory bowel disease: Real-world outcomes and their prediction with machine learning-the IG-IBD LIVE study. Dig Liver Dis 2025:S1590-8658(25)00736-4. [PMID: 40360308 DOI: 10.1016/j.dld.2025.04.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2025] [Revised: 04/09/2025] [Accepted: 04/10/2025] [Indexed: 05/15/2025]
Abstract
BACKGROUND AND AIMS Real-world studies on vedolizumab in inflammatory bowel disease (IBD) are often limited by small sample size and short follow-up. In this study, we investigated the 2-year effectiveness and safety of vedolizumab in patients with IBD, and applied eXplainable Artificial Intelligence (XAI) to identify predictors of both. METHODS The Long-term Italian Vedolizumab Effectiveness (LIVE) study is multicentric, ambispective, observational study enrolling 1111 IBD patients (563 Crohn's disease, CD, 542 ulcerative colitis, UC). Steroid-free clinical remission (SFCR) at 24 months was the primary endpoint. A XAI model (eXtreme Gradient Boosting, XGB) was applied to identify the main clinical predictors of SFCR and development of adverse events (AEs). RESULTS Rates of SFCR at 24 months were 31.6 % and 39.7 % in CD and UC patients, and 0.14 AEs per patient-year was recorded. On XGB analysis, previous exposure to anti-TNFα and older age were the most important drivers for the prediction of SFCR; lower baseline CRP levels and fewer comorbidities were the most important features associated with no development of AEs. CONCLUSIONS Vedolizumab is effective and safe in IBD patients. XAI yielded promising results in identifying the most important predictors of SFCR and development of AEs.
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Affiliation(s)
- Daniela Pugliese
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go A. Gemelli 8, 00168 Rome, Italy; UOC Pronto Soccorso, Medicina d'Urgenza e Medicina Interna, Ospedale Isola Tiberina Gemelli Isola, 00186 Rome, Italy; UOS Gastroenterologia, Ospedale Isola Tiberina Gemelli Isola, 00186 Rome, Italy
| | - Giuseppe Privitera
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | | | | | | | - Nicolò Mezzina
- Department of Biochemical and Clinical Science "L. Sacco" ASST Fatebenefratelli Sacco-University of Milan, Italy
| | | | - Mariangela Allocca
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Lucrezia Laterza
- CEMAD - IBD UNIT, Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Anna Viola
- UOSD Malattie Intestinali Croniche, Dip. Di Medicina Clinica e Sperimentale, Policlinico Messina, Sicily, Italy
| | - Lorenzo Bertani
- Gastroenterology and Digestive Endoscopy Department of Medical Specialties Apuane Hospital, Tuscany North-West ASL, Massa, Italy
| | - Pietro Soru
- Gastroenterology and Endoscopy Unit, La Fondazione IRCCS Ca' Granda Ospedale Maggiore di Milano Policlinico, Department of Pathophysiology and Transplantation, University of Milan, Milano, Lombardia, Italy
| | - Barbara Scrivo
- Head IBD Clinic, Gastroenterology Section, Promise, University of Palermo, Sicily, Italy
| | - Brigida Barberio
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Chiara Ricci
- Gastroenterology Unit, Spedali Civili Hospital, Department of Experimental and Clinical Sciences, University of Brescia, Brescia, Italy
| | - Paola Balestrieri
- Unit of Digestive Disease of Campus Bio Medico University of Rome, Italy
| | - Marco Daperno
- Gastroenterology Unit, Azienda Ospedaliera Ordine Mauriziano di Torino, Torino, Piemonte, Italy
| | - Dario Pluchino
- Gastroenterology Unit, A.O.U. Policlinico "Vittorio Emanuele" Catania Italy
| | - Fernando Rizzello
- Policlinico Sant'Orsola Malpighi, Department of Internal Medicine and Gastroenterology, Bologna, Italy
| | | | - Renato Sablich
- Gastroenterology Unit, Santa Maria degli Angeli Hospital, Pordenone, Italy
| | - Luca Pastorelli
- Gastroenterology and Hepatology Unit, ASST Santi Paolo e Carlo, 20142 Milan, Italy
| | | | - Angela Variola
- IBD Unit, IRCCS Sacro Cuore Don Calabria, Negrar di Valpolicella, Verona, Italy
| | - Antonio Di Sario
- Clinica di Gastroenterologia, Università Politecnica delle Marche, IBD-UNIT and Dipartimento Gastroenterologico e dei Trapianti, Polo Ospedaliero-Universitario "Umberto I-G.M. Lancisi- G. Salesi", Ancona, Italy
| | - Laurino Grossi
- G D'Annunzio University-Digestive Physiopathology Ospedale Spirito Santo Pescara, Pescara, Italy
| | | | - Giuseppe Biscaglia
- Division of Gastroenterology, IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Puglia, Italy
| | - Andrea Buda
- Department of Gastrointestinal Oncological Surgery, Gastroenterology and Endoscopy Unit, S. Maria del Prato Hospital, Feltre, Italy
| | | | - Angelo Viscido
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Maria Carla Di Paolo
- Department of Gastroenterology and Digestive Endoscopy, S. Giovanni Addolorata Hospital, Rome, Italy
| | - Sara Onali
- Gastroenterology Unit, University Hospital AOU Cagliari, Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy
| | - Stefano Rodino'
- Division of Gastroenterology, 'Ciaccio-Pugliese' Hospital, Catanzaro, Italy
| | - Marina Coletta
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | | | - Agnese Miranda
- Gastroenterology and Endoscopy Unit, University of Campania "L. Vanvitelli" Naples, Italy
| | | | - Cristina Bezzio
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IBD Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Carlo Petruzzellis
- Department of Medicine, Gastroenterology and Endoscopy, Fondazione Poliambulanza, Brescia, Italy
| | - Silvia Mazzuoli
- Section of Gastroenterology & Artificial Nutrition, Hospital San Nicola Pellegrino, Bari, Italy
| | - Stefano Festa
- S. Filippo Neri Hospital, IBD Unit, Rome, Lazio, Italy
| | - Alessandro Sartini
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena, AUSL della Romagna, Italy
| | - Davide Checchin
- UO.C. Gastroenterologia, Ospedale HUB di Mestre, Venezia, Italy
| | - Libera Fanigliulo
- Gastroenterology Unit, Ospedale Santissima Annunziata, Taranto, Italy
| | - Sara Gallina
- Division of Gastroenterology, 'Belcolle' Hospital, Viterbo, Italy
| | | | - Giorgia Bodini
- Cattedra di Gastroenterologia, Dipartimento di Medicina Interna, Universita`di Genova, Genova, Italy
| | - Davide Stradella
- Gastroenterologia, A.O.U Maggiore della Caritá di Novara, Piemonte, University of Eastern Piedmont Amedeo Avogadro, Italy
| | - Rocco Spagnuolo
- Gastroenterology and Digestive Endoscopy Department, University of Catanzaro, Catanzaro, Italy
| | - Luisa Guidi
- CEMAD - IBD UNIT, Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Edoardo Savarino
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Maria Cappello
- Head IBD Clinic, Gastroenterology Section, Promise, University of Palermo, Sicily, Italy
| | - Flavio Caprioli
- Gastroenterology and Endoscopy Unit, La Fondazione IRCCS Ca' Granda Ospedale Maggiore di Milano Policlinico, Department of Pathophysiology and Transplantation, University of Milan, Milano, Lombardia, Italy
| | | | - Walter Fries
- UOSD Malattie Intestinali Croniche, Dip. Di Medicina Clinica e Sperimentale, Policlinico Messina, Sicily, Italy
| | - Franco Scaldaferri
- CEMAD - IBD UNIT, Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Gionata Fiorino
- IBD Unit, Gastroenterology and Digestive Endoscopy, San Camillo-Forlanini Hospital, I, Rome, Italy
| | | | - Alessandro Massari
- Department of Biochemical and Clinical Science "L. Sacco" ASST Fatebenefratelli Sacco-University of Milan, Italy
| | | | - Alessandro Armuzzi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IBD Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
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9
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Tarasiuk-Zawadzka A, Fichna J. Interaction between nutritional factors and the enteric nervous system in inflammatory bowel diseases. J Nutr Biochem 2025:109959. [PMID: 40354831 DOI: 10.1016/j.jnutbio.2025.109959] [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: 04/17/2024] [Revised: 01/30/2025] [Accepted: 05/09/2025] [Indexed: 05/14/2025]
Abstract
The enteric nervous system (ENS) is a highly conserved, yet complicated network of neurons and glial cells located throughout the gut wall that controls digestive processes and gastrointestinal (GI) homeostasis. The intestinal epithelium, the immune system, and the gut microbiota are just a few examples of the cellular networks that the ENS interacts with on a variety of levels to maintain GI function. The presence or absence of nutrients in the intestinal lumen may cause short- and/or long-term changes in neurotransmitter expression, excitability, and neuronal survival, which ultimately affect gut motility, secretion, and permeability. Hence, the ENS should be identified as a key factor in initiating coordinated responses to nutrients. In this review we summarize current knowledge on nutrient-dependent ENS activity and how ENS secondary to nutrition may affect likelihood of developing inflammatory bowel disease. Our findings highlight that nutrients interact with enteroendocrine cells in the gut, triggering hormone secretion that plays a crucial role in signaling food-related information to the brain and regulating metabolic processes such as feeding behavior, insulin secretion, and energy balance; however, the complex interactions between nutrients, the ENS, and the immune system require further research to understand their contributions to GI disorders and potential therapeutic applications in treating obesity and metabolic diseases. Lay Summary: The enteric nervous system (ENS) controls digestion and interacts with nutrients in the gut to regulate processes like gut movement and hormone release, affecting metabolism and overall gut health. This review highlights the need for further research on how nutrient-ENS interactions contribute to conditions like inflammatory bowel disease, obesity, and metabolic disorders.
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Affiliation(s)
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 5, 92-215 Lodz, Poland
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10
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Suri K, Pfeifer L, Cvet D, Li A, McCoy M, Singh A, Amiji MM. Oral delivery of stabilized lipid nanoparticles for nucleic acid therapeutics. Drug Deliv Transl Res 2025; 15:1755-1769. [PMID: 39320435 PMCID: PMC11968485 DOI: 10.1007/s13346-024-01709-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2024] [Indexed: 09/26/2024]
Abstract
Gastrointestinal disorders originate in the gastrointestinal tract (GIT), and the therapies can benefit from direct access to the GIT achievable through the oral route. RNA molecules show great promise therapeutically but are highly susceptible to degradation and often require a carrier for cytoplasmic access. Lipid nanoparticles (LNPs) are clinically proven drug-delivery agents, primarily administered parenterally. An ideal Orally Delivered (OrD) LNP formulation should overcome the diverse GI environment, successfully delivering the drug to the site of action. A versatile OrD LNP formulation has been developed to encapsulate and deliver siRNA and mRNA in this paper. The formulations were prepared by the systematic addition of cationic lipid to the base LNP formulation, keeping the total of cationic lipid and ionizable lipid to 50 mol%. Biorelevant media stability depicted increased resistance to bile salt mediated destabilization upon the addition of the cationic lipid, however the in vitro efficacy data underscored the importance of the ionizable lipid. Based on this, OrD LNP was selected comprising of 20% cationic lipid and 30% ionizable lipid. Further investigation revealed the enhanced efficacy of OrD LNP in vitro after incubation in different dilutions of fasted gastric, fasted intestinal media, and mucin. Confocal imaging and flow cytometry confirmed uptake while in vivo studies demonstrated efficacy with siRNA and mRNA as payloads. Taken together, this research introduces OrD LNP to deliver nucleic acid locally to the GIT.
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Affiliation(s)
- Kanika Suri
- Takeda Development Center Americas, Cambridge, MA, USA
- Department of Bioengineering, College of Engineering, Northeastern University, Boston, MA, USA
| | - Liam Pfeifer
- Takeda Development Center Americas, Cambridge, MA, USA
| | - Donna Cvet
- Takeda Development Center Americas, Cambridge, MA, USA
| | - Angela Li
- Takeda Development Center Americas, Cambridge, MA, USA
| | - Michael McCoy
- Takeda Development Center Americas, Cambridge, MA, USA
| | - Amit Singh
- Takeda Development Center Americas, Cambridge, MA, USA
| | - Mansoor M Amiji
- Department of Pharmaceutical Sciences, Bouve College of Health Sciences, Northeastern University, Boston, MA, USA.
- Department of Chemical Engineering, College of Engineering, Northeastern University, Boston, MA, USA.
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11
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Zhu D, Ma X, Wang J, Chen T, Yang J, Liu Y, Lin Z, Wu M, Hu TY, Zhang Y. A Sequential Release Micro-nano System for Colitis Therapy via Gut Microbiota and Immune Regulation. Angew Chem Int Ed Engl 2025; 64:e202424409. [PMID: 39980315 DOI: 10.1002/anie.202424409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/19/2025] [Accepted: 02/19/2025] [Indexed: 02/22/2025]
Abstract
Commencing with the breakdown of the intestinal barrier, various pathogenic factors, such as dysbiosis of the gut microbiota, harmful inflammatory cytokines, and immune system imbalance, collectively contribute to the development of colitis. Numerous interventions focusing on single factors have been developed to provide short-term therapeutic benefits, but the continued existence of unresolved pathogenic factors can lead to disease exacerbation. Here we have designed a multicomponent system-inulin microspheres encapsulating selenium-containing nanomicelles, aiming to tackle the multiple factors associated with colitis. This micro-nano drug delivery platform achieves sequential release of drugs in the inflamed colon, with each component of the system functioning independently and jointly. The outer layer of inulin supplies nutrients for probiotics. The inner core comprises selenocystamine and 3-oxolithocholic acid, which polarize macrophages towards an anti-inflammatory phenotype and regulate adaptive immunity by inhibiting TH17-cell differentiation, respectively. In an acute colitis mouse model, this therapeutic system ameliorates colonic inflammation, enhances the abundance of gut microbiota, and modulates the mucosal immune system, showing potential in preventing colitis.
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Affiliation(s)
- Dongdong Zhu
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xiaocao Ma
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Jingguo Wang
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Tiantian Chen
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Jiahui Yang
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yan Liu
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Zhun Lin
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Minhao Wu
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Tony Y Hu
- Center of Cellular and Molecular Diagnosis, Tulane University School of Medicine, New Orleans, Louisiana, 70112, United States
| | - Yuanqing Zhang
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China
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12
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Tang Y, Guo T, Wang X, Li C, Zhang X, Zhang J. Cyclodextrin-Derived Macromolecular Therapies for Inflammatory Diseases. Macromol Biosci 2025:e2400637. [PMID: 40271896 DOI: 10.1002/mabi.202400637] [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: 12/21/2024] [Revised: 04/02/2025] [Indexed: 04/25/2025]
Abstract
Inflammation is an essential physiological defense mechanism against harmful stimuli, yet dysregulated inflammatory responses are closely associated with the pathogenesis of numerous acute and chronic diseases. Recent advances highlight the remarkable anti-inflammatory potential of bioactive macromolecules, particularly cyclodextrins (CDs) and their engineered derivatives, which are emerging as promising therapeutic agents. This review systematically introduces different CDs and CD-derived macromolecules that demonstrate anti-inflammatory properties, with emphasis on their molecular mechanisms of action. Native CDs exhibit direct therapeutic effects through host-guest interactions, enabling selective sequestration of pathogenic components such as cholesterol crystals and proteins that drive inflammatory cascades. Moreover, chemically modified CD derivatives incorporating functional groups demonstrate enhanced capabilities in neutralizing inflammatory mediators and modulating immune cell responses. This work further discusses the expanding therapeutic applications of these macromolecules across diverse inflammatory conditions, ranging from acute tissue injuries to chronic autoimmune disorders. Finally, this work critically analyzes the crucial challenges and emerging opportunities in translating CD-based macromolecular therapies into clinical practice, addressing key considerations in biocompatibility, targeted delivery, and therapeutic efficacy optimization.
