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Yu W, Huang P, Jin Y, Wu F, Zhang C, Jing L, Chen Y, Xu H, Xiong J, Zhang R, Zhao K, Li X. Vitamin D enhances the therapeutic effect of TNF-α antibodies through lipid metabolism in overweight IBD patients. Cell Mol Life Sci 2025; 82:176. [PMID: 40285831 PMCID: PMC12033164 DOI: 10.1007/s00018-025-05626-8] [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: 12/22/2024] [Revised: 02/03/2025] [Accepted: 02/15/2025] [Indexed: 04/29/2025]
Abstract
The inhibitory effects of the tumor necrosis factor-α (TNF-α) antibody infliximab (IFX) on colitis are well established. Since IFX dosing is weight-based and associated with various side effects, there is a growing interest in identifying combination therapies that can enhance its efficacy, particularly in overweight inflammatory bowel disease (IBD) patients, to maximize the anti-inflammatory effect while minimizing the required dose. Our research revealed that overweight IBD patients present decreased vitamin D levels in the intestinal epithelium alongside elevated TNF-α levels. In mice fed a high-fat diet (HFD) for four weeks, treatment with the vitamin D analog palicalcitol (PAL) reduced lipid synthesis and TNF-α production in intestinal epithelial cells (IECs). In a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced experimental colitis model, PAL treatment mitigated TNF-α-induced damage to the intestinal epithelial barrier and reduced the activation of Th1 and Th17 cells in the lamina propria, thereby reducing colitis development in HFD-fed mice. Notably, the combination of IFX and PAL was more effective than IFX alone in treating colitis in these mice. Overall, our findings suggest that vitamin D inhibits TNF-α production by reducing lipid synthesis in IECs, thereby enhancing IFX therapy in overweight IBD patients.
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Affiliation(s)
- Wei Yu
- Institute of Clinical Medicine Research, Zhejiang Provincial People'S Hospital(Affiliated People'S Hospital), Hangzhou Medical College, Hangzhou, 310013, Zhejiang, China
| | - Pengpeng Huang
- Institute of Clinical Medicine Research, Zhejiang Provincial People'S Hospital(Affiliated People'S Hospital), Hangzhou Medical College, Hangzhou, 310013, Zhejiang, China
| | - Yanling Jin
- Institute of Clinical Medicine Research, Zhejiang Provincial People'S Hospital(Affiliated People'S Hospital), Hangzhou Medical College, Hangzhou, 310013, Zhejiang, China
| | - Fang Wu
- Department of General, Cancer Center, Division of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310013, Zhejiang, China
| | - Cuiping Zhang
- Department of Pathology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264100, Shandong, China
| | - Lili Jing
- Immunology and Pathology Teaching and Research Office, Shandong College of Traditional Chinese Medicine, Yantai, 264199, Shandong, China
| | - Ying Chen
- Institute of Clinical Medicine Research, Zhejiang Provincial People'S Hospital(Affiliated People'S Hospital), Hangzhou Medical College, Hangzhou, 310013, Zhejiang, China
| | - Han Xu
- Institute of Clinical Medicine Research, Zhejiang Provincial People'S Hospital(Affiliated People'S Hospital), Hangzhou Medical College, Hangzhou, 310013, Zhejiang, China
| | - Jiapin Xiong
- Institute of Clinical Medicine Research, Zhejiang Provincial People'S Hospital(Affiliated People'S Hospital), Hangzhou Medical College, Hangzhou, 310013, Zhejiang, China
| | - Rong Zhang
- Institute of Clinical Medicine Research, Zhejiang Provincial People'S Hospital(Affiliated People'S Hospital), Hangzhou Medical College, Hangzhou, 310013, Zhejiang, China
| | - Ke Zhao
- Institute of Clinical Medicine Research, Zhejiang Provincial People'S Hospital(Affiliated People'S Hospital), Hangzhou Medical College, Hangzhou, 310013, Zhejiang, China
| | - Xue Li
- Institute of Clinical Medicine Research, Zhejiang Provincial People'S Hospital(Affiliated People'S Hospital), Hangzhou Medical College, Hangzhou, 310013, Zhejiang, China.
- Department of Urology, Zhejiang Provincial People'S Hospital (Affiliated People'S Hospital), Hangzhou Medical College, Hangzhou, 310013, Zhejiang, China.
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Alqudah A, Qnais E, Gammoh O, Bseiso Y, Wedyan M, Alqudah M, Aljabali AAA, Tambuwala M. Exploring Scopoletin's Therapeutic Efficacy in DSS-Induced Ulcerative Colitis: Insights into Inflammatory Pathways, Immune Modulation, and Microbial Dynamics. Inflammation 2025; 48:575-589. [PMID: 38918333 PMCID: PMC12053357 DOI: 10.1007/s10753-024-02048-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 04/22/2024] [Accepted: 05/07/2024] [Indexed: 06/27/2024]
Abstract
This study aimed to investigate the therapeutic potential of scopoletin in ulcerative colitis, with a primary focus on its impact on crucial inflammatory pathways and immune responses. A male mouse model of DSS-induced colitis was employed with six distinct groups: a control group, a group subjected to DSS only, three groups treated with varying scopoletin doses, and the final group treated with dexamethasone. The investigation included an assessment of the effects of scopoletin on colitis symptoms, including alterations in body weight, Disease Activity Index (DAI), and histopathological changes in colonic tissue. Furthermore, this study scrutinized the influence of scopoletin on cytokine production, PPARγ and NF-κB expression, NLRP3 inflammasome, and the composition of intestinal bacteria. Scopoletin treatment yielded noteworthy improvements in DSS-induced colitis in mice, as evidenced by reduced weight loss and colonic shortening (p < 0.05, < 0.01, respectively). It effectively diminished TNF-α, IL-1β, and IL-12 cytokine levels (p < 0.01, p < 0.05), attenuated NLRP3 inflammasome activation and the associated cytokine release (p < 0.05, p < 0.01), and modulated the immune response by elevating PPARγ expression while suppressing NF-κB pathway activation (p < 0.05, p < 0.01). Additionally, scopoletin induced alterations in the gut microbiota composition, augmenting beneficial Lactobacillus and Bifidobacteria while reducing E. coli (p < 0.05). It also enhanced tight junction proteins, signifying an improvement in the intestinal barrier integrity (p < 0.05, < 0.01). Scopoletin is a promising therapeutic agent for managing ulcerative colitis, showing benefits that extend beyond mere anti-inflammatory actions to encompass regulatory effects on gut microbiota and restoration of intestinal integrity.
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Affiliation(s)
- Abdelrahim Alqudah
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical Sciences, The Hashemite University, Zarqa, Jordan
| | - Esam Qnais
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, Jordan
| | - Omar Gammoh
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Yarmouk University, Irbid, Jordan
| | - Yousra Bseiso
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, Jordan
| | - Mohammed Wedyan
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, Jordan
| | - Mohammad Alqudah
- Physiology Department, School of Medicine and Biomedical Sciences, Arabian Gulf University, Manama, Bahrain
- Department of Physiology and Biochemistry, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Alaa A A Aljabali
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Yarmouk University, Irbid, 21163, Jordan
| | - Murtaza Tambuwala
- College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates.
- Lincoln Medical School, University of Lincoln, Brayford Pool Campus, Lincoln, LN6 7TS, UK.
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Li H, Chen X, Rao S, Zhou M, Lu J, Liang D, Zhu B, Meng L, Lin J, Ding X, Zhang Q, Hu D. Recent development of micro-nano carriers for oral antineoplastic drug delivery. Mater Today Bio 2025; 30:101445. [PMID: 39866789 PMCID: PMC11762190 DOI: 10.1016/j.mtbio.2025.101445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 12/17/2024] [Accepted: 01/02/2025] [Indexed: 01/28/2025] Open
Abstract
Chemotherapy is widely recognized as a highly efficacious modality for cancer treatment, involving the administration of chemotherapeutic agents to target and eradicate tumor cells. Currently, oral administration stands as the prevailing and widely utilized method of delivering chemotherapy drugs. However, the majority of anti-tumor medications exhibit limited solubility and permeability, and poor stability in harsh gastrointestinal environments, thereby impeding their therapeutic efficacy for chemotherapy. Therefore, more and more micro-nano drug delivery carriers have been developed and used to effectively deliver anti-cancer drugs, which can overcome physiological barriers, facilitate oral administration, and ultimately improve drug efficacy. In this paper, we first discuss the effects of various biological barriers on micro-nano drug carriers and oral administration approach. Then, the development of micro-nano drug carriers based on various biomedical components, such as micelles, dendrimers, hydrogels, liposomes, inorganic nanoparticles, etc. were introduced. Finally, the current dilemma and the potential of oral drug delivery for clinical treatment were discussed. The primary objective of this review is to introduce various oral delivery methods and serve as a point of reference for the advancement of novel oral delivery carriers, with the ultimate goal of informing the development of future clinical applications.
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Affiliation(s)
- Hongzheng Li
- Department of Neurological Rehabilitation, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
- Pharmaceutical Sciences Laboratory, Åbo Akademi University, Turku, 20520, Finland
| | - Xiang Chen
- Department of Neurological Rehabilitation, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Shangrui Rao
- Department of Neurological Rehabilitation, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
- Pharmaceutical Sciences Laboratory, Åbo Akademi University, Turku, 20520, Finland
| | - Minyu Zhou
- Department of Neurological Rehabilitation, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Jianhua Lu
- Department of Neurological Rehabilitation, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Danna Liang
- Department of Neurological Rehabilitation, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
- Pharmaceutical Sciences Laboratory, Åbo Akademi University, Turku, 20520, Finland
| | - Bingzi Zhu
- Department of Neurological Rehabilitation, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Letian Meng
- Department of Neurological Rehabilitation, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Ji Lin
- Department of Neurological Rehabilitation, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xiaoya Ding
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China
| | - Qingfei Zhang
- Department of Neurological Rehabilitation, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China
| | - Danhong Hu
- Department of Neurological Rehabilitation, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
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Archontakis-Barakakis P, Mavridis T, Chlorogiannis DD, Barakakis G, Laou E, Sessler DI, Gkiokas G, Chalkias A. Intestinal oxygen utilisation and cellular adaptation during intestinal ischaemia-reperfusion injury. Clin Transl Med 2025; 15:e70136. [PMID: 39724463 DOI: 10.1002/ctm2.70136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 11/06/2024] [Accepted: 12/05/2024] [Indexed: 12/28/2024] Open
Abstract
The gastrointestinal tract can be deranged by ailments including sepsis, trauma and haemorrhage. Ischaemic injury provokes a common constellation of microscopic and macroscopic changes that, together with the paradoxical exacerbation of cellular dysfunction and death following restoration of blood flow, are collectively known as ischaemia-reperfusion injury (IRI). Although much of the gastrointestinal tract is normally hypoxemic, intestinal IRI results when there is inadequate oxygen availability due to poor supply (pathological hypoxia) or abnormal tissue oxygen use and metabolism (dysoxia). Intestinal oxygen uptake usually remains constant over a wide range of blood flows and pressures, with cellular function being substantively compromised when ischaemia leads to a >50% decline in intestinal oxygen consumption. Restoration of perfusion and oxygenation provokes additional injury, resulting in mucosal damage and disruption of intestinal barrier function. The primary cellular mechanism for sensing hypoxia and for activating a cascade of cellular responses to mitigate the injury is a family of heterodimer proteins called hypoxia-inducible factors (HIFs). The HIF system is connected to numerous biochemical and immunologic pathways induced by IRI and the concentration of those proteins increases during hypoxia and dysoxia. Activation of the HIF system leads to augmented transcription of specific genes in various types of affected cells, but may also augment apoptotic and inflammatory processes, thus aggravating gut injury. KEY POINTS: During intestinal ischaemia, mitochondrial oxygen uptake is reduced when cellular oxygen partial pressure decreases to below the threshold required to maintain normal oxidative metabolism. Upon reperfusion, intestinal hypoxia may persist because microcirculatory flow remains impaired and/or because available oxygen is consumed by enzymes, intestinal cells and neutrophils.
