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Chen R, Chai X, Zhang Y, Zhou T, Xia Y, Jiang X, Lv B, Zhang J, Zhou L, Tian X, Wang R, Mao L, Zhao F, Zhang H, Hu J, Qiu J, Zou Z, Chen C. Novel role of FTO in regulation of gut-brain communication via Desulfovibrio fairfieldensis-produced hydrogen sulfide under arsenic exposure. Gut Microbes 2025; 17:2438471. [PMID: 39852343 PMCID: PMC11776478 DOI: 10.1080/19490976.2024.2438471] [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: 12/21/2023] [Revised: 10/26/2024] [Accepted: 11/26/2024] [Indexed: 01/26/2025] Open
Abstract
Fat mass and obesity-associated protein (FTO) is the key demethylase that reverses the abnormally altered N6-methyladenosine (m6A) modification in eukaryotic cells under environmental pollutants exposure. Arsenic is an environmental metalloid and can cause severe symptoms in human mainly through drinking water. However, there is no specific treatment for its toxic effects due to the uncovered mechanisms. We previously revealed that exposure to arsenic increased the level of m6A via down-regulation of FTO, which might serve as a potential target for intervention against arsenic-related disorders. In this study, our results demonstrated that chronic exposure to arsenic significantly disrupted the intestinal barrier and microenvironment. Also, this administration resulted in the enhancement of m6A modification and the reduction of FTO expression in the intestine. By using both CRISPR/Cas9-based FTO knock-in strategy and adeno-associated virus (AAV)-mediated overexpression of FTO in the intestine, we established for the first time that up-regulation of FTO remarkably ameliorated arsenic-induced disruption of intestinal barriers and altered microenvironment of mice. We also firstly identified a dominant gut microbial species, Desulfovibrio fairfieldensis, which was sharply reduced in arsenic-exposed mice, was able to proceed arsenic-induced neurobehavioral impairments by declining the levels of its major metabolite hydrogen sulfide. Administration of Desulfovibrio fairfieldensis could significantly alleviate the neurotoxicity of arsenic. Intriguingly, the beneficial effects of FTO against arsenic neurotoxicity possibly occurred through a novel gut-brain communication via Desulfovibrio fairfieldensis and its produced hydrogen sulfide. Collectively, these findings will provide new ideas for understanding the mechanisms of arsenic-induced toxic effects from a gut-brain communication perspective, and will assist the development of explicit intervention strategy via regulation of a new potential target FTO for prevention and treatment against arsenic-related both intestinal and neurological disorders.
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Affiliation(s)
- Ruonan Chen
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, People’s Republic of China
| | - Xiaoqin Chai
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, People’s Republic of China
| | - Yunxiao Zhang
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, People’s Republic of China
| | - Tianxiu Zhou
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, People’s Republic of China
| | - Yinyin Xia
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, People’s Republic of China
| | - Xuejun Jiang
- Center of Experimental Teaching for Public Health, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing, People’s Republic of China
| | - Bo Lv
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, People’s Republic of China
| | - Jun Zhang
- Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, People’s Republic of China
- Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, People’s Republic of China
| | - Lixiao Zhou
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, People’s Republic of China
| | - Xin Tian
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ruonan Wang
- Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, Chongqing, People’s Republic of China
| | - Lejiao Mao
- Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, People’s Republic of China
| | - Feng Zhao
- Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, Chongqing, People’s Republic of China
| | - Hongyang Zhang
- Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, People’s Republic of China
- Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, Chongqing, People’s Republic of China
| | - Jun Hu
- Department of Neurology, Southwest Hospital, Third Military Medical University, Chongqing, People’s Republic of China
| | - Jingfu Qiu
- Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, People’s Republic of China
- Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, Chongqing, People’s Republic of China
| | - Zhen Zou
- Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, People’s Republic of China
- Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, People’s Republic of China
| | - Chengzhi Chen
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, People’s Republic of China
- Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, People’s Republic of China
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2
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Li XL, Megdadi M, Quadri HS. Interaction between gut virome and microbiota on inflammatory bowel disease. World J Methodol 2025; 15:100332. [DOI: 10.5662/wjm.v15.i3.100332] [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: 08/13/2024] [Revised: 12/31/2024] [Accepted: 01/15/2025] [Indexed: 03/06/2025] Open
Abstract
Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is a chronic condition marked by recurring gastrointestinal inflammation. While immune, genetic, and environmental factors are well-studied, the gut virome has received less attention. This editorial highlights the work which investigates the gut virome’s role in IBD and its interactions with the bacterial microbiome and host immune system. The gut virome consists of bacteriophages, eukaryotic viruses, and endogenous retroviruses. Among these, Caudovirales bacteriophages are predominant and influence bacterial communities via lysogenic and lytic cycles. Eukaryotic viruses infect host cells directly, while endogenous retroviruses impact gene regulation and immune responses. In IBD, the virome shows distinct alterations, including an increased abundance of Caudovirales phages and reduced Microviridae diversity, suggesting a pro-inflammatory viral environment. Dysbiosis, chronic inflammation, and aberrant immune responses contribute to these changes by disrupting microbial communities and modifying virome composition. Phages affect bacterial dynamics through lysis, lysogeny, and horizontal gene transfer, shaping microbial adaptability and resilience. Understanding these interactions is crucial for identifying novel therapeutic targets and restoring microbial balance in IBD.
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Affiliation(s)
- Xiao-Long Li
- Department of Surgery, Ascension St Agnes Hospital, Baltimore, MD 21009, United States
| | - Mueen Megdadi
- Department of Surgery, Ascension St Agnes Hospital, Baltimore, MD 21009, United States
| | - Humair S Quadri
- Department of Surgery, Ascension St Agnes Hospital, Baltimore, MD 21009, United States
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Jori C, Ahmad A, Kumar A, Kumar B, Ali A, Ali N, Tabassum H, Khan R. Bioactive chitosan-BSA Maillard-derived chrysin-loaded nanoparticles: A gastroprotective, biomucoadhesive approach for enhanced oral therapy in ulcerative colitis. Carbohydr Polym 2025; 359:123537. [PMID: 40306769 DOI: 10.1016/j.carbpol.2025.123537] [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: 01/23/2025] [Revised: 03/15/2025] [Accepted: 03/24/2025] [Indexed: 05/02/2025]
Abstract
The current limitations of oral nanomedicines such as aminosalicylates, immunosuppressants, corticosteroids, and antibiotics include the toxic byproducts from nanocarrier synthesis, poor targeting and retention within the inflamed colon, delayed release at inflammation sites, susceptibility to gastric degradation, reduced efficacy under hypoxic conditions, MUC2 homeostasis disruption, and insufficiently addressing the disease's root causes. This research presents an innovative approach of using non-toxic, biodegradable, and biocompatible Maillard reaction-based nanoparticles (MPs) for targeted oral drug delivery in IBD therapy. Through the development of mucoadhevise chitosan-bovine serum albumin Maillard nanoparticles shielded with biocompatible, non-toxic, non-immunogenic, gastroprotective pectin (P@CMPs) encapsulating with chrysin, a flavonoid with anti-inflammatory and hyperoxia properties whose bioavailability is negatively affected by gastric degradation. P@CMPs had a spherical, uniform 300 nm hydrodynamic diameter, confirmed by TEM and FESEM. Chrysin encapsulation efficiency and loading capacity were ∼96 % and 16 %, respectively, demonstrating effective nanoparticle formulation The P@CMPs is designed to withstand the gastrointestinal environment, ensuring targeted delivery and prolonged retention in inflamed colonic regions. In a dextran sodium sulfate-induced colitis mouse model, P@CMPs markedly mitigated inflammation, suppressed proinflammatory cytokine levels, and augmented the expression of MUC2, a crucial factor for maintaining the integrity of the gut barrier. By employing non-toxic, biocompatible and biodegradable materials, our P@CMPs approach offers a promising avenue for advancing IBD treatment, addressing various challenges and precise oral delivery within the gastrointestinal system.
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Affiliation(s)
- Chandrashekhar Jori
- Chemical Biology Unit, Institute of Nano Science and Technology, Sector 81, Knowledge city, Sahibzada Ajit Singh Nagar, Mohali, Punjab 140306, India
| | - Anas Ahmad
- Julia McFarlane Diabetes Research Centre (JMDRC), Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Hotchkiss Brain Institute, Cumming School of Medicine, Foothills Medical Centre, University of Calgary, Calgary, Alberta T2N 4N1, Canada
| | - Ajay Kumar
- Chemical Biology Unit, Institute of Nano Science and Technology, Sector 81, Knowledge city, Sahibzada Ajit Singh Nagar, Mohali, Punjab 140306, India
| | - Bhuvnesh Kumar
- Chemical Biology Unit, Institute of Nano Science and Technology, Sector 81, Knowledge city, Sahibzada Ajit Singh Nagar, Mohali, Punjab 140306, India
| | - Aneesh Ali
- Chemical Biology Unit, Institute of Nano Science and Technology, Sector 81, Knowledge city, Sahibzada Ajit Singh Nagar, Mohali, Punjab 140306, India
| | - Nemat Ali
- Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
| | - Heena Tabassum
- Division of Basic Medical Sciences, Indian Council of Medical Research, Government of India, V. Ramalingaswamy Bhawan, New Delhi 110029, India.
| | - Rehan Khan
- Chemical Biology Unit, Institute of Nano Science and Technology, Sector 81, Knowledge city, Sahibzada Ajit Singh Nagar, Mohali, Punjab 140306, India.
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Steiger MB, Steinauer A, Gao D, Cerrejon DK, Krupke H, Heussi M, Merkl P, Klipp A, Burger M, Martin-Olmos C, Leroux JC. Enzymatic absorption promoters for non-invasive peptide delivery. J Control Release 2025; 382:113675. [PMID: 40164434 DOI: 10.1016/j.jconrel.2025.113675] [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: 01/03/2025] [Revised: 03/24/2025] [Accepted: 03/28/2025] [Indexed: 04/02/2025]
Abstract
Peptide drugs offer considerable potential for treating a diverse range of diseases. Yet, their clinical application is generally restricted to injectable therapies. The main challenge hindering their broader use through globally accessible, patient-friendly, and non-invasive delivery routes such as oral or buccal, lies in their poor ability to cross biological barriers effectively. Here, we demonstrate that enzymes can be harnessed to transiently reduce these barriers and improve absorption. As a proof of concept, we employ a mucin-specific protease (mucinase) and a phospholipase to increase mucus diffusivity and epithelial cell membrane permeability, respectively. In a canine model, we show that enteric capsules containing both enzymes, and the peptide drug desmopressin achieved a relative bioavailability of 155 % compared to the drug alone. Additionally, a buccal patch loaded with phospholipase and semaglutide displayed a 5-fold higher bioavailability and lower variability (71.5 % reduction in the coefficient of variation) compared to the commercially available oral tablet. These results suggest that enzymatic modulation of biological barriers holds promise as a strategy to improve non-invasive delivery of peptides and potentially other macromolecular drugs.
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Affiliation(s)
- Marilena Bohley Steiger
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Angela Steinauer
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland; Laboratory of Biomolecular Engineering and Nanomedicine, EPFL, 1015 Lausanne, Switzerland
| | - Daniel Gao
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
| | - David Klein Cerrejon
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Hanna Krupke
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Miguel Heussi
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Padryk Merkl
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Alexander Klipp
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Michael Burger
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Cristina Martin-Olmos
- Center for Advanced Surface Analysis, Institute of Earth Sciences, UNIL, 1015 Lausanne, Switzerland; School of Architecture, Civil and Environmental Engineering, EPFL, 1015 Lausanne, Switzerland
| | - Jean-Christophe Leroux
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
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5
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Wang M, Li D, Ouyang S, Tong B, Chen Y, Ding B, Wang J, Jiang Z, Xu H, Hu S. Hydrogel derived from decellularized pig small intestine submucosa boosted the therapeutic effect of FGF-20 on TNBS-induced colitis in rats via restoring gut mucosal integrity. Mater Today Bio 2025; 32:101783. [PMID: 40321695 PMCID: PMC12049826 DOI: 10.1016/j.mtbio.2025.101783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2025] [Revised: 04/07/2025] [Accepted: 04/19/2025] [Indexed: 05/08/2025] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by impaired intestinal mucosal barrier function, leading to persistent inflammation and tissue damage. Current therapies often fail to address barrier dysfunction, highlighting the need for innovative treatments. This study developed a novel therapeutic strategy by combining decellularized porcine small intestinal submucosa (D-SIS) with fibroblast growth factor 20 (FGF-20) to promote mucosal repair and restore barrier integrity in a TNBS-induced colitis rat model. The D-SIS-based hydrogel, supplemented with hyaluronic acid (HA), was designed to enhance FGF-20 stability and enable sustained drug release. Results showed that the FGF-20-loaded hydrogel (MAF) exhibited excellent rheological properties, erosion resistance, and controlled drug release, making it suitable for rectal administration. In vitro cell experiments demonstrated that MAF enhanced Caco-2 cell proliferation, migration, and tight junction protein expression, restoring epithelial barrier integrity. In the colitis model, MAF significantly reduced disease activity index (DAI) scores, attenuated inflammation, and restored mucosal morphology. Additionally, MAF promoted goblet cell regeneration, enhanced mucus secretion, and upregulated intestinal stem cell markers, indicating its ability to repair both epithelial and mucus barriers. In conclusion, the MAF hydrogel represents a promising therapeutic approach for UC by combining the regenerative properties of FGF-20 with the bioactive support of D-SIS.
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Affiliation(s)
- Minmin Wang
- Department of Gastrointestinal Surgery Nursing Unit, Ward 442, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province, 325000, China
| | - Dingwei Li
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, 325035, China
| | - Shenyuan Ouyang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, 325035, China
| | - Bingjie Tong
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, 325035, China
| | - Yumo Chen
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, 325035, China
| | - Bingyu Ding
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, 325035, China
| | - Jie Wang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, 325035, China
| | - Zhijiang Jiang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, 325035, China
| | - Helin Xu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, 325035, China
| | - Sunkuan Hu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province, 325000, China
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6
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Yang Q, Chen D, Liu X, Li W, Zheng H, Cai X, Li R. Identification of nanoparticle infiltration in human breast milk: Chemical profiles and trajectory pathways. Proc Natl Acad Sci U S A 2025; 122:e2500552122. [PMID: 40354532 DOI: 10.1073/pnas.2500552122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 04/03/2025] [Indexed: 05/14/2025] Open
Abstract
Breast milk is crucial for infant health, offering essential nutrients and immune protection. However, despite increasing exposure risks from nanoparticles (NPs), their potential infiltration into human breast milk remains poorly understood. This study provides a comprehensive chemical profile of NPs in human breast milk, analyzing their elemental composition, surface charge, hydrodynamic size, and crystallinity. NPs were detected in 42 out of 53 milk samples, with concentrations reaching up to 1.12 × 1011 particles/mL. These particles comprised nine elements, with O, Si, Fe, Cu, and Al being the most frequently detected across all samples. We establish a mechanistic axis for NP infiltration, involving penetration of the intestine/air-blood barriers, circulation in blood vessels, crossing the blood-milk barrier via transcytosis or immune cell-mediated transfer, and eventual accumulation in milk. Structure-activity relationship analysis reveals that smaller, neutral-charged NPs exhibit stronger infiltration capacity, offering potential for regulating NP behavior at biological barriers through engineering design. This study provides the chemical profiles of NPs in human breast milk and uncovers their infiltration pathways.
