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Liu Z, Zhang H, Wang J, Yao Y, Wang X, Liu Y, Fang W, Liu X, Zheng Y. Clca1 deficiency exacerbates colitis susceptibility via impairment of mucus barrier integrity and gut microbiota homeostasis. Microbiol Res 2025; 297:128191. [PMID: 40300372 DOI: 10.1016/j.micres.2025.128191] [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: 02/20/2025] [Revised: 04/21/2025] [Accepted: 04/21/2025] [Indexed: 05/01/2025]
Abstract
The intestinal mucus barrier has emerged as a promising therapeutic target for inflammatory bowel disease. Understanding its regulatory mechanisms is critical for elucidating ulcerative colitis (UC) pathogenesis, improving diagnostics, guiding treatments, and preventing relapse. Chloride Channel Accessory 1 (Clca1), a constituent of the mucus layer, remains understudied in colitis. Here, we investigated Clca1's role in mucosal immunity and intestinal homeostasis using experimental colitis models. Clca1-deficient (Clca1-/-) mice displayed compromised mucus layer integrity, reduced neutrophil infiltration, and gut microbiota dysbiosis. Notably, Clca1-/- mice exhibited exacerbated colitis severity following dextran sulfate sodium (DSS) challenge, accompanied by a diminished goblet cell populations. Fecal microbiota transplantation (FMT) studies revealed that gut microbiota critically modulates divergent phenotypic outcomes between genotypes. Our findings establish Clca1 as a multifunctional regulator of mucus barrier integrity through mechanisms involving goblet cell maintenance, neutrophil-mediated immunity, and host-microbiota crosstalk. These results advance the understanding of UC pathogenesis and identify Clca1-associated pathways as potential targets for barrier restoration therapies.
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Affiliation(s)
- Zhi Liu
- Department of Microbiology, State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Hong Zhang
- Department of Microbiology, State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Jingjing Wang
- Department of Microbiology, State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Yutong Yao
- Department of Microbiology, State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Xiaoyi Wang
- Core Facility Center, The First Afliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Yang Liu
- Department of Microbiology, State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Weijia Fang
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Xingyin Liu
- Department of Microbiology, State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Department of Biochemistry, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
| | - Yi Zheng
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China.
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Feng Y, Zhao Q, Zhao Y, Ma C, Tian M, Hu X, Chen F, Li D. Lactobacillus plantarum-derived extracellular vesicles from dietary barley leaf supplementation attenuate Citrobacter rodentium infection and intestinal inflammation. J Nanobiotechnology 2025; 23:426. [PMID: 40481571 PMCID: PMC12144742 DOI: 10.1186/s12951-025-03504-w] [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: 02/26/2025] [Accepted: 05/27/2025] [Indexed: 06/11/2025] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a gastrointestinal inflammatory disorder characterized by disturbed interactions between gut microbiota and host immune response. Barley leaf (BL) is a traditional Chinese herb recorded to have health-promoting effects. However, little is known about the beneficial role of BL against enteric infection-induced intestinal inflammation. Here, we uncover that BL protects against Citrobacter rodentium (C. rodentium)-induced infectious colitis by improving host-microbiota interactions. METHODS C3H/HeN mice were fed a diet with/without BL and infected with C. rodentium. Transcriptome sequencing, anti-CD4 antibody treatment, and flow cytometry were conducted to investigate the mechanisms of T cell immune modulation. The intervention involved administering anti-CD4 antibody at 500 µg each time for three times before and during C. rodentium infection. Analysis of gut microbiota composition was performed by 16S rRNA gene sequencing on fecal samples. Fecal microbiota transplantation was conducted by administering microbiota from donor group to recipient group via oral gavage to investigate the role of intestinal microbiota in immune modulation. RESULTS BL ameliorated the severity of C. rodentium-induced colitis, and this effect was linked to improved gut homeostasis and enhanced mucosal barrier function. BL enriched the pathways of T helper 1 (Th1)/Th2 and Th17 cell differentiation in the colon, suggesting the involvement of CD4+ T cells. Consistent with this, anti-CD4 antibody treatment abrogated the effect of BL and flow cytometry analysis revealed that BL mitigated C. rodentium-induced pro-inflammatory Th1 immune response. Moreover, the protective effect of BL was associated with alleviation of gut microbiota dysbiosis and increased abundance of Lactobacillus. Our in vivo studies further revealed that live Lactobacillus plantarum (L. plantarum) administration attenuated the pathogenic effects induced by C. rodentium infection, whereas heat-inactivated L. plantarum did not show the same results. Mechanistically, BL supplementation enriched L. plantarum, which subsequently released nanosized extracellular vesicles (EVs) that serve as a key mediator in alleviating C. rodentium-associated pathology and Th1 cell dysregulation. CONCLUSIONS Our work thus provides evidence for utilizing BL and L. plantarum-derived EVs to manage enteric infection-associated IBD.
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Affiliation(s)
- Yu Feng
- Center for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, Engineering Research Centre for Fruits and Vegetable Processing, Ministry of Agriculture, Ministry of Education, China Agricultural University, Beijing, 100083, China
| | - Qian Zhao
- Center for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, Engineering Research Centre for Fruits and Vegetable Processing, Ministry of Agriculture, Ministry of Education, China Agricultural University, Beijing, 100083, China
| | - Yifan Zhao
- Center for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, Engineering Research Centre for Fruits and Vegetable Processing, Ministry of Agriculture, Ministry of Education, China Agricultural University, Beijing, 100083, China
| | - Chen Ma
- Center for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, Engineering Research Centre for Fruits and Vegetable Processing, Ministry of Agriculture, Ministry of Education, China Agricultural University, Beijing, 100083, China
| | - Meiling Tian
- Center for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, Engineering Research Centre for Fruits and Vegetable Processing, Ministry of Agriculture, Ministry of Education, China Agricultural University, Beijing, 100083, China
| | - Xiaosong Hu
- Center for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, Engineering Research Centre for Fruits and Vegetable Processing, Ministry of Agriculture, Ministry of Education, China Agricultural University, Beijing, 100083, China
| | - Fang Chen
- Center for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, Engineering Research Centre for Fruits and Vegetable Processing, Ministry of Agriculture, Ministry of Education, China Agricultural University, Beijing, 100083, China
| | - Daotong Li
- Center for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, Engineering Research Centre for Fruits and Vegetable Processing, Ministry of Agriculture, Ministry of Education, China Agricultural University, Beijing, 100083, China.
- College of Food Science and Nutritional Engineering, China Agricultural University, No. 17, Qinghua East Road, Haidian District, Beijing, 100083, China.
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Hu Y, Tuo B. The function of chloride channels in digestive system disease (Review). Int J Mol Med 2025; 55:99. [PMID: 40314091 PMCID: PMC12045473 DOI: 10.3892/ijmm.2025.5540] [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: 12/16/2024] [Accepted: 03/11/2025] [Indexed: 05/03/2025] Open
Abstract
Cation channels have been extensively studied in the context of digestive disorders, but comparatively little attention has been given to anions and their associated channels. Chloride ions, the most abundant anions in the human body, act as signaling molecules, modulating cellular behavior and playing a key role in regulating multiorgan physiological and pathophysiological mechanisms. The intra‑ and extracellular distributions of chloride ions are primarily controlled by various chloride channels and transporters. Currently, these chloride channels are classified into several groups: The chloride channels family, cystic fibrosis transmembrane conductance regulator, calcium‑activated chloride channels, volume‑regulated anion channels, proton‑activated chloride channels and ligand‑gated anion channels. This review aims to summarize the roles of chloride ion channels and transporter proteins in digestive system diseases, providing a theoretical basis for future research and offering potential new strategies for disease treatment.
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Affiliation(s)
- Yanxia Hu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
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Gao Z, Yu X, Su W, Huang P, Li Z, Lin Y, Chen LL, Cao Y, Liu Y, Chen J, Yang D, Cao G. Atractylenolide-1 Alleviates Ulcerative Colitis via Restraining RhoA/ROCK/MLC Pathway-Mediated Intestinal Barrier Dysfunction. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:12690-12701. [PMID: 40364748 DOI: 10.1021/acs.jafc.4c11976] [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: 05/15/2025]
Abstract
Using Atractylenolide-1 (AT-1) is a confident strategy for the treatment of ulcerative colitis (UC) due to its natural origin and notable pharmacological activity. The study investigated the therapeutic effect of AT-1 in dextran sodium sulfate (DSS)-induced mice and Caco-2 cells while also exploring the underlying molecular mechanisms. In this study, AT-1 treatment could reduce weight loss and colon shortening and significantly reduce disease activity index (DAI), spleen index, and histopathological scores in UC mice. And AT-1 was observed to restore cell necrosis and monolayer damage and restored F-actin-mediated tight junction (TJ) protein redistribution to alleviate mucosal injury in UC mice and Caco-2 cells. Moreover, AT-1 regulated alanine, aspartic acid, and glutamate metabolism; increased the content of related metabolites; and promoted cell proliferation to restore damaged mucous membranes in UC mice. The results of molecular docking and molecular dynamics simulation showed that the binding of AT-1 to RhoA had a stable conformation, and it was speculated that RhoA was the main target of AT-1. Further investigations revealed that the interference of RhoA disrupted the regulatory pathway of AT-1. Thus, AT-1 could inhibit the reduction of TJ proteins, alter DSS-mediated cytoskeletal migration, promote amino acid metabolism, and subsequently reduce the permeability of the colon epithelium, thereby restoring mucosal barrier dysfunction features.
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Affiliation(s)
- Zengxiang Gao
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, People's Republic of China
| | - Xuecheng Yu
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, People's Republic of China
| | - Wenlong Su
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, People's Republic of China
| | - Peng Huang
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, People's Republic of China
| | - Zhenhui Li
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, People's Republic of China
| | - Yunya Lin
- Hubei Shizhen Laboratory,Wuhan 430065, People's Republic of China
| | - Lin-Lin Chen
- Hubei Shizhen Laboratory,Wuhan 430065, People's Republic of China
- Key Laboratory of Traditional Chinese Medicine Resource and Compound Prescription, Ministry of Education, Hubei University of Chinese Medicine,Wuhan 430065, People's Republic of China
| | - Yan Cao
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, People's Republic of China
- Hubei Shizhen Laboratory,Wuhan 430065, People's Republic of China
| | - Yanju Liu
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, People's Republic of China
- Hubei Shizhen Laboratory,Wuhan 430065, People's Republic of China
| | - Jianbei Chen
- Hubei Shizhen Laboratory,Wuhan 430065, People's Republic of China
| | - Desen Yang
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, People's Republic of China
- Hubei Shizhen Laboratory,Wuhan 430065, People's Republic of China
| | - Guosheng Cao
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, People's Republic of China
- Hubei Shizhen Laboratory,Wuhan 430065, People's Republic of China
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Jiang Y, Chen J, Du Y, Fan M, Shen L. Immune modulation for the patterns of epithelial cell death in inflammatory bowel disease. Int Immunopharmacol 2025; 154:114462. [PMID: 40186907 DOI: 10.1016/j.intimp.2025.114462] [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: 01/17/2025] [Revised: 02/23/2025] [Accepted: 03/08/2025] [Indexed: 04/07/2025]
Abstract
Inflammatory bowel disease (IBD) is an inflammatory disease of the intestine whose primary pathological presentation is the destruction of the intestinal epithelium. The intestinal epithelium, located between the lumen and lamina propria, transmits luminal microbial signals to the immune cells in the lamina propria, which also modulate the intestinal epithelium. In IBD patients, intestinal epithelial cells (IECs) die dysfunction and the mucosal barrier is disrupted, leading to the recruitment of immune cells and the release of cytokines. In this review, we describe the structure and functions of the intestinal epithelium and mucosal barrier in the physiological state and under IBD conditions, as well as the patterns of epithelial cell death and how immune cells modulate the intestinal epithelium providing a reference for clinical research and drug development of IBD. In addition, according to the targeting of epithelial apoptosis and necroptotic pathways and the regulation of immune cells, we summarized some new methods for the treatment of IBD, such as necroptosis inhibitors, microbiome regulation, which provide potential ideas for the treatment of IBD. This review also describes the potential for integrating AI-driven approaches into innovation in IBD treatments.
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Affiliation(s)
- Yuting Jiang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Center for Pharmaceutics Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai 201203, China
| | - Jie Chen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Center for Pharmaceutics Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai 201203, China
| | - Yaoyao Du
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Center for Pharmaceutics Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai 201203, China
| | - Minwei Fan
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Lan Shen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Husain N, Kumar A, Anbazhagan AN, Gill RK, Dudeja PK. Intestinal luminal anion transporters and their interplay with gut microbiome and inflammation. Am J Physiol Cell Physiol 2025; 328:C1455-C1472. [PMID: 40047092 PMCID: PMC12023768 DOI: 10.1152/ajpcell.00026.2025] [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: 01/10/2025] [Revised: 01/29/2025] [Accepted: 02/28/2025] [Indexed: 04/16/2025]
Abstract
The intestine, as a critical interface between the external environment and the internal body, plays a central role in nutrient absorption, immune regulation, and maintaining homeostasis. The intestinal epithelium, composed of specialized epithelial cells, harbors apical anion transporters that primarily mediate the transport of chloride and bicarbonate ions, essential for maintaining electrolyte balance, pH homeostasis, and fluid absorption/secretion. In addition, the intestine hosts a diverse population of gut microbiota that plays a pivotal role in various physiological processes including nutrient metabolism, immune regulation, and maintenance of intestinal barrier integrity, all of which are critical for host gut homeostasis and health. The anion transporters and gut microbiome are intricately interconnected, where alterations in one can trigger changes in the other, leading to compromised barrier integrity and increasing susceptibility to pathophysiological states including gut inflammation. This review focuses on the interplay of key apical anion transporters including Down-Regulated in Adenoma (DRA, SLC26A3), Putative Anion Transporter-1 (PAT1, SLC26A6), and Cystic Fibrosis Transmembrane Conductance Regulator [CFTR, ATP-binding cassette subfamily C member 7 (ABCC7)] with the gut microbiome, barrier integrity, and their relationship to gut inflammation.
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Affiliation(s)
- Nazim Husain
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, IL, USA
| | - Anoop Kumar
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, IL, USA
- Jesse Brown VA Medical Center, Chicago, IL, USA
| | - Arivarasu N. Anbazhagan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, IL, USA
| | - Ravinder K Gill
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, IL, USA
- Jesse Brown VA Medical Center, Chicago, IL, USA
| | - Pradeep. K. Dudeja
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, IL, USA
- Jesse Brown VA Medical Center, Chicago, IL, USA
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Zhang Y, Liu J, Zhang D, Qian H. LianChuang ZhiXue Liquid Enema Modulates the Macrophage Polarization of Ulcerative Colitis via Inhibiting the Jagged-1/Notch1 Signaling Pathway. Drug Des Devel Ther 2025; 19:3253-3268. [PMID: 40308738 PMCID: PMC12042834 DOI: 10.2147/dddt.s503483] [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: 10/29/2024] [Accepted: 04/15/2025] [Indexed: 05/02/2025] Open
Abstract
Objective LianChuang ZhiXue Liquid (LCZXL) enema, one of the classic Chinese medicine prescriptions, in which herbal decoction enema acts directly on the intestines, is clinically effective in patients with ulcerative colitis (UC). However, its specific molecular mechanism has not been clarified to explore the underlying macular mechanism of LCZXL enema effect on UC, based on Jagged-1/Notch1 signaling pathway and the macrophage polarization. Methods After modeling of UC mice, the experiment was conducted in two parts: Experiment I: Control, Model, Mesalazine, Low dose of LCZXL (LCZXL-L), High dose of LCZXL (LCZXL-H); Weight and Disease Activity Index (DAI) scores were recorded on days 1, 3, 5, 7, 9, 11, and 13. On day 14, the colon was taken off. Then the colon length was measured and the damage index (CMDI) score of colon mucosal was evaluated. Zonula occludens-1 (Zo-1) Immunohistochemistry (IHC) and Hematoxylin-Eosin (HE) staining were performed to visualize the colon injury. ELISA was used to detect cytokines content in serum. The M1 and M2 markers and Jagged-1/Notch1 signaling pathway-related genes/proteins were quantified by IF double staining, PCR, WB, and flow cytometry. Experiment II: Control, Model, Recombinant mouse Jagged-1 protein/ Fc Chimera Active (Jagged-1/Fc), LCZXL, Jagged-1/Fc+LCZXL. The M1 and M2 markers and Jagged-1 proteins were quantified by WB, and flow cytometry. Results Our results indicated that LCZXL could reduce the colon injury of UC mice effectively, which expressed DAI and CMDI score reduction, and inhibited colon structure damage. DSS induced a significant up-regulation of CD86, iNOS, TNF-α, IL-1β, and IL-6, and a down-regulation of Arg1, CD206, IL-4, IL-10 and increase of Jagged-1, Notch1, and Notch2. LCZXL enema treatment inhibiting the increase of UC modeling-induced CD86, TNF-α, IL-1β, and IL-6 and increased CD206, Arg1, IL-4, and IL-10 expression level. Notch signaling pathway activator Jagged-1/Fc aggravated M1 macrophage polarization and activated the Jagged-1/Notch1 signaling pathway. LCZXL treatment reversed this situation stop the activation of the Jagged-1/Notch1 signaling pathway. Conclusion Our study proved that LCZXL Enema could inhibit the M1 Macrophage Polarization and promote M2 macrophage polarization of ulcerative colitis via regulating the Jagged-1/Notch1 signaling pathway.