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Affiliation(s)
| | - Theodoros Mavridis
- Department of Neurology, Tallaght University Hospital (TUH)/The Adelaide and Meath Hospital incorporating the National Children's Hospital (AMNCH), Dublin, Ireland
| | | | - Georgios Barakakis
- Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Eleni Laou
- Department of Anesthesiology, Agia Sophia Children's Hospital, Athens, Greece
| | - Daniel I Sessler
- Center for Outcomes Research and Department of Anesthesiology, UTHealth, Houston, Texas, USA
- Outcomes Research Consortium®, Houston, Texas, USA
| | - George Gkiokas
- Second Department of Surgery, Aretaieion University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Athanasios Chalkias
- Outcomes Research Consortium®, Houston, Texas, USA
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Department of Critical Care Medicine, Tzaneio General Hospital, Piraeus, Greece
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Herrera-Quintana L, Vázquez-Lorente H, Hinojosa-Nogueira D, Plaza-Diaz J. Relationship between Infant Feeding and the Microbiome: Implications for Allergies and Food Intolerances. CHILDREN (BASEL, SWITZERLAND) 2024; 11:1030. [PMID: 39201963 PMCID: PMC11353207 DOI: 10.3390/children11081030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/16/2024] [Accepted: 08/20/2024] [Indexed: 09/03/2024]
Abstract
Childhood is a critical period for immune system development, which is greatly influenced by the gut microbiome. Likewise, a number of factors affect the gut microbiome composition and diversity, including breastfeeding, formula feeding, and solid foods introduction. In this regard, several studies have previously demonstrated that breastfeeding promotes a favorable microbiome. In contrast, formula feeding and the early incorporation of certain solid foods may adversely affect microbiome development. Additionally, there is increasing evidence that disruptions in the early microbiome can lead to allergic conditions and food intolerances. Thus, developing strategies to promote optimal infant nutrition requires an understanding of the relationship between infant nutrition and long-term health. The present review aims to examine the relationship between infant feeding practices and the microbiome, as well as its implications on allergies and food intolerances in infants. Moreover, this study synthesizes existing evidence on how different eating habits influence the microbiome. It highlights their implications for the prevention of allergies and food intolerances. In conclusion, introducing allergenic solid foods before six months, alongside breastfeeding, may significantly reduce allergies and food intolerances risks, being also associated with variations in gut microbiome and related complications.
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Affiliation(s)
- Lourdes Herrera-Quintana
- Department of Physiology, Schools of Pharmacy and Medicine, University of Granada, 18071 Granada, Spain; (L.H.-Q.); (H.V.-L.)
- Biomedical Research Center, Health Sciences Technology Park, University of Granada, 18016 Granada, Spain
| | - Héctor Vázquez-Lorente
- Department of Physiology, Schools of Pharmacy and Medicine, University of Granada, 18071 Granada, Spain; (L.H.-Q.); (H.V.-L.)
- Biomedical Research Center, Health Sciences Technology Park, University of Granada, 18016 Granada, Spain
| | - Daniel Hinojosa-Nogueira
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Laboratorio del Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario de Málaga (Virgen de la Victoria), 29590 Málaga, Spain;
| | - Julio Plaza-Diaz
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria IBS, GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain
- Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
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Alqudah A, Qnais E, Gammoh O, Bseiso Y, Wedyan M, Alqudah M, Oqal M, Abudalo R, Abdalla SS. Exploring the therapeutic potential of Anastatica hierochuntica essential oil in DSS-induced colitis. Inflammopharmacology 2024; 32:2035-2048. [PMID: 38520575 DOI: 10.1007/s10787-024-01449-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 02/23/2024] [Indexed: 03/25/2024]
Abstract
The aim of this investigation was to explore the protective impacts and mechanisms of Anastatica hierochuntica essential oil (EOAH) against dextran sulfate sodium (DSS)-induced experimental colitis in mice. EOAH demonstrated a reduction in DSS-induced body weight decline, disease activity index (DAI), colon length reduction, colonic tissue damage, and myeloperoxidase (MPO) activity. The essential oil significantly mitigated the production of pro-inflammatory agents including TNF-α, IL-1β, and IL-12. Further analysis revealed that EOAH's anti-inflammatory effects involved the regulation of NF-κB and PPARγ pathways, as well as the inhibition of NLRP3 activation in colitis mice. Notably, EOAH treatment elevated the levels of beneficial commensal bacteria such as Lactobacillus and Bifidobacteria, while reducing Escherichia coli levels in the mice's feces. In addition, EOAH restored the expression of occludin and ZO-1 proteins in colonic tissues affected by ulcerative colitis (UC). These findings indicate that supplementing with EOAH might offer a novel therapeutic approach for UC prevention.
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Affiliation(s)
- Abdelrahim Alqudah
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical Sciences, The Hashemite University, Zarqa, Jordan.
| | - Esam Qnais
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, Jordan
| | - Omar Gammoh
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Yarmouk University, Irbid, Jordan
| | - Yousra Bseiso
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, Jordan
| | - Mohammed Wedyan
- Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, Jordan
| | - Mohammed Alqudah
- Physiology Department, School of Medicine and Biomedical Sciences, Arabian Gulf University, Manama, Bahrain
- Department of Physiology and Biochemistry, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Muna Oqal
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, The Hashemite University, Zarqa, Jordan
| | - Rawan Abudalo
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical Sciences, The Hashemite University, Zarqa, Jordan
| | - Shtaywy S Abdalla
- Department of Biological Sciences, Faculty of Science, University of Jordan, Amman, Jordan
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Wang Y, Xiao J, Wei S, Su Y, Yang X, Su S, Lan L, Chen X, Huang T, Shan Q. Protective effect of zinc gluconate on intestinal mucosal barrier injury in antibiotics and LPS-induced mice. Front Microbiol 2024; 15:1407091. [PMID: 38855764 PMCID: PMC11157515 DOI: 10.3389/fmicb.2024.1407091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 05/07/2024] [Indexed: 06/11/2024] Open
Abstract
Objective The aim of the study is to investigate the function and mechanism of Zinc Gluconate (ZG) on intestinal mucosal barrier damage in antibiotics and Lipopolysaccharide (LPS)-induced mice. Methods We established a composite mouse model by inducing intestinal mucosal barrier damage using antibiotics and LPS. The animals were divided into five groups: Control (normal and model) and experimental (low, medium, and high-dose ZG treatments). We evaluated the intestinal mucosal barrier using various methods, including monitoring body weight and fecal changes, assessing pathological damage and ultrastructure of the mouse ileum, analyzing expression levels of tight junction (TJ)-related proteins and genes, confirming the TLR4/NF-κB signaling pathway, and examining the structure of the intestinal flora. Results In mice, the dual induction of antibiotics and LPS led to weight loss, fecal abnormalities, disruption of ileocecal mucosal structure, increased intestinal barrier permeability, and disorganization of the microbiota structure. ZG restored body weight, alleviated diarrheal symptoms and pathological damage, and maintained the structural integrity of intestinal epithelial cells (IECs). Additionally, ZG reduced intestinal mucosal permeability by upregulating TJ-associated proteins (ZO-1, Occludin, Claudin-1, and JAM-A) and downregulating MLCK, thereby repairing intestinal mucosal barrier damage induced by dual induction of antibiotics and LPS. Moreover, ZG suppressed the TLR4/NF-κB signaling pathway, demonstrating anti-inflammatory properties and preserving barrier integrity. Furthermore, ZG restored gut microbiota diversity and richness, evidenced by increased Shannon and Observed features indices, and decreased Simpson's index. ZG also modulated the relative abundance of beneficial human gut bacteria (Bacteroidetes, Firmicutes, Verrucomicrobia, Parabacteroides, Lactobacillus, and Akkermansia) and harmful bacteria (Proteobacteria and Enterobacter), repairing the damage induced by dual administration of antibiotics and LPS. Conclusion ZG attenuates the dual induction of antibiotics and LPS-induced intestinal barrier damage and also protects the intestinal barrier function in mice.
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Affiliation(s)
- Yongcai Wang
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Dazhou Central Hospital, Dazhou, China
| | - Juan Xiao
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Sumei Wei
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Ying Su
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xia Yang
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Shiqi Su
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Liancheng Lan
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiuqi Chen
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Ting Huang
- Guangxi Key Laboratory of Aquatic Genetic Breeding and Healthy Aquaculture, Guangxi Academy of Fishery Sciences, Nanning, China
| | - Qingwen Shan
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Sun J, Du J, Liu X, An J, Li Y, Yu Y, Li M, Zheng L, Wu C, Hu L. Preparation of chitosan-coated hollow tin dioxide nanoparticles and their application in improving the oral bioavailability of febuxostat. Int J Pharm X 2023; 6:100199. [PMID: 37521247 PMCID: PMC10384222 DOI: 10.1016/j.ijpx.2023.100199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/07/2023] [Accepted: 07/08/2023] [Indexed: 08/01/2023] Open
Abstract
The aim of this study was to design a chitosan-coated hollow tin dioxide nanosphere (CS-HSn) for loading febuxostat (FEB) using an adsorption method to obtain a sustained-release system (CS-HSn-FEB) to improve the oral bioavailability of FEB. The morphological characteristics of hollow tin dioxide nanospheres (HSn) and CS-HSn were analyzed by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The hemolysis test and CCK-8 test were used to assess the biosafety of HSn and CS-HSn. Powder X-ray diffraction (PXRD) and differential scanning thermal analysis (DSC) were performed on CS-HSn-FEB to analyze the drug presence status. The dissolution behavior and changes in plasma drug concentration of CS-HSn-FEB were evaluated in vitro and in vivo. Sections of intestinal tissues from SD rats were obtained to observe whether chitosan could increase the distribution of nanoparticles in the intestinal tissues. The results showed that FEB was present in CS-HSn in an amorphous state. Moreover, CS-HSn, with good biosafety, significantly improved the water solubility and oral absorption of FEB, indicating that CS-HSn has great potential to improve the intestinal absorption and oral bioavailability of insoluble drugs.
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Affiliation(s)
- Junpeng Sun
- Pharmacy School, Jinzhou Medical University, Jinzhou, Liaoning 121001, China
| | - Jiaqun Du
- Pharmacy School, Jinzhou Medical University, Jinzhou, Liaoning 121001, China
| | - Xiaobang Liu
- Pharmacy School, Jinzhou Medical University, Jinzhou, Liaoning 121001, China
| | - Jinyu An
- Pharmacy School, Jinzhou Medical University, Jinzhou, Liaoning 121001, China
| | - Yingqiao Li
- Pharmacy School, Jinzhou Medical University, Jinzhou, Liaoning 121001, China
| | - Yanan Yu
- Medical College of Jinzhou Medical University, Jinzhou Medical University, 121010, China
| | - Minghui Li
- Jinzhou Medical University, Jinzhou, Liaoning 121001, China
| | - Li Zheng
- Pharmacy School, Jinzhou Medical University, Jinzhou, Liaoning 121001, China
| | - Chao Wu
- Pharmacy School, Jinzhou Medical University, Jinzhou, Liaoning 121001, China
| | - Lili Hu
- Pharmacy School, Jinzhou Medical University, Jinzhou, Liaoning 121001, China
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Yin J, Cheng L, Hong Y, Li Z, Li C, Ban X, Zhu L, Gu Z. A Comprehensive Review of the Effects of Glycemic Carbohydrates on the Neurocognitive Functions Based on Gut Microenvironment Regulation and Glycemic Fluctuation Control. Nutrients 2023; 15:5080. [PMID: 38140339 PMCID: PMC10745758 DOI: 10.3390/nu15245080] [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: 11/15/2023] [Revised: 12/05/2023] [Accepted: 12/08/2023] [Indexed: 12/24/2023] Open
Abstract
Improper glycemic carbohydrates (GCs) consumption can be a potential risk factor for metabolic diseases such as obesity and diabetes, which may lead to cognitive impairment. Although several potential mechanisms have been studied, the biological relationship between carbohydrate consumption and neurocognitive impairment is still uncertain. In this review, the main effects and mechanisms of GCs' digestive characteristics on cognitive functions are comprehensively elucidated. Additionally, healthier carbohydrate selection, a reliable research model, and future directions are discussed. Individuals in their early and late lives and patients with metabolic diseases are highly susceptible to dietary-induced cognitive impairment. It is well known that gut function is closely related to dietary patterns. Unhealthy carbohydrate diet-induced gut microenvironment disorders negatively impact cognitive functions through the gut-brain axis. Moreover, severe glycemic fluctuations, due to rapidly digestible carbohydrate consumption or metabolic diseases, can impair neurocognitive functions by disrupting glucose metabolism, dysregulating calcium homeostasis, oxidative stress, inflammatory responses, and accumulating advanced glycation end products. Unstable glycemic status can lead to more severe neurological impairment than persistent hyperglycemia. Slow-digested or resistant carbohydrates might contribute to better neurocognitive functions due to stable glycemic response and healthier gut functions than fully gelatinized starch and nutritive sugars.
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Affiliation(s)
- Jian Yin
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (J.Y.); (Y.H.); (Z.L.); (C.L.); (X.B.); (L.Z.)
| | - Li Cheng
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (J.Y.); (Y.H.); (Z.L.); (C.L.); (X.B.); (L.Z.)
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
| | - Yan Hong
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (J.Y.); (Y.H.); (Z.L.); (C.L.); (X.B.); (L.Z.)
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
| | - Zhaofeng Li
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (J.Y.); (Y.H.); (Z.L.); (C.L.); (X.B.); (L.Z.)
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
| | - Caiming Li
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (J.Y.); (Y.H.); (Z.L.); (C.L.); (X.B.); (L.Z.)
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
| | - Xiaofeng Ban
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (J.Y.); (Y.H.); (Z.L.); (C.L.); (X.B.); (L.Z.)
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
| | - Ling Zhu
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (J.Y.); (Y.H.); (Z.L.); (C.L.); (X.B.); (L.Z.)