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Affiliation(s)
- Qing Yang
- Center for Genetic Epidemiology and Genomics, School of Public Health, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China
| | - Di Chen
- Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China
| | - Xi Liu
- Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China
| | - Wenjie Li
- Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China
| | - Huizhen Zheng
- Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China
| | - Xiaoming Cai
- Center for Genetic Epidemiology and Genomics, School of Public Health, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China
| | - Ruibin Li
- Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu 215123, China
- Nanotechnology Centre, Centre for Energy and Environmental Technologies, Vysoká škola báňská-Technical University of Ostrava, Ostrava 70800, Czech Republic
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Liu J, Huang H, Zhang X, Shen Y, Jiang D, Hu S, Li S, Yan Z, Hu W, Luo J, Yao H, Chen Y, Tang B. Unveiling the Cuproptosis in Colitis and Colitis-Related Carcinogenesis: A Multifaceted Player and Immune Moderator. RESEARCH (WASHINGTON, D.C.) 2025; 8:0698. [PMID: 40370501 PMCID: PMC12076167 DOI: 10.34133/research.0698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 04/07/2025] [Accepted: 04/18/2025] [Indexed: 05/16/2025]
Abstract
Cuproptosis represents a novel mechanism of cellular demise characterized by the intracellular buildup of copper ions. Unlike other cell death mechanisms, its distinct process has drawn considerable interest for its promising applications in managing inflammatory bowel disease (IBD) and colorectal cancer (CRC). Emerging evidence indicates that copper metabolism and cuproptosis may exert dual regulatory effects within pathological cellular environments, specifically modulating oxidative stress responses, metabolic reprogramming, and immunotherapeutic efficacy. An appropriate level of copper may promote disease progression and exert synergistic effects, but exceeding a certain threshold, copper can inhibit disease development by inducing cuproptosis in pathological cells. This makes abnormal copper levels a potential new therapeutic target for IBD and CRC. This review emphasizes the dual function of copper metabolism and cuproptosis in the progression of IBD and CRC, while also exploring the potential application of copper-based therapies in disease treatment. The analysis further delineates the modulatory influence of tumor immune microenvironment on cuproptosis dynamics, while establishing the therapeutic potential of cuproptosis-targeted strategies in circumventing resistance to both conventional chemotherapeutic agents and emerging immunotherapies. This provides new research directions for the development of future cuproptosis inducers. Finally, this article discusses the latest advances in potential molecular targets of cuproptosis and their related genes in the treatment of IBD and CRC, highlighting future research priorities and unresolved issues.
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Affiliation(s)
- Jingwen Liu
- Department of Gastroenterology, the Second Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Hairuo Huang
- China Medical University, Shenyang 110122, China
| | - Xiaojie Zhang
- The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Yang Shen
- Department of Radiation Oncology, Zhongshan Hospital,
Fudan University, Shanghai 200000, China
| | - DeMing Jiang
- Biosensor National Special Laboratory, Key Laboratory for Biomedical Engineering of Education Ministry, Department of Biomedical Engineering,
Zhejiang University, Hangzhou 310007, China
| | - Shurong Hu
- Department of Gastroenterology, the Second Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Shuyan Li
- Department of Nursing, the Second Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Zelin Yan
- Department of Gastroenterology, the First Affiliated Hospital of Zhejiang Chinese Medical University,
Zhejiang Provincial Key Laboratory of Gastrointestinal Diseases Pathophysiology, Hangzhou 310006, China
| | - Wen Hu
- Department of Gastroenterology, the First Affiliated Hospital of Zhejiang Chinese Medical University,
Zhejiang Provincial Key Laboratory of Gastrointestinal Diseases Pathophysiology, Hangzhou 310006, China
| | - Jinhua Luo
- The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China
| | - Haibo Yao
- Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People’s Hospital,
Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou 310014, China
| | - Yan Chen
- Department of Gastroenterology, the Second Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Bufu Tang
- Department of Interventional Radiology, Zhongshan Hospital,
Fudan University, Shanghai 200000, China
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8
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Arora A, Rizvi MS, Grenci G, Dilasser F, Fu C, Ganguly M, Vaishnavi S, Paramsivam K, Budnar S, Noordstra I, Yap AS, Viasnoff V. Viscous dissipation in the rupture of cell-cell contacts. NATURE MATERIALS 2025:10.1038/s41563-025-02232-8. [PMID: 40355570 DOI: 10.1038/s41563-025-02232-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 04/04/2025] [Indexed: 05/14/2025]
Abstract
Cell-cell adhesions mediated by adherens junctions, structures connecting cells to each other and to the cortical cytoskeleton, are essential for epithelial physical and biological integrity. Nonetheless, how such structures resist mechanical stimuli that prompt cell-cell rupture is still not fully understood. Here we challenge the conventional views on cell-cell adhesion stability, highlighting the importance of viscous dissipation at the cellular level. Using microdevices to measure the rupture energy of cell-cell junctions and synthetic cadherins to discriminate cadherin binding energy from downstream cytoskeletal regulation, we demonstrate that the balance between cortical tension and cell shape recovery time determines a transition from ductile to brittle fracture in cell-cell contact. These findings suggest that junction toughness, defined as the junction disruption energy, is a more accurate measure of junctional stability, challenging the current emphasis on bond energy and tension. Overall, our results highlight the role and the regulation of energy dissipation through the cytoskeleton during junction deformation for epithelial integrity.
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Affiliation(s)
- Aditya Arora
- Mechanobiology Institute, National University of Singapore, Singapore, Singapore
| | - Mohd Suhail Rizvi
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Telangana, India
| | - Gianluca Grenci
- Mechanobiology Institute, National University of Singapore, Singapore, Singapore
| | - Florian Dilasser
- Mechanobiology Institute, National University of Singapore, Singapore, Singapore
| | - Chaoyu Fu
- Mechanobiology Institute, National University of Singapore, Singapore, Singapore
| | - Modhura Ganguly
- Mechanobiology Institute, National University of Singapore, Singapore, Singapore
| | - Sree Vaishnavi
- Mechanobiology Institute, National University of Singapore, Singapore, Singapore
| | - Kathirvel Paramsivam
- Mechanobiology Institute, National University of Singapore, Singapore, Singapore
| | - Srikanth Budnar
- Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, Australia
| | - Ivar Noordstra
- Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, Australia
| | - Alpha S Yap
- Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, Australia
| | - Virgile Viasnoff
- Mechanobiology Institute, National University of Singapore, Singapore, Singapore.
- CNRS, IRL3639, Singapore, Singapore.
- CNRS, CINaM UMR7325, Marseille, France.
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Chen C, Qi M, Xu Z, Wen J, Tang W, Diao H, Li Z, Chu Y, Feng F, Tang Z. Sesamin improved growth and overall health in young animals by enhancing gut-liver axis function. Food Funct 2025. [PMID: 40351157 DOI: 10.1039/d4fo05933f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2025]
Abstract
The immature gastrointestinal development of infants and young animals made them more vulnerable to stress-related damage, which affected the gut-liver axis and consequently impaired their health and growth. This study used weaned piglets as a model to investigate how dietary sesamin regulated the gut-liver axis and impacted young animal health. We assessed gut-liver tissue morphology, measured key indicators of intestinal barrier damage, mucosal repair, antioxidant and immune pathways in the gut-liver system and serum, and analyzed microbial composition. We further explored the interactions between sesamin and the gut-liver axis through PLS-PM and molecular docking analysis. Results showed that sesamin enhanced intestinal barrier function, reduced liver damage, decreased oxidative stress, promoted anti-inflammatory immune responses, and enriched beneficial microbes, thereby promoting overall growth. Sesamin can enhance the health of young animals by regulating the function of the gut-liver axis.
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Affiliation(s)
- Chen Chen
- Laboratory for Bio-feed and Molecular Nutrition, College of Animal Science and Technology, Southwest University, Chongqing 400715, China.
| | - Min Qi
- Yunnan Animal Husbandry Station, Kunming 650225, China
| | - Zhiran Xu
- Laboratory for Bio-feed and Molecular Nutrition, College of Animal Science and Technology, Southwest University, Chongqing 400715, China.
| | - Jincheng Wen
- Laboratory for Bio-feed and Molecular Nutrition, College of Animal Science and Technology, Southwest University, Chongqing 400715, China.
| | - Wenjie Tang
- Animal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu 610066, China
- Livestock and Poultry Biological Products Key Laboratory of Sichuan Province, Sichuan Animtche Group Co., Ltd., Chengdu 610066, China
| | - Hui Diao
- Animal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu 610066, China
- Livestock and Poultry Biological Products Key Laboratory of Sichuan Province, Sichuan Animtche Group Co., Ltd., Chengdu 610066, China
| | - Zhangcheng Li
- Laboratory for Bio-feed and Molecular Nutrition, College of Animal Science and Technology, Southwest University, Chongqing 400715, China.
| | - Yunyun Chu
- Laboratory for Bio-feed and Molecular Nutrition, College of Animal Science and Technology, Southwest University, Chongqing 400715, China.
| | - Fu Feng
- Laboratory for Bio-feed and Molecular Nutrition, College of Animal Science and Technology, Southwest University, Chongqing 400715, China.
| | - Zhiru Tang
- Laboratory for Bio-feed and Molecular Nutrition, College of Animal Science and Technology, Southwest University, Chongqing 400715, China.
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10
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Wang HT, Weng JY, Amadou I, Song J, Jiang MQ, Ci WJ, Zhu JJ. Ligninoformic acid improved DSS-induced chronic colitis in mice by regulating intestinal flora and intestinal barrier. Microb Pathog 2025; 205:107670. [PMID: 40339622 DOI: 10.1016/j.micpath.2025.107670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 02/23/2025] [Accepted: 05/04/2025] [Indexed: 05/10/2025]
Abstract
Inflammatory Bowel Disease (IBD) is a complex intestinal disorder that typically triggers inflammatory responses, immune dysregulation, and gut microbiota imbalance. Lignoformic acid (LFA) is a lignin-derived compound containing benzene rings and hydroxyl functional groups. It has antioxidant properties and can regulate intestinal pH. This study aimed to investigate the improve effects of LFA on dextran sulfate sodium (DSS)-induced chronic colitis in mice. The results showed that LFA treatment significantly improved body weight and Disease Activity Index (DAI) in mice and alleviated colon damage. In terms of oxidative stress and anti-inflammatory effects, the expression of antioxidant enzymes such as Glutathione Peroxidase (GSH-PX) and Superoxide Dismutase (SOD) was dose-dependently enhanced in DSS-induced mice. LFA reduced the expression of Tumor Necrosis Factor-alpha (TNF-α) by modulating the TLR4/MyD88/NF-κB signaling pathway. Furthermore, LFA dose-dependently increased the abundance of beneficial bacteria, including Akkermansia and Lachnospiraceae, and promoted the production of short-chain fatty acids (SCFAs). These findings suggest that LFA could serve as a therapeutic agent for colitis by enhancing intestinal barrier integrity, regulating inflammation, and restoring gut microbiota balance.
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Affiliation(s)
- Hong-Tao Wang
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu, China; State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Jia-Yi Weng
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu, China; State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Issoufou Amadou
- Laboratory of Food Science and Technology, Faculty of Agriculture and Environment Sciences, Dan Dicko Dankoulodo University of Maradi, Niger
| | - Jie Song
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu, China; State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Meng-Qi Jiang
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu, China; State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Wen-Jia Ci
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu, China; State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Jian-Jin Zhu
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu, China; State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, 214122, Jiangsu, China.
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11
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Zhao Q, Mu G, Zheng Y, Du W, Zhao A, Sun Q, Sun P, Wu X, Kong F. Targeted hydrolysis of α-lactalbumin to reduce allergenicity based on the synergistic effect of pepsin and papain. Int J Biol Macromol 2025; 311:144016. [PMID: 40339859 DOI: 10.1016/j.ijbiomac.2025.144016] [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: 02/03/2025] [Revised: 04/21/2025] [Accepted: 05/05/2025] [Indexed: 05/10/2025]
Abstract
Enzymolysis can effectively reduce the allergenicity of α-lactalbumin (ALA). Herein, complex enzymes targeted enzymolysis technology was developed to reduce the allergenicity of ALA, and the allergenicity of hydrolysates (WM) were investigated from multiple perspectives. The results showed that compared with the single enzyme hydrolysates, the degree of hydrolysis and antigen reduction rate of WM were increased by 5.57 % and 25.31 %, and linear allergenic epitopes were further eliminated. The spatial conformation of WM was disrupted, manifested by decreasing in α-helix content and surface hydrophobicity. In addition, WM could alleviate allergic symptoms in mice, reduced the binding ability with IgE and IgG1 and the release of mast cells degranulation, maintained the balance of Th1/Th2 cells and intestinal barrier function. Spearman's correlation analysis further revealed the correlation between the relative abundance of marker genus and allergy related indicators. This study will provide theoretical basis for the development of low allergenic dairy-based materials.
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Affiliation(s)
- Qing Zhao
- School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, Liaoning, China; Dalian Key Laboratory of Functional Probiotics, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
| | - Guangqing Mu
- School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, Liaoning, China; Dalian Key Laboratory of Functional Probiotics, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
| | - Yijia Zheng
- School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, Liaoning, China
| | - Wenjiao Du
- School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, Liaoning, China
| | - Anqi Zhao
- School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, Liaoning, China
| | - Qi Sun
- School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, Liaoning, China; Dalian Key Laboratory of Functional Probiotics, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
| | - Peng Sun
- School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, Liaoning, China; Dalian Key Laboratory of Functional Probiotics, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
| | - Xiaomeng Wu
- School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, Liaoning, China; Dalian Key Laboratory of Functional Probiotics, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China; Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta T6G 2P5, Canada
| | - Fanhua Kong
- School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, Liaoning, China; SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, Collaborative Innovation Center of Seafood Deep Processing, National & Local Joint Engineering, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China; Laboratory for Marine Bioactive Polysaccharide Development and Application, Liaoning Key Laboratory of Food Nutrition and Health, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China.
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12
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Abdollahi S, Zarin B, Vatani M, Vajhadin F, Hassani M, Jalali P, Kim K, Sanati-Nezhad A. Biomimetic culture substrates for modelling homeostatic intestinal epithelium in vitro. Nat Commun 2025; 16:4120. [PMID: 40316543 PMCID: PMC12048609 DOI: 10.1038/s41467-025-59459-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 04/22/2025] [Indexed: 05/04/2025] Open
Abstract
The increasing interest in utilizing three-dimensional (3D) in vitro models with innovative biomaterials to engineer functional tissues arises from the limitations of conventional cell culture methods in accurately reproducing the complex physiological conditions of living organisms. This study presents a strategy for replicating the intricate microenvironment of the intestine by cultivating intestinal cells within bioinspired 3D interfaces that recapitulate the villus-crypt architecture and 3D tissue arrangement of the intestine. Intestinal cells cultured on these biomimetic substrates exhibited phenotypes and differentiation characteristics resembling intestinal-specific cell types, effectively replicating intestinal tissue. Notably, tissue proliferation and differentiation were achieved within 72-120 h-significantly faster than the several weeks required by conventional bioengineered materials, which often pose risks of tissue necrosis or cross-contamination. Additionally, the differentiated cells on these villi-crypts mimicking bio-interfaces exhibit higher production of natural antimicrobial peptides, resulting in reduced pathogenic infection compared to control samples. Furthermore, our method stands out for simplicity in fabrication, eliminating the need for cleanroom procedures and complex microfabrication techniques.
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Affiliation(s)
- Sorosh Abdollahi
- Department of Biomedical Engineering, University of Calgary, Calgary, Alberta, T2N 1N4, Canada
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, T2N 2T8, Canada
| | - Bahareh Zarin
- Department of Biomedical Engineering, University of Calgary, Calgary, Alberta, T2N 1N4, Canada
| | - Maryam Vatani
- Department of Biomedical Engineering, University of Calgary, Calgary, Alberta, T2N 1N4, Canada
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, T2N 2T8, Canada
| | - Fereshteh Vajhadin
- Department of Biomedical Engineering, University of Calgary, Calgary, Alberta, T2N 1N4, Canada
| | - Mohsen Hassani
- Department of Mechanical & Manufacturing Engineering, University of Calgary, Calgary, Alberta, T2N 1N4, Canada
| | - Pezhman Jalali
- Department of Biomedical Engineering, University of Calgary, Calgary, Alberta, T2N 1N4, Canada
| | - Keekyoung Kim
- Department of Biomedical Engineering, University of Calgary, Calgary, Alberta, T2N 1N4, Canada
- Department of Mechanical & Manufacturing Engineering, University of Calgary, Calgary, Alberta, T2N 1N4, Canada
| | - Amir Sanati-Nezhad
- Department of Biomedical Engineering, University of Calgary, Calgary, Alberta, T2N 1N4, Canada.