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MESH Headings
- Animals
- Colitis, Ulcerative/drug therapy
- Colitis, Ulcerative/metabolism
- Colitis, Ulcerative/pathology
- Colitis, Ulcerative/chemically induced
- Jagged-1 Protein/metabolism
- Jagged-1 Protein/antagonists & inhibitors
- Mice
- Signal Transduction/drug effects
- Macrophages/drug effects
- Macrophages/metabolism
- Receptor, Notch1/metabolism
- Receptor, Notch1/antagonists & inhibitors
- Drugs, Chinese Herbal/administration & dosage
- Drugs, Chinese Herbal/pharmacology
- Male
- Enema
- Dose-Response Relationship, Drug
- Disease Models, Animal
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Affiliation(s)
- Yongli Zhang
- Department of Anorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China
- Department of Anorectal Surgery, Xi’an Hospital of Traditional Chinese Medicine, Xi’an, Shaanxi, 710016, People’s Republic of China
| | - Jiali Liu
- Department of Anorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China
| | - Dan Zhang
- Department of Anorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China
| | - Haihua Qian
- Department of Anorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China
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Ye Z, Tan Q, Woltemate S, Tan X, Römermann D, Grassl GA, Vital M, Seidler U, Kini A. Escherichia coli Nissle Improves Short-Chain Fatty Acid Absorption and Barrier Function in a Mouse Model for Chronic Inflammatory Diarrhea. Inflamm Bowel Dis 2025; 31:1109-1120. [PMID: 39708301 PMCID: PMC11985405 DOI: 10.1093/ibd/izae294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Indexed: 12/23/2024]
Abstract
BACKGROUND Defects in SLC26A3, the major colonic Cl-/HCO3- exchanger, result in chloride-rich diarrhea, a reduction in short-chain fatty acid (SCFA)-producing bacteria, and a high incidence of inflammatory bowel disease in humans and in mice. Slc26a3-/- mice are, therefore, an interesting animal model for spontaneous but mild colonic inflammation and for testing strategies to reverse or prevent the inflammation. This study investigates the effect of Escherichia coli Nissle (EcN) application on the microbiome, SCFA production, barrier integrity, and mucosal inflammation in slc26a3-/- mice. METHODS In vivo fluid absorption and bicarbonate secretion were assessed in the gut of slc26a3+/+ and slc26a3-/- mice before and during luminal perfusion with 100 mM sodium acetate. Age-matched slc26a3+/+ and slc26a3-/- mice were intragastrically gavaged twice daily with 2 × 108 CFU/100 µL of EcN for 21 days. Body weight and stool water content were assessed daily, and stool and tissues were collected for further analysis. RESULTS Addition of sodium acetate to the lumen of the proximal colon significantly increased fluid absorption and luminal alkalinization in the slc26a3-/- mice. Gavage with EcN resulted in a significant increase in SCFA levels and the expression of SCFA transporters in the slc26a3-/- cecum, the predominant habitat of EcN in mice. This was accompanied by an increase in mucus-producing goblet cells and a decrease in the expression of inflammatory markers as well as host defense antimicrobial peptides. EcN did not improve the overall diversity of the luminal microbiome but resulted in a significant increase in SCFA producers Lachnospiraceae and Ruminococcaceae in the slc26a3-/- feces. CONCLUSIONS These findings suggest that EcN is able to proliferate in the inflamed cecum, resulting in increased microbial SCFA production, decreased inflammation, and improved gut barrier properties. In sufficient dosage, probiotics may thus be an effective anti-inflammatory strategy in the diseased gut.
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Affiliation(s)
- Zhenghao Ye
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Qinghai Tan
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Department of Gastroenterology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Sabrina Woltemate
- Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Xinjie Tan
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dorothee Römermann
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Guntram A Grassl
- Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research DZIF, Partner Site Hannover-Braunschweig, Braunschweig, Germany
| | - Marius Vital
- Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Ursula Seidler
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Archana Kini
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
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Xiang M, Wu S, Liu M, Zhang B, Xia X, Tan W, Xiang S. Iota-carrageenan oligosaccharide ameliorates DSS-induced colitis in mice by mediating gut microbiota dysbiosis and modulating SCFAs-PI3K-AKT pathway. Inflammopharmacology 2025:10.1007/s10787-025-01718-w. [PMID: 40167852 DOI: 10.1007/s10787-025-01718-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 03/04/2025] [Indexed: 04/02/2025]
Abstract
Iota-carrageenan oligosaccharides (iCOs), derived from marine red algae, are traditionally used as antithrombotic and anti-inflammatory agents in folk medicinal practice. Despite the prevailing emphasis on these aspects in their applications, the potential of iCOs as a prebiotic agent for gut health and its subsequent impact on intestinal disorders such as colitis remains largely unexplored. A DSS-induced colitis model was employed in C57BL/6 male mice to analyze the gut microbiota via 16S rRNA sequencing. Fecal microbiota transplantation (FMT) was used to assess the therapeutic effects of iCOs on colitis. RNA sequencing (RNA-Seq) identified pathways and genes affected by iCOs. ELISA measured inflammatory cytokines, while western blot and RT-qPCR evaluated protein and gene expressions, respectively. The iCOs increased beneficial bacteria, such as Lactobacillus, Bifidobacterium, and Akkermansia. They enhanced short-chain fatty acid production and upregulated GPR41, GPR43, and GPR109A mRNA, influencing cytokine secretion. The iCOs reduced mRNA of SPHK1, BDKRB1, LCN2, and so on, potentially through PI3K-Akt pathway inhibition, and promoted tight junction protein expression. Our findings highlight the novel therapeutic potential of iCOs in colitis, indicating a multifaceted approach to treatment that includes gut microbiota modulation, intestinal barrier restoration, and the suppression of inflammatory responses.
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Affiliation(s)
- Meixian Xiang
- School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, Hubei, People's Republic of China.
| | - Songtao Wu
- Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, School of Pharmacy, Hubei University of Chinese Medicine, Hongshan District, No. 16, Huangjiahu West Road, Wuhan, 430065, People's Republic of China
| | - Minxin Liu
- School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, Hubei, People's Republic of China
| | - Bin Zhang
- Department of Pharmacy, Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266000, People's Republic of China
| | - Xiankun Xia
- School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, Hubei, People's Republic of China
| | - Wenjing Tan
- School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, Hubei, People's Republic of China
| | - Shijian Xiang
- Department of Pharmacy, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong, 518107, People's Republic of China.
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10
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Ülger Y, Delik A. Gene expression profile in ulcerative colitis patients: FOXO4, ALDOB, SLC26A3, SOD2 genes as potential biomarkers. Genes Genomics 2025:10.1007/s13258-025-01625-y. [PMID: 40153227 DOI: 10.1007/s13258-025-01625-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 02/14/2025] [Indexed: 03/30/2025]
Abstract
BACKGROUND Ulcerative colitis (UC) is a complex, chronic inflammatory disease that primarily impacts the colon mucosa. One of the key pathological contributors to the development and progression of inflammatory bowel disease (IBD) is oxidative stress, which results in reactive oxygen species (ROS)-induced mucosal damage. This stress leads to dysfunction of the intestinal barrier. OBJECTIVES The purpose of this study is to examine the expression levels of genes involved in various inflammatory pathways, including autophagy, unfolded protein response (UPR), ubiquitination, metabolic pathways, and immune responses in the colon mucosa of patients with UC. MATERIAL AND METHODS Patients diagnosed with UC at Çukurova University, Balcalı Hospital, Gastroenterology Department between December 2023 and January 2024 were included in this prospective study. A total of 40 participants were included in the study: 27 ulcerative colitis patients and 13 controls. To isolate high-quality RNA, colon biopsy material obtained during colonoscopy was immediately placed in stabilization solution and stored at - 80 degrees Celsius. The relative quantification of target gene mRNA was determined using a Light Cycler. Subsequently, differences in gene expression between patients and the control group were evaluated using the Mann-Whitney U and Kruskal-Wallis tests. RESULTS In our study, FOXO4 gene expression increased in UC patients during both active and remission phases compared to the control group. The high expression of this gene is associated with its role in inflammation and cell death processes. Additionally, the high expression of ALDOB and SLC26A genes is linked to increased inflammation and energy demand. Lastly, the elevated expression of the SOD2 gene can be considered a response to oxidative stress-related inflammatory processes in the disease. CONCLUSION These findings propose that these genes could serve as potential biomarkers for genomic identification and understanding the pathogenesis of UC.
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Affiliation(s)
- Yakup Ülger
- Division of Gastroenterology, Faculty of Medicine, Cukurova University, 01330, Adana, Turkey.
- Balcalı Hospital, Sarıcam, Adana, Turkey.
| | - Anıl Delik
- Division of Gastroenterology, Faculty of Medicine, Cukurova University, 01330, Adana, Turkey
- Balcalı Hospital, Sarıcam, Adana, Turkey
- Division of Biology, Faculty of Science and Literature, Cukurova University, 01330, Adana, Turkey
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11
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He J, Wu J, Tan J, Yang P, Bai T, Song J, Hou X, Zhang L. Role of declined electrogenic Na +/HCO 3- cotransporter NBCe1 in mucus barrier impairment and colonic inflammation. Int Immunopharmacol 2025; 150:114282. [PMID: 39946770 DOI: 10.1016/j.intimp.2025.114282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/24/2025] [Accepted: 02/08/2025] [Indexed: 03/03/2025]
Abstract
BACKGROUND Electrogenic Na+/HCO3- co-transporter 1 (NBCe1) plays a pivotal role in epithelial bicarbonate transport involved in the maintenance of the intestinal mucus barrier. However, the specific role of NBCe1 in colitis remains unknown. METHODS NBCe1 was identified by bioinformatics analysis methods including GO/KEGG/GSEA, protein-protein interaction (PPI) network analysis, immune infiltration analysis, and Mendelian randomization (MR) analysis. Expression level of NBCe1 was detected in patients with IBD and in DSS-induced colitis mice. The role of NBCe1 in intestinal mucus barrier and colitis was accessed by S0859 pretreatment in DSS model. The function of NBCe1 and related bicarbonate secretion were evaluated using short-circuit current (Isc) measurements in Ussing chamber system. RESULTS Bioinformatic analyses indicated that SLC4A4 (NBCe1) was a signature gene in bicarbonate transport implicated in ulcerative colitis (UC) development and was negatively associated with the risk of UC. NBCe1's expression was significantly diminished in colonic mucosa of UC patients and DSS-treated mice. More severe intestinal inflammation and impaired mucus barrier were observed in S0859-treated mice. Moreover, S0859 administration led a significant decrease in mucus secretion rate and an significant increase in Isc of colonic mucosa. The forskolin-induced ΔIsc was also suppressed by S0859 pretreatment. CONCLUSION NBCe1 has been identified as a valuable signature gene may have a protective effect against the onset of colitis. Function of NBCe1 is diminished in colitis, which is associated with impaired mucus barrier and declined HCO3- secretion both contributing to the development of IBD.
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Affiliation(s)
- Jing He
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 China
| | - Jiacheng Wu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 China
| | - Jun Tan
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 China
| | - Pengcheng Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 China
| | - Tao Bai
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 China
| | - Jun Song
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 China
| | - Xiaohua Hou
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 China.
| | - Lei Zhang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 China.
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Zhou Q, Yang L, Verne ZT, Zhang BB, Fields JZ, Thacker AT, Verne GN. Human colonic EVs induce murine enteric neuroplasticity via the lncRNA GAS5/miR-23/NMDA NR2B axis. JCI Insight 2025; 10:e178631. [PMID: 40059833 PMCID: PMC11949048 DOI: 10.1172/jci.insight.178631] [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: 12/18/2023] [Accepted: 01/28/2025] [Indexed: 03/29/2025] Open
Abstract
Postinfectious, diarrhea-predominant, irritable bowel syndrome (PI-IBS-D) is difficult to treat owing to its unknown pathophysiology. Extracellular vesicles (EVs) derived from human colon tissue and long noncoding RNAs (lncRNAs), such as growth arrest-specific 5 (GAS5), may play key roles in the pathophysiology of PI-IBS-D. To determine whether altered colonic EV lncRNA signaling leads to gastrointestinal dysfunction and heightened visceral nociception in patients with PI-IBS-D via the GAS5/miR-23ab/NMDA NR2B axis, we conducted translational studies, including those on (a) the role of colonic EV lncRNAs in patients with PI-IBS-D, human colonoids, and PI-IBS-D tissues; (b) i.p. injection of colonic EVs from patients with PI-IBS-D into Rab27a/b-/- mice (P-EV mice) to investigate whether colonic EVs drive visceral hypersensitivity in vivo via the GAS5/miR-23ab/NMDA NR2B axis; and (c) treatment of mice with oligo-miR-23 precursors and anti-GAS5 Vivo-Morpholinos for GAS5/miR-23ab/NMDA NR2B axis mechanisms. Colonic EVs from patients with PI-IBS-D, but not from control participants, demonstrated reduced miR-23a/b expression caused by enhanced GAS5 expression, which drives increased NR2B expression. Intraperitoneal injection of anti-GAS5-Vivo-Morpholino into P-EV mice increased miR-23 levels and decreased NR2B expression and VMR to CD. EVs are internal messengers that alter gastrointestinal function and increase visceral nociception in patients with PI-IBS-D. Strategies to deliver EVs to modulate GAS5/miR-23ab/NMDA NR2B axis signaling may lead to new and innovative treatments for patients with PI-IBS-D.
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Affiliation(s)
- QiQi Zhou
- College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
- Lt. Col. Luke Weathers, Jr. VA Medical Center, Research Service, Memphis, Tennessee, USA
| | - Liuqing Yang
- College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Zachary T. Verne
- College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Benjamin B. Zhang
- College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Jeremy Z. Fields
- College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Amber T. Thacker
- College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - G. Nicholas Verne
- College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
- Lt. Col. Luke Weathers, Jr. VA Medical Center, Research Service, Memphis, Tennessee, USA
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13
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Tian R, Ding Y, Zhang S, Li M, Wang Y, Wu Q, Ding H, Song C, Shi C, Xue M. Chlorogenic acid alleviates the intestinal barrier dysfunction and intestinal microbiota disorder induced by cisplatin. Front Microbiol 2025; 16:1508891. [PMID: 40104593 PMCID: PMC11919278 DOI: 10.3389/fmicb.2025.1508891] [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: 10/11/2024] [Accepted: 02/03/2025] [Indexed: 03/20/2025] Open
Abstract
Introduction The intestinal mucosal barrier is an important line of defense for the body, protecting it from intestinal bacteria, endotoxins, and antigens. Cisplatin, a clinical important chemotherapy medicine, is found the side effect with impairing intestinal epithelial cells' structure and function, even causes intestinal mucositis which causes patients immense suffering and hinders the process of cancer treatment. Chlorogenic acid, as the component only second to caffeine in coffee, has been proved the contribution on cardiovascular and gastrointestinal benefits. So, we investigate the protective effect of chlorogenic acid on cisplatin induced intestinal barrier structure and function injury in mice from the perspective of gut microbiota. Methods C57BL/6J mice were divided into 4 groups, including the control group, a cisplatin group, a chlorogenic acid treatment group receiving intraperitoneal injections alongside cisplatin (Cis + CGA1), and the last group pre-treated with chlorogenic acid before cisplatin administration (Cis + CGA2). The inflammation factor of IL-6, IL-1β, and TNF-α in colonic tissue and serum were detected, respectively. To explore the protection of chlorogenic acid on mucosal barrier's integrity, we also detected the fecal LPS and the expression of occludin and ZO-1 proteins in colon tissue. And H&E staining was used to study the histopathological conditions of the colon tissue. Moreover, this article also utilized16S rDNA sequencing to analyze the gut microbiota of feces. Results Chlorogenic acid administration reduced IL-6, IL-1β, and TNF-α level in both colon tissue and serum compared to the cisplatin alone treatment group. Furthermore, chlorogenic acid pretreatment notably improved intestinal barrier integrity by enhancing the expression of occludin and ZO-1 proteins in colon tissues. Moreover, 16S rDNA sequencing showed that compared with the control group, cisplatin group showed a reduced microbiota diversity, elevating abundance of Proteobacteria and pro-inflammatory environment of the increased Firmicutes/Bacteroidetes (F/B) ratio. However, chlorogenic acid treatment especially the pretreatment reversed the reduced microbiota diversity, elevating abundance of Proteobacteria and F/B ratio. Discussion Microbiota diversity and all results suggest that chlorogenic acid treatment was able to mitigate these intestinal microbiota disorder and diversity reduction induced by cisplatin, effectively offer a protective effect against the inflammatory response and destruction of the mucosal barrier in the intestines caused by cisplatin.
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Affiliation(s)
- Ruiqi Tian
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
| | - Yinchuan Ding
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
| | - Shijie Zhang
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
| | - Min Li
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
| | - Yiran Wang
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
| | - Qi Wu
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
| | - Huanhuan Ding
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
| | - Chengjie Song
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
| | - Ce Shi
- Department of Orthopedics, Nanjing Gulou Hospital Group Suqian Hospital, Suqian, China
| | - Min Xue
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
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14
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Kumar A, Husain N, Anbazhagan AN, Jayawardena D, Priyamvada S, Singhal M, Jain C, Kaur P, Guzman G, Saksena S, Dudeja PK. Dexamethasone Upregulates the Expression of the Human SLC26A3 (DRA, Down-Regulated in Adenoma) Transporter (an IBD Susceptibility Gene) in Intestinal Epithelial Cells and Attenuates Gut Inflammation. Inflamm Bowel Dis 2025; 31:625-635. [PMID: 39657154 DOI: 10.1093/ibd/izae271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Indexed: 12/17/2024]
Abstract
BACKGROUND Down-Regulated in Adenoma (DRA) plays a critical role in intestinal chloride absorption and a decrease in its expression is a key event in diarrheal disorders. Recently, DRA has emerged as an Inflammatory Bowel Disease (IBD) susceptibility gene. Therefore, the strategies to upregulate DRA expression are potentially novel approaches to not only treat IBD-associated diarrhea but also gut inflammation. In this study, the effect of dexamethasone (DEX), an anti-inflammatory corticosteroid on DRA expression was investigated. METHODS GR (glucocorticoid receptor) overexpressed Caco-2 cells and C57BL/6/J mice and anti-αIL-10R mAb model of IBD were used. Protein expression was assessed by immunoblotting and immunofluorescence. Transcript levels were assessed by quantative-real-time polymerase chain reaction (qRT-PCR) and promoter activity was measured by luciferase assays. RESULTS Our results showed that DEX significantly increased DRA mRNA and protein expression in GR overexpressing Caco-2 cells. DEX-induced upregulation of DRA was GR dependent and appeared at least in part to occur via a transcriptional mechanism, as promoter activity of the DRA construct (-1183/+114 bp) was significantly increased in response to DEX. The increase in DRA mRNA was abrogated in the presence of MKP-1 inhibitor, triptolide. Administration of DEX (2 mg/kg body weight) to mice for 24 and 48 hours significantly increased the DRA expression in mouse colon. DEX treatment to mice for 7 days in the αIL-10R mAb model of colitis was able to significantly attenuate the gut inflammation and associated decrease in DRA expression. CONCLUSIONS We demonstrate that DEX stimulates DRA expression via transcriptional mechanisms and suggest that upregulation of DRA may contribute to both anti-inflammatory and pro-absorptive effects of DEX.