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
| | - Zhengbiao Gu
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (J.Y.); (Y.H.); (Z.L.); (C.L.); (X.B.); (L.Z.)
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
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10
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Dunleavy KA, Raffals LE, Camilleri M. Intestinal Barrier Dysfunction in Inflammatory Bowel Disease: Underpinning Pathogenesis and Therapeutics. Dig Dis Sci 2023; 68:4306-4320. [PMID: 37773554 PMCID: PMC10798146 DOI: 10.1007/s10620-023-08122-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 09/19/2023] [Indexed: 10/01/2023]
Abstract
The intestinal barrier is composed of several essential elements including luminal enzymes, bile acids, water layer, epithelial layer, and enterocyte layer. It acts as a dynamic interface between the luminal contents of food, commensal and pathogenic bacteria, and the gastrointestinal tract. The role of barrier dysfunction is of significant research interest in the development and targeted treatment of chronic inflammatory gastrointestinal conditions, such as inflammatory bowel disease. This review aims to examine the role of intestinal barrier dysfunction in the development of inflammatory bowel disease, the pathophysiology of increased barrier permeability in inflammatory bowel disease, and to explore potential treatment targets and clinical applications.
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Affiliation(s)
- Katie A Dunleavy
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St. S.W., Rochester, MN, 55905, USA
| | - Laura E Raffals
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St. S.W., Rochester, MN, 55905, USA.
| | - Michael Camilleri
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St. S.W., Rochester, MN, 55905, USA
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, MN, USA
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11
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Tóth Š, Fagová Z, Holodová M, Zeidan D, Hartel P, Čurgali K, Mechírová E, Maretta M, Nemcová R, Gancarčíková S, Danková M. Influence of Escherichia coli infection on intestinal mucosal barrier integrity of germ-free piglets. Life Sci 2023; 331:122036. [PMID: 37633417 DOI: 10.1016/j.lfs.2023.122036] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/11/2023] [Accepted: 08/21/2023] [Indexed: 08/28/2023]
Abstract
AIMS We focused on investigating the influence of Escherichia coli (E. coli) on the intestinal barrier. MATERIAL AND METHODS We studied changes in the distribution and secretory activities of goblet cells and enteroendocrine cells (EECs), as well as changes in the population of mast cells (MCs) in the jejunal and colonic mucosa of germ-free (GF) piglets as a healthy control group and GF piglets whose intestines were colonised with E. coli bacteria on day 5. KEY FINDINGS The results suggest that the colon of GF piglets is more resistant and less prone to coliform bacterial infection compared to the jejunum. This can be confirmed by a lower degree of histopathological injury index as well as an improvement of the morphometric parameters of the colonic mucosa, together with a significantly increased (p < 0.05) expression of MUC1/EMA, and ZO-3. We also observed a significant decrease in the population of activated MCs (p < 0.001) and EECs (p < 0.001). These findings may indicate a rapid response and better preparation of the intestinal barrier for possible pathological attacks and the subsequent development of mucosal lesions during the development and progression of the intestinal diseases. SIGNIFICANCE To date, gut-targeted therapeutic approaches that can modulate bacterial translocation and chronic inflammation are still in their infancy but represent one of the most promising areas of research for the development of new effective treatments or clinical strategies in the future. Therefore, a better understanding of these processes can significantly contribute to the development of these targeted strategies for disease prevention and treatment.
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Affiliation(s)
- Štefan Tóth
- Pavol Jozef Šafárik University, Faculty of Medicine, Department of Histology and Embryology, Šrobárova 2, 040 01 Košice, Slovak Republic
| | - Zuzana Fagová
- Pavol Jozef Šafárik University, Faculty of Medicine, Department of Histology and Embryology, Šrobárova 2, 040 01 Košice, Slovak Republic
| | - Monika Holodová
- Pavol Jozef Šafárik University, Faculty of Medicine, Department of Histology and Embryology, Šrobárova 2, 040 01 Košice, Slovak Republic
| | - Dema Zeidan
- Pavol Jozef Šafárik University, Faculty of Medicine, Department of Histology and Embryology, Šrobárova 2, 040 01 Košice, Slovak Republic
| | - Patrick Hartel
- Pavol Jozef Šafárik University, Faculty of Medicine, Department of Histology and Embryology, Šrobárova 2, 040 01 Košice, Slovak Republic
| | - Kristína Čurgali
- Pavol Jozef Šafárik University, Faculty of Medicine, Department of Histology and Embryology, Šrobárova 2, 040 01 Košice, Slovak Republic
| | - Eva Mechírová
- Pavol Jozef Šafárik University, Faculty of Medicine, Department of Histology and Embryology, Šrobárova 2, 040 01 Košice, Slovak Republic
| | - Milan Maretta
- Pavol Jozef Šafárik University, Faculty of Medicine, Department of Neurology and L. Pasteur University Hospital, Trieda SNP 1, 040 01 Košice, Slovak Republic
| | - Radomíra Nemcová
- University of Veterinary Medicine and Pharmacy in Košice, Department of Microbiology and Immunology, Komenského 73, 041 70 Košice, Slovak Republic
| | - Soňa Gancarčíková
- University of Veterinary Medicine and Pharmacy in Košice, Department of Microbiology and Immunology, Komenského 73, 041 70 Košice, Slovak Republic
| | - Marianna Danková
- Comenius University in Bratislava, Faculty of Medicine, Institute of Histology and Embryology, Sasinkova 4, 811 04 Bratislava, Slovak Republic.
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12
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Xie K, Yang Q, Yan Z, Gao X, Huang X, Wang P, Li J, Li J, Wang Z, Gao Y, Gun S. Overexpression of SIRT1 alleviates oxidative damage and barrier dysfunction in CPB2 toxin-infected IPEC-J2 cells. Microb Pathog 2023:106181. [PMID: 37276895 DOI: 10.1016/j.micpath.2023.106181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 05/27/2023] [Accepted: 05/28/2023] [Indexed: 06/07/2023]
Abstract
Clostridium perfringens (C. perfringens) beta2 (CPB2) toxin may induce necrotizing enteritis (NE) in pigs. Sirtuin1 (SIRT1) is involved in inflammatory intestinal diseases and affects intestinal barrier function. However, the effects of SIRT1 on piglet intestinal disease caused by CPB2 toxin are unclear. This study revealed the role of pig SIRT1 in CPB2 toxin-exposed intestinal porcine epithelial cells (IPEC-J2). Herein, we manifested that SIRT1 was dramatically decreased in IPEC-J2 cells infected with CPB2 toxin. Subsequently, we silenced and overexpressed SIRT1 using siRNA and a overexpression vector in CPB2 toxin-treated IPEC-J2 cells. The results indicated that overexpression of SIRT1 suppressed reactive oxygen species (ROS) generates, the expression tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and Bax, nuclear factor-kappa B (NF-κB p65), phospho (p)-NF-kB p65 and lactate dehydrogenase (LDH) activity and apoptosis in CPB2 toxin-treated IPEC-J2 cells, and increased IL-10, mitochondrial membrane potential (ΔΨm), Bcl-2, Claudin1 and Occludin levels and cell viability. These results indicated that SIRT1 protects IPEC-J2 cells against CPB2 toxin-induced oxidative damage and tight junction (TJ) disruption, which provides a theoretical basis for further study of the molecular regulatory mechanism of SIRT1 in C. perfringens-infected NE in piglets.
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Affiliation(s)
- Kaihui Xie
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China
| | - Qiaoli Yang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China
| | - Zunqiang Yan
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China
| | - Xiaoli Gao
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China
| | - Xiaoyu Huang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China
| | - Pengfei Wang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China
| | - Jie Li
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China
| | - Jiyou Li
- Gansu General Station of Animal Husbandry Technology Extension, Lanzhou, 730070, China
| | - Zike Wang
- Gansu General Station of Animal Husbandry Technology Extension, Lanzhou, 730070, China
| | - Yi Gao
- Jilin Rongtai Agricultural Development Co, Ltd, Changchun, Jilin, 130507, China
| | - Shuangbao Gun
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, 730070, China; Gansu Research Center for Swine Production Engineering and Technology, Lanzhou, 730070, China.
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13
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Zhan M, Liang X, Chen J, Yang X, Han Y, Zhao C, Xiao J, Cao Y, Xiao H, Song M. Dietary 5-demethylnobiletin prevents antibiotic-associated dysbiosis of gut microbiota and damage to the colonic barrier. Food Funct 2023; 14:4414-4429. [PMID: 37097253 DOI: 10.1039/d3fo00516j] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2023]
Abstract
5-Demethylnobiletin (5DN) is an important ingredient of citrus extract that is rich in polymethoxyflavones (PMFs). In this study, we systemically investigated the preventive effects of 5DN on antibiotic-associated intestinal disturbances. Experimental mice were gavaged 0.2 mL per day of the antibiotic cocktail (12.5 g L-1 cefuroxime and 10 g L-1 levofloxacin) for 10 days, accompanied by dietary 0.05% 5DN for 10 and 20 days. The results showed that the combination of cefuroxime and levofloxacin caused swelling of the cecum and injury to the colon tissue. Meanwhile, the balance of intestinal oxidative stress and the barrier function of mice was also damaged by the antibiotics through upregulation of the relative mRNA levels of superoxide dismutase 3 (SOD3), quinine oxidoreductase 1 (NQO1) and glutathione peroxidase 1 (GPX1), and downregulation of the relative protein levels of tight junction proteins (TJs). Moreover, antibiotic exposure led to disorder of the gut microbiota, particularly increased harmful bacteria (Proteobacteria) and decreased beneficial bacteria (Bacteroideta). However, dietary 5DN could reduce antibiotic-associated intestinal damage, evidenced by the results that 5DN alleviated gut oxidative damage and attenuated intestinal barrier injury via increasing the expression of TJs including occludin and zonula occluden1 (ZO1). Additionally, dietary 5DN modulated the composition of the gut microbiota in antibiotic-treated mice by increasing the relative levels of beneficial bacteria, such as Dubosiella and Lactobacillus. Moreover, PMFs increased the contents of isobutyric acid and butyric acid, which were almost eliminated by antibiotic exposure. In conclusion, 5DN could alleviate antibiotic-related imbalance of intestinal oxidative stress, barrier function damage, intestinal flora disorders and the reduction of short-chain fatty acids (SCFAs), which lays a foundation for exploring safer and more effective ways to prevent or mitigate antibiotic-associated intestinal damage.
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Affiliation(s)
- Minmin Zhan
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Sciences, South China Agricultural University, Guangzhou, China.
| | - Xinyan Liang
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Sciences, South China Agricultural University, Guangzhou, China.
| | - Jiaqi Chen
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Sciences, South China Agricultural University, Guangzhou, China.
| | - Xiaoshuang Yang
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Sciences, South China Agricultural University, Guangzhou, China.
| | - Yanhui Han
- Department of Food Science, University of Massachusetts, Amherst, Massachusetts 01003, USA
| | - Chenxi Zhao
- Department of Food Science and Nutrition, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, China
| | - Jie Xiao
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Sciences, South China Agricultural University, Guangzhou, China.
| | - Yong Cao
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Sciences, South China Agricultural University, Guangzhou, China.
| | - Hang Xiao
- Department of Food Science, University of Massachusetts, Amherst, Massachusetts 01003, USA
| | - Mingyue Song
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Sciences, South China Agricultural University, Guangzhou, China.
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14
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Sharkey KA, Mawe GM. The enteric nervous system. Physiol Rev 2023; 103:1487-1564. [PMID: 36521049 PMCID: PMC9970663 DOI: 10.1152/physrev.00018.2022] [Citation(s) in RCA: 138] [Impact Index Per Article: 69.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
Of all the organ systems in the body, the gastrointestinal tract is the most complicated in terms of the numbers of structures involved, each with different functions, and the numbers and types of signaling molecules utilized. The digestion of food and absorption of nutrients, electrolytes, and water occurs in a hostile luminal environment that contains a large and diverse microbiota. At the core of regulatory control of the digestive and defensive functions of the gastrointestinal tract is the enteric nervous system (ENS), a complex system of neurons and glia in the gut wall. In this review, we discuss 1) the intrinsic neural control of gut functions involved in digestion and 2) how the ENS interacts with the immune system, gut microbiota, and epithelium to maintain mucosal defense and barrier function. We highlight developments that have revolutionized our understanding of the physiology and pathophysiology of enteric neural control. These include a new understanding of the molecular architecture of the ENS, the organization and function of enteric motor circuits, and the roles of enteric glia. We explore the transduction of luminal stimuli by enteroendocrine cells, the regulation of intestinal barrier function by enteric neurons and glia, local immune control by the ENS, and the role of the gut microbiota in regulating the structure and function of the ENS. Multifunctional enteric neurons work together with enteric glial cells, macrophages, interstitial cells, and enteroendocrine cells integrating an array of signals to initiate outputs that are precisely regulated in space and time to control digestion and intestinal homeostasis.