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, T2N 2T8, Canada.
- Department of Mechanical & Manufacturing Engineering, University of Calgary, Calgary, Alberta, T2N 1N4, Canada.
- Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, T2N 2T8, Canada.
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13
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Tram NDT, Xu J, Chan KH, Rajamani L, Ee PLR. Bacterial clustering biomaterials as anti-infective therapies. Biomaterials 2025; 316:123017. [PMID: 39708775 DOI: 10.1016/j.biomaterials.2024.123017] [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: 08/13/2024] [Revised: 11/23/2024] [Accepted: 12/13/2024] [Indexed: 12/23/2024]
Abstract
In Nature, bacterial clustering by host-released peptides or nucleic acids is an evolutionarily conserved immune defense strategy employed to prevent adhesion of pathogenic microbes, which is prerequisite for most infections. Synthetic anti-adhesion strategies present as non-lethal means of targeting bacteria and may potentially be used to avoid resistance against antimicrobial therapies. From bacteria-agglutinating biomolecules discovered in nature to synthetic designs involving peptides, cationic polymers and nanoparticles, the modes of actions appear broad and unconsolidated. Herein, we present a critical review and update of the state-of-the-art in synthetic bacteria-clustering designs with proposition of a more streamlined nomenclature and classification. Overall, this review aims to consolidate the conceptual framework in the field of bacterial clustering and highlight its potentials as an avenue for discovering novel antibacterial biomaterials.
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Affiliation(s)
- Nhan Dai Thien Tram
- Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, 18 Science Drive 4, Singapore, 117559, Singapore
| | - Jian Xu
- Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, 18 Science Drive 4, Singapore, 117559, Singapore
| | - Kiat Hwa Chan
- Division of Science, Yale-NUS College, 16 College Avenue West, Singapore, 138527, Singapore; NUS College, National University of Singapore, 18 College Avenue East, Singapore, 138593, Singapore
| | - Lakshminarayanan Rajamani
- Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, 18 Science Drive 4, Singapore, 117559, Singapore; Ocular Infections and Anti-Microbials Research Group, Singapore Eye Research Institute, Singapore, 169856, Singapore; Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Graduate Medical School, Singapore, 169857, Singapore
| | - Pui Lai Rachel Ee
- Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, 18 Science Drive 4, Singapore, 117559, Singapore.
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14
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Yang JZ, Li JH, Liu JL, Zhou AD, Wang H, Xie XL, Zhang KK, Wang Q. Multiomics analysis revealed the effects of polystyrene nanoplastics at different environmentally relevant concentrations on intestinal homeostasis. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2025; 372:126050. [PMID: 40086783 DOI: 10.1016/j.envpol.2025.126050] [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: 11/25/2024] [Revised: 02/16/2025] [Accepted: 03/11/2025] [Indexed: 03/16/2025]
Abstract
Nanoplastics pollution is a global issue, with the digestive tract being one of the first affected organs, requiring further research on its impact on intestinal health. This study involved orally exposing mice to polystyrene nanoplastics (PS-NPs) at doses of 0.1, 0.5, or 2.5 mg/d for 42 days. The effects on intestinal health were thoroughly assessed via microbiomics, metabolomics, transcriptomics, and molecular biology. Our study demonstrated that the administration of all three doses of PS-NPs resulted in increased colonic permeability, heightened colonic and peripheral inflammation, reduced levels of antimicrobial peptides, and shortened colonic length. These effects may be attributed to a reduction in the abundance of probiotic bacteria, such as Clostridia_UCG-014, Roseburia, and Akkermansia, alongside an increase in the abundance of the pathogenic bacterium Desulfovibrionaceae induced by PS-NPs. Furthermore, we underscored the crucial role of histidine metabolism in PS-NPs-induced colonic injury, characterized by a significant reduction of L-histidine, which is closely related to microbial ecological dysregulation. Corresponding to microbiota deterioration and metabolic dysregulation, transcriptome analysis revealed that PS-NPs may disrupt colonic immune homeostasis by activating the TLR4/MyD88/NF-κB/NLRP3 signaling pathway. In conclusion, this study provided novel insights into the mechanisms by which PS-NPs disrupt intestinal homeostasis through integrated multiomics analysis, revealing critical molecular pathway and providing a scientific basis for future risk assessment of nanoplastics exposure.
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Affiliation(s)
- Jian-Zheng Yang
- Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Ji-Hui Li
- Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Jia-Li Liu
- Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - An-Ding Zhou
- Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Hui Wang
- Department of Pediatric Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, National Children's Medical Center for South Central Region, Guangzhou, 510623, China
| | - Xiao-Li Xie
- Department of Toxicology, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), Guangzhou, Guangdong, 510515, China
| | - Kai-Kai Zhang
- Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China.
| | - Qi Wang
- Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China.
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15
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Hao Y, Wang C, Wang L, Hu L, Duan T, Zhang R, Yang X, Li T. Nondigestible stachyose alleviates cyclophosphamide-induced small intestinal mucosal injury in mice by regulating intestinal exosomal miRNAs, independently of the gut microbiota. Food Res Int 2025; 209:116258. [PMID: 40253186 DOI: 10.1016/j.foodres.2025.116258] [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: 01/02/2025] [Revised: 02/16/2025] [Accepted: 03/11/2025] [Indexed: 04/21/2025]
Abstract
Stachyose has traditionally been considered to exert prebiotic effects primarily through its interaction with gut microbiota. However, this study reveals a novel mechanism by which stachyose alleviates cyclophosphamide (CY)-induced small intestinal mucosa disruption by regulating the intestinal exosomal miRNAs, without relying on the gut microbiota. Specifically, stachyose significantly mitigates CY-caused damage to the intestinal permeability, oxidative stress, and the structure of intestinal villi and crypts in pseudo-germ-free (PGF) mice. The immunofluorescence staining and qPCR analyses show that stachyose treatment restores CY-caused abnormal changes on the levels of tight junction proteins including MUC2, Occludin, Claudin-1, and ZO-1, and pro-inflammatory cytokines including TNF-α, IL-1β, and IL-2. Furthermore, by conducting fecal miRNA transplantation experiment, we further demonstrated that, similar to stachyose, stachyose-shaped intestinal miRNAs protect against CY-induced intestinal mucosal damage in PGF mice. In summary, this study provides new scientific evidence for the direct interaction between nondigestible stachyose and the proximal small intestine. It also opens new avenues for further investigation into the systemic nutritional functions of stachyose, particularly the health benefits of stachyose in the upper gastrointestinal tract.
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Affiliation(s)
- Yuhang Hao
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, and Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
| | - Chennan Wang
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, and Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
| | - Lu Wang
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, and Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
| | - Lili Hu
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, and Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
| | - Tianchi Duan
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, and Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
| | - Runguang Zhang
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, and Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
| | - Xingbin Yang
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, and Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
| | - Ting Li
- Shaanxi Engineering Laboratory for Food Green Processing and Safety Control, and Shaanxi Key Laboratory for Hazard Factors Assessment in Processing and Storage of Agricultural Products, College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China..
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16
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Tang Z, Zhu Y, Hu X, Lui K, Li S, Song X, Cai C, Guan X. Improving Intestinal Barrier Function in Sepsis by Partially Hydrolysed Guar Gum via the Suppression of the NF-κB/MLCK Pathway. Mol Biotechnol 2025; 67:2035-2045. [PMID: 38789715 DOI: 10.1007/s12033-024-01180-z] [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: 08/02/2023] [Accepted: 04/12/2024] [Indexed: 05/26/2024]
Abstract
Partially hydrolyzed guar gum (PHGG) protects against intestinal barrier dysfunction and can ameliorate some intestinal diseases. However, whether PHGG has a role in protecting intestinal barrier function (IBF) during sepsis remains unclear. This study aimed to investigate the role and probable mechanism of PHGG in the intestinal mucosa in sepsis. A rat sepsis model was constructed using cecal ligation and puncture (CLP). FITC-dextran 4 (FD-4) flux, serum inflammatory mediator levels, tight junction (TJ) levels, jejunum mucosa pathology, and epithelial intercellular junction ultrastructure were monitored to evaluate the effect of PHGG on IBF. Caco-2 monolayers were used to study the impact and mechanism of PHGG on lipopolysaccharide (LPS)-induced barrier dysfunction in vitro. The expression of zonula occludens protein-1 and occludin and the location of P65 were studied by immunofluorescence. Nuclear factor kappa B (NF-κB) and myosin light chain kinase 3 (MLCK) pathway-related protein expression was verified by quantitative reverse transcriptase polymerase chain reaction or western blotting. The results indicated that the jejunal mucosa structure was destroyed, the villi were disrupted and shortened, and neutrophil infiltration was evident in the septic rats. Compared to Sham group, spetic rats had increased Chiu's score, serum inflammatory mediator levels, and FD-4 flux but decreased TJ and gap junction density. In addition, the expression of MLCK, p-MLC, and TJ proteins and the expression of P65 in the nucleus were increased in septic rats. Furthermore, compared to those in the Control group, LPS-treated Caco-2 cells showed lower cell viability and transepithelial electrical resistance, while had higher FD-4 flux and the expression of MLCK, p-MLC, TJ proteins and P65 in the nucleus. PHGG pretreatment reversed the above effects induced by CLP or LPS treatment. Moreover, SN50, an NF-κB inhibitor, attenuated the above effects of LPS on Caco-2 cells. Overall, PHGG reduced inflammation, increased TJ protein expression and localization, and relieved damage to the TJ structure and intestinal permeability through suppression of the NF-κB/MLCK pathway. This study provides new insights into the role of PHGG in sepsis therapy.
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Affiliation(s)
- Zhaoxia Tang
- Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, China
| | - Yanping Zhu
- Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, China
| | - Xiaoguang Hu
- Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, China
| | - Kayin Lui
- Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, China
| | - Shuhe Li
- Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, China
| | - Xiaodong Song
- Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, China
| | - Changjie Cai
- Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, China.
| | - Xiangdong Guan
- Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan Er Road, Guangzhou, 510080, China.
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17
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Murugesan R, Kumar J, Leela KV, Meenakshi S, Srivijayan A, Thiruselvam S, Satheesan A, Chaithanya V. The role of gut microbiota and bacterial translocation in the pathogenesis and management of type 2 diabetes mellitus: Mechanisms, impacts, and dietary therapeutic strategies. Physiol Behav 2025; 293:114838. [PMID: 39922411 DOI: 10.1016/j.physbeh.2025.114838] [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: 12/06/2024] [Revised: 01/17/2025] [Accepted: 01/31/2025] [Indexed: 02/10/2025]
Abstract
PURPOSE OF REVIEW The influence of gut microbiota on Type 2 Diabetes Mellitus (T2DM) is an emerging area of research. This review investigates the relationship between gut microbiota dysbiosis, bacterial translocation, and T2DM. It aims to elucidate how microbial imbalances contribute to the progression of T2DM through bacterial translocation and to evaluate dietary and therapeutic strategies to manage these effects. RECENT FINDINGS Recent studies highlight that dysbiosis in T2DM patients often leads to increased systemic inflammation, impaired glucose metabolism, and disrupted gut barrier integrity. These disruptions promote elevated levels of harmful bacterial components, such as lipopolysaccharides, in the bloodstream. This, in turn, is linked to worsening insulin resistance and metabolic dysfunction. Advances in molecular methods and biomarkers have provided deeper insights into bacterial translocation and its impact on diabetes. Dietary interventions, including nutraceutical agents, high-fiber and low-glycemic index diets, as well as the use of probiotics and prebiotics, have shown promise in restoring gut health and mitigating bacterial translocation. CONCLUSION Maintaining a balanced gut microbiota and intestinal barrier integrity is crucial for managing T2DM. Therapeutic strategies, including dietary modifications and nutraceuticals, have demonstrated potential in reducing bacterial translocation and systemic inflammation. Continued research is needed to refine these approaches and explore novel treatment modalities for improving metabolic health in T2DM patients.
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Affiliation(s)
- Ria Murugesan
- Department of Microbiology, SRM Medical College Hospital and Research Centre, SRMIST, Kattankulathur, Chengalapattu 603203, Tamil Nadu, India.
| | - Janardanan Kumar
- Department of General Medicine, SRM Medical College Hospital and Research Centre, SRMIST, Kattankulathur, Chengalapattu 603203, Tamil Nadu, India.
| | - Kakithakara Vajravelu Leela
- Department of Microbiology, SRM Medical College Hospital and Research Centre, SRMIST, Kattankulathur, Chengalapattu 603203, Tamil Nadu, India
| | - Sachdev Meenakshi
- Department of Dietary, Tamil Nadu Government Multi Super Speciality Hospital, Chennai 600002, Tamil Nadu, India
| | - Appandraj Srivijayan
- Department of Internal Medicine, Melmaruvathur Adhiparasakthi Institute of Medical Sciences and Research, Melmaruvathur 603319, Tamil Nadu, India
| | - Shubhashree Thiruselvam
- Department of Obstetrics and Gynaecology, SRM Medical College Hospital and Research Centre, SRMIST, Kattankulathur, Chengalapattu 603203, Tamil Nadu, India
| | - Abhishek Satheesan
- Department of Microbiology, SRM Medical College Hospital and Research Centre, SRMIST, Kattankulathur, Chengalapattu 603203, Tamil Nadu, India
| | - Venkata Chaithanya
- Department of Microbiology, SRM Medical College Hospital and Research Centre, SRMIST, Kattankulathur, Chengalapattu 603203, Tamil Nadu, India
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18
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Chen Y, Li X, Sun X, Kou Y, Ma X, Song L, Zhang H, Xie F, Song Z, Yuan C, Huang S, Wu Y. Joint transcriptomics and metabolomics unveil the protective mechanism of tamarind seed polysaccharide against antibiotic-induced intestinal barrier damage. Int J Biol Macromol 2025; 305:140999. [PMID: 39952497 DOI: 10.1016/j.ijbiomac.2025.140999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 01/13/2025] [Accepted: 02/11/2025] [Indexed: 02/17/2025]
Abstract
Intestinal barrier damage is frequently caused by antibiotic therapy, potentially leading to bacterial translocation and toxin leakage, which triggers inflammation and increases the risk of various diseases. In this study, Tamarind seed polysaccharides (TSP) with different molecular weights were administered to mice during the recovery phase from clindamycin-induced intestinal barrier damage. The results indicated that TSP restored the shortened colon length, reduced the enlarged cecum index, and decreased the elevated level of inflammatory infiltration. Biochemical testing revealed that TSP decreased the levels of intestinal permeability biomarkers and inflammatory factors that were elevated by clindamycin treatment. Transcriptomics and non-targeted metabolomics analyses respectively uncovered changes in colon gene expression and fecal metabolites. The joint analysis of these omics data identified critical pathways, including arachidonic acid metabolism, retinol metabolism, and steroid hormone biosynthesis. These findings suggest that TSP could be a promising dietary supplement for protecting the intestinal barrier and alleviating inflammation.