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Affiliation(s)
- Anoop Kumar
- Jesse Brown VA Medical Center, Research and Development, Chicago, IL, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Nazim Husain
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Arivarasu N Anbazhagan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Dulari Jayawardena
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Shubha Priyamvada
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Megha Singhal
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Charu Jain
- Jesse Brown VA Medical Center, Research and Development, Chicago, IL, USA
| | - Prabhdeep Kaur
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Grace Guzman
- Department of Pathology, College of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Seema Saksena
- Jesse Brown VA Medical Center, Research and Development, Chicago, IL, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Pradeep K Dudeja
- Jesse Brown VA Medical Center, Research and Development, Chicago, IL, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
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15
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Wang Y, Gao P, Wu Z, Jiang B, Wang Y, He Z, Zhao B, Tian X, Gao H, Cai L, Li W. Exploring the therapeutic potential of Chinese herbs on comorbid type 2 diabetes mellitus and Parkinson's disease: A mechanistic study. JOURNAL OF ETHNOPHARMACOLOGY 2025; 338:119095. [PMID: 39537117 DOI: 10.1016/j.jep.2024.119095] [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: 08/21/2024] [Revised: 10/12/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Type 2 diabetes mellitus (T2DM) and Parkinson's disease (PD) are chronic conditions that affect the aging population, with increasing prevalence globally. The rising prevalence of comorbidity between these conditions, driven by demographic shifts, severely impacts the quality of life of patients, posing a significant burden on healthcare resources. Chinese herbal medicine has been used to treat T2DM and PD for millennia. Pharmacological studies have demonstrated that medicinal herbs effectively lower blood glucose levels and exert neuroprotective effects, suggesting their potential as adjunctive therapy for concurrent management of T2DM and PD. AIM OF THE STUDY To elucidate the shared mechanisms underlying T2DM and PD, particularly focusing on the potential mechanisms by which medicinal herbs (including herbal formulas, single herbs, and active compounds) may treat these diseases, to provide valuable insights for developing therapeutics targeting comorbid T2DM and PD. MATERIALS AND METHODS Studies exploring the mechanisms underlying T2DM and PD, as well as the treatment of these conditions with medicinal herbs, were extracted from several electronic databases, including PubMed, Web of Science, Google Scholar, and China National Knowledge Infrastructure (CNKI). RESULTS Numerous studies have shown that inflammation, oxidative stress, insulin resistance, impaired autophagy, gut microbiota dysbiosis, and ferroptosis are shared mechanisms underlying T2DM and PD mediated through the NLRP3 inflammasome, NF-κB, MAPK, Keap1/Nrf2/ARE, PI3K/AKT, AMPK/SIRT1, and System XC--GSH-GPX4 signaling pathways. Thirty-four medicinal herbs, including 2 herbal formulas, 4 single herbs, and 28 active compounds, have been reported to potentially exert anti-T2DM and anti-PD effects by targeting these shared mechanisms. CONCLUSIONS Traditional Chinese medicine effectively combats T2DM and PD through shared pathological mechanisms, highlighting their potential for application in treating these comorbid conditions.
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Affiliation(s)
- Yan Wang
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, 730000, China; Encephalopathy Department, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Pengpeng Gao
- Department of Preventive Treatment, Ningxia Integrated Chinese and Western Medicine Hospital, Yinchuan, 750004, China
| | - Zicong Wu
- Encephalopathy Department, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Bing Jiang
- Department of Integrated Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, 730000, China
| | - Yanru Wang
- Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, China
| | - Zhaxicao He
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, 730000, China
| | - Bing Zhao
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, 730000, China
| | - Xinyun Tian
- Encephalopathy Department, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Han Gao
- Encephalopathy Department, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Li Cai
- Encephalopathy Department, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.
| | - Wentao Li
- Encephalopathy Department, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.
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Chao X, Fan Z, Wu J, Ye C, Wang X, Li R, Chen S, Zhang X, Fang C, Luo Q. Application of mRNA-Seq and Metagenomic Sequencing to Study Salmonella pullorum Infections in Chickens. Int J Mol Sci 2025; 26:1448. [PMID: 40003915 PMCID: PMC11855712 DOI: 10.3390/ijms26041448] [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: 01/15/2025] [Revised: 02/03/2025] [Accepted: 02/05/2025] [Indexed: 02/27/2025] Open
Abstract
The disease caused by Salmonella pullorum has been demonstrated to exert a deleterious effect on the performance of poultry, giving rise to elevated mortality and considerable economic losses within the breeding industry. However, there is a paucity of research investigating the relationship between cecal gene expression and different isomer and Salmonella pullorum infection, and research on the relationship between intestinal microbiota and Salmonella pullorum infection is also limited. In this study, mRNA-Seq and metagenomic sequencing were performed on the cecal tissues and fresh feces of individuals who tested positive (n = 4) and negative (n = 4) for Salmonella pullorum, with the aim of exploring the chickens infected with Salmonella pullorum from two perspectives: the gene transcription level and the microbial level. The mRNA sequencing results revealed 1560 differentially expressed genes (DEGs), of which 380 genes were found to be up-regulated and 1180 genes were down-regulated. A number of genes were reported to be associated with immunity, including AQP8, SLC26A3, CBS, IFI6, DDX60, IL8L1 and IL8L2. Furthermore, a total of 1047 differentially expressed alternative splicings (DEASs) were identified through alternative splicing analysis, including CBS, SLC6A9, ILDR2, OCRL, etc. The joint analysis of DEGs and DEASs revealed 70 genes that exhibited both differentially expressed alternative splicings and differential expression, including CTNND1, TPM1, SPPL2A, etc. The results of metagenomic sequencing demonstrated that the abundances of Bacteroides, Firmicutes, and Verrucobacteria underwent a significant alteration subsequent to the infection of Salmonella pullorum. In summary, the present study conducted a preliminary exploration of the genetic basis of chickens infected with Salmonella pullorum. TPM1 and SPPL2A were found to be differentially expressed by mRNA-Seq, and differences in alternative splicing events. Furthermore, metagenomic sequencing revealed significant changes in the microbial communities of Bacteroidetes, Firmicutes, and Verrucobacteria during infection with Salmonella pullorum.
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Affiliation(s)
- Xiaohuan Chao
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou 510642, China (X.Z.)
| | - Zhexia Fan
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou 510642, China (X.Z.)
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Jiongwen Wu
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou 510642, China (X.Z.)
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Chutian Ye
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou 510642, China (X.Z.)
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Xiaomeng Wang
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou 510642, China (X.Z.)
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Ruina Li
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou 510642, China (X.Z.)
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Shuya Chen
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou 510642, China (X.Z.)
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Xiquan Zhang
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou 510642, China (X.Z.)
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Cheng Fang
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou 510642, China (X.Z.)
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Qingbin Luo
- State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou 510642, China (X.Z.)
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China
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Gong W, Liu P, Liu J, Li Y, Jiang H, Li W, Kang J, Jiao F, Wu X, Zhao Y, Ren J. Gasdermin B modulates intestinal epithelial homeostasis via regulating hyperactive unfolded protein response in Crohn's disease. J Crohns Colitis 2025; 19:jjaf012. [PMID: 39831701 DOI: 10.1093/ecco-jcc/jjaf012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Indexed: 01/22/2025]
Abstract
BACKGROUND Impaired intestinal epithelial barrier has been considered to be associated with an increasing variety of gastrointestinal diseases, especially inflammatory bowel disease (IBD) encompassing Crohn's disease (CD) and ulcerative colitis (UC). We aimed to investigate the role of Gasdermin B (GSDMB) in modulating intestinal epithelial barrier integrity and proposed a promising therapeutic strategy. METHODS Gasdermin B expression was evaluated in adult CD samples by molecular biology means and single-cell transcriptomes. We generated GSDMB (Rosa26-lsl/lsl-GSDMB;Villin-Cre) and one of its functional missense variant rs2305480 (Rosa26-lsl/lsl-GSDMB-MU;Villin-Cre) intestinal epithelial-specific knock in mice to observe the functions of GSDMB in intestinal epithelial barrier. RNA-seq analysis as well as human and murine intestine-derived organoids were used to determine the pathogenic mechanism of GSDMB. RESULTS The expression of GSDMB was increased during active intestinal inflammation and principally localized in intestinal epithelial cells (IECs). Rosa26-lsl/lsl-GSDMB;Villin-Cre mice developed enterocolitis and exhibited aberrant intestinal barrier integrity. Mechanistically, epithelial GSDMB modulated hyperactive unfolded protein response of IECs by up-regulating BHLHA15 to mediate intestinal barrier injury. Rosa26-lsl/lsl-GSDMB-MU;Villin-Cre mice with the mutant rs2305480 of GSDMB aggravated such inflammatory effects. CONCLUSION We have uncovered an important and previously unrecognized role of GSDMB in intestinal homeostasis, which represents a potential therapeutic target for intestinal inflammation.
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Affiliation(s)
- Wenbin Gong
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Peizhao Liu
- Medical School of Nanjing University, Department of General Surgery, Jinling Hospital, Nanjing 210002, China
| | - Juanhan Liu
- Medical School of Nanjing University, Department of General Surgery, Jinling Hospital, Nanjing 210002, China
| | - Yangguang Li
- Medical School of Nanjing University, Department of General Surgery, Jinling Hospital, Nanjing 210002, China
| | - Haiyang Jiang
- BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing 210019, China
| | - Weizhen Li
- Medical School of Nanjing University, Department of General Surgery, Jinling Hospital, Nanjing 210002, China
- The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Jiaqi Kang
- Medical School of Nanjing University, Department of General Surgery, Jinling Hospital, Nanjing 210002, China
| | - Fan Jiao
- BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing 210019, China
| | - Xiuwen Wu
- Medical School of Nanjing University, Department of General Surgery, Jinling Hospital, Nanjing 210002, China
| | - Yun Zhao
- BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing 210019, China
| | - Jianan Ren
- Medical School of Nanjing University, Department of General Surgery, Jinling Hospital, Nanjing 210002, China
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Wang J, Zhang N, Liu HZ, Wang JL, Zhang YB, Su DD, Zhang LM, Li BD, Miao HT, Miao J. Hydrogen Sulfide (H 2S) Generated in the Colon Induces Neuropathic Pain by Activating Spinal NMDA Receptors in a Rodent Model of Chronic Constriction Injury. Neurochem Res 2025; 50:90. [PMID: 39883291 DOI: 10.1007/s11064-025-04342-w] [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: 10/08/2024] [Revised: 12/27/2024] [Accepted: 01/17/2025] [Indexed: 01/31/2025]
Abstract
Neuropathic pain (NP) imposes a significant burden on individuals, manifesting as nociceptive anaphylaxis, hypersensitivity, and spontaneous pain. Previous studies have shown that traumatic stress in the nervous system can lead to excessive production of hydrogen sulfide (H2S) in the gut. As a toxic gas, it can damage the nervous system through the gut-brain axis. However, whether traumatic stress in the nervous system leading to excessive production of H2S in the gut can ultimately cause neuropathic pain through the gut-brain axis remains to be investigated. This study established a model of chronic constriction injury (CCI) in mice to determine its effects on gut H2S production, the associated damage via the gut-brain axis, the potential neuropathic pain, as well as the probable mechanism. A CCI mouse model was developed using a spinal nerve ligation approach. Subsequently, the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were used to determine the mice's pain thresholds. A variety of assays were performed, including immunofluorescence, western blotting, real-time quantitative Polymerase Chain Reaction (PCR), and membrane clamp whole-cell recordings. Mice subjected to CCI showed decreased MWT and TWL, decreased ZO-1 staining, decreased HuD staining, increased Glial fibrillary acidic protein (GFAP) staining, increased expression of tumor necrosis factor-alpha (TNF-α) protein and interleukin-6 (IL-6) protein, increased expression of NMDAR2B (NR2B) protein and NR2B mRNA, increased colocalization of vGlut2- and c-fos-positive cells, and a higher amplitude of evoked excitatory postsynaptic potential (EPSP) compared to Sham group. These changes were significantly reversed by H2S inhibitor treatment, and the specific NMDA receptor inhibitor MK-801 effectively restored the neurotoxicity of H2S. H2S is involved in CCI-induced neuropathic pain in mice, which might be mediated by the activation of the NMDA signaling pathway.
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Affiliation(s)
- Jun Wang
- Department of Orthopaedics, Tianjin Hospital, Tianjin University, Tianjin, China
| | - Nan Zhang
- Department of Orthopaedics, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China
| | - Hong-Zheng Liu
- Department of Orthopaedics, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China
| | - Jin-Liang Wang
- Department of Orthopaedics, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China
| | - Yong-Bo Zhang
- Department of Orthopaedics, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China
| | - Dong-Dong Su
- Department of Orthopaedics, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China
| | - Li-Min Zhang
- Department of Anesthesiology, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China
| | - Bao-Dong Li
- Department of Neurology, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China
| | - Hui-Tao Miao
- Department of Anesthesiology, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China
- Hebei Key Laboratory of Integrated Traditional and Western Medicine in Osteoarthrosis Research (Preparing), Cangzhou, China
- Hebei Province Key Laboratory of Integrated Traditional and Western Medicine in Neurological Rehabilitation, Cangzhou, China
| | - Jun Miao
- Department of Orthopaedics, Tianjin Hospital, Tianjin University, Tianjin, China.
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19
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Hu C, Wang Y, Liao S, Zhang L, Li C, Zhou D, Lv L, Mei Z. Neutrophil-macrophage hybrid membrane-coated prussian blue nanozyme for ulcerative colitis treatment and mechanistic insights. J Nanobiotechnology 2025; 23:43. [PMID: 39849556 PMCID: PMC11761742 DOI: 10.1186/s12951-025-03123-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 01/13/2025] [Indexed: 01/25/2025] Open
Abstract
BACKGROUND Ulcerative colitis (UC) is a chronic and recurrent digestive tract disease that can lead to significant morbidity and mortality. The pathogenesis of UC is intricately associated with the presence of reactive oxygen species (ROS). Prussian blue (PB), an inorganic nanozyme with potent antioxidant properties, has been extensively applied in the treatment of various inflammatory conditions and tumors. However, despite the explicit antioxidant properties, the underlying molecular mechanism of PB nanozyme in the treatment of UC remains poorly understood. Furthermore, there is a deficiency in antioxidants that possess specific targeting capabilities towards UC lesions. The present study pioneered the fabrication of neutrophil (N)-macrophage (M) hybrid membrane-coated PB (NM-PB) nanozyme for the treatment of UC and investigated its underlying molecular mechanism. RESULTS We have successfully constructed PB, N-PB, M-PB, and NM-PB nanozymes. In both the colitis cell model and UC mouse model, compared with PB, N-PB, and M-PB nanozymes, NM-PB nanozymes exhibited remarkable targeting capabilities, significantly enhancing the localization and uptake of PB nanozymes at the lesion site. NM-PB nanozymes significantly reduced levels of ROS (•OH, •OOH, and H2O2) and decreased the production of proinflammatory cytokines (TNF-α, IL-6, IL-1β). Meanwhile, these nanozymes regulated the expression of intestinal mucosal barrier-related proteins (ZO-1, E-cadherin, and Occludin) and apoptosis-related proteins (Bcl2, Bax). Furthermore, NM-PB nanozymes facilitated the polarization of proinflammatory M1-phenotype macrophage towards an anti-inflammatory M2-phenotype. The mechanistic studies demonstrated that NM-PB nanozymes mitigated the progression of UC by inhibiting the pathway of cytokine-cytokine receptor interaction. CONCLUSION The NM-PB nanozymes provide a promising and innovative alternative for the treatment of UC, offering enhanced targeting and efficacy through their unique design and mechanism of action.
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Affiliation(s)
- Chunli Hu
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P.R. China
| | - Yanhui Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P.R. China
| | - Shengtao Liao
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P.R. China
| | - Liang Zhang
- Department of Ultrasound, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042, P.R. China
| | - Chuanfei Li
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P.R. China
| | - Di Zhou
- Department of Radiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042, P.R. China.
| | - Lin Lv
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P.R. China.
| | - Zhechuan Mei
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P.R. China.