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Affiliation(s)
- Yige Tang
- College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China
- International Medical College, Chongqing Medical University, Chongqing, 400016, China
| | - Tao Guo
- College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China
| | - Xuanran Wang
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Chenwen Li
- Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Xiangjun Zhang
- College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China
| | - Jianxiang Zhang
- Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Yu-Yue Pathology Scientific Research Center, 313 Gaoteng Avenue, Jiulongpo District, Chongqing, 400039, China
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13
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Minato I, Mena P, Ricciardiello L, Scaioli E, Belluzzi A, Rotondo E, Derlindati E, Montanini B, Michelini C, Tosi N, Agullò Garcià V, Picone G, Mengucci C, Dobani S, Salamanca P, Rosi A, Dall'Asta M, Bresciani L, Curti C, Spisni E, Dei Cas A, Bordoni A, Tomás-Barberán FA, Ferguson LR, Del Rio D, Danesi F. Evidence for a Modulatory Effect of a 12-Week Pomegranate Juice Intervention on the Transcriptional Response in Inflammatory Bowel Disease Patients Reducing Fecal Calprotectin Levels: Findings From a Proof-of-Principle Study. Mol Nutr Food Res 2025:e70067. [PMID: 40255128 DOI: 10.1002/mnfr.70067] [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: 12/27/2024] [Revised: 03/27/2025] [Accepted: 04/02/2025] [Indexed: 04/22/2025]
Abstract
This study aimed at investigating the effects of pomegranate juice (POMJ) consumption on inflammatory biomarkers and gene expression in patients with inflammatory bowel disease (IBD) in clinical remission. In this randomized, placebo-controlled trial, 16 subjects with IBD in remission consumed POMJ or placebo for 12 weeks. POMJ consumption significantly reduced fecal calprotectin (FC) and plasma endotoxin levels. Transcriptomic analysis of peripheral blood mononuclear cells revealed upregulation of genes involved in mucosal immunity, including aryl hydrocarbon receptor (AHR), neutrophil cytosolic factor 4 (NCF4), and nuclear factor, interleukin 3 regulated (NFIL3). Urolithin metabotypes were predominantly of the B type, associated with intestinal dysbiosis. No significant changes were observed in serum inflammatory markers or colonic mucosal cytokine expression. POMJ consumption reduced markers of intestinal inflammation and modulated gene expression related to mucosal immunity and barrier function in patients with IBD. These findings suggest the potential of POMJ as a beneficial dietary intervention for maintaining remission in IBD, highlighting the promise of targeted nutritional strategies in managing chronic inflammatory conditions. Further research is needed to elucidate the long-term clinical implications of these molecular changes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03000101.
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Affiliation(s)
- Ilaria Minato
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy
- Interdepartmental Center for Innovation in Health Products, Biopharmanet-TEC, University of Parma, Parma, Italy
| | - Pedro Mena
- Department of Food and Drug, University of Parma, Parma, Italy
- Microbiome Research Hub, University of Parma, Parma, Italy
| | - Luigi Ricciardiello
- IRCCS - St. Orsola-Malpighi Hospital, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | | | - Enrica Rotondo
- Department of Agricultural and Food Sciences, University of Bologna, Cesena, Italy
| | - Eleonora Derlindati
- Department of Agricultural and Food Sciences, University of Bologna, Cesena, Italy
| | - Barbara Montanini
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy
- Interdepartmental Center for Innovation in Health Products, Biopharmanet-TEC, University of Parma, Parma, Italy
| | | | - Nicole Tosi
- Department of Food and Drug, University of Parma, Parma, Italy
| | | | - Gianfranco Picone
- Department of Agricultural and Food Sciences, University of Bologna, Cesena, Italy
| | - Carlo Mengucci
- Department of Agricultural and Food Sciences, University of Bologna, Cesena, Italy
| | - Sara Dobani
- Department of Food and Drug, University of Parma, Parma, Italy
| | | | - Alice Rosi
- Department of Food and Drug, University of Parma, Parma, Italy
| | - Margherita Dall'Asta
- Department of Food and Drug, University of Parma, Parma, Italy
- Department of Animal Science, Food and Nutrition, Università Cattolica del Sacro Cuore, Piacenza, Italy
| | | | - Claudio Curti
- Department of Food and Drug, University of Parma, Parma, Italy
| | - Enzo Spisni
- Department of Biological, Geological, and Environmental Sciences, University of Bologna, Bologna, Italy
| | - Alessandra Dei Cas
- Department of Medicine and Surgery - Division of Endocrinology and Metabolic Diseases, University of Parma, Parma, Italy
| | - Alessandra Bordoni
- Department of Agricultural and Food Sciences, University of Bologna, Cesena, Italy
| | | | - Lynnette R Ferguson
- Department of Nutrition, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Daniele Del Rio
- Department of Food and Drug, University of Parma, Parma, Italy
- Microbiome Research Hub, University of Parma, Parma, Italy
| | - Francesca Danesi
- Department of Agricultural and Food Sciences, University of Bologna, Cesena, Italy
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14
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Zhang Y, Li L, Kong J, Long Y, Lu X, Erb CJ, Miao Y, Kammula SV, Popov J, Tinana AJ, Selaru FM, Mao HQ. Long-acting injectable nanoparticle formulation for sustained release of anti-TNF-α antibody therapeutic in ulcerative colitis treatment. J Control Release 2025; 380:1005-1016. [PMID: 39978474 DOI: 10.1016/j.jconrel.2025.02.043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 12/16/2024] [Accepted: 02/18/2025] [Indexed: 02/22/2025]
Abstract
Inflammatory bowel diseases (IBD) are chronic, remitting, and relapsing conditions of the gastrointestinal tract with incompletely elucidated etiology. The anti-TNF-α mAbs represent one of aflash nanocomplexation and flash nanoprecipitation process, resulting in particles with a narrow size distribution and tunable release profile, with the longest in vitro release lasting over four months. These mAb-releasing NPs are then incorporated into hyaluronic acid hydrogel microparticles (MPs) to enhance tissue retention, thus extending the duration of mAb release in vivo. A single i.m. injection of the LAI can maintain the serum mAb level above the therapeutically effective concentration for over 100 days in healthy mice. In a 9-week study using a dextran sulfate-induced chronic colitis model, the anti-TNF-α LAI formulation demonstrates substantial therapeutic efficacy and a better safety profile than free mAb injections. This work demonstrates the effectiveness of this LAI system in maintaining a persistent serum mAb level and its potential as a versatile, safer, and effective delivery system for antibody therapeutics.
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Affiliation(s)
- Yicheng Zhang
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MD, USA
| | - Ling Li
- Division of Gastroenterology and Hepatology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Jiayuan Kong
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MD, USA
| | - Yuanmuhuang Long
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Department of Biomedical Engineering, Whiting School of Engineering and School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Xiaoya Lu
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MD, USA
| | - Christopher J Erb
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MD, USA
| | - Yurun Miao
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA
| | - Sachin V Kammula
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Jordan Popov
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MD, USA; Department of Biomedical Engineering, Whiting School of Engineering and School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Alexander J Tinana
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MD, USA
| | - Florin M Selaru
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Division of Gastroenterology and Hepatology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Department of Biomedical Engineering, Whiting School of Engineering and School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Department of Oncology, Sidney Kimmel Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
| | - Hai-Quan Mao
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MD, USA; Department of Biomedical Engineering, Whiting School of Engineering and School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
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15
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Nakase H, Danese S, Reinisch W, Ritter T, Liang Y, Wendt E, Levesque BG, Yoon OK, Tian Y, Zhuo L, Karouzakis E, Bauer Y, Oortwijn A, Kaise T, Malkov VA, Hibi T. Mediators of Filgotinib Treatment Effects in Ulcerative Colitis: Exploring Circulating Biomarkers in the Phase 2b/3 SELECTION Study. Inflamm Bowel Dis 2025; 31:1095-1108. [PMID: 39656830 PMCID: PMC11985404 DOI: 10.1093/ibd/izae278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Indexed: 12/17/2024]
Abstract
BACKGROUND We utilized patient samples from the large, phase 2b/3 SELECTION trial to identify circulating biomarkers of ulcerative colitis (UC) and potential early mediators of filgotinib treatment effects. METHODS Samples were collected at baseline and during the induction phase of the SELECTION trial. Evaluated biomarkers comprised serum and stool proteins (measured by enzyme-linked immunosorbent assay), whole-blood cell counts, and whole-blood RNA-seq-derived gene-expression factors identified via exploratory factor analysis. Biomarker levels were assessed by baseline disease severity (endoscopy/bleeding/stool and Mayo Clinic Score) and biologic status (naive vs experienced). Effects of filgotinib on biomarker levels, including week 4 biomarker changes that may mediate week 10 clinical improvements, were assessed. RESULTS The biomarker analysis set included 598 biologic-naive patients and 592 biologic-experienced patients. Systemic inflammatory biomarkers (C-reactive protein [CRP], interleukin-6 [IL-6], serum amyloid A [SAA], and platelet cell counts) had the strongest positive correlations with baseline UC disease severity. CRP, IL-6, SAA, and neutrophil activation biomarkers (including neutrophil gelatinase-associated lipocalin [NGAL], tumor necrosis factor ɑ, and oncostatin M [OSM]), as well as platelet, neutrophil, and monocyte cell counts were increased in biologic-experienced versus biologic-naive patients. Gene-expression-derived plasmablast and cell proliferation factors were positively correlated with disease severity; B cell, T-cell activation, and plasmacytoid dendritic cell factors were negatively correlated. Filgotinib reduced nearly all proinflammatory biomarkers correlated with baseline UC disease activity; reduced SAA, CRP, IL-6, NGAL, and OSM at week 4 were identified as mediators of improved week 10 clinical scores. CONCLUSIONS Filgotinib significantly impacted circulating biomarkers related to UC pathology. Several proinflammatory and neutrophil activation biomarkers may be early mediators of filgotinib treatment effects. CLINICALTRIALS.GOV IDENTIFIER NCT02914522.
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Affiliation(s)
- Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Silvio Danese
- Inflammatory Bowel Diseases Center, Humanitas Research Hospital, Milan, Italy
| | - Walter Reinisch
- Department of Internal Medicine and Gastroenterology, Medical University of Vienna, Vienna, Austria
| | | | - Yan Liang
- Gilead Sciences, Inc., Foster City, CA, USA
| | | | | | | | - Yuan Tian
- Gilead Sciences, Inc., Foster City, CA, USA
| | | | | | | | | | | | | | - Toshifumi Hibi
- Center for Advanced IBD Research and Treatment, Kitasato Institute Hospital, Kitasato University, Tokyo, Japan
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Golob JL, Hou G, Swanson BJ, Berinstein JA, Bishu S, Grasberger H, Zataari ME, Lee A, Kao JY, Kamada N, Bishu S. Inflammation-Induced Th17 Cells Synergize with the Inflammation-Trained Microbiota to Mediate Host Resiliency Against Intestinal Injury. Inflamm Bowel Dis 2025; 31:1082-1094. [PMID: 39851236 DOI: 10.1093/ibd/izae293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Indexed: 01/26/2025]
Abstract
BACKGROUND AND AIMS Inflammation can generate pathogenic Th17 cells and cause an inflammatory dysbiosis. In the context of inflammatory bowel disease (IBD), these inflammatory Th17 cells and dysbiotic microbiota may perpetuate injury to intestinal epithelial cells. However, many models of IBD like T-cell transfer colitis and IL-10-/- mice rely on the absence of regulatory pathways, so it is difficult to tell if inflammation can also induce protective Th17 cells. METHODS We subjected C57BL6, RAG1-/-, or JH-/- mice to systemic or gastrointestinal (GI) Citrobacter rodentium (Cr). Mice were then subjected to 2.5% dextran sodium sulfate (DSS) to cause epithelial injury. Fecal microbiota transfer was performed by bedding transfer and co-housing. Flow cytometry, qPCR, and histology were used to assess mucosal and systemic immune responses, cytokines, and tissue inflammation. 16s sequencing was used to assess gut bacterial taxonomy. RESULTS Transient inflammation with GI but not systemic Cr was protective against subsequent intestinal injury. This was replicated with sequential DSS collectively indicating that transient inflammation provides tissue-specific protection. Inflammatory Th17 cells that have a tissue-resident memory (TRM) signature expanded in the intestine. Experiments with reconstituted RAG1-/-, JH-/- mice, and cell trafficking inhibitors showed that inflammation-induced Th17 cells were required for protection. Fecal microbiota transfer showed that the inflammation-trained microbiota was necessary for protection, likely by maintaining protective Th17 cells in situ. CONCLUSION Inflammation can generate protective Th17 cells that synergize with the inflammation-trained microbiota to provide host resiliency against subsequent injury, indicating that inflammation-induced Th17 TRM T cells are heterogenous and contain protective subsets.
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Affiliation(s)
- Jonathan L Golob
- Division of Infectious Diseases, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
| | - Guoqing Hou
- Division of Gastroenterology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
| | - Benjamin J Swanson
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 42 and Emile, Omaha, NE 68198, USA
| | - Jeffrey A Berinstein
- Division of Gastroenterology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
| | - Shreenath Bishu
- Laboratory and Pathology Diagnostics LLC, 1220 Hobson Road, Suite 244, Naperville, IL 60540, USA
| | - Helmut Grasberger
- Division of Gastroenterology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
| | - Mohamed El Zataari
- Division of Gastroenterology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
| | - Allen Lee
- Division of Infectious Diseases, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
| | - John Y Kao
- Division of Gastroenterology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
| | - Nobuhiko Kamada
- Division of Gastroenterology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
| | - Shrinivas Bishu
- Division of Gastroenterology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
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Riaz B, Ryu HM, Choi B, Sohn S. Tartaric Acid Exacerbates DSS-Induced Colitis by Promoting Eosinophilic Inflammation via IL-13 and IL-5Rα Upregulation. Pathogens 2025; 14:366. [PMID: 40333150 PMCID: PMC12030069 DOI: 10.3390/pathogens14040366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 04/01/2025] [Accepted: 04/05/2025] [Indexed: 05/09/2025] Open
Abstract
Eosinophils are granulocytes involved in the effector phase of type 2 T cell immune responses, which are elevated in inflammatory conditions like ulcerative colitis (UC) and other allergic diseases. UC is a chronic inflammatory colon disease, marked by excessive eosinophil infiltration and elevated Th2 cytokines, which contribute to mucosal inflammation and tissue damage. Dietary factors, including certain organic acids, can influence UC progression by modulating gut immune responses. This research is the first to explore the dose-dependent effects of tartaric acid (TA), a naturally occurring organic acid widely used in the food industry, on eosinophil activation and Th2 cytokine response in both normal mice and a dextran sulfate sodium (DSS)-induced colitis model. Normal mice were treated with TA at varying doses (5 µg, 25 µg, and 50 µg/mouse/day), while colitis mice received 50 µg TA. Eosinophil activation markers (CD11b+, SiglecF+, and CCR3+), Th2 cytokines (IL-4, IL-13, and IL-31), and IL-17 were assessed in peripheral blood leukocytes, lymph nodes, and splenocytes using flow cytometry. Additionally, mRNA expression levels of eosinophil-associated chemokines and cytokines in the splenocytes were quantified with real-time qPCR. Our results demonstrate a dose-dependent effect of TA, with the highest dose (50 µg) significantly increasing eosinophil activation markers, Th2 cytokines, IL-17, and mRNA expression of SiglecF, CCL11, and toll-like receptor 4 in normal mice. In colitis mice, treatment with 50 µg TA showed marked increases in IL-13 levels compared to those of untreated colitis mice, reflecting increased eosinophil recruitment to inflamed tissues. Moreover, mRNA expression of IL-5Rα was elevated in normal mice and colitis mice administered with TA. These results suggest that TA enhances eosinophil proliferation, the upregulation of their regulatory molecules, and Th2 immune profiles, potentially worsening the severity of colitis.