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Affiliation(s)
- Yinan Chen
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Xujiao Li
- Institute for Agro-food Standards and Testing Technology, Laboratory of Quality & Safety Risk Assessment for Agro-products (Shanghai), Ministry of Agriculture and Rural Affairs, Shanghai Academy of Agricultural Sciences, Shanghai 201403, China
| | - Xianbao Sun
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yuxing Kou
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Xuan Ma
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Lihua Song
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Hui Zhang
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Fan Xie
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Zibo Song
- Yunnan Maoduoli Group Food Co., Ltd., Yuxi 653100, China; Yunnan Special Favor Biotechnology Co., Ltd., Yuxi 653100, China
| | - Chunmei Yuan
- Yunnan Maoduoli Group Food Co., Ltd., Yuxi 653100, China; Yunnan Special Favor Biotechnology Co., Ltd., Yuxi 653100, China
| | - Siyan Huang
- Yunnan Maoduoli Group Food Co., Ltd., Yuxi 653100, China; Yunnan Special Favor Biotechnology Co., Ltd., Yuxi 653100, China
| | - Yan Wu
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
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19
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Lin W, Ruishi X, Caijiao X, Haoming L, Xuefeng H, Jiyou Y, Minqiang L, Shuo Z, Ming Z, Dongyang L, Xiaoxue F. Potential applications and mechanisms of natural products in mucosal-related diseases. Front Immunol 2025; 16:1594224. [PMID: 40370438 PMCID: PMC12075308 DOI: 10.3389/fimmu.2025.1594224] [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: 03/15/2025] [Accepted: 04/09/2025] [Indexed: 05/16/2025] Open
Abstract
The mucosal barrier serves as a crucial defense against external pathogens and allergens, being widely distributed across the respiratory, gastrointestinal, urogenital tracts, and oral cavity. Its disruption can lead to various diseases, including inflammatory bowel disease, asthma, urinary tract infections, and oral inflammation. Current mainstream treatments for mucosa-associated diseases primarily involve glucocorticoids and immunosuppressants, but their long-term use may cause adverse effects. Therefore, the development of safer and more effective therapeutic strategies has become a focus of research. Natural products, with their multi-target and multi-system regulatory advantages, offer a promising avenue for the treatment of mucosal diseases. This review summarizes the potential applications of natural products in diseases of mucosal barrier dysfunction through mechanisms such as immune modulation, inflammation inhibition, tight junction protein restoration, and gut microbiota regulation, with the aim of providing insights for the exploration of novel therapeutic strategies.
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Affiliation(s)
- Wang Lin
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Xie Ruishi
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Xu Caijiao
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Luo Haoming
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Hua Xuefeng
- The First People’s Hospital of Guangzhou, Department of Hepatobiliary and Pancreatic Surgery, Guangzhou, China
| | - Yao Jiyou
- The First People’s Hospital of Guangzhou, Department of Hepatobiliary and Pancreatic Surgery, Guangzhou, China
| | - Lu Minqiang
- The First People’s Hospital of Guangzhou, Department of Hepatobiliary and Pancreatic Surgery, Guangzhou, China
| | - Zhou Shuo
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Zhu Ming
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Li Dongyang
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Fang Xiaoxue
- Changchun University of Chinese Medicine, Changchun, China
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
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20
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Li J, Qiao J, Li Y, Qin G, Xu Y, Lao K, Wang Y, Fan Y, Tang P, Han L. Metabolic disorders in polycystic ovary syndrome: from gut microbiota biodiversity to clinical intervention. Front Endocrinol (Lausanne) 2025; 16:1526468. [PMID: 40357203 PMCID: PMC12066289 DOI: 10.3389/fendo.2025.1526468] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 03/31/2025] [Indexed: 05/15/2025] Open
Abstract
Polycystic ovary syndrome (PCOS) is a prevalent gynecologic endocrine disorder characterized by menstrual irregularities, elevated androgen levels, and ovulatory dysfunction. Its etiology is multifactorial. Emerging evidence indicates that PCOS patients exhibit diminished gut microbiota (GM) diversity and altered microbial ratios, contributing to the metabolic derangements observed in these individuals. This review elucidates the role of GM in the pathogenesis and metabolic disorders of PCOS, encompassing insulin resistance (IR), hormonal imbalances, bile acid metabolic disorders, Interleukin-22-mediated immune dysregulation, and brain-gut axis disturbances. Additionally, it synthesizes current therapeutic strategies targeting the GM, aiming to furnish a theoretical framework for prospective clinical interventions.
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Affiliation(s)
- Jiyuan Li
- The First School of Clinical Medicine, Binzhou Medical University Hospital, Binzhou Medical University, Binzhou, Shandong, China
| | - Jiashen Qiao
- The First School of Clinical Medicine, Binzhou Medical University Hospital, Binzhou Medical University, Binzhou, Shandong, China
| | - Yihan Li
- The First School of Clinical Medicine, Binzhou Medical University Hospital, Binzhou Medical University, Binzhou, Shandong, China
| | - Gaofeng Qin
- Department of Traditional Chinese Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Yingjiang Xu
- Department of Interventional Vascular Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Kaixue Lao
- Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Yanlin Wang
- Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Yang Fan
- Department of Clinical Nutrition, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Peiyi Tang
- Department of Clinical Nutrition, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Lei Han
- Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, China
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21
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Li C, Liu W, Fu A, Yang H, Yi G. Potential therapeutic strategies targeting efferocytosis for inflammation resolution and tissue repair in inflammatory bowel disease. Cell Immunol 2025; 411-412:104957. [PMID: 40315792 DOI: 10.1016/j.cellimm.2025.104957] [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: 08/21/2024] [Revised: 04/11/2025] [Accepted: 04/19/2025] [Indexed: 05/04/2025]
Abstract
Efferocytosis, the process by which apoptotic cells (ACs) are recognized and cleared by phagocytes, is a critical mechanism in maintaining intestinal immune homeostasis and promoting the resolution of inflammation. Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is characterized by chronic intestinal inflammation, wherein defective efferocytosis contributes to the accumulation of ACs, secondary necrosis, and sustained mucosal damage. This review delineates the molecular mechanisms underlying efferocytosis and systematically examines its functional roles across five key intestinal phagocytic cell types: macrophages, dendritic cells (DCs), neutrophils, intestinal epithelial cells (IECs), and Paneth cells (PCs). Particular emphasis is placed on the dysregulation of efferocytosis capacity in IBD pathogenesis and the consequences of impaired apoptotic cell clearance in both professional and non-professional phagocytes. Furthermore, we evaluate emerging therapeutic strategies designed to restore or enhance efferocytosis, including modulation of macrophage polarization, LC3-associated phagocytosis pathways, nanotechnology-enabled delivery systems, and stem cell-based interventions. A comprehensive understanding of cell-type-specific efferocytosis in the intestinal microenvironment offers promising directions for the development of targeted, inflammation-resolving therapies for IBD.
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Affiliation(s)
- Chaoquan Li
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Wanting Liu
- Institute of Pharmacy and Pharmacology, Hunan province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China
| | - Aoni Fu
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Haotian Yang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Guanghui Yi
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; Institute of Pharmacy and Pharmacology, Hunan province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China.
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22
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Jiang D, Zhang J, Ji Y, Dai Z, Yang Y, Wu Z. Glutamate Supplementation Regulates Nitrogen Metabolism in the Colon and Liver of Weaned Rats Fed a Low-Protein Diet. Nutrients 2025; 17:1465. [PMID: 40362775 DOI: 10.3390/nu17091465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 04/03/2025] [Accepted: 04/11/2025] [Indexed: 05/15/2025] Open
Abstract
Background: Glutamate, a nutritionally non-essential amino acid, is a key intermediate in nitrogen metabolism. Despite more studies on its functional role in intestine health, it remains unknown how glutamate regulates nitrogen metabolism in animals fed a low-protein diet. Methods: Herein, we investigated the effects of glutamate supplementation on colonic amino acid transport, barrier protein expression, microbiota alterations, fecal nitrogen emissions, hepatic amino acid transport, and protein synthesis in weaned rats. Results: We found that protein restriction diminished the mucus thickness, reduced goblet cell numbers, and the expression of EAAT3, y+LAT2 in the colon. In contrast, glutamate supplementation reversed these effects, increasing the colon length and enhancing the expression of ZO-1, Occludin, and Claudin-1 in the colon. At the genus level, glutamate increased the abundance of Lactococcus and Clostridia_sensu_stricto_18. Additionally, glutamate supplementation resulted in an increased apparent nitrogen digestibility, reduced the ratio of fecal nitrogen to total nitrogen intake, and increased the ratio of fecal microbial nitrogen to total nitrogen intake. Protein restriction decreased the mRNA level of ATP1A1, EAAT3, SNAT9/2, and ASCT2, and the protein level of p-mTOR, mTOR, p-mTOR/mTOR, and p-p70S6K/p70S6K as well as p-4EBP1/4EBP1 in the liver. These effects were reversed by glutamate supplementation. Conclusions: In conclusion, glutamate supplementation upregulates amino acid transporters and barrier protein expression in the colon, modulates microbiota composition to reduce fecal nitrogen excretion, and enhances amino acid transport and protein synthesis in the liver by activating the mTOR/p70S6K/4EBP1 pathway, which influences nitrogen metabolism in weaned rats fed a low-protein diet.
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Affiliation(s)
- Da Jiang
- State Key Laboratory of Animal Nutrition and Feed Science, China Agricultural University, Beijing 100193, China
| | - Jing Zhang
- State Key Laboratory of Animal Nutrition and Feed Science, China Agricultural University, Beijing 100193, China
| | - Yun Ji
- State Key Laboratory of Animal Nutrition and Feed Science, China Agricultural University, Beijing 100193, China
| | - Zhaolai Dai
- State Key Laboratory of Animal Nutrition and Feed Science, China Agricultural University, Beijing 100193, China
| | - Ying Yang
- State Key Laboratory of Animal Nutrition and Feed Science, China Agricultural University, Beijing 100193, China
| | - Zhenlong Wu
- State Key Laboratory of Animal Nutrition and Feed Science, China Agricultural University, Beijing 100193, China
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23
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Cicia D, Biscu F, Iannotti FA, Miraglia M, Ferrante C, Iaccarino N, Cadenas de Miguel S, Chiavaroli A, Schiano Moriello A, De Cicco P, Nanì MF, Zanoletti L, Ke BJ, van Baarle L, Talavera K, Randazzo A, Elia I, Capasso R, Matteoli G, Pagano E, Izzo AA. Dietary targeting of TRPM8 rewires macrophage immunometabolism reducing colitis severity. Cell Death Dis 2025; 16:343. [PMID: 40280909 PMCID: PMC12032354 DOI: 10.1038/s41419-025-07553-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 02/24/2025] [Accepted: 03/17/2025] [Indexed: 04/29/2025]
Abstract
The interplay between diet, host genetics, microbiota, and immune system has a key role in the pathogenesis of inflammatory bowel disease (IBD). Although the causal pathophysiological mechanisms remain unknown, numerous dietary nutrients have been shown to regulate gut mucosal immune function, being effective in influencing innate or adaptive immunity. Here, we proved that transient receptor potential melastatin 8 (TRPM8), a non-selective cation channel, mediates LPS- evoked Ca2+ influx in macrophages leading to their activation. Additionally, we showed that TRPM8 is selectively blocked by the dietary flavonoid luteolin, which induced a pro-tolerogenic phenotype in pro-inflammatory macrophages. Accordingly, genetic deletion of Trpm8 in macrophages caused a deficit in the activation of pro-inflammatory metabolic and transcriptional reprogramming, leading to reduced production of key pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. The TRPM8 anti-inflammatory effect was found to be dependent on lactate which in turn induces IL-10 gene expression. Adoptive transfer of TRPM8-deficient bone marrow in wild-type mice improved intestinal inflammation in a model of colitis. Accordingly, oral administration of luteolin protected mice against colitis through an impairment in the innate immune response. Our study reveals the potential of targeting TRPM8 through specific nutrient interventions to regulate immune function in sub-clinical scenarios or to treat inflammatory diseases, primarily driven by chronic immune responses, such as IBD.
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Affiliation(s)
- D Cicia
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
- Laboratory of Mucosal Immunology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - F Biscu
- Laboratory of Mucosal Immunology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | - F A Iannotti
- Institute of Biomolecular Chemistry ICB, CNR, Pozzuoli, Naples, Italy
| | - M Miraglia
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - C Ferrante
- Department of Pharmacy, Gabriele d'Annunzio University, Chieti, Italy
| | - N Iaccarino
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - S Cadenas de Miguel
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute, Leuven, Belgium
| | - A Chiavaroli
- Department of Pharmacy, Gabriele d'Annunzio University, Chieti, Italy
| | | | - P De Cicco
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - M F Nanì
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - L Zanoletti
- Laboratory of Mucosal Immunology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, Pavia, Italy
| | - B-J Ke
- Laboratory of Mucosal Immunology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - L van Baarle
- Laboratory of Mucosal Immunology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - K Talavera
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven and VIB Center for Brain and Disease Research, Leuven, Belgium
| | - A Randazzo
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - I Elia
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute, Leuven, Belgium
| | - R Capasso
- Department of Agricultural Sciences, University of Naples Federico II, Naples, Italy
| | - G Matteoli
- Laboratory of Mucosal Immunology, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.
| | - E Pagano
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy.
| | - A A Izzo
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
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24
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Xu Y, Chen L, Hu X, Lai Z, Chen B, Wu M, Mai L, Su Z, Chen J, Lai Z, Ai W, Xie J, Liao H, Xie Y. Brusatol ameliorates intestinal mucosal injury in ulcerative colitis via activating IL-22/STAT3 pathway. Int Immunopharmacol 2025; 153:114482. [PMID: 40101416 DOI: 10.1016/j.intimp.2025.114482] [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: 01/07/2025] [Revised: 02/23/2025] [Accepted: 03/10/2025] [Indexed: 03/20/2025]
Abstract
Brusatol (BR) is an active compounds isolated from Brucea javanica, a Chinese herbal medicine that is famous for its anti-diarrheal effect. We have previously reported that BR mitigated inflammation in murine ulcerative colitis (UC) models. However, BR's role in intestinal mucosal healing, which is recently established as central strategy for the prevention and treatment of UC, remains unknown. In this study, the ameliorative effect of BR on intestinal mucosal damage was investigated in DSS-induced UC mice. BR significantly alleviated colitis symptoms, improved intestinal barrier function by preventing loss of goblet cells and downregulation of mucins and tight junction proteins, as well as maintained proliferative and apoptotic homeostasis in the colonic epithelium of UC mice. Mechanistically, BR enhanced the level and secretion of IL-22, but inhibited IL-22BP, an inhibitory protein of IL-22, in the blood serum and intestinal tissues of UC mice, as well as in MNK3 cells which is an effective cell model for studying ILC3s. Additionally, BR elevated the expressions of receptors for IL-22 (IL-10R2 and IL-22R1), and activated its downstream STAT3 signaling pathway. Furthermore, the involvement of IL-22 was further investigated by using recombinant IL-22 (rIL-22) and IL-22 antibody (anti-IL-22). BR demonstrated comparable effects with rIL-22 on alleviating intestinal inflammation and repairing intestinal mucosal injury. Treatment with anti-IL-22 abrogated the mucosal protective effects of BR. The present findings shed novel insights into the role of BR in intestinal mucosal healing via activating IL-22/STAT3 signaling pathway in UC.
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Affiliation(s)
- Ying Xu
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Li Chen
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China; Pharmacy Center, Shenzhen Nanshan Medical Group Headquarters, Shenzhen, PR China
| | - Xiaoxia Hu
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Zixuan Lai
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Baoyi Chen
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Minghui Wu
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Liting Mai
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Ziren Su
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Jiannan Chen
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Zhengquan Lai
- Department of Pharmacy, Shenzhen University General Hospital/Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen, PR China
| | - Weipeng Ai
- Department of Pharmacy, Shenzhen University General Hospital/Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen, PR China
| | - Jianhui Xie
- Guangdong Provincial Key Laboratory of Clinical Research on TCM Syndrome, Guangzhou, PR China
| | - Huijun Liao
- Pharmacy Center, Shenzhen Nanshan Medical Group Headquarters, Shenzhen, PR China; Department of Clinical Pharmacy and Pharmaceutical Services, Shenzhen Nanshan People's Hospital, Shenzhen, PR China.
| | - Youliang Xie
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China; Guangdong Provincial Key Laboratory of Clinical Research on TCM Syndrome, Guangzhou, PR China.