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20
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Arumugam P, Saha K, Nighot P. Intestinal Epithelial Tight Junction Barrier Regulation by Novel Pathways. Inflamm Bowel Dis 2025; 31:259-271. [PMID: 39321109 DOI: 10.1093/ibd/izae232] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Indexed: 09/27/2024]
Abstract
Intestinal epithelial tight junctions (TJs), a dynamically regulated barrier structure composed of occludin and claudin family of proteins, mediate the interaction between the host and the external environment by allowing selective paracellular permeability between the luminal and serosal compartments of the intestine. TJs are highly dynamic structures and can undergo constant architectural remodeling in response to various external stimuli. This is mediated by an array of intracellular signaling pathways that alters TJ protein expression and localization. Dysfunctional regulation of TJ components compromising the barrier homeostasis is an important pathogenic factor for pathological conditions including inflammatory bowel disease (IBD). Previous studies have elucidated the significance of TJ barrier integrity and key regulatory mechanisms through various in vitro and in vivo models. In recent years, considerable efforts have been made to understand the crosstalk between various signaling pathways that regulate formation and disassembly of TJs. This review provides a comprehensive view on the novel mechanisms that regulate the TJ barrier and permeability. We discuss the latest evidence on how ion transport, cytoskeleton and extracellular matrix proteins, signaling pathways, and cell survival mechanism of autophagy regulate intestinal TJ barrier function. We also provide a perspective on the context-specific outcomes of the TJ barrier modulation. The knowledge on the diverse TJ barrier regulatory mechanisms will provide further insights on the relevance of the TJ barrier defects and potential target molecules/pathways for IBD.
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Affiliation(s)
- Priya Arumugam
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA, USA
| | - Kushal Saha
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Prashant Nighot
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA, USA
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21
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Börding T, Janik T, Bischoff P, Morkel M, Sers C, Horst D. GPA33 expression in colorectal cancer can be induced by WNT inhibition and targeted by cellular therapy. Oncogene 2025; 44:30-41. [PMID: 39472498 DOI: 10.1038/s41388-024-03200-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 10/09/2024] [Accepted: 10/15/2024] [Indexed: 01/07/2025]
Abstract
GPA33 is a promising surface antigen for targeted therapy in colorectal cancer (CRC). It is expressed almost exclusively in CRC and intestinal epithelia. However, previous clinical studies have not achieved expected response rates. We investigated GPA33 expression and regulation in CRC and developed a GPA33-targeted cellular therapy. We examined GPA33 expression in CRC cohorts using immunohistochemistry and immunofluorescence. We analyzed GPA33 regulation by interference with oncogenic signaling in vitro and in vivo using inhibitors and conditional inducible regulators. Furthermore, we engineered anti-GPA33-CAR T cells and assessed their activity in vitro and in vivo. GPA33 expression showed consistent intratumoral heterogeneity in CRC with antigen loss at the infiltrative tumor edge. This pattern was preserved at metastatic sites. GPA33-positive cells had a differentiated phenotype and low WNT activity. Low GPA33 expression levels were linked to tumor progression in patients with CRC. Downregulation of WNT activity induced GPA33 expression in vitro and in GPA33-negative tumor cell subpopulations in xenografts. GPA33-CAR T cells were activated in response to GPA33 and reduced xenograft growth in mice after intratumoral application. GPA33-targeted therapy may be improved by simultaneous WNT inhibition to enhance GPA33 expression. Furthermore, GPA33 is a promising target for cellular immunotherapy in CRC.
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Affiliation(s)
- Teresa Börding
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Tobias Janik
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Philip Bischoff
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Cancer Consortium (DKTK) Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Clinician Scientist Program, Berlin, Germany
| | - Markus Morkel
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Cancer Consortium (DKTK) Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christine Sers
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Cancer Consortium (DKTK) Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - David Horst
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
- German Cancer Consortium (DKTK) Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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22
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Kumar A, Jayawardena D, Priyamvada S, Anbazhagan AN, Chatterjee I, Saksena S, Dudeja PK. SLC26A3 (DRA, the Congenital Chloride Diarrhea Gene): A Novel Therapeutic Target for Diarrheal Diseases. Cell Mol Gastroenterol Hepatol 2024; 19:101452. [PMID: 39736385 PMCID: PMC12003007 DOI: 10.1016/j.jcmgh.2024.101452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 12/22/2024] [Accepted: 12/22/2024] [Indexed: 01/01/2025]
Abstract
Diarrhea associated with enteric infections, gut inflammation, and genetic defects poses a major health burden and results in significant morbidity and mortality. Impaired fluid and electrolyte absorption or secretion in the intestine are the hallmark of diarrhea. Electroneutral NaCl absorption in the mammalian GI tract involves the coupling of Na+/H+ and Cl-/HCO3- exchangers. SLC26A3 (Down Regulated in Adenoma, DRA) is the major anion exchanger involved in luminal Cl- absorption and HCO3- secretion. Mutations in the SLC26A3 gene cause a severe disease called congenital chloride diarrhea (CLD). Multiple studies have shown that DRA function or expression is downregulated in infectious diarrheal disorders caused by EPEC, C rodentium, Salmonella, Clostridioides difficile and Cryptosporidium parvum infection. In addition, DRA levels are severely depleted in colonic mucosa of IBD patients and in mouse models of IBD (eg, DSS, TNBS, adoptive T-cell transfer, anti-CD-40, and IL-10 KO colitis). In addition, genetic defects exhibiting diarrhea including microvillus inclusion disease (MVID), keratin-8 depletion, knock-out mouse models of transcriptional factors (eg, CDX-2 and HNF1α/1β) also exhibit severe down regulation of DRA. Also, recent studies have shown that DRA is not only critical for chloride absorption but also plays a key role in maintaining gut epithelial barrier integrity, microbiome composition, and has now emerged as an IBD susceptibility gene. In this review, we provide strong evidence that DRA may serve as a novel therapeutic target with dual benefits in not only correcting diarrheal phenotype but also improving gut barrier integrity and inflammation in pathogen infection or IBD.
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Affiliation(s)
- Anoop Kumar
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, Illinois; Jesse Brown VA Medical Center, Chicago, Illinois
| | - Dulari Jayawardena
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, Illinois
| | - Shubha Priyamvada
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, Illinois
| | - Arivarasu N Anbazhagan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, Illinois
| | - Ishita Chatterjee
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, Illinois
| | - Seema Saksena
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, Illinois; Jesse Brown VA Medical Center, Chicago, Illinois
| | - Pradeep K Dudeja
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, Illinois; Jesse Brown VA Medical Center, Chicago, Illinois.
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23
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Gou Y, Lin F, Dan L, Zhang D. Exposure to toluene diisocyanate induces dysbiosis of gut-lung homeostasis: Involvement of gut microbiota. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 363:125119. [PMID: 39414067 DOI: 10.1016/j.envpol.2024.125119] [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: 05/19/2024] [Revised: 09/29/2024] [Accepted: 10/12/2024] [Indexed: 10/18/2024]
Abstract
Toluene diisocyanate (TDI) is a major industrial compound that induces occupational asthma with steroid-resistant properties. Recent studies suggest that the gastrointestinal tract may be an effective target for the treatment of respiratory diseases. However, the alterations of the gut-lung axis in TDI-induced asthma remain unexplored. Therefore, in this study, a model of stable occupational asthma caused by TDI exposure was established to detect the alteration of the gut-lung axis. Exposure to TDI resulted in dysbiosis of the gut microbiome, with significant decreases in Barnesiella_intestinihominis, Faecalicoccus_pleomorphus, Lactobacillus_apodemi, and Lactobacillus_intestinalis, but increases in Alistipes_shahii and Odoribacter_laneus. The largest change in abundance was in Barnesiella_intestinihominis, which decreased from 12.14 per cent to 6.18 per cent. The histopathological abnormalities, including shorter length of intestinal villi, thinner thickness of muscularis, reduced number of goblet cells and inflammatory cell infiltration, were found in TDI-treated mice compared to control mice. In addition, increased permeability (evidenced by significantly reduced levels of ZO-1, Occludin and Claudin-1) and activation of TLR4/NF-κB signaling were observed in the intestine of these TDI-exposed mice. Concurrently, exposure to TDI resulted in airway hyperresponsiveness, overt cytokine production (e.g., IL-4, IL-5, IL-13, IL-25, and IL-33), and elevated IgE level within the respiratory tract. The expression of tight junction proteins is reduced and TLR4/NF-κB signaling is activated in the lung following TDI treatment. In addition, correlation analyses showed that changes in the gut microbiota were correlated with TDI exposure-induced airway inflammation. In conclusion, the present study suggests that the immune gut-lung axis may be involved in the development of TDI-induced asthma, which may have implications for potential interventions against steroid-resistant asthma.
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Affiliation(s)
- Yuxuan Gou
- Clinical Medical School, Guizhou Medical University, Guiyang, Guizhou, 561113, China.
| | - Fu Lin
- Clinical Medical School, Guizhou Medical University, Guiyang, Guizhou, 561113, China
| | - Li Dan
- Clinical Medical School, Guizhou Medical University, Guiyang, Guizhou, 561113, China
| | - Dianyu Zhang
- Clinical Medical School, Guizhou Medical University, Guiyang, Guizhou, 561113, China
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24
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Leow SS, Khoo JS, Lee WK, Hoh CC, Fairus S, Sambanthamurthi R, Hayes KC. RNA-Seq transcriptome profiling of Nile rat livers reveals novel insights on the anti-diabetic mechanisms of Water-Soluble Palm Fruit Extract. J Appl Genet 2024; 65:867-895. [PMID: 38890243 DOI: 10.1007/s13353-024-00880-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 04/08/2024] [Accepted: 05/15/2024] [Indexed: 06/20/2024]
Abstract
Water-Soluble Palm Fruit Extract (WSPFE) has been shown to confer anti-diabetic effects in the Nile rat (NR) (Arvicanthis niloticus). Liquid and powder WSPFE both deterred diabetes onset in NRs fed a high-carbohydrate (hiCHO) diet, but the liquid form provided better protection. In this study, NRs were fed either a hiCHO diet or the same diet added with liquid or powder WSPFE. Following feeding of the diets for 8 weeks, random blood glucose levels were measured to categorize NRs as either diabetes-resistant or diabetes-susceptible, based on a cut-off value of 75 mg/dL. Livers were then obtained for Illumina HiSeq 4000 paired end RNA-sequencing (RNA-Seq) and the data were mapped to the reference genome. Consistent with physiological and biochemical parameters, the gene expression data obtained indicated that WSPFE was associated with protection against diabetes. Among hepatic genes upregulated by WSPFE versus controls, were genes related to insulin-like growth factor binding protein, leptin receptor, and processes of hepatic metabolism maintenance, while those downregulated were related to antigen binding, immunoglobulin receptor, inflammation- and cancer-related processes. WSPFE supplementation thus helped inhibit diabetes progression in NRs by increasing insulin sensitivity and reducing both the inflammatory effects of a hiCHO diet and the related DNA-damage compensatory mechanisms contributing to liver disease progression. In addition, the genetic permissiveness of susceptible NRs to develop diabetes was potentially associated with dysregulated compensatory mechanisms involving insulin signaling and oxidative stress over time. Further studies on other NR organs associated with diabetes and its complications are warranted.
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Affiliation(s)
- Soon-Sen Leow
- Malaysian Palm Oil Board, No. 6, Persiaran Institusi, Bandar Baru Bangi, 43000, Kajang, Selangor, Malaysia.
| | - Jia-Shiun Khoo
- Codon Genomics Sdn Bhd, No. 26, Jalan Dutamas 7, Taman Dutamas Balakong, 43200, Seri Kembangan, Selangor, Malaysia
| | - Wei-Kang Lee
- Codon Genomics Sdn Bhd, No. 26, Jalan Dutamas 7, Taman Dutamas Balakong, 43200, Seri Kembangan, Selangor, Malaysia
| | - Chee-Choong Hoh
- Codon Genomics Sdn Bhd, No. 26, Jalan Dutamas 7, Taman Dutamas Balakong, 43200, Seri Kembangan, Selangor, Malaysia
| | - Syed Fairus
- Malaysian Palm Oil Board, No. 6, Persiaran Institusi, Bandar Baru Bangi, 43000, Kajang, Selangor, Malaysia
| | - Ravigadevi Sambanthamurthi
- Malaysian Palm Oil Board, No. 6, Persiaran Institusi, Bandar Baru Bangi, 43000, Kajang, Selangor, Malaysia
- Academy of Sciences Malaysia, Level 20, West Wing, MATRADE Tower, Jalan Sultan Haji Ahmad Shah, Off Jalan Tuanku Abdul Halim, 50480, Kuala Lumpur, Malaysia
| | - K C Hayes
- Brandeis University, 415 South Street, Waltham, MA, 02454, USA
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25
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Peng K, Xiao S, Xia S, Li C, Yu H, Yu Q. Butyrate Inhibits the HDAC8/NF-κB Pathway to Enhance Slc26a3 Expression and Improve the Intestinal Epithelial Barrier to Relieve Colitis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:24400-24416. [PMID: 39440960 DOI: 10.1021/acs.jafc.4c04456] [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: 10/25/2024]
Abstract
Dietary fiber is known to promote the production of short-chain fatty acids (SCFAs) by gut bacteria, which can enhance intestinal epithelial barrier function and ameliorate intestinal inflammation in patients with inflammatory bowel disease (IBD). Interestingly, some IBD patients show reduced expression of solute carrier family member 3 (Slc26a3) in intestinal epithelial cells. The objective of this research was to investigate the interaction between SCFAs and Slc26a3 during colitis and assess how this interaction affects intestinal epithelial barrier function. We showed that butyrate alleviated colonic inflammation in a dose-dependent manner in a dextran sulfate sodium salt (DSS)-induced colitis model. Consistent with this, butyrate increased Slc26a3 and tight junction protein levels. In addition, butyrate inhibited histone deacetylase (HDAC) levels and significantly increased the expression of Slc26a3 by the acetylation of histones in Caco-2BBe cells. The utilization of a pan-HDAC inhibitor or inhibitors specific to certain classes of HDACs revealed that butyrate primarily suppressed HDAC8 to blunt the NF-κB pathways and enhance the expression of Slc26a3. Notably, we demonstrated that HDAC8 activation counteracted the beneficial effect of butyrate in DSS-induced colitis. Therefore, we concluded that butyrate improves the expression of Slc26a3 via inhibition of the HDAC8/NF-κB pathway, leading to increased intestinal epithelial barrier function.
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Affiliation(s)
- Kaixin Peng
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Siqi Xiao
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Suhong Xia
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Congxin Li
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Hongbing Yu
- Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City 66160, Kansas, United States
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver V6H 3N1, British Columbia, Canada
| | - Qin Yu
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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26
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Zhao L, Dou D, Zhang D, Deng X, Ding N, Ma Y, Ji X, Zhang S, Li C. ROS/pH dual-responsive quercetin-loaded guanosine borate supramolecular hydrogel enema in dextran sulfate sodium-induced colitis in mice. J Mater Chem B 2024; 12:10861-10876. [PMID: 39359122 DOI: 10.1039/d4tb01659a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2024]
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease that predominantly impacts the colon, typically starting in the rectum. A significant characteristic of UC is its propensity to affect the distal colon, which is particularly beneficial for targeted treatments such as enemas. This localized approach ensures that the medication is delivered directly to the affected areas, resulting in minimal systemic absorption. In this research, we have formulated a novel stimuli-responsive quercetin-loaded guanosine borate supramolecular hydrogel (named GBQ hydrogel), designed to prolong the residence time of the drug and protect the ulcerated intestinal tissues. The GBQ hydrogel has exhibited excellent injectability, self-healing capabilities, and biocompatibility, rendering it an ideal candidate for enema administration. In vitro studies have highlighted its ROS/pH dual-responsive release profile, which mimics the microenvironment of intestinal inflammation. Furthermore, we assessed the efficacy of the GBQ hydrogel on dextran sulfate sodium (DSS)-induced colitis, a common animal model for UC. Our findings indicate that the GBQ hydrogel significantly reduces disease activity, mitigates oxidative stress, restores the intestinal mucosal barrier, and prevents colonic cell apoptosis. Collectively, this study underscores the therapeutic potential of the GBQ hydrogel in managing inflammatory bowel conditions and paves the way for a novel hydrogel enema-based treatment strategy for UC.
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Affiliation(s)
- Luqing Zhao
- Digestive Disease Center, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, No. 23, Back Street, Art Museum, Dongcheng District, Beijing 100010, China.
| | - Dan Dou
- Digestive Disease Center, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, No. 23, Back Street, Art Museum, Dongcheng District, Beijing 100010, China.
| | - Di Zhang
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, No. 15 Beisanhuan Road East, Chaoyang District, Beijing 100029, China.
| | - Xin Deng
- Digestive Disease Center, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, No. 23, Back Street, Art Museum, Dongcheng District, Beijing 100010, China.
| | - Ning Ding
- Digestive Disease Center, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, No. 23, Back Street, Art Museum, Dongcheng District, Beijing 100010, China.
| | - Yun Ma
- Beijing University of Chinese Medicine, Beijing 100029, China.
| | - Xingyu Ji
- Digestive Disease Center, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, No. 23, Back Street, Art Museum, Dongcheng District, Beijing 100010, China.
| | - Shengsheng Zhang
- Digestive Disease Center, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, No. 23, Back Street, Art Museum, Dongcheng District, Beijing 100010, China.
| | - Chao Li
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, No. 15 Beisanhuan Road East, Chaoyang District, Beijing 100029, China.
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Wang YN, Zhai XY, Wang Z, Gao CL, Mi SC, Tang WL, Fu XM, Li HB, Yue LF, Li PF, Xi SY. Jianpi-Huatan-Huoxue-Anshen formula ameliorates gastrointestinal inflammation and microecological imbalance in chemotherapy-treated mice transplanted with H22 hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:4209-4231. [DOI: 10.4251/wjgo.v16.i10.4209] [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: 04/07/2024] [Revised: 08/06/2024] [Accepted: 09/03/2024] [Indexed: 09/26/2024] Open
Abstract
BACKGROUND Jianpi-Huatan-Huoxue-Anshen formula [Tzu-Chi cancer-antagonizing & life-protecting II decoction (TCCL)] is a Chinese medical formula that has been clinically shown to reduce the gastrointestinal side effects of chemotherapy in cancer patients and improve their quality of life. However, its effect and mechanism on the intestinal microecology after chemotherapy are not yet clear.
AIM To discover the potential mechanisms of TCCL on gastrointestinal inflammation and microecological imbalance in chemotherapy-treated mice transplanted with hepatocellular carcinoma (HCC).