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Affiliation(s)
- Bushra Riaz
- Department of Biomedical Sciences, Ajou University School of Medicine, Suwon 16499, Republic of Korea;
| | - Hye-Myung Ryu
- Department of Microbiology, Ajou University School of Medicine, Suwon 16499, Republic of Korea;
| | - Bunsoon Choi
- Institute of Medical Science, Ajou University School of Medicine, Suwon 16499, Republic of Korea;
| | - Seonghyang Sohn
- Department of Biomedical Sciences, Ajou University School of Medicine, Suwon 16499, Republic of Korea;
- Department of Microbiology, Ajou University School of Medicine, Suwon 16499, Republic of Korea;
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18
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Souza RF, Machado FA, Caetano MAF, De Paulo CB, Castelucci P. Effect of Anti-TNF Monoclonal Antibody on Enteric Neurons and Enteric Glial Cells in Experimental Colitis. Dig Dis Sci 2025; 70:1375-1394. [PMID: 39946069 DOI: 10.1007/s10620-025-08872-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 01/14/2025] [Indexed: 04/06/2025]
Abstract
BACKGROUND Inflammatory bowel diseases (IBD) affect both enteric neurons and enteric glia, with tumor necrosis factor-alpha (TNF-α) playing a role as an inflammatory mediator. AIMS Analyze the effects of the anti-TNF monoclonal antibody on the myenteric plexus in an experimental model of colitis. METHODS C57BL/6 mice received 3% dextran sodium sulfate (DSS) in drinking water for 7 days in both the DSS and DSS + ADA groups. The Sham group received water. The DSS + ADA group received ADA anti-TNF-α on day 2 of DSS intake. The ADA group was given water throughout the period and received an anti-TNF-α injection on day 2. The study evaluated the number of neurons per ganglion, and the area of the neuronal nitric oxide synthase (nNOS), choline acetyltransferase (ChAT), pan-neuronal marker (PGP9.5), and tumor necrosis factor receptor 2 (TNFR2) immunoreactive (-ir). Double labeling of PGP9.5 with an enteric glial marker (GFAP) was also performed. RESULTS DSS successfully induced experimental colitis (EC). TNFR2 was detected in the myenteric neurons in all groups. EC affected the enteric neurons, showing a decrease in the number of TNFR2-ir, ChAT-ir, nNOS-ir, and PGP9.5-ir neurons, whereas enteric glial cells increased in both the DSS and DSS + ADA groups. The DSS + ADA group showed number of nNOS-ir, ChAT-ir, and PGP9.5-ir neurons per ganglion similar to Sham group. EC also affected the neuronal profile, resulting in smaller areas in the DSS and DSS + ADA groups. CONCLUSION Myenteric neurons are immunoreactive to the TNFR2. DSS altered the myenteric plexus, and anti-TNF monoclonal antibody treatment proved effective against EC due to preventing the pathology from developing.
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Affiliation(s)
- Roberta Figueiroa Souza
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, Av. Professor Lineu Prestes, 2415, São Paulo, 05508-000, Brasil
| | - Felipe Alexandre Machado
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, Av. Professor Lineu Prestes, 2415, São Paulo, 05508-000, Brasil
| | - Marcos Antônio Ferreira Caetano
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, Av. Professor Lineu Prestes, 2415, São Paulo, 05508-000, Brasil
| | - Caroline Bures De Paulo
- Department of Surgery, School of Veterinary Medicine and Animal Sciences, University of São Paulo, São Paulo, 05508-270, Brazil
| | - Patricia Castelucci
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, Av. Professor Lineu Prestes, 2415, São Paulo, 05508-000, Brasil.
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19
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Chen C, Lin XH, Xie YM, Xiong SL, Hou SZ, Huang S, Jian HL, Wen YF, Jiang XY, Liang J. Shengjiang Xiexin Decoction ameliorates DSS-induced ulcerative colitis via activating Wnt/β-Catenin signaling to enhance epithelium renovation and modulating intestinal flora. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 139:156456. [PMID: 39914063 DOI: 10.1016/j.phymed.2025.156456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/26/2025] [Accepted: 01/31/2025] [Indexed: 05/07/2025]
Abstract
BACKGROUND Shengjiang Xiexin Decoction (SJXXD) is a recognized formulation in traditional Chinese medicine that is commonly employed in diarrhea treatment. It has the potential to be a viable alternative for treating ulcerative colitis (UC), but its therapeutic effects and mechanisms remain unclear. PURPOSE This study aims to explore the effects and underlying mechanism of SJXXD in a mouse model of UC induced by dextran sulfate sodium (DSS). METHOD The components of SJXXD were analyzed using HPLC-Q/TOF-MS. UC mice model was established by freely drinking of 3% DSS, and SJXXD was administered as an intervention. After 7 days, body weight change, diarrhea, blood stools, colon length, cytokine levels, and key barrier proteins were evaluated to assess the therapeutic effect of SJXXD on UC. Additionally, transcriptome sequencing, quantitative polymerase chain reaction (qPCR), western blotting, intestinal organoids, 16S rRNA sequencing, and heat correlation analysis were employed to investigate the potential mechanisms of SJXXD on treating UC. RESULTS SJXXD significantly inhibited weight loss, reduce diarrhea and bloody stools, lower disease activity index (DAI) score, suppressed inflammatory cell infiltration and cytokines secretion in colonic tissues in UC mice. Additionally, SJXXD also enhances the expression of tight junction and mucins. Transcriptome sequencing results indicate that SJXXD primarily activates the Wnt/β-Catenin pathway, thereby enhancing the expression of genes linked to intestinal stem cells and intestinal regeneration markers. At phylum level, SJXXD significantly increases the relative abundance of Verrucomicrobiota, while inhibiting Campylobacterota and Fusobacteriota. Importantly, the relative abundance of these bacterial phyla is significantly correlated with UC and Wnt/β-Catenin signaling pathway. CONCLUSION These results indicate that SJXXD can significantly treat DSS-induced mouse UC model by activating the Wnt/β-Catenin pathway and modulating intestinal flora. SJXXD may serve as a promising therapeutic approach for the management of UC.
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Affiliation(s)
- Chen Chen
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Xiao-He Lin
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Yi-Min Xie
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Shi-Lin Xiong
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Shao-Zhen Hou
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Song Huang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Hong-Liang Jian
- Gaozhou Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese Medicine, Maoming 525200, China
| | - Yi-Fan Wen
- Pharmacy Department, Zhuzhou People's Hospital, Zhuzhou, Hunan 412000, China.
| | - Xiao-Yan Jiang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China; Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, China.
| | - Jian Liang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China.
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20
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Asada N, Ginsberg P, Paust HJ, Song N, Riedel JH, Turner JE, Peters A, Kaffke A, Engesser J, Wang H, Zhao Y, Khatri R, Gild P, Dahlem R, Diercks BP, Das S, Ignatova Z, Huber TB, Prinz I, Gagliani N, Mittrücker HW, Krebs CF, Panzer U. The integrated stress response pathway controls cytokine production in tissue-resident memory CD4 + T cells. Nat Immunol 2025; 26:557-566. [PMID: 40050432 PMCID: PMC11957990 DOI: 10.1038/s41590-025-02105-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 02/04/2025] [Indexed: 03/12/2025]
Abstract
Tissue-resident memory T (TRM) cells are a specialized T cell population that reside in tissues and provide a rapid protective response upon activation. Here, we showed that human and mouse CD4+ TRM cells existed in a poised state and stored messenger RNAs encoding proinflammatory cytokines without protein production. At steady state, cytokine mRNA translation in TRM cells was suppressed by the integrated stress response (ISR) pathway. Upon activation, the central ISR regulator, eIF2α, was dephosphorylated and stored cytokine mRNA was translated for immediate cytokine production. Genetic or pharmacological activation of the ISR-eIF2α pathway reduced cytokine production and ameliorated autoimmune kidney disease in mice. Consistent with these results, the ISR pathway in CD4+ TRM cells was downregulated in patients with immune-mediated diseases of the kidney and the intestine compared to healthy controls. Our results indicated that stored cytokine mRNA and translational regulation in CD4+ TRM cells facilitate rapid cytokine production during local immune response.
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Affiliation(s)
- Nariaki Asada
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Pauline Ginsberg
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hans-Joachim Paust
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ning Song
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jan-Hendrik Riedel
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jan-Eric Turner
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anett Peters
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anna Kaffke
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jonas Engesser
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Huiying Wang
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Yu Zhao
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Institute of Medical Systems Biology, Center for Biomedical AI, Center for Molecular Neurobiology Hamburg, Hamburg, Germany
| | - Robin Khatri
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Institute of Medical Systems Biology, Center for Biomedical AI, Center for Molecular Neurobiology Hamburg, Hamburg, Germany
| | - Philipp Gild
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Roland Dahlem
- Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Björn-Philipp Diercks
- The Calcium Signalling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sarada Das
- Institute of Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany
| | - Zoya Ignatova
- Institute of Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany
| | - Tobias B Huber
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Immo Prinz
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Institute of Systems Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nicola Gagliani
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hans-Willi Mittrücker
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Institute for Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian F Krebs
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ulf Panzer
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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Ma J, Wang FY, Tang XD. Involvement of the NLRP3/IL-1β pathway in activation and effector functions of γδT17 cells in patients with ulcerative colitis. World J Gastroenterol 2025; 31:98174. [PMID: 40182600 PMCID: PMC11962846 DOI: 10.3748/wjg.v31.i12.98174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 10/29/2024] [Accepted: 12/23/2024] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND The interleukin-17 (IL-17) mediated aberrant immune-inflammatory response plays a paramount role in ulcerative colitis (UC). γδT17 cells are one of the critical sources of IL-17, but the role they play in UC remains under debate. AIM To clarify the role of γδT17 cells in patients with mild-to-moderate UC. METHODS A single-centre observational pragmatic study was conducted on patients with UC who attended the outpatient and inpatient departments of Xiyuan Hospital of the China Academy of Traditional Chinese Medicine from September 2020 to December 2022. The research population consisted of two groups of adult patients. The first group consisted of healthy volunteers with no significant abnormalities on colonoscopy, and the other group consisted of patients with mild-to-moderate ulcerative colitis. Serum samples from healthy volunteers and patients with UC were collected for the detection of relevant inflammatory factors. Moreover, five colon mucosa samples were randomly selected from each group for testing and analyses. RESULTS An increased number of γδT17 cells and hyperactivation of the NLR family pyrin domain containing 3/IL-1β signaling pathway were observed in colonic mucosal tissues from patients with UC. CONCLUSION Hyperactivation of the NLR family pyrin domain containing 3/IL-1β signaling pathway promotes the activation of γδT17 cells in colonic mucosal tissues of patients with UC.
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Affiliation(s)
- Jing Ma
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Feng-Yun Wang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Xu-Dong Tang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China
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22
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He J, Wu J, Tan J, Yang P, Bai T, Song J, Hou X, Zhang L. Role of declined electrogenic Na +/HCO 3- cotransporter NBCe1 in mucus barrier impairment and colonic inflammation. Int Immunopharmacol 2025; 150:114282. [PMID: 39946770 DOI: 10.1016/j.intimp.2025.114282] [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: 12/04/2024] [Revised: 01/24/2025] [Accepted: 02/08/2025] [Indexed: 03/03/2025]
Abstract
BACKGROUND Electrogenic Na+/HCO3- co-transporter 1 (NBCe1) plays a pivotal role in epithelial bicarbonate transport involved in the maintenance of the intestinal mucus barrier. However, the specific role of NBCe1 in colitis remains unknown. METHODS NBCe1 was identified by bioinformatics analysis methods including GO/KEGG/GSEA, protein-protein interaction (PPI) network analysis, immune infiltration analysis, and Mendelian randomization (MR) analysis. Expression level of NBCe1 was detected in patients with IBD and in DSS-induced colitis mice. The role of NBCe1 in intestinal mucus barrier and colitis was accessed by S0859 pretreatment in DSS model. The function of NBCe1 and related bicarbonate secretion were evaluated using short-circuit current (Isc) measurements in Ussing chamber system. RESULTS Bioinformatic analyses indicated that SLC4A4 (NBCe1) was a signature gene in bicarbonate transport implicated in ulcerative colitis (UC) development and was negatively associated with the risk of UC. NBCe1's expression was significantly diminished in colonic mucosa of UC patients and DSS-treated mice. More severe intestinal inflammation and impaired mucus barrier were observed in S0859-treated mice. Moreover, S0859 administration led a significant decrease in mucus secretion rate and an significant increase in Isc of colonic mucosa. The forskolin-induced ΔIsc was also suppressed by S0859 pretreatment. CONCLUSION NBCe1 has been identified as a valuable signature gene may have a protective effect against the onset of colitis. Function of NBCe1 is diminished in colitis, which is associated with impaired mucus barrier and declined HCO3- secretion both contributing to the development of IBD.
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Affiliation(s)
- Jing He
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 China
| | - Jiacheng Wu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 China
| | - Jun Tan
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 China
| | - Pengcheng Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 China
| | - Tao Bai
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 China
| | - Jun Song
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 China
| | - Xiaohua Hou
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 China.
| | - Lei Zhang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 China.