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25
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Zhou Z, Wang L, Liao R, Chen Q, Liu C, Song J, Deng C, Huang X. The Effect of GB1 on DSS-Induced Colitis in WT and Nlrp3 -/- Mice. Int J Mol Sci 2025; 26:4016. [PMID: 40362256 DOI: 10.3390/ijms26094016] [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: 03/19/2025] [Revised: 04/21/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
This study investigated the protective effects of Garcinia biflavonoid 1 (GB1) against dextran sulfate sodium (DSS)-induced ulcerative colitis and its underlying mechanisms. Using wild-type (WT) and NLRP3 knockout (Nlrp3-/-) mice, we demonstrated that GB1 administration significantly ameliorated colitis symptoms, as evidenced by improved body weight, disease activity index (DAI) scores, colon length, and histological damage in WT mice. Mechanistically, GB1 downregulated pro-inflammatory mediators (IL-6, NF-κB, and CD11b) while attenuating the expression of NLRP3 inflammasome components (ASC, Caspase-1, and IL-1β). Notably, these protective effects were abolished in Nlrp3-/- mice, confirming the essential role of NLRP3 in GB1-mediated mitigation of colitis. Furthermore, GB1 reinforced intestinal barrier integrity by preserving tight junctions, reducing permeability, and attenuating mucosal inflammation. Collectively, our findings highlight GB1 as a promising therapeutic candidate for colitis treatment, primarily through NLRP3 inflammasome suppression and intestinal barrier restoration.
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MESH Headings
- Animals
- NLR Family, Pyrin Domain-Containing 3 Protein/genetics
- NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
- NLR Family, Pyrin Domain-Containing 3 Protein/deficiency
- Dextran Sulfate/adverse effects
- Mice
- Mice, Knockout
- Inflammasomes/metabolism
- Biflavonoids/pharmacology
- Biflavonoids/therapeutic use
- Colitis/chemically induced
- Colitis/drug therapy
- Colitis/pathology
- Colitis/metabolism
- Mice, Inbred C57BL
- Colitis, Ulcerative/chemically induced
- Colitis, Ulcerative/drug therapy
- Colitis, Ulcerative/pathology
- Colitis, Ulcerative/metabolism
- Disease Models, Animal
- Male
- Intestinal Mucosa/drug effects
- Intestinal Mucosa/metabolism
- Intestinal Mucosa/pathology
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Affiliation(s)
- Ziyi Zhou
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Lixian Wang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Ruhe Liao
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Qin Chen
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Changhui Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Jianping Song
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Changsheng Deng
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing 100700, China
| | - Xinan Huang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
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26
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Ye R, Guo J, Yang Z, Wang Z, Chen Y, Huang J, Dong Y. Somatostatin and Mannooligosaccharide Modified Selenium Nanoparticles with Dual-Targeting for Ulcerative Colitis Treatment. ACS NANO 2025; 19:14914-14930. [PMID: 40214514 DOI: 10.1021/acsnano.5c00355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/23/2025]
Abstract
Inflammatory bowel disease (IBD) is a prevalent condition worldwide, characterized by complex etiologies, limited efficacy of clinical drug treatments, and potential adverse effects. In this study, we designed 269 nm selenium nanoparticles with double-cell targeting for ulcerative colitis treatment. Somatostatin (SST) and mannooligosaccharide (MOS) were employed to functionalize an Eucommia ulmoides polysaccharide selenium nanoparticle (EUP-SeNP), resulting in the formulation of SST/MOS@EUP-SeNP. Nanoparticles were engineered to target intestinal epithelial cells and macrophages through specific cell surface receptors, enabling dual-targeted treatment. In addition, sodium alginate (SA) microspheres incorporating SST/MOS@EUP-SeNP were prepared for oral administration, protecting the nanoparticles from gastric fluid. The results showed that SA/SST/MOS@EUP-SeNP could preferentially target the inflamed colon tissue and adhere to the colon, enhance the intestinal barrier function, regulate the level of colon inflammation, enhance antioxidant capacity, and regulate the composition of intestinal microbes to effectively relieve the colitis induced by sodium glucan sulfate (DSS). Meanwhile, SA/SST/MOS@EUP-SeNP had excellent biocompatibility both in vivo and in vitro. To some extent, this study can provide a reference for the treatment of IBD.
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Affiliation(s)
- Ruihua Ye
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Jianying Guo
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Zhongjin Yang
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
- Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China
| | - Zixu Wang
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Yaoxing Chen
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Jiaqiang Huang
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100193, China
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China
| | - Yulan Dong
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
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Zhao Z, Xu Y, Hu Y. Acid-resistant chemotactic DNA micromotors for probiotic delivery in inflammatory bowel disease. Nat Commun 2025; 16:3778. [PMID: 40263286 PMCID: PMC12015548 DOI: 10.1038/s41467-025-59172-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Accepted: 04/13/2025] [Indexed: 04/24/2025] Open
Abstract
Microcapsules composed of synthetic polymeric matrices have attracted considerable attention in delivering oral probiotics. However, existing polymeric microcapsules demonstrate inadequate acid resistance and adaptability, as well as deficiency in the inflamed colon-specificity and uncontrolled release of probiotics therein. Herein, a DNA microcapsule is prepared as a probiotic-transporting micromotor through photo-crosslinking of hyaluronic acid methacrylate and acrydite-modified A-/C-rich oligomers within the microfludically generated droplets in the presence of nitric oxide-cleavable crosslinker and gas donor manganese carbonyl (MnCO). As the microcapsules traverse stomach, duodenum, and ultimately colon, the formation and dissociation of A-motif and i-motif structures instigate a reversible shrinking-swelling transition of microcapsules to preserve probiotic viability. Subsequently, the microcapsules exhibit chemotaxis towards inflamed colon site, driven by a gas-generating reaction between MnCO and elevated reactive oxygen species. Following disintegration of the microcapsules, triggered by endogenous nitric oxide, probiotics are released to reshape the dysbiosis of intestinal microflora. This advanced delivery system offers significant promise for the effective clinical management of inflammatory bowel disease.
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Affiliation(s)
- Zinan Zhao
- Department of Polymeric Materials, School of Materials Science and Engineering, Tongji University, Shanghai, 201804, P. R. China
| | - Yao Xu
- Department of Polymeric Materials, School of Materials Science and Engineering, Tongji University, Shanghai, 201804, P. R. China
| | - Yong Hu
- Department of Polymeric Materials, School of Materials Science and Engineering, Tongji University, Shanghai, 201804, P. R. China.
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Duan Q, Yu B, Huang Z, Luo Y, Zheng P, Mao X, Yu J, Luo J, Yan H, He J. Sialyllactose Attenuates Inflammation and Injury of Intestinal Epithelial Cells upon Enterotoxigenic Escherichia coli Infection. Int J Mol Sci 2025; 26:3860. [PMID: 40332525 PMCID: PMC12027521 DOI: 10.3390/ijms26083860] [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: 03/19/2025] [Revised: 04/11/2025] [Accepted: 04/15/2025] [Indexed: 05/08/2025] Open
Abstract
Sialyllactose (SL), a bioactive trisaccharide abundant in porcine colostrum, demonstrates multifunctional properties including antimicrobial activity, immune regulation, and apoptosis inhibition. This research uncovers the mechanisms by which SL mitigates enterotoxigenic Escherichia coli (ETEC)-mediated damage to intestinal barrier integrity, employing IPEC-J2 porcine epithelial models. SL pre-treatment effectively blocked pathogen adhesion by competitively binding to cellular receptors, concurrently mitigating inflammation through significant suppression of TNF-α, IL-1β, and IL-6 expression (p < 0.05). Notably, SL exhibited functional parallels to the NF-κB inhibitor BAY11-7082, jointly enhancing tight junction integrity via ZO-1 protein stabilization and inhibiting pro-inflammatory signaling through coordinated suppression of IκB-α/NF-κB phosphorylation cascades. The dual-action mechanism combines molecular interception of microbial attachment with intracellular modulation of the TLR4/MyD88/NF-κB pathway, effectively resolving both pathogenic colonization and inflammatory amplification. These findings position SL as a potential therapeutic application nutraceutical for livestock, with the capacity to address post-weaning porcine enteritis through functional feed formulations that synergistically enhance intestinal barrier resilience while curbing ETEC-mediated inflammatory pathogenesis.
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Affiliation(s)
- Qiming Duan
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China; (Q.D.)
- Key Laboratory for Animal Disease-Resistance Nutrition, Chengdu 611130, China
| | - Bing Yu
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China; (Q.D.)
- Key Laboratory for Animal Disease-Resistance Nutrition, Chengdu 611130, China
| | - Zhiqing Huang
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China; (Q.D.)
- Key Laboratory for Animal Disease-Resistance Nutrition, Chengdu 611130, China
| | - Yuheng Luo
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China; (Q.D.)
- Key Laboratory for Animal Disease-Resistance Nutrition, Chengdu 611130, China
| | - Ping Zheng
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China; (Q.D.)
- Key Laboratory for Animal Disease-Resistance Nutrition, Chengdu 611130, China
| | - Xiangbing Mao
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China; (Q.D.)
- Key Laboratory for Animal Disease-Resistance Nutrition, Chengdu 611130, China
| | - Jie Yu
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China; (Q.D.)
- Key Laboratory for Animal Disease-Resistance Nutrition, Chengdu 611130, China
| | - Junqiu Luo
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China; (Q.D.)
- Key Laboratory for Animal Disease-Resistance Nutrition, Chengdu 611130, China
| | - Hui Yan
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China; (Q.D.)
- Key Laboratory for Animal Disease-Resistance Nutrition, Chengdu 611130, China
| | - Jun He
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China; (Q.D.)
- Key Laboratory for Animal Disease-Resistance Nutrition, Chengdu 611130, China
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Zhang C, Zhen Y, Weng Y, Lin J, Xu X, Ma J, Zhong Y, Wang M. Research progress on the microbial metabolism and transport of polyamines and their roles in animal gut homeostasis. J Anim Sci Biotechnol 2025; 16:57. [PMID: 40234982 PMCID: PMC11998418 DOI: 10.1186/s40104-025-01193-x] [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: 12/03/2024] [Accepted: 03/09/2025] [Indexed: 04/17/2025] Open
Abstract
Polyamines (putrescine, spermidine, and spermine) are aliphatic compounds ubiquitous in prokaryotes and eukaryotes. Positively charged polyamines bind to negatively charged macromolecules, such as nucleic acids and acidic phospholipids, and are involved in physiological activities including cell proliferation, differentiation, apoptosis and gene regulation. Intracellular polyamine levels are regulated by biosynthesis, catabolism and transport. Polyamines in the body originate from two primary sources: dietary intake and intestinal microbial metabolism. These polyamines are then transported into the bloodstream, through which they are distributed to various tissues and organs to exert their biological functions. Polyamines synthesized by intestinal microorganisms serve dual critical roles. First, they are essential for maintaining polyamine concentrations within the digestive tract. Second, through transcriptional and post-transcriptional mechanisms, these microbial-derived polyamines modulate the expression of genes governing key processes in intestinal epithelial cells-including proliferation, migration, apoptosis, and cell-cell interactions. Collectively, these regulatory effects help maintain intestinal epithelial homeostasis and ensure the integrity of the gut barrier. In addition, polyamines interact with the gut microbiota to maintain intestinal homeostasis by promoting microbial growth, biofilm formation, swarming, and endocytosis vesicle production, etc. Supplementation with polyamines has been demonstrated to be important in regulating host intestinal microbial composition, enhancing nutrient absorption, and improving metabolism and immunity. In this review, we will focus on recent advances in the study of polyamine metabolism and transport in intestinal microbes and intestinal epithelial cells. We then summarize the scientific understanding of their roles in intestinal homeostasis, exploring the advances in cellular and molecular mechanisms of polyamines and their potential clinical applications, and providing a rationale for polyamine metabolism as an important target for the treatment of intestinal-based diseases.
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Affiliation(s)
- Chong Zhang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, China
| | - Yongkang Zhen
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, China
| | - Yunan Weng
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, China
| | - Jiaqi Lin
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, China
| | - Xinru Xu
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, China
| | - Jianjun Ma
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, China
| | - Yuhong Zhong
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, China
| | - Mengzhi Wang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, China.
- State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural Reclamation Sciences, Shihezi, 832000, China.
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30
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Emílio-Silva MT, Rodrigues VP, Fioravanti MM, Ruiz-Malagon AJ, Naia Fioretto M, Raimundo PR, Ohara R, Assunção R, Bueno G, Dario FL, Justulin LA, Rodríguez-Nogales A, da Rocha LRM, Gálvez J, Hiruma-Lima CA. Citral protects against metabolic endotoxemia, and systemic disorders caused by high-fat diet-induced obesity via intestinal modulation. Front Pharmacol 2025; 16:1567217. [PMID: 40260376 PMCID: PMC12009827 DOI: 10.3389/fphar.2025.1567217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Accepted: 03/24/2025] [Indexed: 04/23/2025] Open
Abstract
Background Obesity is a growing global epidemic associated with changes in the gut microenvironment and metabolic endotoxemia, which can exacerbate metabolic and inflammatory processes. Citral (CT), a monoterpene present in essential oils, has been investigated for its anti-inflammatory, antioxidant, and immunomodulatory properties. However, its role in modulating the gut axis during metabolic and inflammatory alterations in obesity remains unknown. In this study, we investigated the effects of CT on intestinal and metabolic impairment induced by lipopolysaccharide (LPS) and high-fat diet (HFD) in in vitro and in vivo models. Methods Male C57BL/6J mice were fed a standard diet and HFD for 17 weeks, with daily oral administration of CT treatment (25, 100, or 300 mg/kg) or vehicle. Morphological and histological parameters, lipid profiles, adipose index, cytokine levels, and colonic gene expression were determined. In vitro, murine rectal carcinoma (CMT-93) cells were stimulated with LPS (10 μg/mL) to assess tight junction and inflammatory protein expression. Results CT treatment showed anti-obesity activity against HFD-induced body mass gain in mice, which was attributed to a significant reduction in body fat, glycemia, and cholesterol levels. Systemic inflammation during obesity also decreased after CT treatment, with a significant reduction in serum levels of endotoxin, interleukin-1β, and tumor necrosis factor-α. Additionally, CT stimulation reduced inducible nitric oxide synthase expression and maintained ZO-1 levels in LPS-stimulated CMT-93 cells. Conclusion CT has anti-obesogenic, anti-inflammatory, and anti-hyperlipidemic properties mediated by its protective effects on the intestinal epithelium in obesity. Thus, our results highlight the promising preclinical results of CT treatment as a protective agent against the detrimental effects of HFD and LPS in mice.