METHODS Ninety-six mice were inoculated subcutaneously with HCC cells. One week later, the mice received a large dose of 5-fluorouracil by intraperitoneal injection to establish a HCC chemotherapy model. Thirty-six mice were randomly selected before administration, and feces, ileal tissue, and ileal contents were collected from each mouse. The remaining mice were randomized into normal saline, continuous chemotherapy, Yangzheng Xiaoji capsules-treated, and three TCCL-treated groups. After treatment, feces, tumors, liver, spleen, thymus, stomach, jejunum, ileum, and colon tissues, and ileal contents were collected. Morphological changes, serum levels of IL-1β, IL-6, IL-8, IL-10, IL-22, TNF-α, and TGF-β, intestinal SIgA, and protein and mRNA expression of ZO-1, NF-κB, Occludin, MUC-2, Claudin-1, and IκB-α in colon tissues were documented. The effect of TCCL on the abundance and diversity of intestinal flora was analyzed using 16S rDNA sequencing.
RESULTS TCCL treatment improved thymus and spleen weight, thymus and spleen indexes, and body weight, decreased tumor volumes and tumor tissue cell density, and alleviated injury to gastric, ileal, and colonic mucosal tissues. Among proteins and genes associated with inflammation, IL-10, TGF-β, SIgA, ZO-1, MUC-2, and Occludin were upregulated, whereas NF-κB, IL-1β, IL-6, TNF-α, IL-22, IL-8, and IκB-α were downregulated. Additionally, TCCL increased the proportions of fecal Actinobacteria, AF12, Adlercreutzia, Clostridium, Coriobacteriaceae, and Paraprevotella in the intermediate stage of treatment, decreased the proportions of Mucipirillum, Odoribacter, RF32, YS2, and Rikenellaceae but increased the proportions of p_Deferribacteres and Lactobacillus at the end of treatment. Studies on ileal mucosal microbiota showed similar findings. Moreover, TCCL improved community richness, evenness, and the diversity of fecal and ileal mucosal flora.
CONCLUSION TCCL relieves pathological changes in tumor tissue and chemotherapy-induced gastrointestinal injury, potentially by reducing the release of pro-inflammatory factors to repair the gastrointestinal mucosa, enhancing intestinal barrier function, and maintaining gastrointestinal microecological balance. Hence, TCCL is a very effective adjuvant to chemotherapy.
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Affiliation(s)
- Ya-Nan Wang
- Department of TCM, Xiang’an Hospital, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Xiang-Yang Zhai
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Zheng Wang
- Department of TCM, Xiang’an Hospital, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Chun-Ling Gao
- Department of Radiotherapy, Chenggong Hospital of Xiamen University, PLA 73rd Army Hospital, Xiamen 361003, Fujian Province, China
| | - Sui-Cai Mi
- Department of Oncology, Xiamen Hospital of Traditional Chinese Medicine, Xiamen 361015, Fujian Province, China
| | - Wen-Li Tang
- Department of TCM, Xiang’an Hospital, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Xue-Min Fu
- Department of TCM, Xiang’an Hospital, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Huai-Bang Li
- Department of TCM, Xiang’an Hospital, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Li-Feng Yue
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Peng-Fei Li
- Department of TCM, Xiang’an Hospital, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Sheng-Yan Xi
- Department of TCM, Xiang’an Hospital, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
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Cao W, Xiong Y, Chen D. Contradiction: Inhibiting inflammation and immunosuppression in the treatment of IBD. Proc Natl Acad Sci U S A 2024; 121:e2415439121. [PMID: 39284069 PMCID: PMC11441512 DOI: 10.1073/pnas.2415439121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2024] Open
Affiliation(s)
- Wenfu Cao
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian City, Liaoning Province 116044, China
| | - Yongjian Xiong
- First Affiliated Hospital of Dalian Medical University, Dalian City, Liaoning province 116044, China
| | - Dapeng Chen
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian City, Liaoning Province 116044, China
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Jayawardena D, Anbazhagan AN, Majumder A, Akram R, Nazmi A, Kaur R, Kumar A, Saksena S, Olivares-Villagómez D, Dudeja PK. Ion Transport Basis of Diarrhea, Paneth Cell Metaplasia, and Upregulation of Mechanosensory Pathway in Anti-CD40 Colitis Mice. Inflamm Bowel Dis 2024; 30:1454-1466. [PMID: 38300738 PMCID: PMC12102476 DOI: 10.1093/ibd/izae002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Indexed: 02/03/2024]
Abstract
BACKGROUND Anti-Cluster of differentiation (CD)-40-induced colitis, driven by innate inflammatory responses in the intestine, is a potent animal model exhibiting IBD pathophysiology including diarrhea. However, the ion transport basis of diarrhea and some key mucosal pathways (Paneth cells, stem cell niche, and mechanosensory) in this model have not been investigated. METHODS Mucosal scrapings and intestinal tissue from control and CD40 antibody (150 µg) treated Rag2-/- mice were examined for gut inflammation, Paneth cell numbers, expression of key transporters, tight/adherens junction proteins, stem cell niche, and mechanosensory pathway via hematoxylin and eosin staining, quantitative polymerase chain reaction, and western blotting. RESULTS Compared with control, anti-CD40 antibody treatment resulted in a significant loss of body weight (P < .05) and diarrhea at day 3 postinjection. Distal colonic tissues of anti-CD40 mice exhibited increased inflammatory infiltrates, higher claudin-2 expression, and appearance of Paneth cell-like structures indicative of Paneth cell metaplasia. Significantly reduced expression (P < .005) of downregulated in adenoma (key Cl- transporter), P-glycoprotein/multidrug resistantance-1 (MDR1, xenobiotic transporter), and adherens junction protein E-cadherin (~2-fold P < .05) was also observed in the colon of anti-CD40 colitis mice. Interestingly, there were also marked alterations in the stem cell markers and upregulation of the mechanosensory YAP-TAZ pathway, suggesting the activation of alternate regeneration pathway post-tissue injury in this model. CONCLUSION Our data demonstrate that the anti-CD40 colitis model shows key features of IBD observed in the human disease, hence making it a suitable model to investigate the pathophysiology of ulcerative colitis (UC).
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Affiliation(s)
- Dulari Jayawardena
- Division of Gastroenterology and Hepatology, Dept. of Medicine, University of Illinois at Chicago, IL, USA
| | - Arivarasu N Anbazhagan
- Division of Gastroenterology and Hepatology, Dept. of Medicine, University of Illinois at Chicago, IL, USA
| | - Apurba Majumder
- Division of Gastroenterology and Hepatology, Dept. of Medicine, University of Illinois at Chicago, IL, USA
| | - Ramsha Akram
- Division of Gastroenterology and Hepatology, Dept. of Medicine, University of Illinois at Chicago, IL, USA
| | - Ali Nazmi
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Animal Sciences, The Ohio State University, Columbus, OH, USA
| | - Ramandeep Kaur
- Division of Gastroenterology and Hepatology, Dept. of Medicine, University of Illinois at Chicago, IL, USA
| | - Anoop Kumar
- Division of Gastroenterology and Hepatology, Dept. of Medicine, University of Illinois at Chicago, IL, USA
- Jesse Brown VA Medical Center, Chicago, IL, USA
| | - Seema Saksena
- Division of Gastroenterology and Hepatology, Dept. of Medicine, University of Illinois at Chicago, IL, USA
- Jesse Brown VA Medical Center, Chicago, IL, USA
| | - Danyvid Olivares-Villagómez
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Pradeep K Dudeja
- Division of Gastroenterology and Hepatology, Dept. of Medicine, University of Illinois at Chicago, IL, USA
- Jesse Brown VA Medical Center, Chicago, IL, USA
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30
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Anbazhagan AN, Ge Y, Priyamvada S, Kumar A, Jayawardena D, Palani ARV, Husain N, Kulkarni N, Kapoor S, Kaur P, Majumder A, Lin YD, Maletta L, Gill RK, Alrefai WA, Saksena S, Zadeh K, Hong S, Mohamadzadeh M, Dudeja PK. A Direct Link Implicating Loss of SLC26A6 to Gut Microbial Dysbiosis, Compromised Barrier Integrity, and Inflammation. Gastroenterology 2024; 167:704-717.e3. [PMID: 38735402 DOI: 10.1053/j.gastro.2024.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 04/27/2024] [Accepted: 05/02/2024] [Indexed: 05/14/2024]
Abstract
BACKGROUND & AIMS Putative anion transporter-1 (PAT1, SLC26A6) plays a key role in intestinal oxalate and bicarbonate secretion. PAT1 knockout (PKO) mice exhibit hyperoxaluria and nephrolithiasis. Notably, diseases such as inflammatory bowel disease are also associated with higher risk of hyperoxaluria and nephrolithiasis. However, the potential role of PAT1 deficiency in gut-barrier integrity and susceptibility to colitis is currently elusive. METHODS Age-matched PKO and wild-type littermates were administered 3.5% dextran sulfate sodium in drinking water for 6 days. Ileum and colon of control and treated mice were harvested. Messenger RNA and protein expression of tight junction proteins were determined by reverse transcription polymerase chain reaction and western blotting. Severity of inflammation was assessed by measuring diarrheal phenotype, cytokine expression, and hematoxylin and eosin staining. Gut microbiome and associated metabolome were analyzed by 16S ribosomal RNA sequencing and mass spectrometry, respectively. RESULTS PKO mice exhibited significantly higher loss of body weight, gut permeability, colonic inflammation, and diarrhea in response to dextran sulfate sodium treatment. In addition, PKO mice showed microbial dysbiosis and significantly reduced levels of butyrate and butyrate-producing microbes compared with controls. Co-housing wild-type and PKO mice for 4 weeks resulted in PKO-like signatures on the expression of tight junction proteins in the colons of wild-type mice. CONCLUSIONS Our data demonstrate that loss of PAT1 disrupts gut microbiome and related metabolites, decreases gut-barrier integrity, and increases host susceptibility to intestinal inflammation. These findings, thus, highlight a novel role of the oxalate transporter PAT1 in promoting gut-barrier integrity, and its deficiency appears to contribute to the pathogenesis of inflammatory bowel diseases.
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Affiliation(s)
- Arivarasu N Anbazhagan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Yong Ge
- Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health, San Antonio, Texas
| | - Shubha Priyamvada
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Anoop Kumar
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Dulari Jayawardena
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Arvind Raj Vishnu Palani
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Nazim Husain
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Neelkanth Kulkarni
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Shaunik Kapoor
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Prabhdeep Kaur
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Apurba Majumder
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Yang-Ding Lin
- Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health, San Antonio, Texas
| | - Leeany Maletta
- Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health, San Antonio, Texas
| | - Ravinder K Gill
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Waddah A Alrefai
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Seema Saksena
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Kimia Zadeh
- Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Sungmo Hong
- Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health, San Antonio, Texas
| | - Mansour Mohamadzadeh
- Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health, San Antonio, Texas; South Texas Veterans Health Care System, San Antonio, Texas
| | - Pradeep K Dudeja
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois.
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Marie C, Das S, Coomes D, Ahmed T, Ali SA, Iqbal J, Kelly P, Mahfuz M, Moore SR, Petri WA, Tarr PI, Denson LA. Duodenal transcriptomics demonstrates signatures of tissue inflammation and immune cell infiltration in children with environmental enteric dysfunction across global centers. Am J Clin Nutr 2024; 120 Suppl 1:S51-S64. [PMID: 39300663 PMCID: PMC11562032 DOI: 10.1016/j.ajcnut.2024.02.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 12/28/2023] [Accepted: 02/22/2024] [Indexed: 09/22/2024] Open
Abstract
BACKGROUND Environmental enteric dysfunction (EED) is an inflammatory condition of the small intestine that is prevalent in children residing in low- and middle-income countries. EED is accompanied by profound histopathologic changes in the small bowel, loss of absorptive capacity, increased intestinal permeability, increased microbial translocation, and nutrient loss. OBJECTIVES We sought to identify dysregulated genes and pathways that might underlie pediatric EED. METHODS RNA-sequencing libraries were generated from endoscopically obtained duodenal tissue from undernourished children with EED from 3 prospective cohorts of children with EED. The EED transcriptome was defined in comparison to North American children without EED. Weighted gene coexpression network analysis (WGCNA) was tested for gene modules associated with EED and its histologic features. RESULTS The 1784 upregulated genes in EED were highly enriched for immune and inflammatory processes, including IL-17 and JAK-STAT signaling, and cytokine-cytokine receptor interactions. The 1388 downregulated genes included genes corresponding to xenobiotic metabolism, detoxification, and antioxidant capacities. A gene coexpression module enriched for antimicrobial responses and chemokine activity was significantly associated with villous blunting, goblet cell depletion, and overall histologic severity of EED. CONCLUSIONS The transcriptome signatures of EED include specific innate and adaptive immune responses that are consistently elevated across study centers, coupled with reduced detoxification and antioxidant capacities. These data may have implications for targeted interventions to improve EED outcomes.
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Affiliation(s)
- Chelsea Marie
- Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, United States.
| | - Subhasish Das
- Nutrition Research Division, International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka, Bangladesh
| | - David Coomes
- Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, United States
| | - Tahmeed Ahmed
- Nutrition Research Division, International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka, Bangladesh
| | - S Asad Ali
- Department of Paediatrics and Child Health, Aga Khan University, Karachi, Pakistan
| | - Junaid Iqbal
- Department of Paediatrics and Child Health, Aga Khan University, Karachi, Pakistan
| | - Paul Kelly
- Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom
| | - Mustafa Mahfuz
- Nutrition Research Division, International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka, Bangladesh
| | - Sean R Moore
- Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, United States
| | - William A Petri
- Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, United States
| | - Phillip I Tarr
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
| | - Lee A Denson
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
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Kou RW, Li ZQ, Wang JL, Jiang SQ, Zhang RJ, He YQ, Xia B, Gao JM. Ganoderic Acid A Mitigates Inflammatory Bowel Disease through Modulation of AhR Activity by Microbial Tryptophan Metabolism. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:17912-17923. [PMID: 39078661 DOI: 10.1021/acs.jafc.4c01166] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/31/2024]
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a complex gastrointestinal condition influenced by genetic, microbial, and environmental factors, among which the gut microbiota plays a crucial role and has emerged as a potential therapeutic target. Ganoderic acid A (GAA), which is a lanostane triterpenoid compound derived from edible mushroom Ganoderma lucidum, has demonstrated the ability to modulate gut dysbiosis. Thus, we investigated the impact of GAA on IBD using a dextran sodium sulfate (DSS)-induced colitis mouse model. GAA effectively prevented colitis, preserved epithelial and mucus layer integrity, and modulated the gut microbiota. In addition, GAA promoted tryptophan metabolism, especially 3-IAld generation, activated the aryl hydrocarbon receptor (AhR), and induced IL-22 production. Fecal microbiota transplantation validated the mediating role of the gut microbiota in the IBD protection conferred by GAA. Our study suggests that GAA holds potential as a nutritional intervention for ameliorating IBD by influencing the gut microbiota, thereby regulating tryptophan metabolism, enhancing AhR activity, and ultimately improving gut barrier function.
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Affiliation(s)
- Rong-Wei Kou
- School of Science, Xi'an University of Technology, Xi'an 710048, Shaanxi, People's Republic of China
| | - Zhi-Qing Li
- College of Food Science and Engineering, Northwest A&F University, Yangling 712100, Shaanxi, People's Republic of China
| | - Jia-Lin Wang
- College of Food Science and Engineering, Northwest A&F University, Yangling 712100, Shaanxi, People's Republic of China
| | - Shi-Qi Jiang
- College of Food Science and Engineering, Northwest A&F University, Yangling 712100, Shaanxi, People's Republic of China
| | - Rui-Jing Zhang
- College of Food Science and Engineering, Northwest A&F University, Yangling 712100, Shaanxi, People's Republic of China
| | - Yang-Qing He
- School of Science, Xi'an University of Technology, Xi'an 710048, Shaanxi, People's Republic of China
| | - Bing Xia
- College of Food Science and Engineering, Northwest A&F University, Yangling 712100, Shaanxi, People's Republic of China
| | - Jin-Ming Gao
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, Shaanxi, People's Republic of China
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Lan J, Zhang Y, Jin C, Chen H, Su Z, Wu J, Ma N, Zhang X, Lu Y, Chen Y, Zeng X, Zhang H, Zheng G, Sun Y, Wang C, Hu Y, Wang Y, Liu Y, Zeng Z, Shi L, He J, Cao A, Wang Y, Pan X, Jin G, Wang Y, Jiang X, Shen H, Tang Q, Xie X, Xiao Y, Zhong X, Zhang X, Zeng L, Ye L, Xie J, Geng L, Li Z, Wu X, Wang Y, Mao R, Zhang S, Huang S, Liu S, Zeng H, Xu W, Gong S, Guo Y, Yang M. Gut Dysbiosis Drives Inflammatory Bowel Disease Through the CCL4L2-VSIR Axis in Glycogen Storage Disease. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2309471. [PMID: 38889269 PMCID: PMC11321658 DOI: 10.1002/advs.202309471] [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: 12/05/2023] [Revised: 05/04/2024] [Indexed: 06/20/2024]
Abstract
Patients with glycogen storage disease type Ib (GSD-Ib) frequently have inflammatory bowel disease (IBD). however, the underlying etiology remains unclear. Herein, this study finds that digestive symptoms are commonly observed in patients with GSD-Ib, presenting as single or multiple scattered deep round ulcers, inflammatory pseudo-polyps, obstructions, and strictures, which differ substantially from those in typical IBD. Distinct microbiota profiling and single-cell clustering of colonic mucosae in patients with GSD are conducted. Heterogeneous oral pathogenic enteric outgrowth induced by GSD is a potent inducer of gut microbiota immaturity and colonic macrophage accumulation. Specifically, a unique population of macrophages with high CCL4L2 expression is identified in response to pathogenic bacteria in the intestine. Hyper-activation of the CCL4L2-VSIR axis leads to increased expression of AGR2 and ZG16 in epithelial cells, which mediates the unique progression of IBD in GSD-Ib. Collectively, the microbiota-driven pathomechanism of IBD is demonstrated in GSD-Ib and revealed the active role of the CCL4L2-VSIR axis in the interaction between the microbiota and colonic mucosal immunity. Thus, targeting gut dysbiosis and/or the CCL4L2-VISR axis may represent a potential therapy for GSD-associated IBD.