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Zhong R, Wen C, Qiu Y, Shen X, Sun Z, Peng L, Liu T, Huang S, Peng X. Anti-inflammatory and immunomodulatory effects of Glycyrrhiza uralensis fisch. On ulcerative colitis in rats: Role of nucleotide-binding oligomerization domain 2/receptor-interacting protein 2/nuclear factor-kappa B signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2025; 344:119457. [PMID: 39929400 DOI: 10.1016/j.jep.2025.119457] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 02/01/2025] [Accepted: 02/06/2025] [Indexed: 03/04/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE As a traditional Chinese herb, Glycyrrhiza uralensis Fisch. exhibits a range of pharmacological activities, including anti-inflammatory, immunomodulatory and antifibrotic, which suggests its therapeutic potential for inflammatory bowel disease, and related mechanisms need to be further clarified. AIM OF THE STUDY To evaluate in vivo anti-inflammatory effects of Glycyrrhiza uralensis Fisch. aqueous extract (GE) on 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced acute experimental colitis rat model and its potential mechanisms. MATERIALS AND METHODS The protective effects of GE on IBD were evaluated in vivo using a TNBS and 75% ethanol-induced ulcerative colitis (UC) model. The evaluated clinical and anatomical indexes included body weight, colon length, disease activity index (DAI) score, Colonic Mucosal Damage Index (CMDI) score. The percentages of T, B lymphocytes, NK cells, and macrophages in the colon, spleen and peripheral blood were investigated by flow cytometry. Colon tissues were stained with Hematoxylin and Eosin (H&E) for histopathological examination. After using transcriptome sequencing to screen targeted genes, the expression of related genes was detected by Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) and Western blot (WB). RESULTS The decrease of food intake, soft feces, and colon histopathological injury were observed in colitis rats, which were alleviated by GE, with the best therapeutic effect in the 100 mg/kg GE group. The average CMDI scores of colon in UC rats were decreased from 4.0 to 1.5. The percentages of CD161a+ NK cells, CD68+ total macrophages, CD68+/CD161a+ M1 type macrophages, CD3+ T lymphocytes, and CD45RA+ B lymphocytes were decreased in the spleen and colon. The transcriptomics analysis of colon showed that the results were mainly related to the TNF signaling pathway and NF-κB signaling pathway. The RT-qPCR and WB results determined that the upregulated expression of nucleotide-binding oligomerization domain 2 (NOD2), receptor-interacting protein 2 (RIP2), nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α) in the colon of the colitis rats were downregulated by GE treatment. CONCLUSION The research results indicate that GE can exert therapeutic effects on TNBS-induced UC in rats by alleviating cell injury and inflammatory responses, and its mechanisms may be related to the regulation of NOD2/RIP2/NF-κB signaling pathway.
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Affiliation(s)
- Rao Zhong
- Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, 610106, Chengdu, China
| | - Changlin Wen
- Sichuan Youngster Technology Co., Ltd., No. 733, Furong Avenue, Wenjiang District, 611130, Chengdu, China
| | - Yi Qiu
- Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, 610106, Chengdu, China
| | - Xuemei Shen
- Sichuan Youngster Technology Co., Ltd., No. 733, Furong Avenue, Wenjiang District, 611130, Chengdu, China
| | - Zhenhua Sun
- Sichuan Youngster Technology Co., Ltd., No. 733, Furong Avenue, Wenjiang District, 611130, Chengdu, China
| | - Li Peng
- Geriatric Diseases Institute of Chengdu, Department of Geriatrics, Chengdu Fifth People's Hospital, Wenjiang District, 611130, Chengdu, China
| | - Tao Liu
- Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, 610106, Chengdu, China
| | - Shiyuan Huang
- Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, 610106, Chengdu, China
| | - Xi Peng
- Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, 610106, Chengdu, China.
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Peruhova M, Stoyanova D, Miteva DG, Kitanova M, Mirchev MB, Velikova T. Genetic factors that predict response and failure of biologic therapy in inflammatory bowel disease. World J Exp Med 2025; 15:97404. [PMID: 40115750 PMCID: PMC11718585 DOI: 10.5493/wjem.v15.i1.97404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 10/09/2024] [Accepted: 11/14/2024] [Indexed: 12/26/2024] Open
Abstract
Inflammatory bowel disease (IBD) represents a significant disease burden marked by chronic inflammation and complications that adversely affect patients' quality of life. Effective diagnostic strategies involve clinical assessments, endoscopic evaluations, imaging studies, and biomarker testing, where early diagnosis is essential for effective management and prevention of long-term complications, highlighting the need for continual advancements in diagnostic methods. The intricate interplay between genetic factors and the outcomes of biological therapy is of critical importance. Unraveling the genetic determinants that influence responses and failures to biological therapy holds significant promise for optimizing treatment strategies for patients with IBD on biologics. Through an in-depth examination of current literature, this review article synthesizes critical genetic markers associated with therapeutic efficacy and resistance in IBD. Understanding these genetic actors paves the way for personalized approaches, informing clinicians on predicting, tailoring, and enhancing the effectiveness of biological therapies for improved outcomes in patients with IBD.
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Affiliation(s)
- Milena Peruhova
- Department of Gastroenterology, University Hospital Heart and Brain, Burgas 1000, Bulgaria
| | - Daniela Stoyanova
- Department of Gastroenterology, Military Medical Academy, Sofia 1606, Bulgaria
| | | | - Meglena Kitanova
- Department of Genetics, Faculty of Biology, Sofia University St. Kliment Ohridski, Sofia 1164, Bulgaria
| | | | - Tsvetelina Velikova
- Department of Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
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25
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Calvello R, Caponio GR, Cianciulli A, Porro C, Ruggiero M, Celano G, De Angelis M, Panaro MA. Antioxidant Activity and Anti-Inflammatory Effect of Blood Orange By-Products in Treated HT-29 and Caco-2 Colorectal Cancer Cell Lines. Antioxidants (Basel) 2025; 14:356. [PMID: 40227443 PMCID: PMC11939351 DOI: 10.3390/antiox14030356] [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: 02/17/2025] [Revised: 03/14/2025] [Accepted: 03/15/2025] [Indexed: 04/15/2025] Open
Abstract
Blood orange peel flour (BO-pf)-a by-product of the citrus supply chain-still contains bioactive molecules with known health benefits, such as antiradical scavenging activity or an antiproliferative activity regarding tumors. In vitro studies have demonstrated that orange polyphenols showed potential involvement in necroptosis. In addition to previous research, we tested BO-pf on two colorectal cancer cell lines. Using HT29 and Caco2 cells, our experiments confirmed the regulation of inflammasome expression. They provided valuable insights into how BO-pf influences the cancer cell features (i.e., viability, proliferation, and pro- and anti-inflammatory activity). Notably, BO-pf extract is a rich source of polyphenolic compounds with antioxidant properties. Western blot and real-time PCR analyses showed that treatment with BO-pf extract demonstrated beneficial effects by influencing the expression of both pro-inflammatory cytokines (IL-1β, IL-6) through the modulation of the TLR4/NF-kB/NLRP3 inflammasome signaling. Moreover, the results of this study demonstrate that BO-pf extracts can enhance the expression of anti-inflammatory cytokines, such as IL-10 and TGFβ, suggesting that BO-pf extracts may represent a promising functional ingredient to counteract the intestinal inflammatory responses involved in IBD.
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Affiliation(s)
- Rosa Calvello
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Via Orabona 125, 70125 Bari, Italy; (R.C.); (G.R.C.); (A.C.); (M.R.)
| | - Giusy Rita Caponio
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Via Orabona 125, 70125 Bari, Italy; (R.C.); (G.R.C.); (A.C.); (M.R.)
| | - Antonia Cianciulli
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Via Orabona 125, 70125 Bari, Italy; (R.C.); (G.R.C.); (A.C.); (M.R.)
| | - Chiara Porro
- Department of Clinical and Experimental Medicine, University of Foggia, Via A. Gramsci 89/91, 71121 Foggia, Italy;
| | - Melania Ruggiero
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Via Orabona 125, 70125 Bari, Italy; (R.C.); (G.R.C.); (A.C.); (M.R.)
| | - Giuseppe Celano
- Department of the Soil, Plant and Food Sciences (DiSSPA), University of Bari Aldo Moro, Via Amendola, 165/a, 70126 Bari, Italy; (G.C.); (M.D.A.)
| | - Maria De Angelis
- Department of the Soil, Plant and Food Sciences (DiSSPA), University of Bari Aldo Moro, Via Amendola, 165/a, 70126 Bari, Italy; (G.C.); (M.D.A.)
| | - Maria Antonietta Panaro
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Via Orabona 125, 70125 Bari, Italy; (R.C.); (G.R.C.); (A.C.); (M.R.)
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Wang Y, Xie Z, Du L, Wang Q, Zhang L, Wu Y, Han J. Heat-killed Lacticaseibacillus paracasei 6235 is more effective than live on DSS-induced colitis via modulation of intestinal microbiota and MAPK/NF-κB signaling pathways. Food Funct 2025; 16:2247-2261. [PMID: 39569739 DOI: 10.1039/d4fo04873c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2024]
Abstract
This study compared the protective effects of both live Lacticaseibacillus paracasei 6235 (LLP 6235) and heat-killed Lacticaseibacillus paracasei 6235 (HK-LP 6235) on ulcerative colitis. Using a dextran sulfate sodium (DSS)-induced colitis mouse model, we evaluated physiological state, colon tissue integrity, inflammatory factors, tight junction (TJ) proteins, and intestinal microbiota variations. The findings demonstrated that both LLP 6235 and HK-LP 6235 have the capacity to mitigate colitis damage, enhance TJ protein levels, and restore colon morphology. In addition, these interventions modulated the intestinal inflammatory response by inhibiting pro-inflammatory factors and upregulating anti-inflammatory factors through the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways. Moreover, treatment with LLP 6235 and HK-LP 6235 significantly altered intestinal microbiota diversity, increased the relative abundance of beneficial bacteria, and regulated the short-chain fatty acid (SCFA) levels. Spearman correlation analysis revealed a strong association between TJ proteins, SCFAs, intestinal microbiota, and inflammatory response, suggesting that LLP 6235 and HK-LP 6235 may provide an effective approach to colitis prevention. In conclusion, LLP 6235 and HK-LP 6235 have similar abilities; furthermore, HK-LP 6235 modulated the intestinal microbiota through lipid metabolic pathways, resulting in a greater improvement. Moreover, considering the high stability and safety of prebiotics and their wide applicability, HK-LP 6235 is recommended for use as a modulator of intestinal inflammatory diseases.
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Affiliation(s)
- Yucong Wang
- College of Food Science, Northeast Agricultural University, Harbin, 150030, China
| | - Zhixin Xie
- College of Food Science, Northeast Agricultural University, Harbin, 150030, China
| | - Lei Du
- College of Food Science, Northeast Agricultural University, Harbin, 150030, China
| | - Qi Wang
- LS CORPORATION CO., LTD, Tokyo, 0611374, Japan
| | - Lili Zhang
- College of Food Science, Northeast Agricultural University, Harbin, 150030, China
| | - Yunzhou Wu
- College of Life Science, Northeast Agricultural University, Harbin, 150030, China
| | - Jianchun Han
- College of Food Science, Northeast Agricultural University, Harbin, 150030, China
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Kou F, Li XY, Feng Z, Hua J, Wu X, Gao H, Lin J, Kang D, Li A, Li J, Ding Y, Ban T, Zhang Q, Liu Z. GPR171 restrains intestinal inflammation by suppressing FABP5-mediated Th17 cell differentiation and lipid metabolism. Gut 2025:gutjnl-2024-334010. [PMID: 40074327 DOI: 10.1136/gutjnl-2024-334010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 03/02/2025] [Indexed: 03/14/2025]
Abstract
BACKGROUND GPR171 suppresses T cell immune responses involved in antitumour immunity, while its role in inflammatory bowel disease (IBD) pathogenesis remains unclear. OBJECTIVE We aimed to investigate the role of GPR171 in modulating CD4+ T cell effector functions in IBD and evaluate its therapeutic potential. DESIGN We analysed GPR171 expression in colon biopsies and peripheral blood samples from patients with IBD and assessed the impact of GPR171 on CD4+ T cell differentiation through administration of its endogenous ligand (BigLEN). We further determined the role of GPR171 in dextran sulfate sodium (DSS)-induced colitis and CD45RBhighCD4+ T-cell transfer colitis model and deciphered the underlying mechanisms using RNA sequencing (RNA-seq) and lipidomics. We developed a novel BigLEN-based Fc fusion protein (BigLEN-Fc) and evaluated its potential in preventing and treating colitis. RESULTS GPR171 was markedly increased in inflamed mucosa and CD4+ T cells of patients with IBD compared with controls. BigLEN-triggered GPR171 activation inhibited Th17 cell differentiation in vitro. GPR171 deficiency exacerbated DSS- and CD45RBhighCD4+ T cell-induced colitis in mice, characterised by increased Th17 cell responses in intestinal mucosa. Mechanistically, GPR171 deficiency promoted Th17 cell differentiation and altered lipidome profile in Th17 cells via the cAMP-pCREB-FABP5 axis. Blockage of FABP5 reduced Th17 cell differentiation in vitro and ameliorated DSS-induced colitis in Gpr171 -/- mice. Furthermore, BigLEN-mutFc administration potently mitigated colitis in mice. CONCLUSIONS GPR171 deficiency promotes Th17 cell differentiation and causes lipid metabolism perturbation, contributing to intestinal inflammation in a FABP5-dependent manner. Target therapy (eg, BigLEN-Fc) represents a novel therapeutic approach for IBD treatment.
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Affiliation(s)
- Fushun Kou
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Tongji University School of Medicine, Shanghai Tenth People's Hospital, Shanghai, China
| | - Xiao-Yu Li
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Tongji University School of Medicine, Shanghai Tenth People's Hospital, Shanghai, China
| | - Zhongsheng Feng
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Tongji University School of Medicine, Shanghai Tenth People's Hospital, Shanghai, China
| | - Jinghan Hua
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Tongji University School of Medicine, Shanghai Tenth People's Hospital, Shanghai, China
| | - Xiaohan Wu
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Tongji University School of Medicine, Shanghai Tenth People's Hospital, Shanghai, China
| | - Han Gao
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Tongji University School of Medicine, Shanghai Tenth People's Hospital, Shanghai, China
| | - Jian Lin
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Tongji University School of Medicine, Shanghai Tenth People's Hospital, Shanghai, China
| | - Dengfeng Kang
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Tongji University School of Medicine, Shanghai Tenth People's Hospital, Shanghai, China
| | - Ai Li
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Tongji University School of Medicine, Shanghai Tenth People's Hospital, Shanghai, China
| | - Junxiang Li
- Department of Gastroenterology, Beijing University of Chinese Medicine, Dongfang Hospital, Beijing, China
| | - Yao Ding
- Ailomics Therapeutics Co Ltd, Shanghai, China
| | - Ting Ban
- Ailomics Therapeutics Co Ltd, Shanghai, China
| | - Qing Zhang
- Ailomics Therapeutics Co Ltd, Shanghai, China
| | - Zhanju Liu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Shanghai, China
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28
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de Zawadzki A, Leeming DJ, Sanyal AJ, Anstee QM, Schattenberg JM, Friedman SL, Schuppan D, Karsdal MA. Hot and cold fibrosis: The role of serum biomarkers to assess immune mechanisms and ECM-cell interactions in human fibrosis. J Hepatol 2025:S0168-8278(25)00148-5. [PMID: 40056933 DOI: 10.1016/j.jhep.2025.02.039] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 02/18/2025] [Accepted: 02/23/2025] [Indexed: 05/24/2025]
Abstract
Fibrosis is a pathological condition characterised by excessive accumulation of extracellular matrix (ECM) components, particularly collagens, leading to tissue scarring and organ dysfunction. In fibrosis, an imbalance between collagen synthesis (fibrogenesis) and degradation (fibrolysis) results in the deposition of fibrillar collagens disrupting the structural integrity of the ECM and, consequently, tissue architecture. Fibrosis is associated with a wide range of chronic diseases, including cirrhosis, kidney fibrosis, pulmonary fibrosis, and autoimmune diseases. Recently, the concept of "hot" and "cold" fibrosis has emerged, referring to the immune status within fibrotic tissues and the nature of fibrogenic signalling. Hot fibrosis is characterised by active immune cell infiltration and inflammation, while cold fibrosis is associated with auto- and paracrine myofibroblast activation, immune cell exclusion and quiescence. In this article, we explore the relationship between hot and cold fibrosis, the role of various types of collagens and their biologically active fragments in modulating the immune system, and how serological ECM biomarkers can help improve our understanding of the disease-relevant interactions between immune and mesenchymal cells in fibrotic tissues. Additionally, we draw lessons from immuno-oncology research in solid tumours to shed light on potential strategies for fibrosis treatment and highlight the advantage of having a "hot fibrotic environment" to treat fibrosis by enhancing collagen degradation through modulation of the immune system.