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Affiliation(s)
- Maycon Tavares Emílio-Silva
- Department of Structural and Functional Biology, Physiology Sector, Institute of Bioscience, São Paulo State University (UNESP), Botucatu, Brazil
| | - Vinicius Peixoto Rodrigues
- Department of Structural and Functional Biology, Physiology Sector, Institute of Bioscience, São Paulo State University (UNESP), Botucatu, Brazil
| | - Mariana Moraes Fioravanti
- Department of Structural and Functional Biology, Physiology Sector, Institute of Bioscience, São Paulo State University (UNESP), Botucatu, Brazil
| | - Antonio Jesús Ruiz-Malagon
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
| | - Matheus Naia Fioretto
- Department of Structural and Functional Biology, Morphology Sector, Institute of Bioscience, São Paulo State University, (UNESP), Botucatu, Brazil
| | - Priscila Romano Raimundo
- Department of Structural and Functional Biology, Physiology Sector, Institute of Bioscience, São Paulo State University (UNESP), Botucatu, Brazil
| | - Rie Ohara
- Department of Structural and Functional Biology, Physiology Sector, Institute of Bioscience, São Paulo State University (UNESP), Botucatu, Brazil
| | - Renata Assunção
- Department of Structural and Functional Biology, Physiology Sector, Institute of Bioscience, São Paulo State University (UNESP), Botucatu, Brazil
| | - Gabriela Bueno
- Department of Structural and Functional Biology, Physiology Sector, Institute of Bioscience, São Paulo State University (UNESP), Botucatu, Brazil
| | - Felipe Lima Dario
- Department of Structural and Functional Biology, Physiology Sector, Institute of Bioscience, São Paulo State University (UNESP), Botucatu, Brazil
| | - Luis Antonio Justulin
- Department of Structural and Functional Biology, Morphology Sector, Institute of Bioscience, São Paulo State University, (UNESP), Botucatu, Brazil
| | - Alba Rodríguez-Nogales
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
| | - Lucia Regina Machado da Rocha
- Department of Structural and Functional Biology, Physiology Sector, Institute of Bioscience, São Paulo State University (UNESP), Botucatu, Brazil
| | - Júlio Gálvez
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
- CIBER de Enfermedades Hepáticas y Digestivas (CIBER-EHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Clélia Akiko Hiruma-Lima
- Department of Structural and Functional Biology, Physiology Sector, Institute of Bioscience, São Paulo State University (UNESP), Botucatu, Brazil
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31
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Aljumaah MR, Roach J, Hu Y, Gunstad J, Azcarate-Peril MA. Microbial dipeptidyl peptidases of the S9B family as host-microbe isozymes. SCIENCE ADVANCES 2025; 11:eads5721. [PMID: 40173242 PMCID: PMC11964003 DOI: 10.1126/sciadv.ads5721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 02/26/2025] [Indexed: 04/04/2025]
Abstract
Human dipeptidyl peptidase 4 (hDPP-4) has been a pharmacological target for metabolic diseases, particularly diabetes, since the early 2000s. As a ubiquitous enzyme found in both prokaryotic and eukaryotic organisms, hDPP-4 plays crucial roles in host homeostasis and disease progression. While many studies have explored hDPP-4's properties, research on gut microbially derived DPP-4 (mDPP-4) remains limited. This review discusses the significance of mDPP-4 and its health implications, analyzing crystal structures of mDPP-4 in comparison to human counterparts. We examine how hDPP-4 inhibitors could influence gut microbiome composition and mDPP-4 activity. Additionally, this review connects ongoing discussions regarding DPP-4 substrate specificity and potential access routes for mDPP-4, emphasizing the urgent need for further research on mDPP-4's role in health and improve the precision of DPP-4 inhibitor therapies.
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Affiliation(s)
- Mashael R. Aljumaah
- Center for Gastrointestinal Biology and Disease (CGIBD), Department of Medicine, Division of Gastroenterology and Hepatology, School of Medicine, UNC Microbiome Core, University of North Carolina, Chapel Hill, NC, USA
- Department of Plant and Microbial Biology, North Carolina State University, Raleigh, NC, USA
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Jeffery Roach
- Center for Gastrointestinal Biology and Disease (CGIBD), Department of Medicine, Division of Gastroenterology and Hepatology, School of Medicine, UNC Microbiome Core, University of North Carolina, Chapel Hill, NC, USA
| | - Yunan Hu
- Center for Gastrointestinal Biology and Disease (CGIBD), Department of Medicine, Division of Gastroenterology and Hepatology, School of Medicine, UNC Microbiome Core, University of North Carolina, Chapel Hill, NC, USA
| | - John Gunstad
- Department of Psychological Sciences, Kent State University, Kent, OH, USA
| | - M. Andrea Azcarate-Peril
- Center for Gastrointestinal Biology and Disease (CGIBD), Department of Medicine, Division of Gastroenterology and Hepatology, School of Medicine, UNC Microbiome Core, University of North Carolina, Chapel Hill, NC, USA
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Wu S, Gao J, Han Y, Zhang W, Li X, Kong D, Wang H, Zuo L. Balancing act: The dual role of claudin-2 in disease. Ann N Y Acad Sci 2025; 1546:75-89. [PMID: 40101185 DOI: 10.1111/nyas.15311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2025]
Abstract
Claudin-2 (CLDN2), a tight junction protein, is predominantly found in leaky epithelial cell layers where it plays a pivotal role in forming paracellular pores necessary for the efficient transport of cations and water. Its abundance is intricately regulated by upstream signals, modulating its synthesis, transport, and localization to adapt to diverse environmental changes. Aberrant expression levels of CLDN2 are observed in numerous pathological conditions including cancer, inflammation, immune disorders, fibrosis, and kidney and biliary stones. Recent advances have uncovered the mechanisms by which the loss or restoration of CLDN2 affects functions such as epithelial barrier, cell proliferation, renewal, migration, invasion, and tissue regeneration. This exerts a dual-directional influence on the pathogenesis, perpetuation, and progression of diseases, indicating the potential to both accelerate and decelerate the course of disease evolution. Here, we discuss these nuanced bidirectional regulatory effects mediated by CLDN2, and how it may contribute to the progression or regression of disease when it becomes unbalanced.
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Affiliation(s)
- Shanshan Wu
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Jia Gao
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yiran Han
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Wenzhe Zhang
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Xue Li
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Derun Kong
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hua Wang
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Li Zuo
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, China
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, China
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Yu H, Nie Y, Zhang B, Xue J, Xue K, Huang X, Zhang X. Creatine supplementation in largemouth bass (Micropterus salmoides) diets: Improving intestinal health and alleviating enteritis. FISH & SHELLFISH IMMUNOLOGY 2025; 159:110164. [PMID: 39894092 DOI: 10.1016/j.fsi.2025.110164] [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: 10/28/2024] [Revised: 01/26/2025] [Accepted: 01/27/2025] [Indexed: 02/04/2025]
Abstract
Creatine plays an important role in regulating intestinal epithelial cell energy metabolism, epithelial integrity, and intestinal barrier function. In this study, three feeds with varying creatine concentrations (0 %, 0.5 %, and 4 %, labeled CR0, CR0.5, and CR4, respectively) were formulated and administered to juvenile largemouth bass (Micropterus salmoides) for 8 weeks. Creatine-containing diets significantly improved growth performance and intestinal villus height. Microbiota analysis revealed that creatine-containing diets changed the beta diversity of gut microbes and increased the relative proportion of Cetobacterium. Enteritis was induced for 7 days using the corresponding feeds containing creatine and 2 % DSS (labeled CR0, DCR0, DCR0.5, and DCR4). Enteritis resulted in an increase in hif1α expression in the DCR0.5 and DCR4 groups and a significant increase expression of creatine transporter SLC6A8. QPCR and Western blotting of intestinal barrier-related genes (e.g., Claudin1, Claudin4, and ZO1), MUC2 immunohistochemistry, and PAS mucus staining were used to show intestinal barrier status, these results suggest that dietary creatine attenuates the extent of intestinal barrier damage. After TUNEL and KI67 immunofluorescence analyses of the intestine and detection of the expression of relevant genes at the protein and transcript levels, the results showed that dietary addition of creatine significantly alleviated intestinal apoptosis and cellular inflammatory responses due to DSS-induced enteritis. These findings indicate long-term dietary supplementation with creatine modulated the microbial composition of the intestinal lumen of juvenile largemouth bass, promoted intestinal health, and improved anti-inflammatory properties following enteritis induction. This study provides a theoretical foundation for largemouth bass feed formulation optimization and fish enteritis control.
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Affiliation(s)
- Haodong Yu
- College of Fisheries, Huazhong Agricultural University, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Hubei Provincial Engineering Laboratory for Pond Aquaculture, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Yukang Nie
- College of Fisheries, Huazhong Agricultural University, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Hubei Provincial Engineering Laboratory for Pond Aquaculture, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Boran Zhang
- College of Fisheries, Huazhong Agricultural University, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Hubei Provincial Engineering Laboratory for Pond Aquaculture, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Jiajie Xue
- College of Fisheries, Huazhong Agricultural University, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Hubei Provincial Engineering Laboratory for Pond Aquaculture, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Kun Xue
- College of Fisheries, Huazhong Agricultural University, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Hubei Provincial Engineering Laboratory for Pond Aquaculture, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Xixuan Huang
- College of Fisheries, Huazhong Agricultural University, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Hubei Provincial Engineering Laboratory for Pond Aquaculture, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Xuezhen Zhang
- College of Fisheries, Huazhong Agricultural University, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Hubei Provincial Engineering Laboratory for Pond Aquaculture, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China; Research Institute of Huanong-Tianchen, Wuhan, 430070, China.
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Nishioka K, Ogino H, Ihara E, Chinen T, Kimura Y, Esaki M, Bai X, Minoda Y, Tanaka Y, Wada M, Hata Y, Ambrosini YM, Ogawa Y. Importance of rectal over colon status in ulcerative colitis remission: the role of microinflammation and mucosal barrier dysfunction in relapse. J Gastroenterol 2025; 60:416-429. [PMID: 39672976 DOI: 10.1007/s00535-024-02199-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 12/03/2024] [Indexed: 12/15/2024]
Abstract
BACKGROUND Ulcerative colitis (UC) is a refractory inflammatory disease that affects the rectum and colon, with pivotal involvement of the rectal environment in relapse initiation. This study was conducted in two phases to examine the differences in gene expression between the rectum and colon and to identify relapse factors. METHODS In ***Study 1, RNA sequencing was performed on biopsies from the colon and rectum of patients with active UC, those with remission UC, and controls. In Study 2, the mucosal impedance (MI) values reflecting mucosal barrier function and the mRNA expression of tight junction proteins and inflammatory cytokines were examined in 32 patients with remission UC and 22 controls. Relapse was monitored prospectively. RESULTS In Study 1, comprehensive genetic analysis using RNA sequencing revealed distinct gene profiles in the rectum and sigmoid colon of patients with remission UC. The rectum of these patients exhibited an enriched immune response and apical junction phenotype with persistent upregulation of CLDN2 gene expression. In Study 2, even in patients with remission UC, the MI values in the rectum, but not in the sigmoid colon, were significantly decreased, whereas they were negatively correlated with CLDN2, IL-1β, and IL-6 expressions. CONCLUSION The status of the rectum in patients with remission UC differs from that of the colon, with microinflammation and impaired mucosal barrier function, which are associated with the upregulation of CLDN2, playing a role in relapse.
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Affiliation(s)
- Kei Nishioka
- Department of Gastroenterology, Saiseikai Futsukaichi Hospital, Chikushino, Japan
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Haruei Ogino
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eikichi Ihara
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Takatoshi Chinen
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yusuke Kimura
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Mitsuru Esaki
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, USA
| | - Xiaopeng Bai
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yosuke Minoda
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshimasa Tanaka
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masafumi Wada
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshitaka Hata
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoko M Ambrosini
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, USA
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Chen D, Shen Q, Huang R, Zhao Z, Yu Y, Cui S, Wang J, Chen Z, Wu P, Tang G. Genome-wide association study and subsequent functional analysis reveal regulatory mechanism underlying piglet diarrhea. Anim Biosci 2025; 38:612-628. [PMID: 39482997 PMCID: PMC11917426 DOI: 10.5713/ab.24.0547] [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: 07/29/2024] [Revised: 08/29/2024] [Accepted: 10/22/2024] [Indexed: 11/03/2024] Open
Abstract
OBJECTIVE Piglet diarrhea poses a serious threat to piglet health and the livestock economy, and is one of the most pressing problems in animal husbandry. This study aims to investigate the genetic factors involved in piglet diarrhea and to identify key genes that regulate this condition. METHODS We screened 600 diarrheal piglets based on unique diarrhea scores for resequencing and conducted a genome-wide association study (GWAS). Through this process, we identified 308 single nucleotide polymorphisms (SNPs) and annotated 151 candidate genes. Extensive functional validation and systematic analysis were performed on key candidate genes KSR1, SKAP1, SLC35F6, and OR12. RESULTS The study found that the four key genes were involved in the regulation of piglet diarrhea through various mechanisms. OR12 affects the levels of ZO-1 and claudin-1. Changes in the expression levels of KSR1 could alter the expression of IL1-β, IL6, and TNF-α, as well as cell migration and proliferation. SKAP1 could affect the expression of CD3 and CD4, and influence the migration and proliferation ability of cells. SLC35F6 is involved in cell apoptosis through the Bcl2/BAX/caspase3 pathway and can also affect mitochondrial membrane potential. CONCLUSION The results of this study provide strong support for breeding programs aimed at disease resistance and offer potential solutions to the problem of piglet diarrhea.
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Affiliation(s)
- Dong Chen
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Key Laboratory of Agricultural Bioinformatics, Ministry of Education, Sichuan Agricultural University, Chengdu 625014,
China
| | - Qi Shen
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Key Laboratory of Agricultural Bioinformatics, Ministry of Education, Sichuan Agricultural University, Chengdu 625014,
China
| | - Rui Huang
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Key Laboratory of Agricultural Bioinformatics, Ministry of Education, Sichuan Agricultural University, Chengdu 625014,
China
| | - Zhenjian Zhao
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Key Laboratory of Agricultural Bioinformatics, Ministry of Education, Sichuan Agricultural University, Chengdu 625014,
China
| | - Yang Yu
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Key Laboratory of Agricultural Bioinformatics, Ministry of Education, Sichuan Agricultural University, Chengdu 625014,
China
| | - Shengdi Cui
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Key Laboratory of Agricultural Bioinformatics, Ministry of Education, Sichuan Agricultural University, Chengdu 625014,
China
| | - Junge Wang
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Key Laboratory of Agricultural Bioinformatics, Ministry of Education, Sichuan Agricultural University, Chengdu 625014,
China
| | - Ziyang Chen
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Key Laboratory of Agricultural Bioinformatics, Ministry of Education, Sichuan Agricultural University, Chengdu 625014,
China
| | - Pingxian Wu
- National Center of Technology Innovation for Pigs, Rongchang 402460,
China
| | - Guoqing Tang
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 625014,
China
- Key Laboratory of Agricultural Bioinformatics, Ministry of Education, Sichuan Agricultural University, Chengdu 625014,
China
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Zhang XQ, Li JM, Wang FQ, Ren YH, Wu SX, Wu Y, Tang Y. The clinical significance and biological function of tropomyosin 3 in ulcerative colitis. Tissue Cell 2025; 93:102770. [PMID: 39938429 DOI: 10.1016/j.tice.2025.102770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 01/23/2025] [Accepted: 01/27/2025] [Indexed: 02/14/2025]
Abstract
BACKGROUND Ulcerative colitis (UC) is a lifelong chronic inflammatory disease that is characterized by the absence of specific markers for diagnosis and prognosis. TPM3 is an integral component of the thin filament, responsible for the structural stability of actin filaments and modulation of cytoskeletal function. This study investigated the regulatory role of TPM3 in UC and its potential mechanisms. METHODS At the clinical level, TPM3 levels were assessed in serum and mucosal tissues of UC and other enteric disease. At the cellular level, the effects of TMP3 overexpressing lentivirus on Caco-2 cell phenotype and the barrier of IL-1β-induced UC model were explored. At the animal level, the effects of TMP3 overexpressing lentivirus on symptoms and colonic damage in a DSS-induced UC model were explored. RESULTS TPM3 expression in serum of UC patients was significantly lower than that of other enteric disease, and TPM3 levels in the intestinal mucosa showed a negative correlation with the Mayo score of UC patients. TPM3 overexpression alleviates IL-1β-induced apoptosis and inhibition of invasion and migration in UC model in vitro. In monolayer Caco-2 cells, TPM3 overexpression rescued the IL-1β-induced decrease in transepithelial electrical resistance and tight junction markers (ZO-1 and Occludin) and increase in permeability. In animal experiments, TPM3 overexpression increased body weight and colon length and decreased disease activity index in a DSS-induced UC model. In tissue staining, it alleviated pathological damage and upregulated Occuludin and TPM3 levels in the colon. CONCLUSION TPM3 levels correlated with UC disease course and TPM3 overexpression alleviated symptoms/phenotypes and barrier damage in UC models in vivo and in vitro. TPM3 may serve as a potential novel biomarker for UC diagnosis and prognosis.