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Li Y, Wu L, Yong Y, Niu X, Gao Y, Zhou Q, Xie H, Liu X, Li Y, Yu Z, Abd El-Aty AM, Ju X. Enhancing gut barrier integrity: Upregulation of tight junction proteins by chitosan oligosaccharide through the ERK1/2 signaling pathway. Nutrition 2024; 124:112428. [PMID: 38663127 DOI: 10.1016/j.nut.2024.112428] [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: 12/05/2023] [Revised: 02/29/2024] [Accepted: 03/15/2024] [Indexed: 06/17/2024]
Abstract
OBJECTIVES This study aimed to explore the protective mechanism of chitosan oligosaccharide (COS) against lipopolysaccharide (LPS)-induced inflammatory responses in IEC-6 cells and dextran sodium sulfate (DSS)-induced colitis in mice. METHODS The cell inflammation model was constructed by LPS in vitro and enteritis model by DSS in vivo. RESULTS Following LPS exposure, IEC-6 cell proliferation significantly decreased, epithelial cell integrity was compromised, and TNF-α and IL-1β levels were increased. However, COS pretreatment reversed these changes. In vivo, DSS-treated mice exhibited evident pathological alterations, including heightened inflammatory levels and significantly decreased expression of tight junction proteins and critical proteins in the Mitogen activated proteins kinase signaling pathway. Nevertheless, COS administration notably reduced inflammatory levels and increased the expression of tight junction proteins and key proteins in the Mitogen activated proteins kinase signaling pathway. CONCLUSIONS Our findings suggest that COS safeguards gut barrier integrity by upregulating tight junction proteins through the ERK1/2 signaling pathway. Therefore, COS has emerged as a promising candidate for novel drug interventions against inflammatory bowel disease.
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Affiliation(s)
- Yin Li
- Department of Veterinary Medicine, College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang, China; Marine Medical Research and Development Centre, Shenzheng Institute of Guangdong Ocean University, Shenzheng, China
| | - Lianyun Wu
- Department of Veterinary Medicine, College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang, China
| | - Yanhong Yong
- Department of Veterinary Medicine, College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang, China
| | - Xueting Niu
- Department of Veterinary Medicine, College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang, China; Marine Medical Research and Development Centre, Shenzheng Institute of Guangdong Ocean University, Shenzheng, China
| | - Yuan Gao
- Department of Veterinary Medicine, College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang, China; Marine Medical Research and Development Centre, Shenzheng Institute of Guangdong Ocean University, Shenzheng, China
| | - Qiu Zhou
- Department of Veterinary Medicine, College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang, China; Marine Medical Research and Development Centre, Shenzheng Institute of Guangdong Ocean University, Shenzheng, China
| | - Huili Xie
- Department of Veterinary Medicine, College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang, China; Marine Medical Research and Development Centre, Shenzheng Institute of Guangdong Ocean University, Shenzheng, China
| | - Xiaoxi Liu
- Department of Veterinary Medicine, College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang, China
| | - Youquan Li
- Department of Veterinary Medicine, College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang, China
| | - Zhichao Yu
- Department of Veterinary Medicine, College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang, China
| | - A M Abd El-Aty
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, Turkey
| | - Xianghong Ju
- Department of Veterinary Medicine, College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang, China; Marine Medical Research and Development Centre, Shenzheng Institute of Guangdong Ocean University, Shenzheng, China.
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Shi J, Zhou J, Liu B, Lin K, Xie X, Han X, Sheng Y, Liu Y, He C, Zhou Y, Zhu N, Yang Q, Luo R, Li Y. Enzyme/ROS dual-sensitive nanoplatform with on-demand Celastrol release capacity for enhanced ulcerative colitis therapy by ROS scavenging, microbiota rebalancing, inflammation alleviating. J Nanobiotechnology 2024; 22:437. [PMID: 39061092 PMCID: PMC11282782 DOI: 10.1186/s12951-024-02725-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND The oral administration of drugs for treating ulcerative colitis (UC) is hindered by several factors, including inadequate gastrointestinal stability, insufficient accumulation in colonic lesions, and uncontrolled drug release. METHODS A multiple sensitive nano-delivery system comprising β-cyclodextrin (CD) and 4-(hydroxymethyl)phenylboronic acid (PAPE) with enzyme/reactive oxygen species (ROS) sensitivity was developed to load celastrol (Cel) as a comprehensive treatment for UC. RESULTS Owing to the positive charge in the site of inflamed colonic mucosa, the negatively charged nanomedicine (Cel/NPs) could efficiently accumulate. Expectedly, Cel/NPs showed excellent localization ability to colon in vitro and in vivo tests. The elevated concentration of ROS and intestinal enzymes in the colon microenvironment quickly break the CD, resulting in Cel release partially to rebalance microbiota and recover the intestinal barrier. The accompanying cellular internalization of residual Cel/NPs, along with the high concentration of cellular ROS to trigger Cel burst release, could decrease the expression of inflammatory cytokines, inhibit colonic cell apoptosis, promote the macrophage polarization, scavenge ROS, and regulate the TLR4/NF-κB signaling pathway, which certified that Cel/NPs possessed a notably anti-UC therapy outcome. CONCLUSIONS We provide a promising strategy for addressing UC symptoms via an enzyme/ROS-sensitive oral platform capable of releasing drugs on demand.
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Affiliation(s)
- Jinfeng Shi
- College of Pharmacy, Chengdu Medical College, No.783 Xindu Avenue, Xindu District, Chengdu, 610500, China
| | - Jiahui Zhou
- College of Pharmacy, Chengdu Medical College, No.783 Xindu Avenue, Xindu District, Chengdu, 610500, China
| | - Bo Liu
- College of Pharmacy, Chengdu Medical College, No.783 Xindu Avenue, Xindu District, Chengdu, 610500, China
| | - Kezhou Lin
- College of Pharmacy, Chengdu Medical College, No.783 Xindu Avenue, Xindu District, Chengdu, 610500, China
| | - Xingliang Xie
- College of Pharmacy, Chengdu Medical College, No.783 Xindu Avenue, Xindu District, Chengdu, 610500, China
| | - Xue Han
- College of Pharmacy, Chengdu Medical College, No.783 Xindu Avenue, Xindu District, Chengdu, 610500, China
| | - Yanmei Sheng
- College of Pharmacy, Chengdu Medical College, No.783 Xindu Avenue, Xindu District, Chengdu, 610500, China
| | - Yihan Liu
- College of Pharmacy, Chengdu Medical College, No.783 Xindu Avenue, Xindu District, Chengdu, 610500, China
| | - Congjian He
- College of Pharmacy, Chengdu Medical College, No.783 Xindu Avenue, Xindu District, Chengdu, 610500, China
| | - Yujin Zhou
- College of Pharmacy, Chengdu Medical College, No.783 Xindu Avenue, Xindu District, Chengdu, 610500, China
| | - Nan Zhu
- College of Pharmacy, Chengdu Medical College, No.783 Xindu Avenue, Xindu District, Chengdu, 610500, China
| | - Qian Yang
- College of Pharmacy, Chengdu Medical College, No.783 Xindu Avenue, Xindu District, Chengdu, 610500, China
| | - Ruifeng Luo
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR, 999078, China.
| | - Yi Li
- College of Pharmacy, Chengdu Medical College, No.783 Xindu Avenue, Xindu District, Chengdu, 610500, China.
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Han H, Gao M, Wang F, Luo Z, Jiang X, Qiu Y, Su J, Duan X, Luo S, Tang S, Khan A, Zou Z, Chen C, Yin Q, Qiu J, Zhang H. Protective effects of patchouli alcohol against DSS-induced ulcerative colitis. Sci Rep 2024; 14:16745. [PMID: 39033185 PMCID: PMC11271309 DOI: 10.1038/s41598-024-66259-8] [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: 02/22/2024] [Accepted: 07/01/2024] [Indexed: 07/23/2024] Open
Abstract
Patchouli alcohol (PA) is a widely used pharmaceutical ingredient in various Chinese traditional herbal medicine (THM) formulations, known for its modulatory effects on the gut microbiota. The present study investigated PA's anti-inflammatory and regulatory effects on gut microbiota and its mode of action (MOA). Based on the assessments of ulcerative colitis (UC) symptoms, PA exhibited promising preventions against inflammatory response. In accordance, the expressions of pro-inflammatory factors, including interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and chemokine ligand 5 were significantly attenuated under PA treatment. Furthermore, PA enhanced the intestinal barrier damage caused by dextran sodium sulfate (DSS). Interestingly, PA exhibited negligible inventions on DSS-induced gut microbiota dysbiosis. PA did not affect the diversity of the DSS gut microbiota, it did alter the composition, as evidenced by a significant increase in the Firmicutes-Bacteroidetes (F/B) ratio. Finally, the MOA of PA against inflammation in DSS-treated mice was addressed by suppressing the expressions of heme oxygenase-1 (HO-1) and inducible nitric oxide synthase (iNOS). In conclusion, PA prevented inflammatory response in the DSS-induced UC mice model via directly suppressing HO-1 and iNOS-associated antioxidant signal pathways, independent of its effects on gut microbiota composition.
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Affiliation(s)
- Huifang Han
- Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, People's Republic of China
| | - Min Gao
- Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, People's Republic of China
| | - Fanghong Wang
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Zheng Luo
- Jiulongpo District Center for Disease Control and Prevention, Chongqing Municipality, Chongqing, 400039, People's Republic of China
| | - Xuejun Jiang
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People's Republic of China
- Center of Experimental Teaching for Public Health, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Yu Qiu
- Department of Neurology, The Affiliated University-Town Hospital of Chongqing Medical University, Chongqing, 401331, People's Republic of China
| | - Junhao Su
- Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, People's Republic of China
| | - Xinhao Duan
- Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, People's Republic of China
| | - Shiyue Luo
- Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, People's Republic of China
| | - Shixin Tang
- Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, People's Republic of China
| | - Ahmad Khan
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People's Republic of China
- Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Zhen Zou
- Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People's Republic of China
- Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Chengzhi Chen
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People's Republic of China
- Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Qi Yin
- Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, People's Republic of China.
- Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
| | - Jingfu Qiu
- Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, People's Republic of China.
- Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
| | - Hongyang Zhang
- Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, People's Republic of China.
- Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
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Ouahed JD, Griffith A, Collen LV, Snapper SB. Breaking Down Barriers: Epithelial Contributors to Monogenic IBD Pathogenesis. Inflamm Bowel Dis 2024; 30:1189-1206. [PMID: 38280053 PMCID: PMC11519031 DOI: 10.1093/ibd/izad319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Indexed: 01/29/2024]
Abstract
Monogenic causes of inflammatory bowel diseases (IBD) are increasingly being discovered. To date, much attention has been placed in those resulting from inborn errors of immunity. Therapeutic efforts have been largely focused on offering personalized immune modulation or curative bone marrow transplant for patients with IBD and underlying immune disorders. To date, less emphasis has been placed on monogenic causes of IBD that pertain to impairment of the intestinal epithelial barrier. Here, we provide a comprehensive review of monogenic causes of IBD that result in impaired intestinal epithelial barrier that are categorized into 6 important functions: (1) epithelial cell organization, (2) epithelial cell intrinsic functions, (3) epithelial cell apoptosis and necroptosis, (4) complement activation, (5) epithelial cell signaling, and (6) control of RNA degradation products. We illustrate how impairment of any of these categories can result in IBD. This work reviews the current understanding of the genes involved in maintaining the intestinal barrier, the inheritance patterns that result in dysfunction, features of IBD resulting from these disorders, and pertinent translational work in this field.
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Affiliation(s)
- Jodie D Ouahed
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA
| | - Alexandra Griffith
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA
| | - Lauren V Collen
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA
| | - Scott B Snapper
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA
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Ruan Y, Zhu X, Shen J, Chen H, Zhou G. Mechanism of Nicotiflorin in San-Ye-Qing rhizome for anti-inflammatory effect in ulcerative colitis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155564. [PMID: 38554577 DOI: 10.1016/j.phymed.2024.155564] [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: 11/12/2023] [Revised: 03/14/2024] [Accepted: 03/22/2024] [Indexed: 04/01/2024]
Abstract
BACKGROUND The incidence of ulcerative colitis (UC) is on the rise globally and the development of drugs targeting UC is urgent. Finding the target of action of natural products is important for drug discovery, elucidation of drug action mechanism, and disease mechanism. San-Ye-Qing (SYQ), is an ancient herbal medicine, but whether the powder of its rhizome has pharmacological effects against UC and its mechanism of action are not clear. PURPOSE To evaluate the therapeutic effectiveness of rhizome powder of SYQ in treating UC, and conduct an isolation and characterization of the chemical constituents of the powder. Further, screen the most potent compounds among them and determine the potential mechanism for treating UC. METHODS In vivo, the therapeutic effect of SYQ's rhizome powder on UC was assessed by mice's body weight, DAI score, colon length, tissue MPO activity, serum inflammatory markers, etc. Additionally, HPLC was used to isolate and identify the specific chemical components of SYQ's rhizome powder. Then, the most effective compounds and their therapeutic targets were analysed and screened in SYQ rhizome powder using network pharmacology, combined with CCK-8 assay, NO release assay and molecular docking assay, in conjunction with CETSA, DARTS, SPR and enzyme activity assay. Finally, the biological effects of the key compound on the targets were validated using Western blot and ELISA. RESULTS In vivo, SYQ rhizome powder effectively restored mice's body weight, lowered DAI and pathological score, downregulated the expression of inflammatory biomarkers, and restored colon length, as well as the colonic epithelial and mucus barriers. Afterward, 9 compounds were isolated and identified from the powder of the rhizomes of SYQ by HPLC. Nicotiflorin is the primary compound in SYQ with the highest concentration. According to both CCK-8 and NO release tests, Nicotiflorin is also the most efficacious compound. Combined with network pharmacological prediction, molecular docking analysis, CETSA, DARTS, SPR and enzyme activity assay, Nicotiflorin may ultimately suppress inflammation by targeting p65 and inhibiting the NF-κB pathway, thereby attenuating the activation of NLRP3 inflammasome. To verify this conclusion, Western blot and ELISA experiments were conducted. CONCLUSIONS Our results suggest that the extract from SYQ rhizomes has therapeutic properties for UC. Its active ingredient Nicotiflorin exerted potent anti-UC effects by binding to p65 and inhibiting the activation of NF-κB and NLRP3 inflammasomes.
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Affiliation(s)
- Yun Ruan
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong University, NO.20, Xisi Road, Nantong 226001, Jiangsu, China
| | - Xiaolin Zhu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong University, NO.20, Xisi Road, Nantong 226001, Jiangsu, China
| | - Jianbo Shen
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong University, NO.20, Xisi Road, Nantong 226001, Jiangsu, China
| | - Hao Chen
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong University, NO.20, Xisi Road, Nantong 226001, Jiangsu, China.
| | - Guoxiong Zhou
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong University, NO.20, Xisi Road, Nantong 226001, Jiangsu, China.
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Yang Y, Zhao C, Yang Z, Du C, Chang Z, Wen X, Zhang X, Liu Y, Hu L, Gao Z. Myeloid-derived growth factor ameliorates dextran sodium sulfate-induced colitis by regulating macrophage polarization. J Mol Med (Berl) 2024; 102:875-886. [PMID: 38695882 PMCID: PMC11213757 DOI: 10.1007/s00109-024-02447-3] [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: 10/10/2023] [Revised: 03/19/2024] [Accepted: 04/15/2024] [Indexed: 06/29/2024]
Abstract
Inflammatory bowel disease (IBD) is characterized by inflammatory conditions in the gastrointestinal tract. According to reports, IBD prevalence is increasing globally, with heavy economic and physical burdens. Current IBD clinical treatment is limited to pharmacological methods; therefore, new strategies are needed. Myeloid-derived growth factor (MYDGF) secreted by bone marrow-derived mononuclear macrophages has beneficial effects in multiple inflammatory diseases. To this end, the present study aimed to establish an experimental IBD mouse model using dextran sulfate sodium in drinking water. MYDGF significantly alleviated DSS-induced colitis, suppressed lymphocyte infiltration, restored epithelial integrity in mice, and decreased apoptosis in the colon tissue. Moreover, the number of M1 macrophages was decreased and that of M2 macrophages was increased by the action of MYDGF. In MYDGF-treated mice, the NF-κB and MAPK pathways were partially inhibited. Our findings indicate that MYDGF could mitigate DSS-induced mice IBD by reducing inflammation and restoring epithelial integrity through regulation of intestinal macrophage polarization via NF-κB and MAPK pathway inhibition. KEY MESSAGES: MYDGF alleviated DSS-induced acute colitis. MYDGF maintains colon epithelial barrier integrity and relieves inflammation. MYDGF regulates colon macrophage polarization. MYDGF partially inhibited the activation of NF-κB and MAPK pathway.
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Affiliation(s)
- Yang Yang
- Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China
| | - Conghui Zhao
- Department of Pathology, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China
| | - Zi Yang
- Department of Endodontics, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China
| | - Conglin Du
- Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology and Beijing Laboratory of Oral Health, Beijing, 100050, China
| | - Zhichao Chang
- Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology and Beijing Laboratory of Oral Health, Beijing, 100050, China
| | - Xin Wen
- Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology and Beijing Laboratory of Oral Health, Beijing, 100050, China
| | - Xiujuan Zhang
- Nephrology Department, Zhucheng People's Hospital, Shandong, 262200, China
| | - Yi Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, 100050, China.
| | - Liang Hu
- Department of Oral and Maxillofacial Surgery, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China.
| | - Zhenhua Gao
- Department of Oral and Maxillofacial Surgery, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China.