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Affiliation(s)
| | - Diana J Leeming
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
| | - Arun J Sanyal
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health and Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Quentin M Anstee
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK; Newcastle NIHR Biomedical Research Center, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, UK
| | - Jörn M Schattenberg
- Department of Internal Medicine II, Saarland University Medical Centre, Homburg, Germany
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Detlef Schuppan
- Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Harvard Medical School, MA, USA
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29
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Cui Y, David M, Bouchareychas L, Rouquier S, Sajuthi S, Ayrault M, Navarin C, Lara G, Lafon A, Saviane G, Boulakirba S, Menardi A, Demory A, Frikeche J, de la Forest Divonne Beghelli S, Lu HH, Dumont C, Abel T, Fenard D, de la Rosa M, Gertner-Dardenne J. IL23R-Specific CAR Tregs for the Treatment of Crohn's Disease. J Crohns Colitis 2025; 19:jjae135. [PMID: 39252592 PMCID: PMC11945296 DOI: 10.1093/ecco-jcc/jjae135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 07/18/2024] [Accepted: 09/09/2024] [Indexed: 09/11/2024]
Abstract
BACKGROUND AND AIMS Regulatory T cells (Tregs) are key regulators in maintaining tissue homeostasis. Disrupted immune homeostasis is associated with Crohn's disease (CD) pathogenesis. Thus, Treg therapy represents a promising long-acting treatment to restore immune balance in the diseased intestine. Chimeric antigen receptor (CAR) T-cell therapy has revolutionized cancer treatment. This innovative approach also provides the opportunity to improve therapy for CD. By targeting a disease-relevant protein, interleukin-23 receptor (IL23R), we engineered Tregs expressing IL23R-CAR for treating active CD. METHODS Intestinal IL23R expression from active CD was verified by immunohistochemical analysis. Phenotypic and functional characteristics of IL23R-CAR Tregs were assessed using in vitro assays and their migration capacity was monitored in a xenograft tumor model. Transcriptomic and proteomic analyses were performed to associate molecular profiles with IL23R-CAR Treg activation against colon biopsy-derived cells from active CD patients. RESULTS Our study showed that IL23R-CAR displayed negligible tonic signaling and a strong signal-to-noise ratio. IL23R-CAR Tregs maintained regulatory phenotype during in vitro expansion, even when chronically exposed to proinflammatory cytokines and target antigen. IL23R engagement on IL23R-CAR Tregs triggered CAR-specific activation and significantly enhanced their suppressive activity. Also, IL23R-CAR Tregs migrated to IL23R-expressing tissue in humanized mice. Finally, IL23R-CAR Tregs elicited a specific activation against colon biopsy-derived cells from active CD, suggesting an efficient CAR engagement in active CD. Molecular profiling of CD patient biopsies also revealed transcriptomic and proteomic patterns associated with IL23R-CAR activation. CONCLUSIONS Overall, our results demonstrate that IL23R-CAR Tregs represent a promising therapy for active CD.
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Affiliation(s)
- Yue Cui
- Research, Sangamo Therapeutics, Valbonne, France
| | - Marion David
- Research, Sangamo Therapeutics, Valbonne, France
| | | | | | | | | | | | - Gregory Lara
- Research, Sangamo Therapeutics, Valbonne, France
| | - Audrey Lafon
- Research, Sangamo Therapeutics, Valbonne, France
| | | | | | | | | | | | | | | | | | - Tobias Abel
- Research, Sangamo Therapeutics, Valbonne, France
| | - David Fenard
- Research, Sangamo Therapeutics, Valbonne, France
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30
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Baik S, Kim H, Lee Y, Kang T, Shin K, Song C, Park OK, Kang B, Lee N, Kim D, Choi SH, Kim SH, Soh M, Hyeon T, Kim CK. Orally Deliverable Iron-Ceria Nanotablets for Treatment of Inflammatory Bowel Disease. Adv Healthc Mater 2025; 14:e2401994. [PMID: 39235381 DOI: 10.1002/adhm.202401994] [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: 05/30/2024] [Revised: 08/20/2024] [Indexed: 09/06/2024]
Abstract
Ceria-based nanoparticles are versatile in treating various inflammatory diseases, but their feasibility in clinical translation is undermined by safety concerns and a limited delivery system. Meanwhile, the idiopathic nature of inflammatory bowel disease (IBD) calls for a wider variety of therapeutics via moderation of the intestinal immune system. In this regard, the synthesis and oral formulation of iron-ceria nanoparticles (CF NPs) with enhanced nanozymic activity and lower toxicity risk than conventional ceria-based nanoparticles are reported. CF NPs are clustered in calcium phosphate (CaP) and coated with a pH-responsive polymer to provide the enteric formulation of iron-ceria nanotablets (CFNT). CFNT exhibits a marked alleviative efficacy in the dextran sodium sulfate (DSS)-induced enterocolitis model in vivo by modulating the pro-inflammatory behavior of innate immune cells including macrophages and neutrophils, promoting anti-inflammatory cytokine profiles, and downregulating key transcription factors of inflammatory pathways.
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Affiliation(s)
- Seungmin Baik
- School of Chemical and Biological Engineering and Institute of Chemical Process, Seoul National University, Seoul, 08826, Republic of Korea
- Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea
| | - Hyunmin Kim
- Department of Neurology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, 08308, Republic of Korea
- Department of Medical Science, BK21 Plus KUMS Graduate Program, Korea University College of Medicine, Seoul, 08308, Republic of Korea
| | - Yunjung Lee
- School of Chemical and Biological Engineering and Institute of Chemical Process, Seoul National University, Seoul, 08826, Republic of Korea
- Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea
| | - Taegyu Kang
- School of Chemical and Biological Engineering and Institute of Chemical Process, Seoul National University, Seoul, 08826, Republic of Korea
- Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea
| | - Kwangsoo Shin
- School of Chemical and Biological Engineering and Institute of Chemical Process, Seoul National University, Seoul, 08826, Republic of Korea
- Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea
| | - Changyeong Song
- School of Chemical and Biological Engineering and Institute of Chemical Process, Seoul National University, Seoul, 08826, Republic of Korea
- Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea
| | - Ok Kyu Park
- Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea
- Department of Radiology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Byeonggeun Kang
- Bio-MAX Institute, Seoul National University, Seoul, 08826, Republic of Korea
| | - Nohyun Lee
- Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea
- School of Advanced Materials Engineering, Kookmin University, Seoul, 02707, Republic of Korea
| | - Dokyoon Kim
- Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea
- Department of Bionano Engineering and Bionanotechnology, Hanyang University, Ansan, 15558, Republic of Korea
| | - Seung Hong Choi
- Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea
- Department of Radiology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
- Center for Advanced Pharmaceutical Technology, HyeonTechNBio Inc., Seoul, 08826, Republic of Korea
| | - Seung Han Kim
- Department of Gastroenterology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, 08308, Republic of Korea
| | - Min Soh
- School of Chemical and Biological Engineering and Institute of Chemical Process, Seoul National University, Seoul, 08826, Republic of Korea
- Center for Advanced Pharmaceutical Technology, HyeonTechNBio Inc., Seoul, 08826, Republic of Korea
| | - Taeghwan Hyeon
- School of Chemical and Biological Engineering and Institute of Chemical Process, Seoul National University, Seoul, 08826, Republic of Korea
- Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea
| | - Chi Kyung Kim
- Department of Neurology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, 08308, Republic of Korea
- Department of Medical Science, BK21 Plus KUMS Graduate Program, Korea University College of Medicine, Seoul, 08308, Republic of Korea
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Yu Y, Ba X, Li T, Xu W, Zhao J, Zhang N, Zhao Y, Wang T, Zhang X, Wang X, Bai B, Wang B. PTPN22 and the pathogenesis of ulcerative colitis: Insights into T cell differentiation and the JAK/STAT signaling pathway. Cell Signal 2025; 127:111551. [PMID: 39643025 DOI: 10.1016/j.cellsig.2024.111551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 10/20/2024] [Accepted: 12/01/2024] [Indexed: 12/09/2024]
Abstract
70 % of the ulcerative colitis (UC) linked gene loci are associated with other autoimmune or immunodeficient diseases. The phosphatase activity of PTPN22 can regulate the development of T cells and contribute to regulate the level of inflammation in autoimmune diseases. We produced PTPN22-CS thymus-specific transgenic mice, which suppressed PTPN22 enzyme activity in the thymocytes. Overexpressed PTPN22-CS facilitated the development of the thymocytes towards CD4+T cells and resulted in an increased proportion of the Th1 and Treg cells in the UC mesenteric lymph nodes. PTPN22-CS promoted the activation of the JAK/STAT signaling pathway in the Th1 and Treg cells that localized in the colon, resulting in an excessive production of inflammatory mediators such as IL-2 and IFN-γ. Consequently, PTPN22-CS contributes to the inflammatory response of ulcerative colitis. In summary, the tyrosine phosphatase activity of PTPN22 plays a role in modulating UC by regulating T cell differentiation and modulating the JAK/STAT signaling pathway, thereby influencing the inflammatory response in colonic. These findings provide new insight into the association between PTPN22 and the pathogenesis of UC.
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Affiliation(s)
- Yang Yu
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Xinlei Ba
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Tong Li
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Wenying Xu
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Jiahui Zhao
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China
| | - Na Zhang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Yanjiao Zhao
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China
| | - Tao Wang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Xiaonan Zhang
- Department of Pathophysiology, Bengbu Medical University, Longzihu, Bengbu, 233030, Anhui, PR China..
| | - Xipeng Wang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China
| | - Bin Bai
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Bing Wang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
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Wen X, Li W, Li S, Chen D, Zheng J, Wang X, Zhang C, Liu Y, Ning Y, Jia R, Li P, Ji M, Ji C, Li J, Guo W. Longitudinal single-cell RNA sequencing reveals a heterogeneous response of plasma cells to colonic inflammation. Int J Biol Macromol 2025; 294:139307. [PMID: 39753172 DOI: 10.1016/j.ijbiomac.2024.139307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 12/27/2024] [Accepted: 12/27/2024] [Indexed: 01/13/2025]
Abstract
A comprehensive understanding of the dynamic changes in plasma cells (PCs) during inflammation remains elusive. In this study, we analyzed the distinct responses of PCs across different phases of inflammation in a dextran sodium sulfate (DSS)-induced mouse colitis model. Six-week-old male C57BL/6 mice were treated with 2.2 % DSS in distilled water for 5 days to induce colitis, and colonic tissues were collected at the peak of inflammation, during recovery, and at the end of the recovery phase. Single-cell RNA sequencing was performed to investigate temporal changes in the gut immune environment. PCs were categorized into six subsets, with Ube2c + PCs displaying notable alterations during various inflammatory phases. Genes such as Pycard, Gpx1, Lgals3, and Chchd10 were significantly expressed in Ube2c + PCs and appeared critical in resolving DSS-induced inflammation. Transcription factors (TFs), including Atf4, Cebpg, Jund, and Klf6, exhibited high regulatory activity in Ube2c + PCs across inflammatory stages. Additionally, we identified an interaction between Chchd10 and C1qbp in PCs, which stabilized C1qbp, reduced reactive oxygen species (ROS) production, and potentially enhanced PC survival and function under inflammatory conditions. This study highlights dynamic quasi-temporal gene expression and TF regulation in PCs during colitis, providing insights for future PC-targeted immunotherapy research.
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Affiliation(s)
- Xin Wen
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Wei Li
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Shifang Li
- Laboratory of Immunology and Vaccinology, FARAH, ULiège, Liège 4000, Belgium
| | - Dawei Chen
- Department of Physiology, School of Basic Medical Sciences, Department of Colorectal Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Junjie Zheng
- Department of Physiology, School of Basic Medical Sciences, Department of Colorectal Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Xia Wang
- Department of Physiology, School of Basic Medical Sciences, Department of Colorectal Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Cuiyu Zhang
- Department of Physiology, School of Basic Medical Sciences, Department of Colorectal Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Yanting Liu
- Department of Physiology, School of Basic Medical Sciences, Department of Colorectal Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Yao Ning
- Department of Physiology, School of Basic Medical Sciences, Department of Colorectal Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Ruinan Jia
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Peng Li
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Min Ji
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Chunyan Ji
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Jingxin Li
- Department of Physiology, School of Basic Medical Sciences, Department of Colorectal Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
| | - Wei Guo
- Department of Physiology, School of Basic Medical Sciences, Department of Colorectal Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
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Park SH, Kang J, Lee JY, Yoon JS, Hwang SH, Lee JY, Gupta DP, Baek IH, Han KJ, Song GJ. Neuroinflammation in Adaptive Immunodeficient Mice with Colitis-like Symptoms. Exp Neurobiol 2025; 34:34-47. [PMID: 40091637 PMCID: PMC11919638 DOI: 10.5607/en24016] [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: 07/12/2024] [Revised: 02/28/2025] [Accepted: 02/28/2025] [Indexed: 03/19/2025] Open
Abstract
Emerging evidence suggests that systemic inflammation may play a critical role in neurological disorders. Recent studies have shown the connection between inflammatory bowel diseases (IBD) and neurological disorders, revealing a bidirectional relationship through the gut-brain axis. Immunotherapies, such as Treg cells infusion, have been proposed for IBD. However, the role of adaptive immune cells in IBD-induced neuroinflammation remains unclear. In this study, we established an animal model for IBD in mice with severe combined immune-deficient (SCID), an adaptive immune deficiency, to investigate the role of adaptive immune cells in IBD-induced neuroinflammation. Mice were fed 1%, 3%, or 5% dextran sulfate sodium (DSS) for 5 days. We measured body weight, colon length, disease activity index (DAI), and crypt damage. Pro-inflammatory cytokines were measured in the colon, while microglial morphology, neuronal count, and inflammatory cytokines were analyzed in the brain. In the 3% DSS group, colitis symptoms appeared at day 7, with reduced colon length and increased crypt damage showing colitis-like symptoms. By day 21, colon length and crypt damage persisted, while DAI showed recovery. Although colonic inflammation peaked at day 7, no significant increase in inflammatory cytokines or microglial hyperactivation was observed in the brain. By day 21, neuroinflammation was detected, albeit with a slight delay, in the absence of adaptive immune cells. The colitis-induced neuroinflammation model provides insights into the fundamental immune mechanisms of the gut-brain axis and may contribute to developing immune cell therapies for IBD-induced neuroinflammation.