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Affiliation(s)
- Keith A Sharkey
- Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Gary M Mawe
- Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont
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15
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m6A modification in inflammatory bowel disease provides new insights into clinical applications. Biomed Pharmacother 2023; 159:114298. [PMID: 36706633 DOI: 10.1016/j.biopha.2023.114298] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/13/2023] [Accepted: 01/20/2023] [Indexed: 01/26/2023] Open
Abstract
Inflammatory bowel disease (IBD) results from a complex interplay between genetic predisposition, environmental factors, and gut microbes. The role of N6-methyladenosine (m6A) methylation in the pathogenesis of IBD has attracted increasing attention. m6A modification not only regulates intestinal mucosal immunity and intestinal barrier function, but also affects apoptosis and autophagy in intestinal epithelial cells. Additionally, m6A modification participated in the interaction between gut microbes and the host, providing a novel direction to explore the molecular mechanisms of IBD and the theoretical basis for specific microorganism-oriented prevention and treatment measures. m6A regulators are expected to be biomarkers for predicting the prognosis of IBD patients. m6A methylation may be utilized as a novel target in the management of IBD. This review focused on the recent advances in how m6A modification causes the initiation and development of IBD, and provided new insights into optimal prevention and treatment measures for IBD.
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16
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Lechuga S, Braga-Neto MB, Naydenov NG, Rieder F, Ivanov AI. Understanding disruption of the gut barrier during inflammation: Should we abandon traditional epithelial cell lines and switch to intestinal organoids? Front Immunol 2023; 14:1108289. [PMID: 36875103 PMCID: PMC9983034 DOI: 10.3389/fimmu.2023.1108289] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 02/01/2023] [Indexed: 02/18/2023] Open
Abstract
Disruption of the intestinal epithelial barrier is a hallmark of mucosal inflammation. It increases exposure of the immune system to luminal microbes, triggering a perpetuating inflammatory response. For several decades, the inflammatory stimuli-induced breakdown of the human gut barrier was studied in vitro by using colon cancer derived epithelial cell lines. While providing a wealth of important data, these cell lines do not completely mimic the morphology and function of normal human intestinal epithelial cells (IEC) due to cancer-related chromosomal abnormalities and oncogenic mutations. The development of human intestinal organoids provided a physiologically-relevant experimental platform to study homeostatic regulation and disease-dependent dysfunctions of the intestinal epithelial barrier. There is need to align and integrate the emerging data obtained with intestinal organoids and classical studies that utilized colon cancer cell lines. This review discusses the utilization of human intestinal organoids to dissect the roles and mechanisms of gut barrier disruption during mucosal inflammation. We summarize available data generated with two major types of organoids derived from either intestinal crypts or induced pluripotent stem cells and compare them to the results of earlier studies with conventional cell lines. We identify research areas where the complementary use of colon cancer-derived cell lines and organoids advance our understanding of epithelial barrier dysfunctions in the inflamed gut and identify unique questions that could be addressed only by using the intestinal organoid platforms.
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Affiliation(s)
- Susana Lechuga
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Manuel B. Braga-Neto
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Nayden G. Naydenov
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Florian Rieder
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, United States
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Andrei I. Ivanov
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, United States
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17
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Fig latex inhibits the growth of pathogenic bacteria invading human diabetic wounds and accelerates wound closure in diabetic mice. Sci Rep 2022; 12:21852. [PMID: 36528674 PMCID: PMC9759588 DOI: 10.1038/s41598-022-26338-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Impaired wound healing is one of the most critical complications associated with diabetes mellitus. Infections and foot ulcers are major causes of morbidity for diabetic patients. The current treatment of diabetic foot ulcers, commonly used antibiotics, is associated with the development of bacterial resistance. Hence, novel and more effective natural therapeutic antibacterial agents are urgently needed and should be developed against the pathogenic bacteria inhabiting diabetic wounds. Therefore, the current study aimed to investigate the impact of fig latex on pathogenic bacteria and its ability to promote the healing process of diabetic wounds. The pathogenic bacteria were isolated from patients with diabetic foot ulcers admitted to Assiut University Hospital. Fig latex was collected from trees in the Assiut region, and its chemical composition was analyzed using GC‒MS. The antibacterial efficacy of fig latex was assessed on the isolated bacteria. An in vivo study to investigate the effect of fig latex on diabetic wound healing was performed using three mouse groups: nondiabetic control mice, diabetic mice and diabetic mice treated with fig latex. The influence of fig latex on the expression levels of β-defensin-1, PECAM-1, CCL2 and ZO-1 and collagen formation was investigated. The GC‒MS analysis demonstrated the presence of triterpenoids, comprising more than 90% of the total latex content. Furthermore, using a streptozotocin-induced diabetic mouse model, topical treatment of diabetic wound tissues with fig latex was shown to accelerate and improve wound closure by increasing the expression levels of β-defensin-1, collagen, and PECAM-1 compared to untreated diabetic wounds. Additionally, fig latex decreased the expression levels of ZO-1 and CCL2.
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18
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The Protective Effects of Nutraceutical Components in Methotrexate-Induced Toxicity Models—An Overview. Microorganisms 2022; 10:microorganisms10102053. [PMID: 36296329 PMCID: PMC9608860 DOI: 10.3390/microorganisms10102053] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/11/2022] [Accepted: 10/13/2022] [Indexed: 12/04/2022] Open
Abstract
There are multiple concerns associated with methotrexate (MTX), widely recognized for anti-neoplastic and anti-inflammatory effects in life-threatening disease conditions, i.e., acute lymphoblastic leukemia, non-Hodgkin’s lymphoma, psoriasis, and rheumatoid arthritis, due to long-term side effects and associated toxicity, which limits its valuable potential. MTX acts as an inhibitor of dihydrofolate reductase, leading to suppression of purine and pyrimidine synthesis in high metabolic and turnover cells, targeting cancer and dysregulated immune cells. Due to low discrimination between neoplastic cells and naturally high turnover cells, MTX is prone to inhibiting the division of all fast-dividing cells, causing toxicity in multiple organs. Nutraceutical compounds are plant-based or food-derived compounds, used for their preventive and therapeutic role, ascertained in multiple organ dysfunctions, including cardiovascular disease, ischemic stroke, cancer, and neurodegenerative diseases. Gut microbiota and microbiota-derived metabolites take part in multiple physiological processes, their dysregulation being involved in disease pathogenesis. Modulation of gut microbiota by using nutraceutical compounds represents a promising therapeutic direction to restore intestinal dysfunction associated with MTX treatment. In this review, we address the main organ dysfunctions induced by MTX treatment, and modulations of them by using nutraceutical compounds. Moreover, we revealed the protective mechanisms of nutraceuticals in MTX-induced intestinal dysfunctions by modulation of gut microbiota.
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19
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The polysaccharides from the fruits of Lycium barbarum L. modify the gut community profile and alleviate dextran sulfate sodium-induced colitis in mice. Int J Biol Macromol 2022; 222:2244-2257. [DOI: 10.1016/j.ijbiomac.2022.10.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/11/2022] [Accepted: 10/03/2022] [Indexed: 11/05/2022]
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20
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Yu W, Xiao X, Chen D, Yu B, He J, Zheng P, Yu J, Luo J, Luo Y, Yan H, Yi X, Wang J, Wang H, Wang Q, Mao X. Effect of Dietary Lactose Supplementation on Growth Performance and Intestinal Epithelium Functions in Weaned Pigs Challenged by Rotavirus. Animals (Basel) 2022; 12:ani12182336. [PMID: 36139196 PMCID: PMC9495109 DOI: 10.3390/ani12182336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/03/2022] [Accepted: 09/06/2022] [Indexed: 12/02/2022] Open
Abstract
The purpose of this study was to investigate whether dietary lactose supplementation relieves rotavirus (RV)-induced diarrhea and gut dysfunction. Thirty-six crossbred weaned piglets were randomly allocated into three groups and fed diets containing 0, 4%, and 6% lactose for 20 days. On Day 15, half of the piglets in each group were orally infused with RV. RV infection impaired growth performance; induced severe diarrhea; decreased serum D-xylose concentration and morphology and sIgA level of jejunal mucosa; downregulated MUC1, MUC2, occludin, Bcl-2, IL-4, pBD3, pBD2, and pBD1 mRNA expression of jejunal mucosa and/or mesenteric lymph nodes; upregulated Bax, caspase-3, IL-2, IFN-γ, and IFN-β mRNA expression of jejunal mucosa and/or mesenteric lymph nodes; and damaged microbiota and metabolites of cecal digesta in weaned piglets (p < 0.05). Dietary lactose supplementation improved nutrient digestibility and growth performance and relieved the negative influence of RV challenge on intestinal barrier function, mRNA expression of cytokines, and host defense peptides of jejunal mucosa and/or mesenteric lymph nodes in weaned piglets (p < 0.05). Dietary administration of 6% lactose tended to relieve diarrhea (p = 0.07). These results suggest that lactose in feed increases growth performance and has a tendency to alleviate RV-induced diarrhea, derived from the improvement of nutrient utilization, gut barrier function, and immunity.
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Affiliation(s)
- Wei Yu
- Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Xuechun Xiao
- Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Daiwen Chen
- Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Bing Yu
- Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Jun He
- Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Ping Zheng
- Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Jie Yu
- Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Junqiu Luo
- Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Yuheng Luo
- Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Hui Yan
- Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Xuewu Yi
- College of Life Sciences, Leshan Normal University, Leshan 614000, China
| | - Jianping Wang
- Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Huifen Wang
- Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Quyuan Wang
- Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Xiangbing Mao
- Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
- Correspondence: ; Tel.: +86-18783536530; Fax: +86-2886290922
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21
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Du J, Sarkar R, Li Y, He L, Kang W, Liao W, Liu W, Nguyen T, Zhang L, Deng Z, Dougherty U, Kupfer SS, Chen M, Pekow J, Bissonnette M, He C, Li YC. N 6-adenomethylation of GsdmC is essential for Lgr5 + stem cell survival to maintain normal colonic epithelial morphogenesis. Dev Cell 2022; 57:1976-1994.e8. [PMID: 35917813 PMCID: PMC9398964 DOI: 10.1016/j.devcel.2022.07.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 05/15/2022] [Accepted: 07/07/2022] [Indexed: 11/20/2022]
Abstract
Gut epithelial morphogenesis is maintained by intestinal stem cells. Here, we report that depletion of N6-adenosine methyltransferase subunit Mettl14 from gut epithelial cells in mice impaired colon mucosal morphogenesis, leading to increased mucosal permeability, severe inflammation, growth retardation, and premature death. Mettl14 ablation triggered apoptosis that depleted Lgr5+ stem cells and disrupted colonic organoid growth and differentiation, whereas the inhibition of apoptosis rescued Mettl14-deleted mice and organoids. Mettl14 depletion disrupted N6-adenomethylation on GsdmC transcripts and abolished GsdmC expression. Reconstitution of Mettl14-deleted organoids or mice with GSDMC rescued Lgr5 expression and prevented apoptosis and mouse premature death, whereas GSDMC silence eliminated LGR5 and triggered apoptosis in human colonic organoids and epithelial cells. Mechanistically, Mettl14 depletion eliminated mitochondrial GsdmC, disrupted mitochondrial membrane potential, and triggered cytochrome c release that activates the pro-apoptotic pathway. In conclusion, GsdmC N6-adenomethylation protects mitochondrial homeostasis and is essential for Lgr5+ cell survival to maintain normal colonic epithelial regeneration.
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Affiliation(s)
- Jie Du
- Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL, USA; Department of Oral Medicine, School and Hospital of Stomatology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Rajesh Sarkar
- Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL, USA
| | - Yan Li
- Center for Research Informatics, The University of Chicago, Chicago, IL, USA
| | - Lei He
- Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL, USA
| | - Wenjun Kang
- Center for Research Informatics, The University of Chicago, Chicago, IL, USA
| | - Wang Liao
- Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL, USA; Department of Cardiology, Hainan General Hospital, Hainan Clinical Research Institute, Haikou, Hainan, China
| | - Weicheng Liu
- Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL, USA
| | - Tivoli Nguyen
- Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL, USA
| | - Linda Zhang
- Departments of Chemistry, Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA
| | - Zifeng Deng
- Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL, USA
| | - Urszula Dougherty
- Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL, USA
| | - Sonia S Kupfer
- Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL, USA
| | - Mengjie Chen
- Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL, USA; Center for Research Informatics, The University of Chicago, Chicago, IL, USA
| | - Joel Pekow
- Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL, USA
| | - Marc Bissonnette
- Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL, USA
| | - Chuan He
- Departments of Chemistry, Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA; Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, USA
| | - Yan Chun Li
- Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, IL, USA.