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Affiliation(s)
- Xue-Qin Zhang
- The First People's Hospital of Qujing, No. 1, Yuanlin Road, Qujing, Yunnan 655000, China
| | - Jian-Mei Li
- The First People's Hospital of Qujing, No. 1, Yuanlin Road, Qujing, Yunnan 655000, China
| | - Feng-Qian Wang
- The First People's Hospital of Qujing, No. 1, Yuanlin Road, Qujing, Yunnan 655000, China
| | - Yan-Hui Ren
- The First People's Hospital of Qujing, No. 1, Yuanlin Road, Qujing, Yunnan 655000, China
| | - Shi-Xian Wu
- The First People's Hospital of Qujing, No. 1, Yuanlin Road, Qujing, Yunnan 655000, China
| | - Yao Wu
- The First People's Hospital of Qujing, No. 1, Yuanlin Road, Qujing, Yunnan 655000, China
| | - Yuan Tang
- The First People's Hospital of Qujing, No. 1, Yuanlin Road, Qujing, Yunnan 655000, China.
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Du X, Pian H, Zhao D, Zhang Y, Wu X, He J, Chen L, Liu F, Yu D. Enhancing gut-ovary health in aged laying hens: the impact of dietary betaine supplementation. Poult Sci 2025; 104:104894. [PMID: 40020408 PMCID: PMC11910711 DOI: 10.1016/j.psj.2025.104894] [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: 10/10/2024] [Revised: 02/05/2025] [Accepted: 02/06/2025] [Indexed: 03/03/2025] Open
Abstract
The gut-ovary axis involves a complex interplay of various physiological and molecular mechanisms, which significantly impact poultry production and health. This study investigated the effects of betaine (Bet) on the gut-ovary axis of laying hens in aged laying hens. A total of 108 Hy-Line Brown hens, aged 500 days, were randomly divided into three groups (n = 36 per group) and fed diets containing 0, 1000, and 3000 mg/kg of Bet (designated as CON, l-Bet, and H-Bet, respectively) over a 42-day trial. The results indicated that dietary supplementation with Bet improved laying performance. Specifically, H-Bet Supplementation increased villus height (VH) and villus height/crypt depth ratio (VH/CD), and up-regulated the expression of Claudin-1 in the jejunal and ileal mucosa. Additionally, H-Bet enhanced the richness of Bacteroidetes and reduced Firmicutes/Bacterodietes ratio. LEfSe analysis revealed significant enrichment Eubacteriaceae, Merdibacter, Anaerorhabdus_furcosa_group, Syntrophococcus, and Clostridium_innocuum_group in Bet group. Transcriptome sequencing of small yellow follicles (SYFs) showed significant up-regulation of ATP6 and down-regulation of EGR1. KEGG enrichment analysis indicated that H-Bet influenced oxidative phosphorylation, peroxisome, and other pathways, with GESA was primarily enriched in oxidative phosphorylation, and MAPK signaling pathway. Furthermore, H-Bet supplementation increased SOD, CAT, Nrf2, NQO-1, and HO-1 expression in the jejunum, while only HO-1 expression was up-regulated in the ileum. In the ovary, H-Bet differentially affected GPX, and CAT expression. These results demonstrate that dietary supplementation with Bet improves intestinal and ovarian health in aged laying hens, likely due to enhanced antioxidant capacity and improved intestinal morphology.
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Affiliation(s)
- Xubin Du
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China; Joint International Research Laboratory of Animal Health and Food Safety of Ministry of Education & Single Molecule Biochemistry & Bioengineering Laboratory, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China
| | - Huifang Pian
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China
| | - Dong Zhao
- School of Animal Medical, Jiangsu Agri-animal Husbandry Vocational College, Taizhou, Jiangsu, 225300, PR China
| | - Yuchen Zhang
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China
| | - Xinyue Wu
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China
| | - Jiawen He
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China
| | - Li Chen
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China
| | - Fei Liu
- Joint International Research Laboratory of Animal Health and Food Safety of Ministry of Education & Single Molecule Biochemistry & Bioengineering Laboratory, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China
| | - Debing Yu
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China.
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Neu SD, Gurski CJ, Meinhardt NJ, Jennings KC, Dittel BN. Gut IgA-antibody secreting cells segregate into four Blimp1+ subsets based on differential expression of IgA and Ki-67 and are retained following prolonged αCD20 B cell depletion in mice. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025; 214:780-794. [PMID: 40073093 PMCID: PMC12041773 DOI: 10.1093/jimmun/vkae046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 12/02/2024] [Indexed: 03/14/2025]
Abstract
B cell depletion is an efficacious therapy for multiple sclerosis, but its long-term safety profile in the gastrointestinal tract has not been specifically studied. This is of importance because the gut is the largest reservoir of IgA in the body, which maintains gut homeostasis in part by regulating the composition of the gut microbiota. This was addressed by development of a prolonged B cell depletion model using human CD20 transgenic mice and B cell depletion with the anti-human CD20 antibodies rituximab, a humanized mouse monoclonal, and 2H7, the mouse precursor to ocrelizumab. Both antibodies depleted B cells in the spleen, mesenteric lymph nodes, small intestine, and large intestine, with 2H7 being more efficient. Because gut IgA+ antibody secreting cells (ASC) are poorly defined a flow cytometry strategy was developed using differential expression of IgA and Ki-67 by Blimp1+ cells that identified four IgA-ASC subsets across a developmental spectrum. Neither antibody was efficacious in depleting of any IgA-ASC subset in the intestines. Consequently, fecal IgA levels and percentage of IgA-bound fecal microbes were unaltered. Cumulatively, these studies demonstrate that prolonged B cell-depletion did not substantially impact IgA levels nor overall gut health, providing important insight into the safety profile of B cell depletion drugs.
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Affiliation(s)
- Savannah D Neu
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, United States
- Versiti Blood Research Institute, Milwaukee, WI, United States
| | - Cody J Gurski
- Versiti Blood Research Institute, Milwaukee, WI, United States
| | - Nathan J Meinhardt
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, United States
- Versiti Blood Research Institute, Milwaukee, WI, United States
| | - Kevin C Jennings
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Bonnie N Dittel
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, United States
- Versiti Blood Research Institute, Milwaukee, WI, United States
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Villanacci V, Del Sordo R, Lanzarotto F, Ricci C, Sidoni A, Manenti S, Mino S, Bugatti M, Bassotti G. Claudin-2: A marker for a better evaluation of histological mucosal healing in inflammatory bowel diseases. Dig Liver Dis 2025; 57:827-832. [PMID: 39155205 DOI: 10.1016/j.dld.2024.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 07/28/2024] [Accepted: 08/01/2024] [Indexed: 08/20/2024]
Abstract
BACKGROUND Histological mucosal healing has become a paramount target goal to achieve in the treatment of inflammatory bowel diseases. However, there is still a lack of agreement on the best way to reach this goal, since numerous histological scores are available worldwide. AIMS We investigated whether claudin-2, a member of claudin family involved in the regulation of intestinal tight junctions, might be useful to assess the presence of active disease in patients with inflammatory bowel diseases. METHODS Biopsies from 123 patients with ulcerative colitis, Crohn's disease, infectious colitides and irritable bowel syndrome patients where tested with immunohistochemistry for claudin-2. RESULTS Claudin-2 appeared to be a very sensitive marker of disease activity in inflammatory bowel diseases, but was negative in the other kinds of patients. In addition, immunohistochemistry for claudin-2 showed good reproducibility by different pathologists. CONCLUSIONS Should these findings be confirmed in more numerous cohorts of patients, and especially in those with minimal or focal residual disease activity, this simple assessment could be useful in the routine daily practice to facilitate the task of pathologists and clinicians in the diagnosis and management of patients with inflammatory bowel diseases.
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Affiliation(s)
- Vincenzo Villanacci
- Institute of Pathology, ASST Spedali Civili and University of Brescia, Brescia, Italy
| | - Rachele Del Sordo
- Department of Medicine and Surgery, Section of Anatomic Pathology and Histology, University of Perugia, Perugia, Italy.
| | - Francesco Lanzarotto
- Gastroenterology Unit, Department of Clinical and Experimental Sciences, Spedali Civili Hospital, University of Brescia, Brescia, Italy
| | - Chiara Ricci
- Gastroenterology Unit, Department of Clinical and Experimental Sciences, Spedali Civili Hospital, University of Brescia, Brescia, Italy
| | - Angelo Sidoni
- Department of Medicine and Surgery, Section of Anatomic Pathology and Histology, University of Perugia, Perugia, Italy
| | - Stefania Manenti
- Institute of Pathology, ASST Spedali Civili and University of Brescia, Brescia, Italy
| | - Sara Mino
- Institute of Pathology, ASST Spedali Civili and University of Brescia, Brescia, Italy
| | - Mattia Bugatti
- Institute of Pathology, ASST Spedali Civili and University of Brescia, Brescia, Italy
| | - Gabrio Bassotti
- Gastroenterology and Hepatology Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Fu W, Huang Z, Li W, Xu L, Yang M, Ma Y, Liu H, Qian H, Wang W. Copper-luteolin nanocomplexes for Mediating multifaceted regulation of oxidative stress, intestinal barrier, and gut microbiota in inflammatory bowel disease. Bioact Mater 2025; 46:118-133. [PMID: 39760067 PMCID: PMC11697280 DOI: 10.1016/j.bioactmat.2024.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 12/02/2024] [Accepted: 12/02/2024] [Indexed: 01/07/2025] Open
Abstract
Oxidative stress, dysbiosis, and immune dysregulation have been confirmed to play pivotal roles in the complex pathogenesis of inflammatory bowel disease (IBD). Herein, we design copper ion-luteolin nanocomplexes (CuL NCs) through a metal-polyphenol coordination strategy, which plays a multifaceted role in the amelioration of IBD. The fabricated CuL NCs function as therapeutic agents with exceptional antioxidant and anti-inflammatory capabilities because of their great stability and capacity to scavenge reactive oxygen species (ROS). It can effectively modulate the inflammatory microenvironment including facilitating the efficient reduction of pro-inflammatory cytokine levels, protecting intestinal epithelial cells, promoting mucosal barrier repair and regulating intestinal microbiota. In addition, CuL NCs have been found to enhance cellular antioxidant and anti-inflammatory capacities by regulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) oxidative stress pathway and nuclear factor kappa B (NF-κB) signaling pathway, respectively. Notably, CuL NCs demonstrate significant prophylactic and therapeutic efficacy in mouse models with typical IBD, including ulcerative colitis (UC) and Crohn's disease (CD). This study provides a new approach for building multifaceted therapeutic platforms for natural products to treat IBD.
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Affiliation(s)
- Wanyue Fu
- School of Biomedical Engineering, Anhui Provincial Institute of Translational Medicine, Anhui Engineering Research Center for Medical Micro-Nano Devices, Anhui Medical University, Hefei, 230011, PR China
| | - Zhongshi Huang
- Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang, 443002, PR China
| | - Weiqi Li
- School of Biomedical Engineering, Anhui Provincial Institute of Translational Medicine, Anhui Engineering Research Center for Medical Micro-Nano Devices, Anhui Medical University, Hefei, 230011, PR China
| | - Lingling Xu
- School of Biomedical Engineering, Anhui Provincial Institute of Translational Medicine, Anhui Engineering Research Center for Medical Micro-Nano Devices, Anhui Medical University, Hefei, 230011, PR China
| | - Miaomiao Yang
- The First Affiliated Hospital of Anhui Medical University, Anhui Public Health Clinical Center, Hefei, 230012, PR China
| | - Yan Ma
- School of Biomedical Engineering, Anhui Provincial Institute of Translational Medicine, Anhui Engineering Research Center for Medical Micro-Nano Devices, Anhui Medical University, Hefei, 230011, PR China
| | - Hanghang Liu
- Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang, 443002, PR China
| | - Haisheng Qian
- School of Biomedical Engineering, Anhui Provincial Institute of Translational Medicine, Anhui Engineering Research Center for Medical Micro-Nano Devices, Anhui Medical University, Hefei, 230011, PR China
| | - Wanni Wang
- School of Biomedical Engineering, Anhui Provincial Institute of Translational Medicine, Anhui Engineering Research Center for Medical Micro-Nano Devices, Anhui Medical University, Hefei, 230011, PR China
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Kulkarni DH, Newberry RD. Antigen Uptake in the Gut: An Underappreciated Piece to the Puzzle? Annu Rev Immunol 2025; 43:571-588. [PMID: 40279313 PMCID: PMC12068241 DOI: 10.1146/annurev-immunol-082523-090154] [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] [Indexed: 04/27/2025]
Abstract
The mammalian gut is a vast, diverse, and dynamic single-layer epithelial surface exposed to trillions of microbes, microbial products, and the diet. Underlying this epithelium lies the largest collection of immune cells in the body; these cells encounter luminal substances to generate antigen-specific immune responses characterized by tolerance at homeostasis and inflammation during enteric infections. How the outcomes of antigen-specific tolerance and inflammation are appropriately balanced is a central question in mucosal immunology. Furthermore, how substances large enough to generate antigen-specific responses cross the epithelium and encounter the immune system in homeostasis and during inflammation remains largely unexplored. Here we discuss the challenges presented to the gut immune system, the identified pathways by which luminal substances cross the epithelium, and insights suggesting that the pathways used by substances to cross the epithelium affect the ensuing immune response.
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Affiliation(s)
- Devesha H Kulkarni
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Rodney D Newberry
- John T. Milliken Department of Medicine, School of Medicine, Washington University, Saint Louis, Missouri, USA;
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Singlitico A, Grassa D, Kaplan R, Smimmo A, Maccauro G, Vitiello R. The hidden connection between gut microbiota and periprosthetic joint infections: a scoping review. J Bone Jt Infect 2025; 10:85-92. [PMID: 40271508 PMCID: PMC12015178 DOI: 10.5194/jbji-10-85-2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 02/04/2025] [Indexed: 04/25/2025] Open
Abstract
Background: Periprosthetic joint infections (PJIs) pose a significant challenge in orthopedic surgery, and emerging evidence suggests that the gut microbiome may play a crucial role in their development and management. Despite the rarity of these infections, the continuous increase in prosthetic joint arthroplasties has made understanding how to prevent them more pressing. A stronger comprehension of the disruption of the gut microbiome and how this can lead to more of these infections and other pre-surgical risks may be crucial in preventing them. Objective: This article aims to provide a stronger understanding of the topic through the analysis of different pieces of already existing literature to help draw new conclusions and raise potential questions that need answering. Methods: A comprehensive search strategy without filters was employed, and multiple papers were thoroughly analyzed, understood, and compiled into this paper. Conclusions: Despite the limitations of some of the analyzed studies and finite evidence, this paper suggests that there could be a connection between periprosthetic joint infections and a compromised gut microbiome. However, further research is required to draw a definitive conclusion.