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Affiliation(s)
- Sung Hee Park
- Translational Brain Research Center, International St. Mary's Hospital, Catholic Kwandong University, Incheon 22711, Korea
| | - Junghwa Kang
- Research & Development, IMMUNISBIO CO. Ltd., Incheon 22711, Korea
| | - Ji-Young Lee
- Research & Development, IMMUNISBIO CO. Ltd., Incheon 22711, Korea
| | - Jeong Seon Yoon
- Research & Development, IMMUNISBIO CO. Ltd., Incheon 22711, Korea
| | - Sung Hwan Hwang
- Research & Development, IMMUNISBIO CO. Ltd., Incheon 22711, Korea
| | - Ji Young Lee
- Translational Brain Research Center, International St. Mary's Hospital, Catholic Kwandong University, Incheon 22711, Korea
| | - Deepak Prasad Gupta
- Translational Brain Research Center, International St. Mary's Hospital, Catholic Kwandong University, Incheon 22711, Korea
| | - Il Hyun Baek
- Department of Internal Medicine, Catholic Kwandong University College of Medicine, International St. Mary's Hospital, Incheon 22711, Korea
| | - Ki Jun Han
- Department of Internal Medicine, Catholic Kwandong University College of Medicine, International St. Mary's Hospital, Incheon 22711, Korea
| | - Gyun Jee Song
- Translational Brain Research Center, International St. Mary's Hospital, Catholic Kwandong University, Incheon 22711, Korea
- Department of Medical Science, Catholic Kwandong University, Gangneung 25601, Korea
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Yin S, Li L, Chen X, Wang J, Mao Y, Wang J, Xie X, Li J, Yang H. Artesunate alleviated murine ulcerative colitis by regulating immune response through inhibiting endoplasmic reticulum stress. Front Immunol 2025; 16:1545468. [PMID: 40079012 PMCID: PMC11897576 DOI: 10.3389/fimmu.2025.1545468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Accepted: 02/10/2025] [Indexed: 03/14/2025] Open
Abstract
Innate and adaptive immunity are intricately linked to the pathogenesis of ulcerative colitis (UC), with dysregulation of the Treg/Th17 balance and M2/M1 macrophage polarization identified as critical factors. Artesunate (ARS) has previously been shown to alleviate UC by inhibiting endoplasmic reticulum stress (ERS). To further investigate the regulatory effects of ARS on immune dysregulation associated with colitis and the role of ERS in this process, an experimental colitis model was established using dextran sulfate sodium (DSS). Flow cytometry was employed to assess changes in the Th17/Treg cell ratio in the spleen and macrophage polarization in the intestine, while RT-qPCR was used to quantify the transcription levels of relevant genes in colonic tissues. ARS treatment significantly mitigated DSS-induced pathological damage, reduced the proportion of CD4+Th17 cells, and downregulated the mRNA expression of IL-17A, IL-17F, and RORγt, while concurrently increasing the proportion of CD4+Treg cells and upregulating TGF-β expression. Additionally, ARS restored the DSS-induced decline in the M2/M1 macrophage ratio and enhanced the transcription of Arg-1 and IL-10, while suppressing the expression of pro-inflammatory markers, including iNOS, IL-1β, IL-6, and TNF-α. Notably, co-treatment with 4-phenylbutyric acid (4-PBA, ERS inhibitor) augmented the immunoregulatory effects of ARS, whereas 2-deoxy-D-glucose (2-DG, ERS agonist) co-treatment counteracted its protective activity against UC. These findings suggest that ERS plays a crucial role in mediating the therapeutic effects of ARS on UC, particularly by modulating Th17/Treg balance and macrophage polarization. This study provides further insights into the mechanistic basis of ARS in UC treatment offering a potential avenue for therapeutic intervention.
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Affiliation(s)
- Shaojie Yin
- Jiangsu Agri-animal Husbandry Vocational College, Taizhou, China
| | - Liuhui Li
- Jiangsu Agri-animal Husbandry Vocational College, Taizhou, China
| | - Xiaolan Chen
- Jiangsu Agri-animal Husbandry Vocational College, Taizhou, China
| | - Jing Wang
- Jiangsu Agri-animal Husbandry Vocational College, Taizhou, China
| | - Yujuan Mao
- Jiangsu Agri-animal Husbandry Vocational College, Taizhou, China
| | - Jingxuan Wang
- Jiangsu Agri-animal Husbandry Vocational College, Taizhou, China
| | - Xiaoyuting Xie
- College of Applied Technology, Changzhou University, Changzhou, China
| | - Jingui Li
- College of Veterinary Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China
| | - Haifeng Yang
- Jiangsu Agri-animal Husbandry Vocational College, Taizhou, China
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Dzhalilova D, Silina M, Kosyreva A, Fokichev N, Makarova O. Morphofunctional changes in the immune system in colitis-associated colorectal cancer in tolerant and susceptible to hypoxia mice. PeerJ 2025; 13:e19024. [PMID: 40028198 PMCID: PMC11869898 DOI: 10.7717/peerj.19024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 01/29/2025] [Indexed: 03/05/2025] Open
Abstract
Background One of the effective strategies for the treatment of tumor diseases, including colitis-associated colorectal cancer (CAC), is immunotherapy. During inflammation, NF-κB is activated, which is connected with the hypoxia-inducible factor-HIF, regulating the immune cells functioning and influences the CAC development. Organisms differ according to their hypoxia resistance and HIF expression. Therefore, the aim of the study was to characterize the thymus, spleen and mesenteric lymph nodes morphofunctional features, as well as changes in the subpopulation composition of peripheral blood cells and mesenteric lymph nodes in tolerant and susceptible to hypoxia C57Bl/6 mice in CAC. Methods Hypoxia tolerance was assessed by gasping time measurement in hypobaric decompression chamber. Based on the outcome, the mice were assigned to three groups characterized as 'tolerant to hypoxia', 'normal', and 'susceptible to hypoxia'. A month after determining hypoxia resistance CAC was modeled by intraperitoneal azoxymethane (AOM) administration and three cycles of dextran sulfate sodium consumption. Mice were sacrificed on the 141st day after the AOM administration, a morphological, morphometric and immunohistochemical study of tumors, morphological and morphometric study of thymus and spleen, and subpopulation composition of peripheral blood cells and mesenteric lymph nodes assessment were carried out. Results Tumors in tolerant and susceptible to hypoxia mice were represented by glandular intraepithelial neoplasia and adenocarcinomas, the area of which was larger in susceptible mice. Immunohistochemical study revealed a more pronounced Ki-67+ staining in tumors of susceptible mice. In CAC, only in tolerant mice, expansion of the thymic cortex was observed relative to the control group, while in susceptible ones, no changes were detected. Only in susceptible to hypoxia mice, spleen germinal centers of lymphoid follicles enlargement were observed. Only in susceptible mice during CAC, in comparison to the control group, the relative and absolute number of B-lymphocytes and relative-cytotoxic T-lymphocytes in blood increased. The relative cytotoxic T-lymphocytes and NK cells number in peripheral blood during CAC was higher in susceptible to hypoxia mice compared to tolerant ones. In susceptible to hypoxia mice, more pronounced changes in the mesenteric lymph nodes subpopulation composition of cells were revealed-only in them the absolute and relative number of B-lymphocytes and NK cells, the absolute number of cytotoxic T-lymphocytes increased, and the relative number of macrophages decreased. Conclusions Morphofunctional differences in the thymus, spleen, mesenteric lymph nodes and blood immune cells reactions indicated the more pronounced immune response to the CAC development in susceptible to hypoxia mice, which should be taken into account in experimental studies.
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Affiliation(s)
- Dzhuliia Dzhalilova
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Centre of Surgery, Moscow, Russia
| | - Maria Silina
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Centre of Surgery, Moscow, Russia
| | - Anna Kosyreva
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Centre of Surgery, Moscow, Russia
- Research Institute of Molecular and Cellular Medicine, People’s Friendship University of Russia (RUDN University), Moscow, Russia
| | - Nikolai Fokichev
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Centre of Surgery, Moscow, Russia
- Faculty of Biology and Biotechnology, HSE University, Moscow, Russia
| | - Olga Makarova
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Centre of Surgery, Moscow, Russia
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Acharjee A, Shivaji U, Santacroce G, Akiror S, Jeffery L, Varnai C, Reynolds G, Zardo D, Majumder S, Amamou A, Gkoutos GV, Iacucci M, Ghosh S. Novel Transcriptomic Signatures in Fibrostenotic Crohn's Disease: Dysregulated Pathways, Promising Biomarkers, and Putative Therapeutic Targets. Inflamm Bowel Dis 2025:izaf021. [PMID: 39977234 DOI: 10.1093/ibd/izaf021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Indexed: 02/22/2025]
Abstract
BACKGROUND Fibrosis is a common complication in Crohn's disease (CD), often leading to intestinal strictures. This study aims to explore the transcriptomic signature of fibrostenotic ileal CD for a comprehensive characterization of biological and cellular mechanisms underlying intestinal fibrosis. METHODS Nine CD patients undergoing surgery for fibrotic ileal strictures were prospectively recruited. RNA was extracted from fresh resected samples for bulk transcriptomics. Differentially expressed genes (DEGs) were identified (adj. P value < .05), and machine learning analyses were employed to compare gene expression patterns between strictures and non-strictured margins. Pathway enrichment analysis pinpointed relevant pathways. Furthermore, a random forest model was constructed to evaluate the significance of targeted genes. Relevant genes were subsequently validated through qPCR and further analyzed using a publicly available bulk RNA-seq dataset (GSE192786). Single-cell RNA sequencing (scRNA-seq) analysis was performed using the 10× Chromium Controller platform. RESULTS Bulk transcriptomics revealed unique transcriptomes with 81 DEGs, 64 significantly up-regulated, and 17 down-regulated in strictures compared to non-strictured margins. Up-regulated genes were mainly associated with inflammation, matrix and tissue remodeling, adipogenesis and cellular stress, while down-regulated genes were linked to epithelial barrier integrity. LY96, AKAP11, SRM, GREM1, EHD2, SERPINE1, HDAC1, and FGF2 showed high specificity for strictures. scRNA-seq linked up-regulated GREM1 exclusively to fibroblasts, while EHD2 and FGF2 showed upregulation in both fibroblasts and endothelial cells. LY96 and SRM were expressed by immune cells, whereas HDAC1, AKAP11, and SERPINE1 showed low expression across all cellular subsets. CONCLUSIONS This study comprehensively characterizes resected CD ileal strictures, elucidating main dysregulated pathways and identifying promising biomarkers and putative therapeutic targets.
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Affiliation(s)
- Animesh Acharjee
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
- Centre for Health Data Research, University of Birmingham, Birmingham, UK
| | - Uday Shivaji
- Gastroenterology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Giovanni Santacroce
- APC Microbiome Ireland, College of Medicine and Health, University College Cork, Cork, Ireland
| | - Sarah Akiror
- Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, UK
| | - Louisa Jeffery
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Csilla Varnai
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Gary Reynolds
- Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, UK
| | - Davide Zardo
- Department of Pathology, San Bortolo Hospital, Vicenza, Italy
| | - Snehali Majumder
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- APC Microbiome Ireland, College of Medicine and Health, University College Cork, Cork, Ireland
| | - Asma Amamou
- APC Microbiome Ireland, College of Medicine and Health, University College Cork, Cork, Ireland
| | - Georgios V Gkoutos
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
- Centre for Health Data Research, University of Birmingham, Birmingham, UK
| | - Marietta Iacucci
- Gastroenterology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- APC Microbiome Ireland, College of Medicine and Health, University College Cork, Cork, Ireland
| | - Subrata Ghosh
- APC Microbiome Ireland, College of Medicine and Health, University College Cork, Cork, Ireland
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Gao H, Xing D, Wu M, Hu Y, He J, Chen S, Zhang G, Yao F, Ma P, Xue W. Injectable DAT-ALG Hydrogel Mitigates Senescence of Loaded DPMSCs and Boosts Healing of Perianal Fistulas in Crohn's Disease. ACS Biomater Sci Eng 2025; 11:1171-1183. [PMID: 39804997 DOI: 10.1021/acsbiomaterials.4c02043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
Perianal fistulas (PAFs) are a severe complication of Crohn's disease that significantly impact patient prognosis and quality of life. While stem-cell-based strategies have been widely applied for PAF treatment, their efficacy remains limited. Our study introduces an injectable, temperature-controlled decellularized adipose tissue-alginate hydrogel loaded with dental pulp mesenchymal stem cells (DPMSCs) for in vivo fistula treatment. The experimental group demonstrated higher healing rates compared to surgical and DPMSCs groups, as evidenced by magnetic resonance imaging, multiplex immunohistochemical, and ELISA analyses. KEGG enrichment of differential genes suggested cellular senescence involvement in cell therapy efficacy, further confirmed by β-galactosidase staining and senescence markers (p21 and p53). Collectively, our research provides a novel therapy for PAFs and illuminates underlying mechanisms.
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Affiliation(s)
- Hanxu Gao
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China
- Nantong Key Laboratory of Gastrointestinal Oncology, Nantong 226001, China
| | - Danjie Xing
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China
- Nantong Key Laboratory of Gastrointestinal Oncology, Nantong 226001, China
| | - Menglong Wu
- Department of General Surgery, Guangyuan First People's Hospital, Guangyuan 628017, China
| | - Yilin Hu
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China
- Nantong Key Laboratory of Gastrointestinal Oncology, Nantong 226001, China
| | - Jiancheng He
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China
- Nantong Key Laboratory of Gastrointestinal Oncology, Nantong 226001, China
| | - Shun Chen
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China
- Nantong Key Laboratory of Gastrointestinal Oncology, Nantong 226001, China
| | - Guangze Zhang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China
- Nantong Key Laboratory of Gastrointestinal Oncology, Nantong 226001, China
| | - Fangzhou Yao
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Peng Ma
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Wanjiang Xue
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Nantong Key Laboratory of Gastrointestinal Oncology, Nantong 226001, China
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Wu Z, Chen X, Han F, Leeansyah E. MAIT cell homing in intestinal homeostasis and inflammation. SCIENCE ADVANCES 2025; 11:eadu4172. [PMID: 39919191 PMCID: PMC11804934 DOI: 10.1126/sciadv.adu4172] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 01/08/2025] [Indexed: 02/09/2025]
Abstract
Mucosa-associated invariant T (MAIT) cells are a large population of unconventional T cells widely distributed in the human gastrointestinal tract. Their homing to the gut is central to maintaining mucosal homeostasis and immunity. This review discusses the potential mechanisms that guide MAIT cells to the intestinal mucosa during homeostasis and inflammation, emphasizing the roles of chemokines, chemokine receptors, and tissue adhesion molecules. The potential influence of the gut microbiota on MAIT cell homing to different regions of the human gut is also discussed. Last, we introduce how organoid technology offers a potentially valuable approach to advance our understanding of MAIT cell tissue homing by providing a more physiologically relevant model that mimics the human gut tissue. These models may enable a detailed investigation of the gut-specific homing mechanisms of MAIT cells. By understanding the regulation of MAIT cell homing to the human gut, potential avenues for therapeutic interventions targeting gut inflammatory conditions such as inflammatory bowel diseases (IBD) may emerge.