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22
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Zhu W, Oteiza PI. Proanthocyanidins at the gastrointestinal tract: mechanisms involved in their capacity to mitigate obesity-associated metabolic disorders. Crit Rev Food Sci Nutr 2022; 64:220-240. [PMID: 35943169 DOI: 10.1080/10408398.2022.2105802] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
The prevalence of overweight and obesity is continually increasing worldwide. Obesity is a major public health concern given the multiple associated comorbidities. Finding dietary approaches to prevent/mitigate these conditions is of critical relevance. Proanthocyanidins (PACs), oligomers or polymers of flavan-3-ols that are extensively distributed in nature, represent a major part of total dietary polyphenols. Although current evidence supports the capacity of PACs to mitigate obesity-associated comorbidities, the underlying mechanisms remain speculative due to the complexity of PACs' structure. Given their limited bioavailability, the major site of the biological actions of intact PACs is the gastrointestinal (GI) tract. This review discusses the actions of PACs at the GI tract which could underlie their anti-obesity effects. These mechanisms include: i) inhibition of digestive enzymes at the GI lumen, including pancreatic lipase, α-amylase, α-glucosidase; ii) modification of gut microbiota composition; iii) modulation of inflammation- and oxidative stress-triggered signaling pathways, e.g. NF-κB and MAPKs; iv) protection of the GI barrier integrity. Further understanding of the mechanisms and biological activities of PACs at the GI tract can contribute to develop nutritional and pharmacological strategies oriented to mitigate the serious comorbidities of obesity.
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Affiliation(s)
- Wei Zhu
- Department of Nutrition, University of California, Davis, California, USA
- Department of Environmental Toxicology, University of California, Davis, California, USA
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Patricia I Oteiza
- Department of Nutrition, University of California, Davis, California, USA
- Department of Environmental Toxicology, University of California, Davis, California, USA
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23
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Kelm M, Anger F. Mucosa and microbiota – the role of intrinsic parameters on intestinal wound healing. Front Surg 2022; 9:905049. [PMID: 35937599 PMCID: PMC9354512 DOI: 10.3389/fsurg.2022.905049] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 07/06/2022] [Indexed: 11/13/2022] Open
Abstract
Mucosal healing in the gut is an essential process when it comes to chronic inflammatory disorders such as inflammatory bowel diseases (IBD) but also to the creation of intestinal anastomosis. Despite an improvement of surgical techniques, the rates of anastomotic leakage remain substantial and represent a significant health-care and socio-economic burden. Recent research has focused on intrinsic factors such as mucosal linings and differences in the intestinal microbiota and identified specific endoluminal bacteria and epithelial proteins which influence intestinal wound healing and re-establishment of mucosal homeostasis. Despite the lack of large clinical studies, previous data indicate that the identified bacteria such as aerotolerant lactobacilli or wound-associated Akkermansia muciniphila as well as epithelial-expressed sialyl Lewis glycans or CD47 might be critical for wound and anastomotic healing in the gut, thus, providing a potential novel approach for future treatment strategies in colorectal surgery and IBD therapy. Since microbiota and mucosa are interacting closely, we outline the current discoveries about both subsets in this review together to demonstrate the significant interplay
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Khoramjoo SM, Kazemifard N, Baradaran Ghavami S, Farmani M, Shahrokh S, Asadzadeh Aghdaei H, Sherkat G, Zali MR. Overview of Three Proliferation Pathways (Wnt, Notch, and Hippo) in Intestine and Immune System and Their Role in Inflammatory Bowel Diseases (IBDs). Front Med (Lausanne) 2022; 9:865131. [PMID: 35677821 PMCID: PMC9170180 DOI: 10.3389/fmed.2022.865131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 04/14/2022] [Indexed: 12/15/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a disorder, which involves the gastrointestinal (GI) tract consisting Crohn's disease (CD) and ulcerative colitis (UC). The etiology of this disease is not yet clear and, hence, there are numerous medications and treatments for patients with IBD, although a definite and permanent treatment is still missing. Therefore, finding novel therapeutic approaches are vital for curing patients with IBD. In the GI tract, there are various lineages of cells with different roles that their existence is necessary for the barrier function of intestinal epithelial cells (IECs). Therefore, signaling pathways, which manage the hemostasis of cell lineages in intestine, such as Wnt, Notch, and Hippo, could have crucial roles in regulation of barrier function in the intestine. Additionally, these signaling pathways function as a governor of cell growth, tissue homeostasis, and organ size. In patients with IBD, recent studies have revealed that these signaling pathways are dysregulated that it could result in depletion or excess of a cell lineage in the intestine. Moreover, dysregulation of these signaling pathways in different cell lineages of the immune system could lead to dysregulation of the immune system's responses in IBD. In this article, we summarized the components and signaling of Wnt, Notch, and Hippo pathways and their role in the intestine and immune system. Furthermore, we reviewed latest scientific literature on the crosstalk among these three signaling pathways in IBD. An overview of these three signaling pathways and their interactions in IBD could provide a novel insight for prospective study directions into finding efficient medications or treatments.
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Affiliation(s)
- Seyed Mobin Khoramjoo
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nesa Kazemifard
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shaghayegh Baradaran Ghavami
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- *Correspondence: Shaghayegh Baradaran Ghavami
| | - Maryam Farmani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Shahrokh
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ghazal Sherkat
- Faculty of Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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25
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Jackson A, Engen PA, Forsyth CB, Shaikh M, Naqib A, Wilber S, Frausto DM, Raeisi S, Green SJ, Bradaric BD, Persons AL, Voigt RM, Keshavarzian A. Intestinal Barrier Dysfunction in the Absence of Systemic Inflammation Fails to Exacerbate Motor Dysfunction and Brain Pathology in a Mouse Model of Parkinson's Disease. Front Neurol 2022; 13:882628. [PMID: 35665034 PMCID: PMC9159909 DOI: 10.3389/fneur.2022.882628] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 04/14/2022] [Indexed: 01/01/2023] Open
Abstract
Introduction Parkinson's disease (PD) is the second most common neurodegenerative disease associated with aging. PD patients have systemic and neuroinflammation which is hypothesized to contribute to neurodegeneration. Recent studies highlight the importance of the gut-brain axis in PD pathogenesis and suggest that gut-derived inflammation can trigger and/or promote neuroinflammation and neurodegeneration in PD. However, it is not clear whether microbiota dysbiosis, intestinal barrier dysfunction, or intestinal inflammation (common features in PD patients) are primary drivers of disrupted gut-brain axis in PD that promote neuroinflammation and neurodegeneration. Objective To determine the role of microbiota dysbiosis, intestinal barrier dysfunction, and colonic inflammation in neuroinflammation and neurodegeneration in a genetic rodent model of PD [α-synuclein overexpressing (ASO) mice]. Methods To distinguish the role of intestinal barrier dysfunction separate from inflammation, low dose (1%) dextran sodium sulfate (DSS) was administered in cycles for 52 days to ASO and control mice. The outcomes assessed included intestinal barrier integrity, intestinal inflammation, stool microbiome community, systemic inflammation, motor function, microglial activation, and dopaminergic neurons. Results Low dose DSS treatment caused intestinal barrier dysfunction (sugar test, histological analysis), intestinal microbiota dysbiosis, mild intestinal inflammation (colon shortening, elevated MPO), but it did not increase systemic inflammation (serum cytokines). However, DSS did not exacerbate motor dysfunction, neuroinflammation (microglial activation), or dopaminergic neuron loss in ASO mice. Conclusion Disruption of the intestinal barrier without overt intestinal inflammation is not associated with worsening of PD-like behavior and pathology in ASO mice.
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Affiliation(s)
- Aeja Jackson
- Rush Medical College, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
| | - Phillip A. Engen
- Rush Medical College, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
| | - Christopher B. Forsyth
- Rush Medical College, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
- Department of Medicine, Rush University Medical Center, Chicago, IL, United States
- Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, United States
| | - Maliha Shaikh
- Rush Medical College, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
| | - Ankur Naqib
- Rush Medical College, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
| | - Sherry Wilber
- Rush Medical College, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
| | - Dulce M. Frausto
- Rush Medical College, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
| | - Shohreh Raeisi
- Rush Medical College, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
| | - Stefan J. Green
- Department of Medicine, Rush University Medical Center, Chicago, IL, United States
- Genomics and Microbiome Core Facility, Rush University Medical Center, Chicago, IL, United States
| | - Brinda Desai Bradaric
- Bachelor of Science in Health Sciences Program, College of Health Sciences, Rush University Medical Center, Chicago, IL, United States
- Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, United States
| | - Amanda L. Persons
- Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, United States
- Department of Physician Assistant Studies, Rush University Medical Center, Chicago, IL, United States
| | - Robin M. Voigt
- Rush Medical College, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
- Department of Medicine, Rush University Medical Center, Chicago, IL, United States
- Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, United States
| | - Ali Keshavarzian
- Rush Medical College, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States
- Department of Medicine, Rush University Medical Center, Chicago, IL, United States
- Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, United States
- Department of Physiology, Rush University Medical Center, Chicago, IL, United States
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26
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Inczefi O, Bacsur P, Resál T, Keresztes C, Molnár T. The Influence of Nutrition on Intestinal Permeability and the Microbiome in Health and Disease. Front Nutr 2022; 9:718710. [PMID: 35548572 PMCID: PMC9082752 DOI: 10.3389/fnut.2022.718710] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 02/22/2022] [Indexed: 01/09/2023] Open
Abstract
The leakage of the intestinal barrier and the disruption of the gut microbiome are increasingly recognized as key factors in different pathophysiological conditions, such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), chronic liver diseases, obesity, diabetes mellitus, types of cancer, and neuropsychiatric disorders. In this study, the mechanisms leading to dysbiosis and "leaky gut" are reviewed, and a short summary of the current knowledge regarding different diseases is provided. The simplest way to restore intestinal permeability and the microbiota could be ideal nutrition. Further therapeutic options are also available, such as the administration of probiotics or postbiotics or fecal microbiota transplantation.
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Affiliation(s)
- Orsolya Inczefi
- Department of Gastroenterology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Péter Bacsur
- Department of Gastroenterology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Tamás Resál
- Department of Gastroenterology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Csilla Keresztes
- Department for Medical Communication and Translation Studies, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Tamás Molnár
- Department of Gastroenterology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary,*Correspondence: Tamás Molnár,
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27
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The ACE2 Receptor for Coronavirus Entry Is Localized at Apical Cell—Cell Junctions of Epithelial Cells. Cells 2022; 11:cells11040627. [PMID: 35203278 PMCID: PMC8870730 DOI: 10.3390/cells11040627] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/03/2022] [Accepted: 02/09/2022] [Indexed: 02/04/2023] Open
Abstract
Transmembrane proteins of adherens and tight junctions are known targets for viruses and bacterial toxins. The coronavirus receptor ACE2 has been localized at the apical surface of epithelial cells, but it is not clear whether ACE2 is localized at apical Cell—Cell junctions and whether it associates with junctional proteins. Here we explored the expression and localization of ACE2 and its association with transmembrane and tight junction proteins in epithelial tissues and cultured cells by data mining, immunoblotting, immunofluorescence microscopy, and co-immunoprecipitation experiments. ACE2 mRNA is abundant in epithelial tissues, where its expression correlates with the expression of the tight junction proteins cingulin and occludin. In cultured epithelial cells ACE2 mRNA is upregulated upon differentiation and ACE2 protein is widely expressed and co-immunoprecipitates with the transmembrane proteins ADAM17 and CD9. We show by immunofluorescence microscopy that ACE2 colocalizes with ADAM17 and CD9 and the tight junction protein cingulin at apical junctions of intestinal (Caco-2), mammary (Eph4) and kidney (mCCD) epithelial cells. These observations identify ACE2, ADAM17 and CD9 as new epithelial junctional transmembrane proteins and suggest that the cytokine-enhanced endocytic internalization of junction-associated protein complexes comprising ACE2 may promote coronavirus entry.
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28
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Singh V, Garg A, Dewangan HK. Recent Advances in Drug Design and Delivery Across Biological Barriers using Computational Models. LETT DRUG DES DISCOV 2022. [DOI: 10.2174/1570180819999220204110306] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Abstract:
The systemic delivery of pharmacological substances generally exhibits several significant limitations associated with the bio-distribution of active drugs in the body. As per consequence, human body’s defense mechanisms become impediments to drug delivery. Various technologies to overcome these limitations have been evolved including computational approaches and advanced drug delivery. As the body of human has evolved to defend itself from hostile biological as well as chemical invaders, along with that these biological barriers such as ocular barriers, blood-brain barriers, intestinal and skin barriers also limit the passage of drugs across desired sites. Therefore, efficient delivery remains an utmost challenge for researchers and scientists. The present review focuses on the techniques to deliver the drugs with efficient therapeutic efficacy at the targeted sites. This review article considered the insights into main biological barriers along with the application of computational or numerical methods dealing with different barriers by determining the drug flow, temperature and various other parameters. It also summarizes the advanced implantable drug delivery system to circumvent the inherent resistance showed by these biological barriers and in turn to improve the drug delivery.