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Zhang M, Song X, Liu S, Zhang N, Yang M, Gao P, Geng Z, Zuo L, Zhang X, Wang L, Wang Y, Li J, Hu J. Magnolin inhibits intestinal epithelial cell apoptosis alleviating Crohn's disease-like colitis by suppressing the PI3K/AKT signalling pathway. Int Immunopharmacol 2024; 134:112181. [PMID: 38733829 DOI: 10.1016/j.intimp.2024.112181] [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: 03/25/2024] [Revised: 04/26/2024] [Accepted: 04/27/2024] [Indexed: 05/13/2024]
Abstract
BACKGROUND AND AIMS Previous reports have shown that preventing excessive intestinal epithelial cell (IEC) apoptosis is a crucial approach for protecting the intestinal barrier in patients with Crohn's disease (CD). Magnolin (MGL) has various biological activities, including antiapoptotic activities, but its role in CD has largely not been determined. This study investigated how MGL impacts CD-like colitis and the underlying mechanism involved. METHODS Mice were treated with TNBS to establish a disease model, and these mice were used to assess the therapeutic effects of MGL on CD-like colitis. TNF-α-treated colon organoids were used to evaluate the impact of MGL on intestinal barrier function and IEC apoptosis. Enrichment analysis was performed to examine the potential pathways through which MGL inhibits IEC apoptosis. Finally, rescue experiments showed the mechanism by which MGL suppresses IEC apoptosis. RESULTS The animal experiments demonstrated that MGL treatment alleviated the weight loss, colon shortening, elevated disease activity index (DAI) scores, increased colitis histological scores and upregulated inflammatory factor expression that were observed in model mice. MGL ameliorated intestinal barrier dysfunction and the loss of tight junction (TJ) proteins (ZO-1 and Claudin-1) by inhibiting IEC apoptosis in both TNBS-treated mice and TNF-α-treated colon organoids. MGL inhibited the PI3K/AKT signalling pathway, thus safeguarding the intestinal barrier and alleviating CD-like colitis in vivo and in vitro. CONCLUSIONS MGL improves the intestinal barrier integrity and prevents CD-like colitis by inhibiting IEC apoptosis. The potential mechanism of its anti-apoptotic impact on IECs could be associated with the PI3K/AKT pathway, presenting novel approaches and avenues for the clinical management of CD.
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Affiliation(s)
- Min Zhang
- Department of Clinical Laboratory, First Affiliated Hospital of Bengbu Medical University, Bengbu, China; Department of Laboratory Medicine, Bengbu Medical University, Bengbu, China; Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases, Bengbu, China
| | - Xue Song
- Department of Central Laboratory, First Affiliated Hospital of Bengbu Medical University, Bengbu, China; Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases, Bengbu, China
| | - Shengbao Liu
- Department of Pathology, First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Nuo Zhang
- Department of Clinical Laboratory, First Affiliated Hospital of Bengbu Medical University, Bengbu, China; Department of Laboratory Medicine, Bengbu Medical University, Bengbu, China
| | - Ming Yang
- Department of Laboratory Medicine, Bengbu Medical University, Bengbu, China
| | - Pengcheng Gao
- Department of Laboratory Medicine, Bengbu Medical University, Bengbu, China
| | - Zhijun Geng
- Department of Central Laboratory, First Affiliated Hospital of Bengbu Medical University, Bengbu, China; Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases, Bengbu, China
| | - Lugen Zuo
- Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases, Bengbu, China; Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Xiaofeng Zhang
- Department of Central Laboratory, First Affiliated Hospital of Bengbu Medical University, Bengbu, China; Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases, Bengbu, China
| | - Lian Wang
- Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases, Bengbu, China; Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Yueyue Wang
- Department of Clinical Laboratory, First Affiliated Hospital of Bengbu Medical University, Bengbu, China; Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases, Bengbu, China
| | - Jing Li
- Department of Clinical Laboratory, First Affiliated Hospital of Bengbu Medical University, Bengbu, China; Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases, Bengbu, China
| | - Jianguo Hu
- Department of Clinical Laboratory, First Affiliated Hospital of Bengbu Medical University, Bengbu, China; Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases, Bengbu, China.
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Figueiredo CC, Monteiro HF, Cunha F, Bisinotto DZ, Ruiz AR, Duarte GA, Ge Y, Lima FS, Mohamadzadeh M, Galvão KN, Bisinotto RS. Shifts in uterine microbiome associated with pregnancy outcomes at first insemination and clinical cure in dairy cows with metritis. Sci Rep 2024; 14:11864. [PMID: 38789554 PMCID: PMC11126406 DOI: 10.1038/s41598-024-61704-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 05/08/2024] [Indexed: 05/26/2024] Open
Abstract
Objectives were to assess differences in uterine microbiome associated with clinical cure and pregnancy outcomes in dairy cows treated for metritis. Cows with metritis (reddish-brownish, watery, and fetid vaginal discharge) were paired with cows without metritis based on parity and days postpartum. Uterine contents were collected through transcervical lavage at diagnosis, five days later following antimicrobial therapy (day 5), and at 40 days postpartum. Uterine microbiome was assessed by sequencing the V4 hypervariable region of the 16S rRNA gene. Although alpha-diversity based on Chao1, Shannon, and inverse Simpson indexes at diagnosis did not differ between cows with and without metritis, disease was associated with differences in beta-diversity. Prevalence of Porphyromonas, Bacteroides, and Veillonella was greater in cows with metritis. Streptococcus, Sphingomonas, and Ureaplasma were more prevalent in cows without metritis. Differences in beta-diversity between cows with and without metritis persisted on day 5. Uterine microbiome was not associated with clinical cure. Richness and alpha-diversity, but not beta-diversity, of uterine microbiome 40 days postpartum were associated with metritis and pregnancy. No relationship between uterine microbiome and pregnancy outcomes was observed. Results indicate that factors other than changes in intrauterine bacterial community underlie fertility loss and clinical cure in cows with metritis.
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Affiliation(s)
- Caio C Figueiredo
- Department of Large Animal Clinical Sciences, D. H. Barron Reproductive and Perinatal Biology Research Program, University of Florida, Gainesville, 32610, USA
- Department of Veterinary Clinical Sciences, Washington State University, Pullman, 99164, USA
| | - Hugo F Monteiro
- Department of Population Health and Reproduction, University of California, Davis, 95616, USA
| | - Federico Cunha
- Department of Large Animal Clinical Sciences, D. H. Barron Reproductive and Perinatal Biology Research Program, University of Florida, Gainesville, 32610, USA
| | - Danilo Z Bisinotto
- Department of Large Animal Clinical Sciences, D. H. Barron Reproductive and Perinatal Biology Research Program, University of Florida, Gainesville, 32610, USA
| | - Angel Revilla Ruiz
- Department of Animal Sciences, University of Florida, Gainesville, 32611, USA
| | - Gustavo A Duarte
- Department of Animal Sciences, University of Florida, Gainesville, 32611, USA
| | - Yong Ge
- Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health, San Antonio, 78229, USA
| | - Fábio S Lima
- Department of Population Health and Reproduction, University of California, Davis, 95616, USA
| | - Mansour Mohamadzadeh
- Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health, San Antonio, 78229, USA
| | - Klibs N Galvão
- Department of Large Animal Clinical Sciences, D. H. Barron Reproductive and Perinatal Biology Research Program, University of Florida, Gainesville, 32610, USA
| | - Rafael S Bisinotto
- Department of Large Animal Clinical Sciences, D. H. Barron Reproductive and Perinatal Biology Research Program, University of Florida, Gainesville, 32610, USA.
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Zhang X, Zhang F, Li Y, Fan N, Zhao K, Zhang A, Kang J, Lin Y, Xue X, Jiang X. Blockade of PI3K/AKT signaling pathway by Astragaloside IV attenuates ulcerative colitis via improving the intestinal epithelial barrier. J Transl Med 2024; 22:406. [PMID: 38689349 PMCID: PMC11061986 DOI: 10.1186/s12967-024-05168-w] [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: 11/13/2023] [Accepted: 04/05/2024] [Indexed: 05/02/2024] Open
Abstract
BACKGROUND The specific pathogenesis of UC is still unclear, but it has been clear that defects in intestinal barrier function play an important role in it. There is a temporary lack of specific drugs for clinical treatment. Astragaloside IV (AS-IV) is one of the main active ingredients extracted from Astragalus root and is a common Chinese herbal medicine for the treatment of gastrointestinal diseases. This study aimed to determine whether AS-IV has therapeutic value for DSS or LPS-induced intestinal epithelial barrier dysfunction in vivo and in vitro and its potential molecular mechanisms. METHODS The intestinal tissues from UC patients and colitis mice were collected, intestinal inflammation was observed by colonoscopy, and mucosal barrier function was measured by immunofluorescence staining. PI3K/AKT signaling pathway activator YS-49 and inhibitor LY-29 were administered to colitic mice to uncover the effect of this pathway on gut mucosal barrier modulation. Then, network pharmacology was used to screen Astragaloside IV (AS-IV), a core active component of the traditional Chinese medicine Astragalus membranaceus. The potential of AS-IV for intestinal barrier function repairment and UC treatment through blockade of the PI3K/AKT pathway was further confirmed by histopathological staining, FITC-dextran, transmission electron microscopy, ELISA, immunofluorescence, qRT-PCR, and western blotting. Finally, 16 S rRNA sequencing was performed to uncover whether AS-IV can ameliorate UC by regulating gut microbiota homeostasis. RESULTS Mucosal barrier function was significantly damaged in UC patients and murine colitis, and the activated PI3K/AKT signaling pathway was extensively involved. Both in vivo and vitro showed that the AS-IV-treated group significantly relieved inflammation and improved intestinal epithelial permeability by inhibiting the activation of the PI3K/AKT signaling pathway. In addition, microbiome data found that gut microbiota participates in AS-IV-mediated intestinal barrier recovery as well. CONCLUSIONS Our study highlights that AS-IV exerts a protective effect on the integrality of the mucosal barrier in UC based on the PI3K/AKT pathway, and AS-IV may serve as a novel AKT inhibitor to provide a potential therapy for UC.
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Affiliation(s)
- Xinhui Zhang
- Department of Pediatrics, Tangdu Hospital, Air Force Medical University, Xinsi Road, Baqiao District, 710038, Xi'an, Shaanxi, China
- The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, 620 West Chang'an Avenue, Chang 'a District, 710119, Xi'an, Shaanxi, China
| | - Fan Zhang
- Medical College, Yan'an University, 580 ShengDi Road, Baota District, 716099, Yan'an, Shaanxi, China
| | - Yan Li
- The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, 620 West Chang'an Avenue, Chang 'a District, 710119, Xi'an, Shaanxi, China
| | - Na Fan
- Medical College, Yan'an University, 580 ShengDi Road, Baota District, 716099, Yan'an, Shaanxi, China
| | - Ke Zhao
- The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, 620 West Chang'an Avenue, Chang 'a District, 710119, Xi'an, Shaanxi, China
- Department of Nutrition and Health, China Agriculture University, 100091, Beijing, China
| | - Anding Zhang
- Department of Pediatrics, Tangdu Hospital, Air Force Medical University, Xinsi Road, Baqiao District, 710038, Xi'an, Shaanxi, China
| | - Jiefang Kang
- The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, 620 West Chang'an Avenue, Chang 'a District, 710119, Xi'an, Shaanxi, China
| | - Yan Lin
- Department of Pediatrics, Tangdu Hospital, Air Force Medical University, Xinsi Road, Baqiao District, 710038, Xi'an, Shaanxi, China
| | - Xiaochang Xue
- The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, 620 West Chang'an Avenue, Chang 'a District, 710119, Xi'an, Shaanxi, China.
| | - Xun Jiang
- Department of Pediatrics, Tangdu Hospital, Air Force Medical University, Xinsi Road, Baqiao District, 710038, Xi'an, Shaanxi, China.
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Sun Q, Li S, Lin R, Zhao G, Lu J, Liu B, Hu M, Wang W, Yang X, Wei Y, Jia W, Hu Y, Zhang W, Zhu J, Cui D, Zhong L. hUC-MSCs therapy for Crohn's disease: efficacy in TNBS-induced colitis in rats and pilot clinical study. EBioMedicine 2024; 103:105128. [PMID: 38653187 PMCID: PMC11063396 DOI: 10.1016/j.ebiom.2024.105128] [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: 06/27/2023] [Revised: 04/03/2024] [Accepted: 04/06/2024] [Indexed: 04/25/2024] Open
Abstract
BACKGROUND The use of mesenchymal stem cells (MSCs) has recently emerged as a promising new therapeutic strategy for many diseases including perianal fistulizing Crohn's disease (CD). Whether hUC-MSCs can promote the healing of luminal ulcer in CD has not been studied so far. METHODS The model of TNBS-induced colitis in rats was used to confirm the efficacy of hUC-MSCs in the treatment of CD. Then, seventeen CD patients refractory to or unsuitable for currently available therapies were enrolled and received once submucosal local injection through colonoscopy combined with once intravenous drip on the next day. All patients received a 24-week follow-up. Clinical and laboratory assessments were monitored at baseline, week 4, 8, 12, and 24. Endoscopic evaluations were conducted at baseline and week 12. Mucosal specimens were obtained at the margin of lesions by endoscopy biopsies and used for RNA sequencing. Two hUC-MSCs co-culture systems were established in vitro, one with the mucosa specimens and the other with M1 macrophages induced from THP1. The expressions of genes representing inflammation (TNFα, IL-6, and IL-1β) and intestinal barrier function (ZO1, CLAUDIN1, and CDH1) were tested by RT-PCR. FINDINGS hUC-MSCs treatment increased body weight and decreased disease activity index (DAI), colon macroscopic damage index (CMDI), and histopathological score (HPS) of rats with TNBS-induced colitis. The results of the clinical study also showed that this mode of hUC-MSCs application was associated with regression of intestinal ulceration. Eight patients (47%) got endoscopic responses (SES-CD improvement of ≥50% from baseline) and three patients (17.65%) got mucosal healing (SES-CD is zero), with a parallel improvement of clinical and laboratory parameters without serious adverse events. RNA sequencing showed hUC-MSCs therapy was associated with an upregulation of transcripts linked to intestinal epithelial barrier integrity and a downregulation of inflammatory signaling pathways in the intestinal mucosa, especially the TNF signaling pathway, IL-17 signaling pathway, and TLR signaling pathway. RNA expression of intestinal epithelial tight junction protein (ZO1, CLAUDIN1, and CDH1), and the RNA expression of major intestinal inflammatory factors in CD (IL-1β, IL-6, and TNFα, p < 0.001 for all) were improved significantly. Moreover, hUC-MSCs could attenuate the polarization of M1 macrophage induced from THP1, thereby decreasing the mRNA expression of IL-1β, IL-6, and TNFα significantly (p < 0.05 for all). TSG-6 expression was evaluated in hUC-MSCs culture supernatant after treatment with TNFα, IFNγ, and LPS for 48 h. And hUC-MSCs could inhibit the phosphorylation of JAK/STAT1 in the intestinal mucosa of CD patients. INTERPRETATION hUC-MSCs transplantation alleviated TNBS-induced colitis in rats. In this pilot clinical study, preliminary data suggested that this approach to administering hUC-MSCs might have potential for clinical efficacy and manageable safety in treating refractory CD, potentially providing hope for better outcomes. No serious adverse events were observed. FUNDING This work was funded by General Program of National Natural Science Foundation of China (Grant No. 82270639), the Scientific research project of Shanghai Municipal Health Committee (Grant No. 202240001), Specialty Feature Construction Project of Shanghai Pudong New Area Health Commission (Grant No. PWZzb2022-05), Shanghai East Hospital Youth Research and Cultivation Foundation program (Grant No. DFPY2022015), Peak Disciplines (Type IV) of Institutions of Higher Learning in Shanghai and Technology Development Project of Pudong Science, Technology and Economic Commission of Shanghai (Grant No. PKJ2021-Y08).
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Affiliation(s)
- Qinjuan Sun
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Shan Li
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Ritian Lin
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Guangxi Zhao
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Jinlai Lu
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Bin Liu
- Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China; National Engineering Research Center for Nanotechnology, Shanghai 200241, China
| | - Miao Hu
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Wei Wang
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Xiaoqing Yang
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Yushuang Wei
- GMP Laboratory of Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, National Stem Cell Translational Resource Center, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Wenwen Jia
- GMP Laboratory of Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, National Stem Cell Translational Resource Center, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Yanni Hu
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Wei Zhang
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Jiawen Zhu
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Daxiang Cui
- Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China; National Engineering Research Center for Nanotechnology, Shanghai 200241, China.
| | - Lan Zhong
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, China.
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Becker HM, Seidler UE. Bicarbonate secretion and acid/base sensing by the intestine. Pflugers Arch 2024; 476:593-610. [PMID: 38374228 PMCID: PMC11006743 DOI: 10.1007/s00424-024-02914-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 01/15/2024] [Accepted: 01/17/2024] [Indexed: 02/21/2024]
Abstract
The transport of bicarbonate across the enterocyte cell membrane regulates the intracellular as well as the luminal pH and is an essential part of directional fluid movement in the gut. Since the first description of "active" transport of HCO3- ions against a concentration gradient in the 1970s, the fundamental role of HCO3- transport for multiple intestinal functions has been recognized. The ion transport proteins have been identified and molecularly characterized, and knockout mouse models have given insight into their individual role in a variety of functions. This review describes the progress made in the last decade regarding novel techniques and new findings in the molecular regulation of intestinal HCO3- transport in the different segments of the gut. We discuss human diseases with defects in intestinal HCO3- secretion and potential treatment strategies to increase luminal alkalinity. In the last part of the review, the cellular and organismal mechanisms for acid/base sensing in the intestinal tract are highlighted.