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Affiliation(s)
- Zhengyu Wu
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Xingchi Chen
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Fei Han
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Edwin Leeansyah
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
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Zhang Y, Liu J, Li M, Dong Y, Li Z, Yi D, Wu T, Wang L, Zhao D, Hou Y. Zinc Oxide Administration Relieves the Diarrhea of ETEC K88-Infected Piglets by Reducing Ileal Apoptosis and Maintaining Gut Microbial Balance. Vet Sci 2025; 12:115. [PMID: 40005874 PMCID: PMC11861302 DOI: 10.3390/vetsci12020115] [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: 12/16/2024] [Revised: 01/25/2025] [Accepted: 01/25/2025] [Indexed: 02/27/2025] Open
Abstract
The impact of ZnO as a feed additive on growth-performance and intestinal function of Enterotoxigenic Escherichia coli (ETEC) K88-infected piglets remains unclear. Fecal scores of piglets in ETEC group were significantly increased compared to control group. ETEC K88 significantly damages the small intestine, including a reduction in villus height in the jejunum, duodenum, and ileum, and a decrease in total superoxide dismutase activity in the jejunum and catalase activity in the ileum and jejunum. Compared to control group, ETEC K88 infection significantly elevated the mRNA level of gene IL-1β and the level of ileal epithelial cell apoptosis. ZnO administration significantly alleviated these negative effects and improved the antioxidative capability of the ileum. Moreover, ZnO supplementation alleviated the imbalance of gut microbiota by restoring the reduced amount of Enterococcus and Lactobacillus in the jejunum, Clostridium in the ileum, and Lactobacillus in the cecum, as well as the increased amount of total eubacteria in the ileum and Enterococcus in the cecum induced by the ETEC K88 infection. In conclusion, ZnO administration can reduce the diarrhea of piglets infected with ETEC K88 by reducing the structural damage of the intestine, attenuating intestinal oxidative stress and epithelial cell apoptosis, and modulating the gut microbiota.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Yongqing Hou
- Engineering Research Center of Feed Protein Resources on Agricultural By-Products, Ministry of Education, Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430024, China
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Horn V, Cancino CA, Steinheuer LM, Obermayer B, Fritz K, Nguyen AL, Juhran KS, Plattner C, Bösel D, Oldenburg L, Burns M, Schulz AR, Saliutina M, Mantzivi E, Lissner D, Conrad T, Mashreghi MF, Zundler S, Sonnenberg E, Schumann M, Haag LM, Beule D, Flatz L, Trajanoski Z, D'Haens G, Weidinger C, Mei HE, Siegmund B, Thurley K, Hegazy AN. Multimodal Profiling of Peripheral Blood Identifies Proliferating Circulating Effector CD4 + T Cells as Predictors for Response to Integrin α4β7-Blocking Therapy in Inflammatory Bowel Disease. Gastroenterology 2025; 168:327-343. [PMID: 39343250 DOI: 10.1053/j.gastro.2024.09.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 09/06/2024] [Accepted: 09/18/2024] [Indexed: 10/01/2024]
Abstract
BACKGROUND & AIMS Despite the success of biological therapies in treating inflammatory bowel disease, managing patients remains challenging due to the absence of reliable predictors of therapy response. METHODS In this study, we prospectively sampled 2 cohorts of patients with inflammatory bowel disease receiving the anti-integrin α4β7 antibody vedolizumab. Samples were subjected to mass cytometry; single-cell RNA sequencing; single-cell B and T cell receptor sequencing (BCR/TCR-seq); serum proteomics; and multiparametric flow cytometry to comprehensively assess vedolizumab-induced immunologic changes in the peripheral blood and their potential associations with treatment response. RESULTS Vedolizumab treatment led to substantial alterations in the abundance of circulating immune cell lineages and modified the T-cell receptor diversity of gut-homing CD4+ memory T cells. Through integration of multimodal parameters and machine learning, we identified a significant increase in proliferating CD4+ memory T cells among nonresponders before treatment compared with responders. This predictive T-cell signature demonstrated an activated T-helper 1/T-helper 17 cell phenotype and exhibited elevated levels of integrin α4β1, potentially making these cells less susceptible to direct targeting by vedolizumab. CONCLUSIONS These findings provide a reliable predictive classifier with significant implications for personalized inflammatory bowel disease management.
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Affiliation(s)
- Veronika Horn
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Camila A Cancino
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Lisa M Steinheuer
- Institute of Experimental Oncology, Biomathematics Division, University Hospital Bonn, Bonn, Germany
| | - Benedikt Obermayer
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Core Unit Bioinformatics, Berlin, Germany
| | - Konstantin Fritz
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Anke L Nguyen
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Department of Gastroenterology, Central Clinical School, Monash University and Alfred Health, Melbourne, Victoria, Australia
| | - Kim Susan Juhran
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Christina Plattner
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Diana Bösel
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Lotte Oldenburg
- Department of Gastroenterology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Marie Burns
- Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Axel Ronald Schulz
- Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Mariia Saliutina
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Eleni Mantzivi
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Donata Lissner
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Thomas Conrad
- Genomics Technology Platform, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Core Unit Genomics, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Mir-Farzin Mashreghi
- Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany; German Center for Child and Adolescent Health (DZKJ), Partner Site Berlin, Berlin, Germany
| | - Sebastian Zundler
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Elena Sonnenberg
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Michael Schumann
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Lea-Maxie Haag
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Dieter Beule
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Core Unit Bioinformatics, Berlin, Germany
| | - Lukas Flatz
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland; Department of Dermatology, University Hospital Tübingen, University of Tübingen, Tübingen, Germany
| | - Zlatko Trajanoski
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Geert D'Haens
- Department of Gastroenterology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Carl Weidinger
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Henrik E Mei
- Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Britta Siegmund
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Kevin Thurley
- Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany; Institute of Experimental Oncology, Biomathematics Division, University Hospital Bonn, Bonn, Germany.
| | - Ahmed N Hegazy
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin Institute of Health Academy, Clinician Scientist Program, Berlin, Germany.
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Guo Y, Pabitra D, Pan L, Gong L, Li A, Liu S, Xiong J. Quantitative proteomic studies of the intestinal mucosa provide new insights into the molecular mechanism of ulcerative colitis. BMC Gastroenterol 2025; 25:48. [PMID: 39891110 PMCID: PMC11786489 DOI: 10.1186/s12876-025-03647-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 01/23/2025] [Indexed: 02/03/2025] Open
Abstract
BACKGROUND Differentiation between ulcerative colitis (UC) and other intestinal inflammatory diseases is difficult, and the precise etiology of UC is poorly understood. Thus, there is a need for novel diagnostic and prognostic biomarkers for UC. METHODS Intestinal mucosal biopsy tissue specimens of inflamed (ulcerative colitis-inflamed, UC-I) and non-inflamed (ulcerative colitis-noninflamed, UC-N) tissue were obtained simultaneously during colonoscopy from newly diagnosed UC patients prior to any treatments. Label-free liquid chromatography tandem mass spectrometry (LC-MS/MS) quantitative proteomics was used to detect proteomic differences between UC-I, UC-N, and normal control subjects (n = 5). Proteins with a fold-change > 1.5 and P < 0.05 between groups were considered to be differentially expressed (DEPs). Candidate biomarkers were further verified in 8 patients of each group by parallel reaction monitoring (PRM) (a prospective cohort, n = 8). Expression of TXNDC5 was quantified using immunohistochemistry (IHC). RESULTS A total of 4,788 proteins were identified. Multiple upregulated pathways, including leukocyte trans-endothelial migration and natural killer (NK) cell-mediated cytotoxicity, were identified. Network analysis showed that proteins were involved in 4 pathways in UC-I and 3 pathways in UC-N tissues, and participated in protein-protein interactions. Increased expression of 9 DEPs, including TXNDC5, EPX, and ITGAM were detected in UC patients compared to normal control subjects. Subsequent verification of the 9 DEPs by PRM confirmed the reliability of the mass spectrometry data. TXNDC5 expression was significantly increased in UC. CONCLUSIONS The pathways, networks, and proteins identified in this study may provide new insights into the molecular pathogenesis of UC. Further studies are required to determine if the proteins identified may help in the diagnosis and treatment of UC.
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Affiliation(s)
- Yandong Guo
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Dahal Pabitra
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lei Pan
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lanbo Gong
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Aimin Li
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Side Liu
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jing Xiong
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
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Cao H, Liu H, Dai X, Shi B, Yuan J, Shan J, Lin J. Qingchang suppository ameliorates mucosal inflammation in ulcerative colitis by inhibiting the differentiation and effector functions of Th1 and Th17 cells. JOURNAL OF ETHNOPHARMACOLOGY 2025; 337:118865. [PMID: 39343108 DOI: 10.1016/j.jep.2024.118865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/23/2024] [Accepted: 09/25/2024] [Indexed: 10/01/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Qing Chang Suppository (QCS), a traditional Chinese medicine formula, has been shown to effectively alleviate mucosal inflammation in patients with ulcerative colitis (UC). While the mechanism of QCS appears to be related to the regulation of CD4+T cell subset responses, direct evidence demonstrating that QCS inhibits Th1 and Th17 cell activation in UC (particularly based on human data) remains lacking. Additionally, the precise mechanisms through which QCS affects these cells have yet to be fully elucidated. AIM OF STUDY This study aimed to investigate the effects of QCS on Th1 and Th17 cell responses in UC and to explore the underlying mechanisms. MATERIALS AND METHODS Twenty-eight patients with mild-to-moderate UC were recruited and treated with QCS for 12 weeks. Symptoms were assessed every two weeks, with sigmoidoscopies performed at baseline and at week 12. Intestinal mucosal biopsies and peripheral blood (PB) were collected at these time points. At the end of the trial, patients were categorized into responder and non-responder groups based on a modified Mayo disease activity index score. Healthy controls (HCs) were defined as subjects without IBD or colorectal carcinoma but with colon polyps. The frequencies of IFN-γ+CD4+T cells and IL-17A+CD4+T cells in PB and colonic mucosa were measured using flow cytometry. The expression levels and localization of T-bet, RORγT, IFN-γ, TNF-α, and IL-17A were determined via immunofluorescence, and JNK signaling activation was assessed through immunoblotting and immunohistochemistry. All parameters were compared across the three groups. RESULTS At week 12, responders showed a significant reduction in colonic mucosal inflammation compared to baseline, accompanied by decreased frequencies of IFN-γ+CD4+T and IL-17A+CD4+ T cells in both PB and the colonic epithelial layer. Notably, Th1 and Th17 cell activity around intestinal epithelial cells (IECs) was nearly undetectable, as evidenced by the diminished expression of T-bet, RORγT, IFN-γ, TNF-α, and IL-17A. Additionally, JNK phosphorylation in these cells was significantly reduced. In contrast, non-responders exhibited no meaningful improvement; colonic pathology remained unchanged, and elevated levels of IFN-γ+CD4+T and IL-17A+CD 4+T cells persisted in both the PB and colonic epithelial layer. The presence of Th1 and Th17 cells and their associated cytokines around IECs remained substantial, and there was no significant change in JNK activation. CONCLUSION QCS attenuates mucosal inflammation in UC patients by inhibiting the differentiation and effector functions of Th1 and Th17 cells, primarily through the regulation of the JNK signaling pathway.
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Affiliation(s)
- Hui Cao
- Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Spleen and Stomach Diseases, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, China
| | - Huosheng Liu
- Department of Acupuncture and Moxibustion, Shanghai Jiading Hospital of Traditional Chinese Medicine, Shanghai, China
| | - Xiaoling Dai
- Department of Gastroenterology, Shanghai Putuo Traditional Chinese Medicine Hospital, Shanghai 200063, China
| | - Bei Shi
- Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jianye Yuan
- Clinical Research Unit, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jingyi Shan
- Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Jiang Lin
- Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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Pan H, Yang S, Kulyar MF, Ma H, Li K, Zhang L, Mo Q, Li J. Lactobacillus fermentum 016 Alleviates Mice Colitis by Modulating Oxidative Stress, Gut Microbiota, and Microbial Metabolism. Nutrients 2025; 17:452. [PMID: 39940311 PMCID: PMC11820689 DOI: 10.3390/nu17030452] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 01/23/2025] [Accepted: 01/23/2025] [Indexed: 02/14/2025] Open
Abstract
Ulcerative colitis (UC) is a chronic and progressive inflammatory gastrointestinal disease closely associated with gut microbiota dysbiosis and metabolic homeostasis disruption. Although targeted microbial therapies are an emerging intervention strategy for inflammatory bowel disease (IBD), the mechanisms by which specific probiotics, such as Lactobacillus fermentum 016 (LF), alleviate UC remain unclear. The current study evaluated the effects of LF supplementation on gut health in a basal model using C57BL/6 mice. Subsequently, the preventive effects and mechanisms of LF supplementation on DSS-induced UC were systematically investigated. According to our findings, LF supplementation revealed immunoregulatory capabilities with significantly altered gut the composition of microbiota and metabolic activities, particularly enhancing tryptophan metabolism. In the UC model, LF supplementation effectively mitigated weight loss, increased the disease activity index (DAI), and alleviated diarrhea, rectal bleeding, and colon shortening. Moreover, it reduced colonic pathological damage and histological injury scores. LF intervention improved antioxidant markers and intestinal mucosal barrier function with the activation of the Nrf2-Keap1 signaling pathway and regulation of systemic inflammatory markers, i.e., IL-1β, IL-6, TNF-α, IFN-γ, IL-4, and IL-10. Importantly, LF supplementation reversed metabolic disturbances by significantly increasing the abundance of beneficial genera (e.g., g_Dubosiella, g_Faecalibaculum, g_Odoribacter, g_Candidatus_saccharimonas, g_Roseburia, and g_Eubacterium_xylanophilum_group) and elevating tryptophan metabolites (e.g., melatonin, kynurenic acid, 3-indoleacetic acid, 5-methoxytryptophan, and 5-hydroxyindoleacetic acid). In conclusion, Lactobacillus fermentum 016 exhibits potential for regulating gut microbiota homeostasis, enhancing tryptophan metabolism, and alleviating UC, providing critical insights for developing probiotic-based precision therapeutic strategies for IBD.
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Affiliation(s)
- Huachun Pan
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (H.P.); (M.F.K.); (H.M.); (K.L.); (Q.M.)
| | - Shumin Yang
- National Key Laboratory of Agriculture Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China;
| | - Md. F. Kulyar
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (H.P.); (M.F.K.); (H.M.); (K.L.); (Q.M.)
| | - Hongwei Ma
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (H.P.); (M.F.K.); (H.M.); (K.L.); (Q.M.)
| | - Kewei Li
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (H.P.); (M.F.K.); (H.M.); (K.L.); (Q.M.)
| | - Lihong Zhang
- College of Animal Science & Technology, Gansu Agricultural University, Lanzhou 730070, China;
| | - Quan Mo
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (H.P.); (M.F.K.); (H.M.); (K.L.); (Q.M.)
| | - Jiakui Li
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (H.P.); (M.F.K.); (H.M.); (K.L.); (Q.M.)
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Shao Y, Mu Q, Wang R, Luo H, Song Z, Wang P, Song J, Ge C, Zhang J, Min J, Wang F. SLC39A10 is a key zinc transporter in T cells and its loss mitigates autoimmune disease. SCIENCE CHINA. LIFE SCIENCES 2025:10.1007/s11427-024-2817-y. [PMID: 39862347 DOI: 10.1007/s11427-024-2817-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 12/30/2024] [Indexed: 01/27/2025]
Abstract
Zinc homeostasis plays an essential role in maintaining immune function and is tightly regulated by zinc transporters. We previously reported that the zinc transporter SLC39A10, located in the cell membrane, critically regulates the susceptibility of macrophages to inflammatory stimuli; however, the functional role of SLC39A10 in T cells is currently unknown. Here, we identified two SNPs in SLC39A10 that are associated with inflammatory bowel disease (IBD). We then generated transgenic mice with T cell-specific deletion of Slc39a10 (cKO) and found that its loss not only protects against disease progression in IBD and experimental autoimmune encephalomyelitis (EAE), but also induces massive apoptosis via a p53/p21- and Bcl2-independent process. Mechanistically, we show that Slc39a10 serves as a key zinc importer upon activation of T cell receptor to safeguard DNA replication. Together, these findings provide new mechanistic insights and potential targets for the development of new therapeutic strategies for the treatment and/or prevention of T cell-mediated autoimmune diseases.