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Affiliation(s)
- Vanshita Singh
- Institute of Pharmaceutical Research, GLA University Mathura, NH-2 Delhi Mathura Road, PO-Chaumuhan, Mathura, UttarPradesh, India 281406
| | - Akash Garg
- Institute of Pharmaceutical Research, GLA University Mathura, NH-2 Delhi Mathura Road, PO-Chaumuhan, Mathura, UttarPradesh, India 281406
| | - Hitesh Kumar Dewangan
- University Institute of Pharma Sciences (UIPS), Chandigarh University NH-95, Chandigarh Ludhiyana Highway, Mohali Punjab, India
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29
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Abstract
Vitamin D is a conditionally required nutrient that can either be obtained from skin synthesis following UVB exposure from the diet. Once in the body, it is metabolized to produce the endocrine hormone, 1,25 dihydroxyvitamin D (1,25(OH)2D), that regulates gene expression in target tissues by interacting with a ligand-activated transcription factor, the vitamin D receptor (VDR). The first, and most responsive, vitamin D target tissue is the intestine. The classical intestinal role for vitamin D is the control of calcium metabolism through the regulation of intestinal calcium absorption. However, studies clearly show that other functions of the intestine are regulated by the molecular actions of 1,25(OH)2 D that are mediated through the VDR. This includes enhancing gut barrier function, regulation of intestinal stem cells, suppression of colon carcinogenesis, and inhibiting intestinal inflammation. While research demonstrates that there are both classical, calcium-regulating and non-calcium regulating roles for vitamin D in the intestine, the challenge facing biomedical researchers is how to translate these findings in ways that optimize human intestinal health.
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Affiliation(s)
- James C Fleet
- Department of Nutritional Sciences, Dell Pediatric Research Institute, University of Texas, Austin, TX, USA.
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30
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Liu H, Li X, Lei H, Li D, Chen H, Schlenk D, Yan B, Yongju L, Xie L. Dietary Seleno-l-methionine Alters the Microbial Communities and Causes Damage in the Gastrointestinal Tract of Japanese Medaka Oryzias latipes. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2021; 55:16515-16525. [PMID: 34874707 DOI: 10.1021/acs.est.1c04533] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Excess dietary seleno-l-methionine (Se-Met) induces various adverse effects in fish inhabiting the Se-contaminated environments. However, there is an extreme paucity of data on the effects of excess dietary Se-Met on the microbiota in the gastrointestinal (GI) tract in fish. In this study, Japanese medaka Oryzias latipes (three months old) were fed the Se-Met enriched diets at environmentally relevant concentrations: 2.90 (Control: (C), 6.69 (L), 11.89 (M), and 27.05 (H) μg Se/g dw) for 60 d. Histopathological, high throughput sequencing, and biochemical approaches were used to investigate the alterations in histology and microbial communities of the GI tract, enzymatic activity, and transcripts of closely related genes. The results showed that the fish weight was reduced at ∼13% from the L and H treatments. Decreased height and thickness of villus in the GI tract were observed in the H treatment. Meanwhile, the level of D-lactate and activity of diamine oxidase (DAO), protease, and lipase were inhibited in the H treatment. The transcripts of the genes related to the inflammation (i.e., IL-1β and IL-8) were elevated, while those of the genes related to the intestinal barrier (i.e., cdh1, ZO-1, ocln, and cldn7) were inhibited in the H treatment. In addition, alpha diversity at the genus level was higher in the L treatment than the control, and the composition of the microbial community was altered by dietary Se-Met. Furthermore, 5 genera (Rhodobacter, Cloacibacterium, Bdellovibrio, Shinella, and Aeromonas) exhibited the largest variation in abundance among treatments. This study has demonstrated that excess dietary Se-Met inhibits growth, causes hispathological damage to the GI tract, and alters the composition of the microbial community in Oryzias latipes.
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Affiliation(s)
- Hongsong Liu
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China
- School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Xiao Li
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China
- School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Haojun Lei
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China
- School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Dan Li
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China
- School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Hongxing Chen
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China
- School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Daniel Schlenk
- Department of Environmental Sciences, University of California, Riverside, Riverside, California 92507, United States
| | - Bo Yan
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China
- School of Environment, South China Normal University, University Town, Guangzhou 510006, China
| | - Luo Yongju
- Guangxi Academy of Fishery Sciences, Nanning 530021, China
| | - Lingtian Xie
- SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China
- School of Environment, South China Normal University, University Town, Guangzhou 510006, China
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Pu X, Ye N, Lin M, Chen Q, Dong L, Xu H, Luo R, Han X, Qi S, Nie W, He H, Wang Y, Dai L, Lin D, Gao F. β-1,3-d-Glucan based yeast cell wall system loaded emodin with dual-targeting layers for ulcerative colitis treatment. Carbohydr Polym 2021; 273:118612. [PMID: 34561010 DOI: 10.1016/j.carbpol.2021.118612] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 08/06/2021] [Accepted: 08/19/2021] [Indexed: 01/15/2023]
Abstract
Herein, a β-1,3-d-glucan based microcarrier, yeast cell wall microparticles (YPs), was used to develop a food-source-based nano-in-micro oral delivery system for ulcerative colitis (UC) treatment. Briefly, lactoferrin (Lf), which targets intestinal epithelial cells, was used to encapsulate emodin (EMO) to form nanoparticles (EMO-NPs), and then loaded into YPs with the natural macrophages targeting ability, forming a final formula with two outer-inner targeting layers (EMO-NYPs). These dual-targeting strategy could enhance the dual-effects of EMO in anti-inflammatory and mucosal repair effects respectively. As expected, cell uptake assessment confirmed that EMO-NPs and EMO-NYPs could target on the Lf and dection-1 receptors on the membranes of Caco-2 cells and macrophages, respectively. Importantly, EMO-NYPs showed the best anti-UC effects compared to EMO-NPs and free EMO, by inhibiting NF-κB pathway to anti-inflammation and promoting intestinal mucosa repair via MLCK/pMLC2 pathway. The results show that EMO-NYPs are a promising food-based oral delivery system in anti-UC.
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Affiliation(s)
- Xiulan Pu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611130, China
| | - Naijing Ye
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Meisi Lin
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611130, China; Sichuan Provincial Acupuncture School, Chengdu 611731, China
| | - Qiyan Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611130, China
| | - Lingling Dong
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611130, China
| | - Haiting Xu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611130, China
| | - Ruifeng Luo
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611130, China
| | - Xiaoqin Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611130, China
| | - Shanshan Qi
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611130, China
| | - Wenbiao Nie
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611130, China
| | - Haoqi He
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611130, China
| | - Yanli Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611130, China
| | - Linxin Dai
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611130, China
| | - Dasheng Lin
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611130, China; Chengdu Huashen Technology Group Co., Ltd., Chengdu 611137, Sichuan, China.
| | - Fei Gao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611130, China.
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Wang X, Ge X, Liao W, Cao Y, Li R, Zhang F, Zhao B, Du J. ZFP36 promotes VDR mRNA degradation to facilitate cell death in oral and colonic epithelial cells. Cell Commun Signal 2021; 19:85. [PMID: 34380509 PMCID: PMC8355874 DOI: 10.1186/s12964-021-00765-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 07/13/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Vitamin D receptor (VDR) plays a vital protective role in oral and colonic epithelial cells. Albeit we know that VDR expression is reduced in the mucosal epithelial layers of autoimmune diseases, the mechanism by which VDR is decreased remains elusive. METHODS VDR and zinc finger protein 36 (ZFP36) levels in human samples and cell lines were detected by real-time PCR, western blot and immunostaining. Luciferase report assay was used to test cis-elements in VDR gene promoter, real-time PCR was applied to measure mRNA decay and western blot was performed to evaluate protein degradation. RNA affinity chromatography assay was used to test protein-mRNA interaction. Co-immunoprecipitation was used to detect protein-protein interaction. The role of ZFP36 in AU-rich elements (AREs) in the 3' untranslated region (UTR) of VDR mRNA was also measured by luciferase report assay. RESULTS We identify ZFP36 can bind with the AREs in the 3'UTR of VDR mRNA, leading to mRNA degradation in oral and colonic epithelial cells under inflammatory circumstance. Either ZFP36 protein or AREs of VDR mRNA mutation abolishes this protein-mRNA binding process. After the key amino acid's mutation, ZFP36 fails to decrease VDR mRNA expression. We also find that VDR physically binds with Y box-binding protein 1 (YBX-1) to block YBX-1's nuclear translocation and ameliorate cell death in the presence of inflammation. CONCLUSION These findings provide insights into the cause of VDR decrease in oral and colonic epithelial cells under inflammatory condition and explain how VDR maintains cell viability in these cells. Video abstract.
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Affiliation(s)
- Xiangyu Wang
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, No. 63 Xinjian South Road, Taiyuan, 030001, Shanxi, China.,Department of Child Dental and Preventive Dentistry, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China.,Department of Oral Medicine, Shanxi Medical University School and Hospital of Stomatology, No. 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China
| | - Xuejun Ge
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, No. 63 Xinjian South Road, Taiyuan, 030001, Shanxi, China.,Department of Endodontics, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China
| | - Wang Liao
- Department of Cardiology, Hainan General Hospital, Hainan Clinical Medicine Research Institution, Haikou, China
| | - Yong Cao
- Division of Gastroenterology, Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Ran Li
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, No. 63 Xinjian South Road, Taiyuan, 030001, Shanxi, China.,Department of Child Dental and Preventive Dentistry, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China
| | - Fang Zhang
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, No. 63 Xinjian South Road, Taiyuan, 030001, Shanxi, China.,Department of Oral Medicine, Shanxi Medical University School and Hospital of Stomatology, No. 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China
| | - Bin Zhao
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, No. 63 Xinjian South Road, Taiyuan, 030001, Shanxi, China.,Department of Oral Medicine, Shanxi Medical University School and Hospital of Stomatology, No. 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China
| | - Jie Du
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, No. 63 Xinjian South Road, Taiyuan, 030001, Shanxi, China. .,Department of Oral Medicine, Shanxi Medical University School and Hospital of Stomatology, No. 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China. .,Institute of Biomedical Research, Shanxi Medical University, Taiyuan, Shanxi, China.
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Tran L, Jochum SB, Shaikh M, Wilber S, Zhang L, Hayden DM, Forsyth CB, Voigt RM, Bishehsari F, Keshavarzian A, Swanson GR. Circadian misalignment by environmental light/dark shifting causes circadian disruption in colon. PLoS One 2021; 16:e0251604. [PMID: 34086699 PMCID: PMC8177509 DOI: 10.1371/journal.pone.0251604] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 04/29/2021] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Physiological circadian rhythms (CRs) are complex processes with 24-hour oscillations that regulate diverse biological functions. Chronic weekly light/dark (LD) shifting (CR disruption; CRD) in mice results in colonic hyperpermeability. However, the mechanisms behind this phenomenon are incompletely understood. One potential innovative in vitro method to study colonic CRs are colon organoids. The goals of this study were to utilize circadian clock gene Per2 luciferase reporter (Per2::Luc) mice to measure the effects of chronic LD shifting on colonic tissue circadian rhythmicity ex vivo and to determine if organoids made from shifted mice colons recapitulate the in vivo phenotype. METHODS Non-shifted (NS) and shifted (S) BL6 Per2::Luc mice were compared after a 22-week experiment. NS mice had a standard 12h light/12h dark LD cycle throughout. S mice alternated 12h LD patterns weekly, with light from 6am-6pm one week followed by shifting light to 6pm-6am the next week for 22 weeks. Mice were tested for intestinal permeability while colon tissue and organoids were examined for CRs of bioluminescence and proteins of barrier function and cell fate. RESULTS There was no absolute difference in NS vs. S 24h circadian period or phase. However, chronic LD shifting caused Per2::Luc S mice colon tissue to exhibit significantly greater variability in both the period and phase of Per2::Luc rhythms than NS mice colon tissue and organoids. Chronic LD shifting also resulted in increased colonic permeability of the Per2::Luc mice as well as decreased protein markers of intestinal permeability in colonic tissue and organoids from shifted Per2:Luc mice. CONCLUSIONS Our studies support a model in which chronic central circadian disruption by LD shifting alters the circadian phenotype of the colon tissue and results in colon leakiness and loss of colonic barrier function. These CRD-related changes are stably expressed in colon stem cell derived organoids from CRD mice.