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Affiliation(s)
- Holger M Becker
- Department of Gastroenterology, Hannover Medical School, 30625, Hannover, Germany
| | - Ursula E Seidler
- Department of Gastroenterology, Hannover Medical School, 30625, Hannover, Germany.
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Cheng Z, Zhou Y, Xiong X, Li L, Chen Z, Wu F, Dong R, Liu Q, Zhao Y, Jiang S, Yu Q, Chen G. Traditional herbal pair Portulacae Herba and Granati Pericarpium alleviates DSS-induced colitis in mice through IL-6/STAT3/SOCS3 pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 126:155283. [PMID: 38422652 DOI: 10.1016/j.phymed.2023.155283] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 12/01/2023] [Accepted: 12/13/2023] [Indexed: 03/02/2024]
Abstract
BACKGROUND Portulacae Herba and Granati Pericarpium pair (PGP) is a traditional Chinese herbal medicine treatment for colitis, clinically demonstrating a relatively favorable effect on relieving diarrhea and abnormal stools. However, the underlying mechanism remain uncertain. PURPOSE The present study intends to evaluate the efficacy of PGP in treating colitis in mice and investigate its underlying mechanism. METHODS The protective effect of PGP against colitis was determined by monitoring body weight, colon length, colon weight, and survival rate in mice. Colonic inflammation was assessed by serum cytokine levels, colonic H&E staining, and local neutrophil infiltration. The reversal of intestinal epithelial barrier damage by PGP was subsequently analyzed with Western blot and histological staining. Furthermore, RNA-seq analysis and molecular docking were performed to identify potential pathways recruited by PGP. Following the hints of the transcriptomic results, the role of PGP through the IL-6/STAT3/SOCS3 pathway in DSS-induced colitis mice was verified by Western blot. RESULTS DSS-induced colitis in mice was significantly curbed by PGP treatment. PGP treatment significantly mitigated DSS-induced colitis in mice, as evidenced by improvements in body weight, DAI severity, survival rate, and inflammatory cytokines levels in serum and colon. Moreover, PGP treatment up-regulated the level of Slc26a3, thereby increasing the expressions of the tight junction/adherens junction proteins ZO-1, occludin and E-cadherin in the colon. RNA-seq analysis revealed that PGP inhibits the IL-6/STAT3/SOCS3 pathway at the transcriptional level. Molecular docking indicated that the major components of PGP could bind tightly to the proteins of IL-6 and SOCS3. Meanwhile, the result of Western blot revealed that the IL-6/STAT3/SOCS3 pathway was inhibited at the protein level after PGP administration. CONCLUSION PGP could alleviate colonic inflammation and reverse damage to the intestinal epithelial barrier in DSS-induced colitis mice. The underlying mechanism involves the inhibition of the IL-6/STAT3/SOCS3 pathway.
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Affiliation(s)
- Zhe Cheng
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yi Zhou
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xinyu Xiong
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Lingli Li
- Department of Traditional Chinese Medicine, Wuhan Fourth Hospital, Wuhan 430033, China
| | - Zekai Chen
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Fan Wu
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ruolan Dong
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Qiong Liu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yan Zhao
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shujun Jiang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Qin Yu
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Guang Chen
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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Amiri M, Jiang M, Salari A, Xiu R, Alper SL, Seidler UE. Reduced surface pH and upregulated AE2 anion exchange in SLC26A3-deleted polarized intestinal epithelial cells. Am J Physiol Cell Physiol 2024; 326:C829-C842. [PMID: 38223928 PMCID: PMC11193482 DOI: 10.1152/ajpcell.00590.2023] [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: 11/03/2023] [Revised: 12/21/2023] [Accepted: 01/02/2024] [Indexed: 01/16/2024]
Abstract
Loss of function mutations in the SLC26A3 gene cause chloride-losing diarrhea in mice and humans. Although systemic adaptive changes have been documented in these patients and in the corresponding knockout mice, how colonic enterocytes adapt to loss of this highly expressed and highly regulated luminal membrane anion exchanger remains unclear. To address this question, SLC26A3 was deleted in the self-differentiating Caco2BBe colonic cell line by the CRISPR/Cas9 technique. We selected a clone with loss of SLC26A3 protein expression and morphological features indistinguishable from those of the native cell line. Neither growth curves nor development of transepithelial electrical resistance (TEER) differed between wild-type (WT) and SLC26A3 knockout (KO) cells. Real-time qPCR and Western analysis in SLC26A3-KO cells revealed an increase in AE2 expression without significant change in NHE3 expression or localization. Steady-state pHi and apical and basolateral Cl-/HCO3- exchange activities were assessed fluorometrically in a dual perfusion chamber with independent perfusion of luminal and serosal baths. Apical Cl-/HCO3- exchange rates were strongly reduced in SLC26A3-KO cells, accompanied by a surface pH more acidic than that of WT cells. Steady-state pHi was not significantly different from that of WT cells, but basolateral Cl-/HCO3- exchange rates were higher in SLC26A3-KO than in WT cells. The data show that CRISPR/Cas9-mediated SLC26A3 deletion strongly reduced apical Cl-/HCO3- exchange rate and apical surface pH, but sustained a normal steady-state pHi due to increased expression and function of basolateral AE2. The low apical surface pH resulted in functional inhibition of NHE-mediated fluid absorption despite normal expression of NHE3 polypeptide.NEW & NOTEWORTHY SLC26A3 gene mutations cause chloride-losing diarrhea. To understand how colonic enterocytes adapt, SLC26A3 was deleted in Caco2BBe cells using CRISPR/Cas9. In comparison to the wild-type cells, SLC26A3 knockout cells showed similar growth and transepithelial resistance but substantially reduced apical Cl-/HCO3- exchange rates, and an acidic surface pH. Steady-state intracellular pH was comparable between the WT and KO cells due to increased basolateral AE2 expression and function.
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Affiliation(s)
- Mahdi Amiri
- Department of Gastroenterology, Hannover Medical School, Hannover, Germany
| | - Min Jiang
- Department of Gastroenterology, Hannover Medical School, Hannover, Germany
| | - Azam Salari
- Department of Gastroenterology, Hannover Medical School, Hannover, Germany
| | - Renjie Xiu
- Department of Gastroenterology, Hannover Medical School, Hannover, Germany
| | - Seth L Alper
- Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States
| | - Ursula E Seidler
- Department of Gastroenterology, Hannover Medical School, Hannover, Germany
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Nishiyama K, Kato Y, Nishimura A, Mi X, Nagata R, Mori Y, Azuma YT, Nishida M. Pharmacological Activation of TRPC6 Channel Prevents Colitis Progression. Int J Mol Sci 2024; 25:2401. [PMID: 38397074 PMCID: PMC10889536 DOI: 10.3390/ijms25042401] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/15/2024] [Accepted: 02/16/2024] [Indexed: 02/25/2024] Open
Abstract
We recently reported that transient receptor potential canonical (TRPC) 6 channel activity contributes to intracellular Zn2+ homeostasis in the heart. Zn2+ has also been implicated in the regulation of intestinal redox and microbial homeostasis. This study aims to investigate the role of TRPC6-mediated Zn2+ influx in the stress resistance of the intestine. The expression profile of TRPC1-C7 mRNAs in the actively inflamed mucosa from inflammatory bowel disease (IBD) patients was analyzed using the GEO database. Systemic TRPC3 knockout (KO) and TRPC6 KO mice were treated with dextran sulfate sodium (DSS) to induce colitis. The Zn2+ concentration and the mRNA expression levels of oxidative/inflammatory markers in colon tissues were quantitatively analyzed, and gut microbiota profiles were compared. TRPC6 mRNA expression level was increased in IBD patients and DSS-treated mouse colon tissues. DSS-treated TRPC6 KO mice, but not TRPC3 KO mice, showed severe weight loss and increased disease activity index compared with DSS-treated WT mice. The mRNA abundances of antioxidant proteins were basically increased in the TRPC6 KO colon, with changes in gut microbiota profiles. Treatment with TRPC6 activator prevented the DSS-induced colitis progression accompanied by increasing Zn2+ concentration. We suggest that TRPC6-mediated Zn2+ influx activity plays a key role in stress resistance against IBD, providing a new strategy for treating colitis.
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Affiliation(s)
- Kazuhiro Nishiyama
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; (K.N.); (Y.K.); (X.M.)
- Laboratory of Prophylactic Pharmacology, Osaka Metropolitan University Graduate School of Veterinary Science, Osaka 598-8531, Japan;
| | - Yuri Kato
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; (K.N.); (Y.K.); (X.M.)
| | - Akiyuki Nishimura
- National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences, Okazaki 444-8787, Japan;
- Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki 444-8787, Japan
- SOKENDAI (Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies), Okazaki 444-8787, Japan
| | - Xinya Mi
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; (K.N.); (Y.K.); (X.M.)
| | - Ryu Nagata
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan;
| | - Yasuo Mori
- Graduate School of Engineering, Kyoto University, Kyoto 615-8530, Japan;
| | - Yasu-Taka Azuma
- Laboratory of Prophylactic Pharmacology, Osaka Metropolitan University Graduate School of Veterinary Science, Osaka 598-8531, Japan;
| | - Motohiro Nishida
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; (K.N.); (Y.K.); (X.M.)
- National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences, Okazaki 444-8787, Japan;
- Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki 444-8787, Japan
- SOKENDAI (Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies), Okazaki 444-8787, Japan
- Department of Physiology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
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Zhu H, Lu J, Fu M, Chen P, Yu Y, Chen M, Zhao Q, Wu M, Ye M. YAP represses intestinal inflammation through epigenetic silencing of JMJD3. Clin Epigenetics 2024; 16:14. [PMID: 38245781 PMCID: PMC10800074 DOI: 10.1186/s13148-024-01626-w] [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: 08/06/2023] [Accepted: 01/10/2024] [Indexed: 01/22/2024] Open
Abstract
BACKGROUND Epigenetics plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Some studies have reported that YAP is involved in inflammatory response and can regulate target genes through epigenetic modifications. JMJD3, a histone H3K27me3 demethylase, is associated with some inflammatory diseases. In this study, we investigated the role of YAP in the development of IBD and the underlying epigenetic mechanisms. RESULTS YAP expression was significantly increased in both in vitro and in vivo colitis models as well as in patients with IBD. Epithelial-specific knockout of YAP aggravates disease progression in dextran sodium sulfate (DSS)-induced murine colitis. In the TNF-α-activated cellular inflammation model, YAP knockdown significantly increased JMJD3 expression. Coimmunoprecipitation experiments showed that YAP and EZH2 bind to each other, and chromatin immunoprecipitation-PCR (ChIP-PCR) assay indicated that silencing of YAP or EZH2 decreases H3K27me3 enrichment on the promoter of JMJD3. Finally, administration of the JMJD3 pharmacological inhibitor GSK-J4 alleviated the progression of DSS-induced murine colitis. CONCLUSION Our findings elucidate an epigenetic mechanism by which YAP inhibits the inflammatory response in colitis through epigenetic silencing of JMJD3 by recruiting EZH2.
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Affiliation(s)
- Hua Zhu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
- Hubei Clinical Centre and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital, Wuhan University, Wuhan, 430071, Hubei, China
| | - Jiali Lu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
- Hubei Clinical Centre and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital, Wuhan University, Wuhan, 430071, Hubei, China
| | - MingYue Fu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
- Hubei Clinical Centre and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital, Wuhan University, Wuhan, 430071, Hubei, China
| | - Ping Chen
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
- Hubei Clinical Centre and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital, Wuhan University, Wuhan, 430071, Hubei, China
| | - Yali Yu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
- Hubei Clinical Centre and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital, Wuhan University, Wuhan, 430071, Hubei, China
| | - Min Chen
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
- Hubei Clinical Centre and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital, Wuhan University, Wuhan, 430071, Hubei, China
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
- Hubei Clinical Centre and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital, Wuhan University, Wuhan, 430071, Hubei, China
| | - Min Wu
- Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease, Hubei Key Laboratory of Intestinal and Colorectal Diseases, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China
| | - Mei Ye
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China.
- Hubei Clinical Centre and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital, Wuhan University, Wuhan, 430071, Hubei, China.
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Geertsma ER, Oliver D. SLC26 Anion Transporters. Handb Exp Pharmacol 2024; 283:319-360. [PMID: 37947907 DOI: 10.1007/164_2023_698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2023]
Abstract
Solute carrier family 26 (SLC26) is a family of functionally diverse anion transporters found in all kingdoms of life. Anions transported by SLC26 proteins include chloride, bicarbonate, and sulfate, but also small organic dicarboxylates such as fumarate and oxalate. The human genome encodes ten functional homologs, several of which are causally associated with severe human diseases, highlighting their physiological importance. Here, we review novel insights into the structure and function of SLC26 proteins and summarize the physiological relevance of human members.
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Affiliation(s)
- Eric R Geertsma
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
| | - Dominik Oliver
- Department of Neurophysiology, Institute of Physiology and Pathophysiology, Philipps University Marburg, Marburg, Germany.
- Center for Mind, Brain and Behavior (CMBB), Universities of Marburg and Giessen, Marburg, Giessen, Germany.
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Yao Z, Zhang F, Qi C, Wang C, Mao M, Zhao C, Qi M, Wang Z, Zhou G, Jiang X, Xia H. SECTM1 promotes the development of glioblastoma and mesenchymal transition by regulating the TGFβ1/Smad signaling pathway. Int J Biol Sci 2024; 20:78-93. [PMID: 38164182 PMCID: PMC10750278 DOI: 10.7150/ijbs.84591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 09/29/2023] [Indexed: 01/03/2024] Open
Abstract
Objective: Secreted and transmembrane protein 1 (SECTM1) is a gene encoding a transmembrane protein. The role of SECTM1 in glioblastoma (GBM) is unclear. Here, we reported the abnormal expression of SECTM1 in GBM for the first time and studied the role and mechanism of SECTM1 in GBM. Methods: qRT-PCR, Western blotting and immunofluorescence were used to detect the expression of SECTM1 in gliomas of different grades and GBM cell lines. After the knockdown of SECTM1 expression in cell lines by shRNA, the effect of SECTM1 in GBM cell lines was verified by CCK-8, Transwell, EdU and wound healing experiments. We further investigated the effect and mechanism of SECTM1 on GBM in vitro and in vivo. The effect of SECTM1 on glioma growth was detected by subcutaneous tumor xenografts in nude mice in vivo. Results: The results showed that the knockdown of SECTM1 expression in cell lines significantly inhibited the proliferation, migration and invasion of GBM cells while inhibiting the progression of subcutaneous xenograft tumors in nude mice. However, the role and molecular mechanism of SECTM1 in GBM remain unclear. SECTM1 was found to promote GBM epithelial-mesenchymal transition (EMT) like processes. Bioinformatics analysis and Western blotting showed that SECTM1 regulates glioblastoma invasion and EMT-like processes mainly through the TGFβ1/Smad signaling pathway. Conclusion: The low expression of SECTM1 has an inhibitory effect on GBM and is a potential target for GBM treatment. SECTM1 may also be a promising biomarker for the diagnosis and prognosis of GBM.
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Affiliation(s)
- Zhipeng Yao
- School of Chemistry and Chemical Engineering & Zhongda Hospital, School of Medicine, Advanced Institute for Life and Health, Southeast University, Nanjing 210096, China
- The Translational Research Institute for Neurological Disorders, Department of Neurosurgery, the First Affiliated Hospital (Yijishan Hospital), Wannan Medical College, Wuhu 241000, China
| | - Fan Zhang
- School of Chemistry and Chemical Engineering & Zhongda Hospital, School of Medicine, Advanced Institute for Life and Health, Southeast University, Nanjing 210096, China
- The Translational Research Institute for Neurological Disorders, Department of Neurosurgery, the First Affiliated Hospital (Yijishan Hospital), Wannan Medical College, Wuhu 241000, China
| | - Chenxue Qi
- Department of Gynecologic Oncology, Cancer Hospital of Shantou University Medical College, Shantou 515041, China
| | - Cheng Wang
- Department of Pathology, Nanjing Drum Tower Hospital Clinical College & Key Laboratory of Antibody Technique of National Health Commission & Jiangsu Antibody Drug Engineering Research Center, Nanjing Medical University, Nanjing, China
| | - Min Mao
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China
| | - Chenhui Zhao
- The Translational Research Institute for Neurological Disorders, Department of Neurosurgery, the First Affiliated Hospital (Yijishan Hospital), Wannan Medical College, Wuhu 241000, China
| | - Min Qi
- The Translational Research Institute for Neurological Disorders, Department of Neurosurgery, the First Affiliated Hospital (Yijishan Hospital), Wannan Medical College, Wuhu 241000, China
| | - Zhichun Wang
- The Translational Research Institute for Neurological Disorders, Department of Neurosurgery, the First Affiliated Hospital (Yijishan Hospital), Wannan Medical College, Wuhu 241000, China
| | - Guoren Zhou
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Nanjing 210009, China
| | - Xiaochun Jiang
- The Translational Research Institute for Neurological Disorders, Department of Neurosurgery, the First Affiliated Hospital (Yijishan Hospital), Wannan Medical College, Wuhu 241000, China
| | - Hongping Xia
- School of Chemistry and Chemical Engineering & Zhongda Hospital, School of Medicine, Advanced Institute for Life and Health, Southeast University, Nanjing 210096, China
- The Translational Research Institute for Neurological Disorders, Department of Neurosurgery, the First Affiliated Hospital (Yijishan Hospital), Wannan Medical College, Wuhu 241000, China
- Department of Gynecologic Oncology, Cancer Hospital of Shantou University Medical College, Shantou 515041, China
- Department of Pathology, Nanjing Drum Tower Hospital Clinical College & Key Laboratory of Antibody Technique of National Health Commission & Jiangsu Antibody Drug Engineering Research Center, Nanjing Medical University, Nanjing, China
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