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Affiliation(s)
- Alessandro Singlitico
- Department of Orthopaedics, Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Daniele Grassa
- Department of Orthopaedics, Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Rami Kaplan
- Department of Orthopaedics, Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Alessandro Smimmo
- Department of Orthopaedic and Traumatology, Aurelia Hospital Garofalo Healthcare, 00165 Rome, Italy
| | - Giulio Maccauro
- Department of Orthopaedics, Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Raffaele Vitiello
- Department of Orthopaedics, Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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Chafekar D. Optimizing chronic kidney disease management: The potential of a multi-strain probiotic formulation. World J Nephrol 2025; 14:101515. [PMID: 40134645 PMCID: PMC11755232 DOI: 10.5527/wjn.v14.i1.101515] [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: 09/17/2024] [Revised: 10/21/2024] [Accepted: 12/03/2024] [Indexed: 01/20/2025] Open
Abstract
Chronic kidney disease (CKD), which represents a significant global health concern, is characterized by a gradual decline in kidney function, leading to complications such as electrolyte imbalance, cardiovascular disease, and immune dysfunction. Standard CKD management includes dietary modifications, ketoanalogues supplementation, blood pressure and blood glucose control, hydration maintenance, and treatment of the underlying causes. Emerging evidence has indicated a significant role of the gut microbiota in CKD, and that dysbiosis of the gut microbiota contributes to the progression of CKD towards end-stage renal disease. Probiotics and prebiotics have recently garnered attention owing to their potential to enhance gastrointestinal health and well-being by restoring the balance of the gut microbiota. Specific probiotic strains, including Lactobacillus and Bifidobacterium, promote beneficial bacterial growth, suppress harmful bacteria, and exert anti-inflammatory, antihypertensive, and antidiabetic effects. The combination of Streptococcus thermophilus, Lactobacillus acidophilus, Bifidobacterium longum, and Bacillus coagulans has demonstrated potential as a therapeutic formulation for CKD management in various studies, highlighting its promise in treating CKD; however, supporting evidence remains limited, making it crucial to conduct further investigations to determine the specific effects of different probiotic formulations on outcomes in patients with CKD.
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Affiliation(s)
- Deodatta Chafekar
- Dr V N Pawar Medical College, Director Supreme Kidney Care, Nashik 422005, Mahārāshtra, India
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Liu L, Zhang Z, Xiao H, Li Z, Lin H. Dietary AGEs and food allergy: insights into the mechanisms of AGEs-induced food allergy and mitigation strategies. Crit Rev Food Sci Nutr 2025:1-18. [PMID: 40129068 DOI: 10.1080/10408398.2025.2481990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/26/2025]
Abstract
Food allergy (FA) is a significant public health concern, with over one billion individuals globally affected, and its prevalence continues to rise. Advanced glycation end products (AGEs) are common hazards in various diet. Recent investigations have shown that AGEs could influence the pathogenesis of FA by interacting with AGEs receptors. This paper provides a comprehensive review of recent advances on diet AGEs, summarized the mechanisms of AGEs in regulating food allergy and mitigation strategies, analyzed the limitations of current research on AGEs and prospected the future research. AGEs could combine with the receptors for AGEs (RAGE) to induce oxidative stress, inflammation and allergic signaling pathways. AGEs can affect allergen epitopes and conformation and regulate intestinal flora in a non-receptor-dependent manner, as well as affect the intestinal barrier and Th1/Th2 immune balance through receptor-dependent pathways to regulate food allergy. Currently, the approaches to reduce the AGEs-induced food allergy mainly depended on improving food processing methods (e.g., low temperature, short time, low pH and non-thermal processing methods), natural AGEs inhibitors and RAGE inhibitors. This review elucidates the influences of AGEs on food allergy and mitigation strategies, which could provide novel insights into reducing food allergy induced by diet AGEs.
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Affiliation(s)
- Lichun Liu
- State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, Qingdao, China
| | - Ziye Zhang
- State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, Qingdao, China
| | - Hang Xiao
- Department of Food Science, University of Massachusetts, Amherst, MA, USA
| | - Zhenxing Li
- State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, Qingdao, China
| | - Hong Lin
- State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, Qingdao, China
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Perumal SK, Arumugam MK, Osna NA, Rasineni K, Kharbanda KK. Betaine regulates the gut-liver axis: a therapeutic approach for chronic liver diseases. Front Nutr 2025; 12:1478542. [PMID: 40196019 PMCID: PMC11973089 DOI: 10.3389/fnut.2025.1478542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Accepted: 03/03/2025] [Indexed: 04/09/2025] Open
Abstract
Chronic liver disease is defined by persistent harm to the liver that might result in decreased liver function. The two prevalent chronic liver diseases are alcohol-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD). There is ample evidence that the pathogenesis of these two chronic liver diseases is closely linked to gastrointestinal dysfunctions that alters the gut-liver crosstalk. These alterations are mediated through the imbalances in the gut microbiota composition/function that combined with disruption in the gut barrier integrity allows for harmful gut microbes and their toxins to enter the portal circulation and reach the liver to elicit an inflammatory response. This leads to further recruitment of systemic inflammatory cells, such as neutrophils, T-cells, and monocytes into the liver, which perpetuate additional inflammation and the development of progressive liver damage. Many therapeutic modalities, currently used to prevent, attenuate, or treat chronic liver diseases are aimed at modulating gut dysbiosis and improving intestinal barrier function. Betaine is a choline-derived metabolite and a methyl group donor with antioxidant, anti-inflammatory and osmoprotectant properties. Studies have shown that low betaine levels are associated with higher levels of organ damage. There have been several publications demonstrating the role of betaine supplementation in preventing the development of ALD and MASLD. This review explores the protective effects of betaine through its role as a methyl donor and its capacity to regulate the protective gut microbiota and maintain intestinal barrier integrity to prevent the development of these chronic liver diseases. Further studies are needed to enhance our understanding of its therapeutic potential that could pave the way for targeted interventions in the management of not only chronic liver diseases, but other inflammatory bowel diseases or systemic inflammatory conditions.
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Affiliation(s)
- Sathish Kumar Perumal
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Madan Kumar Arumugam
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Cancer Biology Lab, Centre for Molecular and Nanomedical Sciences, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Natalia A. Osna
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, United States
| | - Karuna Rasineni
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Kusum K. Kharbanda
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
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Gu C, Sha G, Zeng B, Cao H, Cao Y, Tang D. Therapeutic potential of fecal microbiota transplantation in colorectal cancer based on gut microbiota regulation: from pathogenesis to efficacy. Therap Adv Gastroenterol 2025; 18:17562848251327167. [PMID: 40104324 PMCID: PMC11915259 DOI: 10.1177/17562848251327167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 02/24/2025] [Indexed: 03/20/2025] Open
Abstract
Colorectal cancer (CRC) remains a leading cause of cancer-related deaths worldwide, with its progression intricately linked to gut microbiota dysbiosis. Disruptions in microbial homeostasis contribute to tumor initiation, immune suppression, and inflammation, establishing the microbiota as a key therapeutic target. Fecal microbiota transplantation (FMT) has emerged as a transformative approach to restore microbial balance, enhance immune responses, and reshape the tumor microenvironment. This review explores the mechanisms underlying FMT's therapeutic potential, evaluates its advantages over other microbiota-based interventions, and addresses challenges such as donor selection, safety concerns, and treatment standardization. Looking forward, the integration of FMT into personalized CRC therapies requires robust clinical trials and the identification of predictive biomarkers to optimize its efficacy and safety.
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Affiliation(s)
- Chen Gu
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, China
| | - Gengyu Sha
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, China
| | - Binbin Zeng
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, China
| | - Herong Cao
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, China
| | - Yibo Cao
- The Second School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Dong Tang
- Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou University, Yangzhou 225000, China
- The Yangzhou Clinical College of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, 221000, China
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People’s Hospital, Yangzhou University, Yangzhou, 225000, China
- Northern Jiangsu People’s Hospital, Clinical Teaching Hospital of Medical School, Nanjing University, Nanjing, 210000, China
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Wu J, Lv D, Lin W, Mao Y, Xia Y, Feng L, Zhao T, Mao X, Shu F, Guo H. Chronic exposure to liquid crystal monomer EBCN at environmentally relevant concentrations induces testicular dysfunction via the gut-testis axis. JOURNAL OF HAZARDOUS MATERIALS 2025; 486:137033. [PMID: 39740548 DOI: 10.1016/j.jhazmat.2024.137033] [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: 09/14/2024] [Revised: 12/27/2024] [Accepted: 12/27/2024] [Indexed: 01/02/2025]
Abstract
4-Cyano-4'-ethoxybiphenyl (EBCN) is a representative cyano liquid crystal monomer (LCM). While prior studies have documented the widespread occurrence of LCMs in diverse environmental and biological samples, research on their reproductive effects in vivo remains limited. This study employed 35-day and 70-day exposure models in mice to assess the short-term and long-term effects of environmentally relevant concentrations of EBCN on testicular health. Our findings indicate that EBCN exposure, irrespective of duration, had minimal impact on body weight, testis weight, and testicular organ coefficient. However, it induced dose-dependent reductions in seminiferous tubule area, sperm count, accompanied by decreases in Leydig cells and spermatogenic cells, along with disruptions in sex hormone levels. Moreover, EBCN exposure led to the upregulation of inflammatory factors in serum, partially attributable to the activation of necroptosis-related pathways. Additionally, 16S rRNA sequencing and metabolomic analysis revealed a decline in gut microbiome diversity and a decrease in anti-inflammatory metabolites, specifically L-carnosine, in the intestine, potentially contributing to the observed testicular toxicity. Supplementation with exogenous L-carnosine mitigated EBCN-induced testicular dysfunction by inhibiting the expression of necroptosis-related genes. In conclusion, our study suggests that prolonged EBCN exposure at environmentally relevant concentrations adversely impacts testicular function via the gut-testis axis.
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Affiliation(s)
- Jun Wu
- Reproductive Medicine Center, Henan Provincial People's Hospital, Zhengzhou, China; Reproductive Medicine Center, Zhengzhou University People's Hospital, Zhengzhou, China; Henan Joint International Research Laboratory of Reproductive Bioengineering, Zhengzhou, China; Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Daojun Lv
- Department of Urology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Wanmei Lin
- Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yiyou Mao
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Yanqing Xia
- Reproductive Medicine Center, Henan Provincial People's Hospital, Zhengzhou, China; Reproductive Medicine Center, Zhengzhou University People's Hospital, Zhengzhou, China; Henan Joint International Research Laboratory of Reproductive Bioengineering, Zhengzhou, China
| | - Leilei Feng
- Reproductive Medicine Center, Henan Provincial People's Hospital, Zhengzhou, China; Reproductive Medicine Center, Zhengzhou University People's Hospital, Zhengzhou, China; Henan Joint International Research Laboratory of Reproductive Bioengineering, Zhengzhou, China
| | - Tianxin Zhao
- Department of Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Xiangming Mao
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
| | - Fangpeng Shu
- Department of Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.
| | - Haibin Guo
- Reproductive Medicine Center, Henan Provincial People's Hospital, Zhengzhou, China; Reproductive Medicine Center, Zhengzhou University People's Hospital, Zhengzhou, China; Henan Joint International Research Laboratory of Reproductive Bioengineering, Zhengzhou, China.
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Mou J, Yang J, Sun Y, Liu J, Zhao Y, Lin H, Yang J. An arabinogalactan from Lycium barbarum mitigated DSS caused intestinal injury via inhibiting mucosal damage and regulating the gut microbiota disorder. Carbohydr Polym 2025; 352:123155. [PMID: 39843060 DOI: 10.1016/j.carbpol.2024.123155] [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: 09/03/2024] [Revised: 12/12/2024] [Accepted: 12/13/2024] [Indexed: 01/24/2025]
Abstract
Intestinal injury and microbiota disorder take part in the development of UC. In this research, we obtained an arabinogalactan (LBP-m) from Lycium barbarum and firstly characterized its physicochemical properties. LBP-m was a homogeneous polysaccharide (172 kDa) consisted of Ara, Gal, Glc, GalA, and GlcA with a mole ratio of 1.00: 0.73: 0.18: 0.20: 0.07, and constructed a →6)-β-Galp(1→ backbone with different Araf branches at O-3 position, which exerted as random coil in PBS with single helical structure. Furthermore, oral administration of LBP-m ameliorated the DSS induced UC from different aspects, including regulating barrier dysfunction by promoting the expression of TJs, elevating the anti-oxidative stress capacity through activating the Nrf2/HO-1 pathway, relieving the mucosal inflammation via inhibiting NF-κB pathway. In addition, LBP-m regulated the gut microbiota disorder by reshaping the microbial composition and enhancing the generation of SCFAs. Our research revealed the physicochemical properties of LBP-m and systematically indicated its mitigative effect against DSS induced UC, which could benefit its application in food and pharmacy fields.
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Affiliation(s)
- Jiaojiao Mou
- School of Public Health, Ningxia Medical University, Yinchuan 750004, Ningxia, China; School of Public Health, Shandong Second Medical University, Weifang 261053, Shandong, China
| | - Jie Yang
- School of Pharmacy, Shandong Second Medical University, Weifang 261053, Shandong, China
| | - Yanying Sun
- School of Public Health, Shandong Second Medical University, Weifang 261053, Shandong, China
| | - Jing Liu
- School of Pharmacy, Shandong Second Medical University, Weifang 261053, Shandong, China
| | - Yuxin Zhao
- School of Public Health, Ningxia Medical University, Yinchuan 750004, Ningxia, China
| | - Hong Lin
- School of Public Health, Ningxia Medical University, Yinchuan 750004, Ningxia, China
| | - Jianjun Yang
- School of Public Health, Ningxia Medical University, Yinchuan 750004, Ningxia, China.
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Ferraro VA, Zanconato S, Carraro S. The Epithelial Barrier Hypothesis in Food Allergies: The State of the Art. Nutrients 2025; 17:1014. [PMID: 40290033 PMCID: PMC11944793 DOI: 10.3390/nu17061014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 03/10/2025] [Accepted: 03/12/2025] [Indexed: 04/30/2025] Open
Abstract
Recently, the "epithelial barrier hypothesis" has been proposed as a key factor in the development of allergic diseases, such as food allergies. Harmful environmental factors can damage epithelial barriers, with detrimental effects on the host immune response and on the local microbial equilibrium, resulting in chronic mucosal inflammation that perpetuates the dysfunction of the epithelial barrier. The increased epithelial permeability allows allergens to access the submucosae, leading to an imbalance between type 1 T-helper (Th1) and type 2 T-helper (Th2) inflammation, with a predominant Th2 response that is the key factor in food allergy development. In this article on the state of the art, we review scientific evidence on the "epithelial barrier hypothesis", with a focus on food allergies. We describe how loss of integrity of the skin and intestinal epithelial barrier and modifications in gut microbiota composition can contribute to local inflammatory changes and immunological unbalance that can lead to the development of food allergies.
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Affiliation(s)
| | | | - Silvia Carraro
- Unit of Pediatric Allergy and Respiratory Medicine, Women’s and Children’s Health Department, University of Padova, 35128 Padova, Italy; (V.A.F.); (S.Z.)
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50
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Williams A, Ravel J, Kaul R, Armstrong E, Huibner S, Holm JB. Temporal Dynamics of the Vaginal Microbiome and Host Immune Markers Before, During, and After Metronidazole Treatment for Bacterial Vaginosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.13.643085. [PMID: 40161639 PMCID: PMC11952498 DOI: 10.1101/2025.03.13.643085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
This study analyzed metagenomic and immune marker profiles of seven individuals before, during, and after a 7-day course of metronidazole treatment for bacterial vaginosis (BV). Treatment reduced BV-associated bacteria and immune marker levels, with distinct early (days 1-4) and late (days 5-7) phases. Post-treatment, variability in microbial and immune marker profiles demonstrated a rapid resurgence of certain BV associated bacteria, highlighting the need for additional strategies like probiotics to maintain a healthy vaginal microbiome. The study found significant host and microbial influences on immune response variance, with IP-10 and sEcad highly correlated with the vaginal microbiome. The findings identify optimal timing for administering live biotherapeutics to restore D-lactic acid-producing Lactobacillus species dominance and underscore the complexity of BV infection and treatment response among different people.
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Affiliation(s)
- Amanda Williams
- Center for Advanced Microbiome Research and Innovation, Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Jacques Ravel
- Center for Advanced Microbiome Research and Innovation, Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Rupert Kaul
- Department of Medicine, University of Toronto; Toronto, Canada
- Department of Medicine, University Health Network, Toronto, Canada
| | - Eric Armstrong
- Department of Medicine, University of Toronto; Toronto, Canada
| | - Sanja Huibner
- Department of Medicine, University of Toronto; Toronto, Canada
| | - Johanna B. Holm
- Center for Advanced Microbiome Research and Innovation, Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA
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