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Affiliation(s)
- Laura Tran
- Rush Medical College, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Sarah B. Jochum
- Department of Surgery, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Maliha Shaikh
- Rush Medical College, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Sherry Wilber
- Rush Medical College, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Lijuan Zhang
- Rush Medical College, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Dana M. Hayden
- Department of Surgery, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Christopher B. Forsyth
- Rush Medical College, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois, United States of America
- Department of Medicine, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Robin M. Voigt
- Rush Medical College, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois, United States of America
- Department of Medicine, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Faraz Bishehsari
- Rush Medical College, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois, United States of America
- Department of Medicine, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Ali Keshavarzian
- Rush Medical College, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois, United States of America
- Department of Medicine, Rush University Medical Center, Chicago, Illinois, United States of America
| | - Garth R. Swanson
- Rush Medical College, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois, United States of America
- Department of Medicine, Rush University Medical Center, Chicago, Illinois, United States of America
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Xue G, Gao R, Liu Z, Xu N, Cao Y, Zhao B, Du J. Vitamin D/VDR signaling inhibits colitis by suppressing HIF-1α activation in colonic epithelial cells. Am J Physiol Gastrointest Liver Physiol 2021; 320:G837-G846. [PMID: 33759562 DOI: 10.1152/ajpgi.00061.2021] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Vitamin D/vitamin D receptor (VDR) signaling is reported to have a protective effect on the onset or progression of inflammatory bowel diseases (IBD), and hypoxia-inducible factor 1α (HIF-1α) activation is demonstrated to be closely associated with chemical-induced colitis. However, the association between vitamin D/VDR signaling and HIF-1α on IBD development remains a mystery. Here, we showed that HIF-1α expression was largely increased in the colonic epithelial cells of diseased tissues from patients with ulcerative colitis (UC). Consistently, HIF-1α activation was also improved in colonic epithelial cells upon TNFα treatment in a NF-κB pathway-dependent manner. HIF-1α inhibitors treatments ameliorated 2,4,6-trinitrobenzenesulfonic acid (TNBS)- or dextran sulfate sodium (DSS)-induced colitis in animal models. In cell or colitis animal models, vitamin D/VDR signaling suppressed HIF-1α overexpression in colonic epithelial cells via regulating NF-κB pathway, resulting in the inhibition of IFNγ and IL-1β overproductions in these cells. Collectively, these data suggest that vitamin D/VDR signaling relieves colitis development in animal models, at least in part, by suppressing HIF-1α expression in colonic epithelial cells.NEW & NOTEWORTHY This study demonstrates vitamin D/VDR signaling inhibits colitis by suppressing HIF-1α activation in colonic epithelial cells. Since the effect of vitamin D/VDR signaling is only apparent on patients who seem to be vitamin D deficient, the benefits of vitamin D supplementation in patients who are not vitamin D deficient need to be proven.
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Affiliation(s)
- Gang Xue
- Department of Gastroenterology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Ruifang Gao
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China
| | - Zhuanzhuan Liu
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China
| | - Na Xu
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China
| | - Yong Cao
- Department of Gastroenterology, Division of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Bin Zhao
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China
| | - Jie Du
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China.,Institute of Biomedical Research, Shanxi Medical University, Taiyuan, Shanxi, China
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35
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Raya-Sandino A, Luissint AC, Kusters DHM, Narayanan V, Flemming S, Garcia-Hernandez V, Godsel LM, Green KJ, Hagen SJ, Conway DE, Parkos CA, Nusrat A. Regulation of intestinal epithelial intercellular adhesion and barrier function by desmosomal cadherin desmocollin-2. Mol Biol Cell 2021; 32:753-768. [PMID: 33596089 PMCID: PMC8108520 DOI: 10.1091/mbc.e20-12-0775] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 02/02/2021] [Accepted: 02/09/2021] [Indexed: 12/26/2022] Open
Abstract
The role of desmosomal cadherin desmocollin-2 (Dsc2) in regulating barrier function in intestinal epithelial cells (IECs) is not well understood. Here, we report the consequences of silencing Dsc2 on IEC barrier function in vivo using mice with inducible intestinal-epithelial-specific Dsc2 knockdown (KD) (Dsc2ERΔIEC). While the small intestinal gross architecture was maintained, loss of epithelial Dsc2 influenced desmosomal plaque structure, which was smaller in size and had increased intermembrane space between adjacent epithelial cells. Functional analysis revealed that loss of Dsc2 increased intestinal permeability in vivo, supporting a role for Dsc2 in the regulation of intestinal epithelial barrier function. These results were corroborated in model human IECs in which Dsc2 KD resulted in decreased cell-cell adhesion and impaired barrier function. It is noteworthy that Dsc2 KD cells exhibited delayed recruitment of desmoglein-2 (Dsg2) to the plasma membrane after calcium switch-induced intercellular junction reassembly, while E-cadherin accumulation was unaffected. Mechanistically, loss of Dsc2 increased desmoplakin (DP I/II) protein expression and promoted intermediate filament interaction with DP I/II and was associated with enhanced tension on desmosomes as measured by a Dsg2-tension sensor. In conclusion, we provide new insights on Dsc2 regulation of mechanical tension, adhesion, and barrier function in IECs.
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Affiliation(s)
- Arturo Raya-Sandino
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Anny-Claude Luissint
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Dennis H. M. Kusters
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Vani Narayanan
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23284
| | - Sven Flemming
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109
| | | | - Lisa M. Godsel
- Departments of Pathology and Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
| | - Kathleen J. Green
- Departments of Pathology and Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611
| | - Susan J. Hagen
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA 02115
| | - Daniel E. Conway
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23284
| | - Charles A. Parkos
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Asma Nusrat
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109
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Basson AR, Ahmed S, Almutairi R, Seo B, Cominelli F. Regulation of Intestinal Inflammation by Soybean and Soy-Derived Compounds. Foods 2021; 10:foods10040774. [PMID: 33916612 PMCID: PMC8066255 DOI: 10.3390/foods10040774] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/30/2021] [Accepted: 04/02/2021] [Indexed: 02/06/2023] Open
Abstract
Environmental factors, particularly diet, are considered central to the pathogenesis of the inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis. In particular, the Westernization of diet, characterized by high intake of animal protein, saturated fat, and refined carbohydrates, has been shown to contribute to the development and progression of IBD. During the last decade, soybean, as well as soy-derived bioactive compounds (e.g., isoflavones, phytosterols, Bowman-Birk inhibitors) have been increasingly investigated because of their anti-inflammatory properties in animal models of IBD. Herein we provide a scoping review of the most studied disease mechanisms associated with disease induction and progression in IBD rodent models after feeding of either the whole food or a bioactive present in soybean.
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Affiliation(s)
- Abigail Raffner Basson
- Division of Gastroenterology & Liver Diseases, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA;
- Digestive Health Research Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA; (S.A.); (B.S.)
- Correspondence:
| | - Saleh Ahmed
- Digestive Health Research Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA; (S.A.); (B.S.)
| | - Rawan Almutairi
- Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA;
| | - Brian Seo
- Digestive Health Research Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA; (S.A.); (B.S.)
| | - Fabio Cominelli
- Division of Gastroenterology & Liver Diseases, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA;
- Digestive Health Research Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA; (S.A.); (B.S.)
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Analysis of Intestinal Mucosa Integrity and GLP-2 Gene Functions upon Porcine Epidemic Diarrhea Virus Infection in Pigs. Animals (Basel) 2021; 11:ani11030644. [PMID: 33804466 PMCID: PMC8000733 DOI: 10.3390/ani11030644] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 02/24/2021] [Accepted: 02/24/2021] [Indexed: 11/17/2022] Open
Abstract
Porcine epidemic diarrhea virus (PEDV) infects intestinal epithelial cells, destroys the intestinal mucosal barrier and then causes diarrhea in piglets. Glucagon-like peptide-2 (GLP-2) is a specific intestinal growth hormone that promotes the repair of damaged intestinal mucosa and improves the intestinal barrier. In this study, we investigated the functions of porcine GLP-2 gene in regulating PEDV infection. The intestinal tissues with damaged intestinal structures caused by PEDV infection were first confirmed and collected. Expression analysis indicated that the GLP-2 gene was expressed in the duodenum, jejunum and ileum tissues, and the mRNA level was significantly down-regulated in jejunum and ileum of piglets with damaged intestinal mucosa. Infection of PEDV to porcine small intestinal epithelial cells in vitro showed that GLP-2 gene was significantly decreased, which was consistent with the expression pattern in intestinal tissues. In addition, we silenced the GLP-2 gene by shRNA interfering and found that the copy numbers of PEDV were remarkably increased in the GLP-2 gene silencing cells. Our findings suggest that the GLP-2 gene was potentially involved in regulating PEDV infection and in maintaining the integrity of the intestinal mucosal barrier structure, which could contribute to our understanding of the mechanisms of PEDV pathogenesis and provide a theoretical basis for the identification and application of resistant genes in pig selective breeding for porcine epidemic diarrhea.
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Ghosh S, Whitley CS, Haribabu B, Jala VR. Regulation of Intestinal Barrier Function by Microbial Metabolites. Cell Mol Gastroenterol Hepatol 2021; 11:1463-1482. [PMID: 33610769 PMCID: PMC8025057 DOI: 10.1016/j.jcmgh.2021.02.007] [Citation(s) in RCA: 372] [Impact Index Per Article: 93.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 02/11/2021] [Accepted: 02/12/2021] [Indexed: 12/11/2022]
Abstract
The human gastrointestinal tract (GI) harbors a diverse population of microbial life that continually shapes host pathophysiological responses. Despite readily available abundant metagenomic data, the functional dynamics of gut microbiota remain to be explored in various health and disease conditions. Microbiota generate a variety of metabolites from dietary products that influence host health and pathophysiological functions. Since gut microbial metabolites are produced in close proximity to gut epithelium, presumably they have significant impact on gut barrier function and immune responses. The goal of this review is to discuss recent advances on gut microbial metabolites in the regulation of intestinal barrier function. While the mechanisms of action of these metabolites are only beginning to emerge, they mainly point to a small group of shared pathways that control gut barrier functions. Amidst expanding technology and broadening knowledge, exploitation of beneficial microbiota and their metabolites to restore pathophysiological balance will likely prove to be an extremely useful remedial tool.
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Affiliation(s)
- Sweta Ghosh
- Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky
| | - Caleb Samuel Whitley
- Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky
| | - Bodduluri Haribabu
- Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky
| | - Venkatakrishna Rao Jala
- Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky.
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Morris NL, Choudhry MA. Maintenance of gut barrier integrity after injury: Trust your gut microRNAs. J Leukoc Biol 2021; 110:979-986. [PMID: 33577717 DOI: 10.1002/jlb.3ru0120-090rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 01/20/2021] [Accepted: 01/21/2021] [Indexed: 12/11/2022] Open
Abstract
The gastrointestinal (GI) tract is a highly dynamic structure essential for digestion, nutrient absorption, and providing an interface to prevent gut bacterial translocation. In order to maintain the barrier function, the gut utilizes many defense mechanisms including proliferation, apoptosis, and apical junctional complexes. Disruption of any of these parameters due to injury or disease could negatively impact the intestinal barrier function and homeostasis resulting in increased intestine inflammation, permeability, bacterial dysbiosis, and tissue damage. MicroRNAs are small noncoding RNA sequences that are master regulators of normal cellular homeostasis. These regulatory molecules affect cellular signaling pathways and potentially serve as candidates for providing a mechanism of impaired gut barrier integrity following GI-related pathologic conditions, ethanol exposure, or trauma such as burn injury. MicroRNAs influence cellular apoptosis, proliferation, apical junction complex expression, inflammation, and the microbiome. Due to their widespread functional affiliations, altered expression of microRNAs are associated with many pathologic conditions. This review explores the role of microRNAs in regulation of intestinal barrier integrity. The studies reviewed demonstrate that microRNAs largely impact intestine barrier function and provide insight behind the observed adverse effects following ethanol and burn injury. Furthermore, these studies suggest that microRNAs are excellent candidates for therapeutic intervention or for biomarkers to manage gut barrier integrity following trauma such as burn injury and other GI-related pathologic conditions.
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Affiliation(s)
- Niya L Morris
- Alcohol Research Program, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Burn & Shock Trauma Research Institute, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Integrative Cell Biology Program, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Current address: Department of Medicine: Pulmonary, Allergy, Critical Care and Sleep, Emory University/Atlanta VA Medical Center, Decatur, Geogia, USA
| | - Mashkoor A Choudhry
- Alcohol Research Program, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Burn & Shock Trauma Research Institute, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Integrative Cell Biology Program, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Department of Surgery, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA
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Mao X, Ding X, Zeng Q, Bai S, Zhang K, Chen D, Yu B, He J, Yu J, Yan H, Luo J, Luo Y, Wang J. The effect of dietary pectic oligosaccharide supplementation on intestinal health of broiler breeders with different egg-laying rates. Poult Sci 2021; 100:100938. [PMID: 33518299 PMCID: PMC7936170 DOI: 10.1016/j.psj.2020.12.035] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 12/02/2020] [Accepted: 12/15/2020] [Indexed: 01/06/2023] Open
Abstract
This study was conducted to explore whether dietary pectic oligosaccharide (POS) supplementation could improve gut health of broiler breeders with different egg-laying rates. A 2 × 2 factorial design was used in this study. Two hundred fifty-six Arbor Acres broiler breeders (48 wk of age), including 128 average egg-laying rate and 128 low egg-laying rate (LELR) birds, were randomly fed with the diets supplemented with or without 200 mg kg−1 of POS (n = 8). The trial lasted for 8 wk. Compared with average egg-laying rate broiler breeders, LELR broiler breeders had lower laying rate and qualified egg rate (P < 0.05), higher egg weight and feed conversion ratio (P < 0.05), higher malondialdehyde (MDA) levels in the jejunum (P < 0.05), higher IL-6 (P < 0.05) and tumor necrosis factor α (TNF-α) (P = 0.07) mRNA expressions in the jejunal mucosa, and lower microflora diversity in cecal digesta. Dietary POS supplementation increased egg weight of broiler breeders (P < 0.05), enhanced superoxide dismutase activity in the jejunum (P < 0.05), decreased MDA level in the jejunum (P < 0.05), upregulated zonula occluden 1 mRNA expression in the jejunal mucosa (P < 0.05), downregulated IL-6 and TNF-α mRNA expressions in the jejunal mucosa (P < 0.05), and regulated relative abundance of some microbiota (including the phylum and genus, P < 0.05). In addition, in LELR broiler breeders, POS administration enhanced villus height (P = 0.08) and ZO-2 mRNA expression (P = 0.09) in the jejunal mucosa, alleviated the increasing MDA level in the jejunum (P < 0.05) and IL-6 and TNF-α mRNA expressions in the jejunal mucosa (P < 0.05), and regulated relative abundance of some microbiota (including the phylum and genus, P < 0.05). These results suggest that supplementing POS in diets may elevate gut health via improvement of intestinal barrier function, antioxidant capacity, and microbiota composition in broiler breeders with different egg-laying rates.