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Affiliation(s)
- Yichang Shao
- The Second Affiliated Hospital, The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Qingdian Mu
- The Second Affiliated Hospital, The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Rong Wang
- The Second Affiliated Hospital, The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Hongbin Luo
- The Second Affiliated Hospital, The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Zijun Song
- The Second Affiliated Hospital, The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Pengfei Wang
- Institute of Immunology and Department of Rheumatology at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Jingshu Song
- The Second Affiliated Hospital, The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Chaodong Ge
- The Second Affiliated Hospital, The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Jiyan Zhang
- Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
- Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Junxia Min
- The Second Affiliated Hospital, The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.
| | - Fudi Wang
- The Second Affiliated Hospital, The First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.
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Huang J, Zhang J, Liu Z, Ma J, Wang Y, Wang F, Tang X. Modified Gegen Qinlian Decoction Ameliorates DSS-Induced Colitis in Mice via the Modulation of NF- κB and Nrf2/HO-1 Pathways. Mediators Inflamm 2025; 2025:7468297. [PMID: 39850943 PMCID: PMC11756944 DOI: 10.1155/mi/7468297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 11/13/2024] [Accepted: 11/23/2024] [Indexed: 01/25/2025] Open
Abstract
Background: This study aims to reveal the potential molecular mechanisms of modified Gegen Qinlian decoction (MGQD) in relieving ulcerative colitis (UC). Methods: C57BL/6J mice were used to establish experimental colitis via dextran sodium sulfate (DSS). Body weight, disease activity index (DAI), spleen weight, colon length, and histopathologic features were measured to evaluate the therapeutic effects of MGQD on mice with UC. The ELISA kits were employed to assess the concentrations of interleukin (IL)-6, IL-1β, tumor necrosis factor-α (TNF-α), glutathione (GSH), reactive oxygen species (ROS), and malondialdehyde (MDA). Western blot analyses were used to assess the levels of IκBα, p65, p-IκBα, p-p65, HO-1, and Nrf2. Moreover, the protein levels of Nrf2 and p-p65 were assessed by immunofluorescence. Results: Colitis-related symptoms in mice were significantly alleviated by MGQD. Moreover, MGQD inhibited the levels of TNF-α, IL-1β, IL-6, MDA, and ROS and increased the level of GSH in mice with UC. Mechanistically, MGQD prevented the activation of the NF-κB pathway and concomitantly promoted the activation of the Nrf2/HO-1 pathway. Conclusion: MGQD alleviated UC by suppressing inflammation and oxidative stress via the modulation of NF-κB and Nrf2/HO-1 pathways, suggesting that MGQD may be a candidate therapy for UC.
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Affiliation(s)
- Jinke Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiaqi Zhang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhihong Liu
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Jing Ma
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Yifan Wang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Fengyun Wang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Xudong Tang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
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Ran X, Li Y, Ren Y, Chang W, Deng R, Wang H, Zhu W, Zhang Y, Cai Y, Hu J, Wang D, Liu Z. RNF128 deficiency in macrophages promotes colonic inflammation by suppressing the autophagic degradation of S100A8. Cell Death Dis 2025; 16:20. [PMID: 39809743 PMCID: PMC11733159 DOI: 10.1038/s41419-025-07338-0] [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: 09/18/2024] [Revised: 12/23/2024] [Accepted: 01/07/2025] [Indexed: 01/16/2025]
Abstract
Macrophages play important roles in maintaining intestinal homeostasis and in the pathogenesis of inflammatory bowel diseases (IBDs). However, the underlying mechanisms that govern macrophage-mediated inflammation are still largely unknown. In this study, we report that RNF128 is downregulated in proinflammatory macrophages. RNF128 deficiency leads to elevated levels of effector cytokines in vitro and accelerates the progression of IBD in mouse models. Bone marrow transplantation experiments revealed that RNF128 deficiency in bone marrow cells contributes to the worsening of DSS-induced colitis. Mechanistically, RNF128 interacts with and destabilizes S100A8 by promoting its autophagic degradation, which is mediated by the cargo receptor Tollip. Moreover, the administration of an S100A8 neutralizing antibody mitigated the development of colitis and improved survival in DSS-treated Rnf128-/- mice. Overall, our study underscores the anti-inflammatory role of RNF128 in macrophages during the progression of colitis and highlights the potential of targeting the RNF128-Tollip-S100A8 axis to attenuate intestinal inflammation for the treatment of colitis.
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Affiliation(s)
- Xianwen Ran
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yue Li
- Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Yahui Ren
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Weilong Chang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Rui Deng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Huifen Wang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Weiwei Zhu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yize Zhang
- Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yudie Cai
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Jia Hu
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan, 430081, China.
| | - Di Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Zhibo Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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47
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Ahn JH, da Silva Pedrosa M, Lopez LR, Tibbs TN, Jeyachandran JN, Vignieri EE, Rothemich A, Cumming I, Irmscher AD, Haswell CJ, Zamboni WC, Yu YRA, Ellermann M, Denson LA, Arthur JC. Intestinal E. coli-produced yersiniabactin promotes profibrotic macrophages in Crohn's disease. Cell Host Microbe 2025; 33:71-88.e9. [PMID: 39701098 DOI: 10.1016/j.chom.2024.11.012] [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: 05/09/2024] [Revised: 11/11/2024] [Accepted: 11/22/2024] [Indexed: 12/21/2024]
Abstract
Inflammatory bowel disease (IBD)-associated fibrosis causes significant morbidity. Mechanisms are poorly understood but implicate the microbiota, especially adherent-invasive Escherichia coli (AIEC). We previously demonstrated that AIEC producing the metallophore yersiniabactin (Ybt) promotes intestinal fibrosis in an IBD mouse model. Since macrophages interpret microbial signals and influence inflammation/tissue remodeling, we hypothesized that Ybt metal sequestration disrupts this process. Here, we show that macrophages are abundant in human IBD-fibrosis tissue and mouse fibrotic lesions, where they co-localize with AIEC. Ybt induces profibrotic gene expression in macrophages via stabilization and nuclear translocation of hypoxia-inducible factor 1-alpha (HIF-1α), a metal-dependent immune regulator. Importantly, Ybt-producing AIEC deplete macrophage intracellular zinc and stabilize HIF-1α through inhibition of zinc-dependent HIF-1α hydroxylation. HIF-1α+ macrophages localize to sites of disease activity in human IBD-fibrosis strictures and mouse fibrotic lesions, highlighting their physiological relevance. Our findings reveal microbiota-mediated metal sequestration as a profibrotic trigger targeting macrophages in the inflamed intestine.
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Affiliation(s)
- Ju-Hyun Ahn
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Marlus da Silva Pedrosa
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Lacey R Lopez
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Taylor N Tibbs
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Joanna N Jeyachandran
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Emily E Vignieri
- Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Aaron Rothemich
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Ian Cumming
- Department of Pulmonary and Critical Care Medicine, Duke University, Durham, NC 27710, USA
| | - Alexander D Irmscher
- UNC Advanced Translational Pharmacology and Analytical Chemistry Lab, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Corey J Haswell
- UNC Advanced Translational Pharmacology and Analytical Chemistry Lab, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - William C Zamboni
- UNC Advanced Translational Pharmacology and Analytical Chemistry Lab, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Yen-Rei A Yu
- Department of Pulmonary and Critical Care Medicine, Duke University, Durham, NC 27710, USA; Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Melissa Ellermann
- Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Lee A Denson
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
| | - Janelle C Arthur
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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48
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Lee H, Ko DS, Heo HJ, Baek SE, Kim EK, Kwon EJ, Kang J, Yu Y, Baryawno N, Kim K, Lee D, Kim YH. Uncovering NK cell sabotage in gut diseases via single cell transcriptomics. PLoS One 2025; 20:e0315981. [PMID: 39752457 PMCID: PMC11698320 DOI: 10.1371/journal.pone.0315981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 12/03/2024] [Indexed: 01/06/2025] Open
Abstract
The identification of immune environments and cellular interactions in the colon microenvironment is essential for understanding the mechanisms of chronic inflammatory disease. Despite occurring in the same organ, there is a significant gap in understanding the pathophysiology of ulcerative colitis (UC) and colorectal cancer (CRC). Our study aims to address the distinct immunopathological response of UC and CRC. Using single-cell RNA sequencing datasets, we analyzed the profiles of immune cells in colorectal tissues obtained from healthy donors, UC patients, and CRC patients. The colon tissues from patients and healthy participants were visualized by immunostaining followed by laser confocal microscopy for select targets. Natural killer (NK) cells from UC patients on medication showed reduced cytotoxicity compared to those from healthy individuals. Nonetheless, a UC-specific pathway called the BAG6-NCR3 axis led to higher levels of inflammatory cytokines and increased the cytotoxicity of NCR3+ NK cells, thereby contributing to the persistence of colitis. In the context of colorectal cancer (CRC), both NK cells and CD8+ T cells exhibited significant changes in cytotoxicity and exhaustion. The GALECTIN-9 (LGALS9)-HAVCR2 axis was identified as one of the CRC-specific pathways. Within this pathway, NK cells solely communicated with myeloid cells under CRC conditions. HAVCR2+ NK cells from CRC patients suppressed NK cell-mediated cytotoxicity, indicating a reduction in immune surveillance. Overall, we elucidated the comprehensive UC and CRC immune microenvironments and NK cell-mediated immune responses. Our findings can aid in selecting therapeutic targets that increase the efficacy of immunotherapy.
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Affiliation(s)
- Hansong Lee
- Medical Research Institute, Pusan National University, Yangsan, Republic of Korea
| | - Dai Sik Ko
- Division of Vascular Surgery, Department of General Surgery, Gachon University College of Medicine, Gil Medical Center, Incheon, Republic of Korea
| | - Hye Jin Heo
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Republic of Korea
| | - Seung Eun Baek
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Republic of Korea
| | - Eun Kyoung Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Republic of Korea
| | - Eun Jung Kwon
- Medical Research Institute, Pusan National University, Yangsan, Republic of Korea
| | - Junho Kang
- Department of Research, Keimyung University Dongsan Medical Center, Daegu, Republic of Korea
| | - Yeuni Yu
- Medical Research Institute, Pusan National University, Yangsan, Republic of Korea
| | - Ninib Baryawno
- Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
| | - Kihun Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Republic of Korea
- Department of Biomedical Informatics, School of Medicine, Pusan National University, Yangsan, Republic of Korea
| | - Dongjun Lee
- Department of Convergence Medicine, School of Medicine, Pusan National University, Yangsan, Republic of Korea
- Transplantation Research Center, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea
| | - Yun Hak Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Republic of Korea
- Department of Biomedical Informatics, School of Medicine, Pusan National University, Yangsan, Republic of Korea
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49
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Qian Y, Ding J, Zhao R, Song Y, Yoo J, Moon H, Koo S, Kim JS, Shen J. Intrinsic immunomodulatory hydrogels for chronic inflammation. Chem Soc Rev 2025; 54:33-61. [PMID: 39499495 DOI: 10.1039/d4cs00450g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2024]
Abstract
The immune system plays a pivotal role in maintaining physiological homeostasis and influencing disease processes. Dysregulated immune responses drive chronic inflammation, which in turn results in a range of diseases that are among the leading causes of death globally. Traditional immune interventions, which aim to regulate either insufficient or excessive inflammation, frequently entail lifelong comorbidities and the risk of severe side effects. In this context, intrinsic immunomodulatory hydrogels, designed to precisely control the local immune microenvironment, have recently attracted increasing attention. In particular, these advanced hydrogels not only function as delivery mechanisms but also actively engage in immune modulation, optimizing interactions with the immune system for enhanced tissue repair, thereby providing a sophisticated strategy for managing chronic inflammation. In this tutorial review, we outline key elements of chronic inflammation and subsequently explore the strategic design principles of intrinsic immunomodulatory hydrogels based on these elements. Finally, we examine the challenges and prospects of such immunomodulatory hydrogels, which are expected to inspire further preclinical research and clinical translation in addressing chronic inflammation.
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Affiliation(s)
- Yuna Qian
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325001, China.
| | - Jiayi Ding
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, Institute of Imaging Diagnosis and Minimally Invasive Intervention, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China
| | - Rui Zhao
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
| | - Yang Song
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610065, China
| | - Jiyoung Yoo
- Department of Chemistry, Korea University, Seoul 02841, Korea
| | - Huiyeon Moon
- Department of Chemistry, Korea University, Seoul 02841, Korea
| | - Seyoung Koo
- Department of Chemical and Molecular Engineering, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Korea.
| | - Jong Seung Kim
- Department of Chemical and Molecular Engineering, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Korea.
| | - Jianliang Shen
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325001, China.
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50
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Yang Y, Shao Y, Gao X, Hu Z, Wang Y, Ma C, Jin G, Zhu F, Dong G, Zhou G. RGS10 Deficiency Alleviated Intestinal Mucosal Inflammation Through Suppression of Th1/Th17 Cell Immune Responses in Ulcerative Colitis. Immunology 2025; 174:139-152. [PMID: 39428350 DOI: 10.1111/imm.13869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 08/22/2024] [Accepted: 10/03/2024] [Indexed: 10/22/2024] Open
Abstract
Regulator of G-protein signalling (RGS) 10 plays critical roles in several immune related diseases. However, whether RGS10 is involved in colonic inflammation of ulcerative colitis (UC) is still obscure. This study aimed to investigate the role of RGS10 in UC. In this study, RGS10 expression was examined by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, immunohistochemistry, and immunofluorescent analysis. Single-cell RNA sequencing of intestinal mucosa was performed to identify key immune cells with differentially expressed RGS10. RGS10 knockout mice were generated and established dextran sulphate sodium (DSS)-induced colitis. Expression of inflammatory cytokines on mRNA and protein levels was detected by qRT-PCR, enzyme-linked immunosorbent assay, and flow cytometry. We found that RGS10 expression was significantly elevated in UC patients, especially in CD4+ T cells, compared with healthy subjects. Intriguingly, RGS10 deficiency markedly alleviated DSS-induced colitis and decreased the proportion of Th1 and Th17 cells in lamina propria mononuclear cells (LPMCs), peripheral blood (PB), spleens, and mesenteric lymph nodes (mLNs). Mechanistically, RGS10 deficiency blocked the differentiation of Th1 and Th17 cells by inhibiting the phosphorylation of signal transducer and activator of transcription (STAT) 1 and STAT3. The co-immunoprecipitation analysis further showed that RGS10 could interact with protein tyrosine phosphatase non-receptor type 2 (PTPN2), and further regulated Th1 and Th17 cells differentiation of CD4+ T cells. In conclusion, RGS10 deficiency alleviated intestinal mucosal inflammation through inhibition of Th1/Th17 cell-mediated immune responses via interaction with PTPN2 in CD4+ T cells. Therefore, targeting RGS10 may represent a novel therapeutic approach for UC treatment.
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Affiliation(s)
- Yonghong Yang
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Yiming Shao
- Department of Burns and Plastic Surgery, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Xizhuang Gao
- Department of Clinical Medicine, Jining Medical University, Jining, Shandong, China
| | - Zongjing Hu
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Yan Wang
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Cuimei Ma
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Guiyuan Jin
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Fengqin Zhu
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Guanjun Dong
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong, China
| | - Guangxi Zhou
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
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