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Affiliation(s)
- Xiangbing Mao
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key laboratory of Animal Disease-resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key laboratory of Animal Disease-resistant Nutrition of Sichuan Province, Chengdu 611130, People's Republic of China
| | - Xuemei Ding
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key laboratory of Animal Disease-resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key laboratory of Animal Disease-resistant Nutrition of Sichuan Province, Chengdu 611130, People's Republic of China
| | - Qiufeng Zeng
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key laboratory of Animal Disease-resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key laboratory of Animal Disease-resistant Nutrition of Sichuan Province, Chengdu 611130, People's Republic of China
| | - Shiping Bai
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key laboratory of Animal Disease-resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key laboratory of Animal Disease-resistant Nutrition of Sichuan Province, Chengdu 611130, People's Republic of China
| | - Keying Zhang
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key laboratory of Animal Disease-resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key laboratory of Animal Disease-resistant Nutrition of Sichuan Province, Chengdu 611130, People's Republic of China
| | - Daiwen Chen
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key laboratory of Animal Disease-resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key laboratory of Animal Disease-resistant Nutrition of Sichuan Province, Chengdu 611130, People's Republic of China
| | - Bing Yu
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key laboratory of Animal Disease-resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key laboratory of Animal Disease-resistant Nutrition of Sichuan Province, Chengdu 611130, People's Republic of China
| | - Jun He
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key laboratory of Animal Disease-resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key laboratory of Animal Disease-resistant Nutrition of Sichuan Province, Chengdu 611130, People's Republic of China
| | - Jie Yu
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key laboratory of Animal Disease-resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key laboratory of Animal Disease-resistant Nutrition of Sichuan Province, Chengdu 611130, People's Republic of China
| | - Hui Yan
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key laboratory of Animal Disease-resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key laboratory of Animal Disease-resistant Nutrition of Sichuan Province, Chengdu 611130, People's Republic of China
| | - Junqiu Luo
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key laboratory of Animal Disease-resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key laboratory of Animal Disease-resistant Nutrition of Sichuan Province, Chengdu 611130, People's Republic of China
| | - Yuheng Luo
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key laboratory of Animal Disease-resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key laboratory of Animal Disease-resistant Nutrition of Sichuan Province, Chengdu 611130, People's Republic of China
| | - Jianping Wang
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key laboratory of Animal Disease-resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key laboratory of Animal Disease-resistant Nutrition of Sichuan Province, Chengdu 611130, People's Republic of China.
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Choo J, Heo G, Pothoulakis C, Im E. Posttranslational modifications as therapeutic targets for intestinal disorders. Pharmacol Res 2021; 165:105412. [PMID: 33412276 DOI: 10.1016/j.phrs.2020.105412] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/14/2020] [Accepted: 12/22/2020] [Indexed: 02/08/2023]
Abstract
A variety of biological processes are regulated by posttranslational modifications. Posttranslational modifications including phosphorylation, ubiquitination, glycosylation, and proteolytic cleavage, control diverse physiological functions in the gastrointestinal tract. Therefore, a better understanding of their implications in intestinal diseases, including inflammatory bowel disease, irritable bowel syndrome, celiac disease, and colorectal cancer would provide a basis for the identification of novel biomarkers as well as attractive therapeutic targets. Posttranslational modifications can be common denominators, as well as distinct biomarkers, characterizing pathological differences of various intestinal diseases. This review provides experimental evidence that identifies changes in posttranslational modifications from patient samples, primary cells, or cell lines in intestinal disorders, and a summary of carefully selected information on the use of pharmacological modulators of protein modifications as therapeutic options.
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Affiliation(s)
- Jieun Choo
- College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea
| | - Gwangbeom Heo
- College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea
| | - Charalabos Pothoulakis
- Section of Inflammatory Bowel Disease & Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA
| | - Eunok Im
- College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.
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Martens K, De Boeck I, Jokicevic K, Kiekens F, Farré R, Vanderveken OM, Seys SF, Lebeer S, Hellings PW, Steelant B. Lacticaseibacillus casei AMBR2 Restores Airway Epithelial Integrity in Chronic Rhinosinusitis With Nasal Polyps. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2021; 13:560-575. [PMID: 34212544 PMCID: PMC8255346 DOI: 10.4168/aair.2021.13.4.560] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 10/16/2020] [Accepted: 11/01/2020] [Indexed: 01/01/2023]
Abstract
Purpose A defective epithelial barrier has been demonstrated in chronic rhinosinusitis with nasal polyps (CRSwNP). Lactobacilli are shown to restore epithelial barrier defects in gastrointestinal disorders, but their effect on the airway epithelial barrier is unknown. In this study, hence, we evaluated whether the nasopharyngeal isolates Lacticaseibacillus casei AMBR2 and Latilactobacillus sakei AMBR8 could restore nasal epithelial barrier integrity in CRSwNP. Methods Ex vivo trans-epithelial tissue resistance and fluorescein isothiocyanate-dextran 4 kDa (FD4) permeability of nasal mucosal explants were measured. The relative abundance of lactobacilli in the maxillary sinus of CRSwNP patients was analyzed by amplicon sequencing of the V4 region of the 16S rRNA gene. The effect of spray-dried L. casei AMBR2 and L. sakei AMBR8 on epithelial integrity was investigated in vitro in primary nasal epithelial cells (pNECs) from healthy controls and patients with CRSwNP as well as in vivo in a murine model of interleukin (IL)-4 induced barrier dysfunction. The activation of Toll-like receptor 2 (TLR2) was explored in vitro by using polyclonal antibodies. Results Patients with CRSwNP had a defective epithelial barrier which positively correlated with the relative abundance of lactobacilli-specific amplicons in the maxillary sinus. L. casei AMBR2, but not L. sakei AMBR8, increased the trans-epithelial electrical resistance (TEER) of pNECs from CRSwNP patients in a time-dependent manner. Treatment of epithelial cells with L. casei AMBR2 promoted the tight junction proteins occludin and zonula occludens-1 reorganization. Furthermore, L. casei AMBR2 prevented IL-4-induced nasal permeability in vivo and in vitro. Finally, the beneficial effect of L. casei AMBR2 on nasal epithelial cells in vitro was TLR2-dependent as blocking TLR2 receptors prevented the increase in TEER. Conclusions A defective epithelial barrier in CRSwNP may be associated with a decrease in relative abundance of lactobacilli-specific amplicons. L. casei AMBR2 would restore nasal epithelial integrity and can be a novel therapeutic strategy for CRSwNP.
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Affiliation(s)
- Katleen Martens
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, Leuven, Belgium.,Department of Bioscience Engineering, Research Group Environmental Ecology and Applied Microbiology, University of Antwerp, Antwerp, Belgium
| | - Ilke De Boeck
- Department of Bioscience Engineering, Research Group Environmental Ecology and Applied Microbiology, University of Antwerp, Antwerp, Belgium
| | - Katarina Jokicevic
- Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp, Belgium
| | - Filip Kiekens
- Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp, Belgium
| | - Ricard Farré
- KU Leuven, Department of Chronic Diseases, Metabolism, and Aging (ChroMeTa), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Olivier M Vanderveken
- ENT, Head and Neck Surgery and Communication Disorders, Antwerp University Hospital, Edegem, Belgium.,Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Sven F Seys
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, Leuven, Belgium
| | - Sarah Lebeer
- Department of Bioscience Engineering, Research Group Environmental Ecology and Applied Microbiology, University of Antwerp, Antwerp, Belgium.
| | - Peter W Hellings
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, Leuven, Belgium.,University Hospitals Leuven Clinical Division of Ear, Nose and Throat Disease, Leuven, Belgium.,Department of Otorhinolaryngology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.,Department of Otorhinolaryngology, Ghent University Hospital, Ghent, Belgium
| | - Brecht Steelant
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, Leuven, Belgium.
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Name JJ, Souza ACR, Vasconcelos AR, Prado PS, Pereira CPM. Zinc, Vitamin D and Vitamin C: Perspectives for COVID-19 With a Focus on Physical Tissue Barrier Integrity. Front Nutr 2020; 7:606398. [PMID: 33365326 PMCID: PMC7750357 DOI: 10.3389/fnut.2020.606398] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 11/16/2020] [Indexed: 12/15/2022] Open
Abstract
Some nutrients play key roles in maintaining the integrity and function of the immune system, presenting synergistic actions in steps determinant for the immune response. Among these elements, zinc and vitamins C and D stand out for having immunomodulatory functions and for playing roles in preserving physical tissue barriers. Considering the COVID-19 pandemic, nutrients that can optimize the immune system to prevent or lower the risk of severe progression and prognosis of this viral infection become relevant. Thus, the present review aims to provide a comprehensive overview of the roles of zinc and vitamins C and D in the immune response to viral infections, focusing on the synergistic action of these nutrients in the maintenance of physical tissue barriers, such as the skin and mucous membranes. The evidence found in the literature shows that deficiency of one or more of these three elements compromises the immune response, making an individual more vulnerable to viral infections and to a worse disease prognosis. Thus, during the COVID-19 pandemic, the adequate intake of zinc and vitamins C and D may represent a promising pharmacological tool due to the high demand for these nutrients in the case of contact with the virus and onset of the inflammatory process. Ongoing clinical trials will help to clarify the role of these nutrients for COVID-19 management.
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Affiliation(s)
- José João Name
- Kilyos Consultoria, Assessoria, Cursos e Palestras, São Paulo, Brazil
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Butt S, Saleh M, Gagnon J. Impact of the Escherichia coli Heat-Stable Enterotoxin b (STb) on Gut Health and Function. Toxins (Basel) 2020; 12:E760. [PMID: 33276476 PMCID: PMC7761119 DOI: 10.3390/toxins12120760] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 11/24/2020] [Accepted: 11/26/2020] [Indexed: 12/25/2022] Open
Abstract
Enterotoxigenic Escherichia coli (ETEC) produces the heat-stable enterotoxin b (STb), which is responsible for secretory diarrhea in humans and animals. This toxin is secreted within the intestinal lumen of animals and humans following ETEC colonization, becoming active on enterocytes and altering fluid homeostasis. Several studies have outlined the nature of this toxin and its effects on gut health and the integrity of the intestinal epithelium. This review summarizes the mechanisms of how STb alters the gastrointestinal tract. These include the manipulation of mucosal tight junction protein integrity, the formation of enterocyte cellular pores and toxin internalization and the stimulation of programmed cell death. We conclude with insights into the potential link between STb intoxication and altered gut hormone regulation, and downstream physiology.
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Affiliation(s)
| | | | - Jeffrey Gagnon
- Department of Biology, Laurentian University, 935 Ramsey Lake Rd., Sudbury, ON P3E 2C6, Canada; (S.B.); (M.S.)
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Aguanno D, Coquant G, Postal BG, Osinski C, Wieckowski M, Stockholm D, Grill JP, Carrière V, Seksik P, Thenet S. The intestinal quorum sensing 3-oxo-C12:2 Acyl homoserine lactone limits cytokine-induced tight junction disruption. Tissue Barriers 2020; 8:1832877. [PMID: 33100129 PMCID: PMC7714502 DOI: 10.1080/21688370.2020.1832877] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The intestine is home to the largest microbiota community of the human body and strictly regulates its barrier function. Tight junctions (TJ) are major actors of the intestinal barrier, which is impaired in inflammatory bowel disease (IBD), along with an unbalanced microbiota composition. With the aim to identify new actors involved in host-microbiota interplay in IBD, we studied N-acyl homoserine lactones (AHL), molecules of the bacterial quorum sensing, which also impact the host. We previously identified in the gut a new and prominent AHL, 3-oxo-C12:2, which is lost in IBD. We investigated how 3-oxo-C12:2 impacts the intestinal barrier function, in comparison to 3-oxo-C12, a structurally close AHL produced by the opportunistic pathogen P. aeruginosa. Using Caco-2/TC7 cells as a model of polarized enterocytes, we compared the effects on paracellular permeability and TJ integrity of these two AHL, separately or combined with pro-inflammatory cytokines, Interferon-γ and Tumor Necrosis Factor-α, known to disrupt the barrier function during IBD. While 3-oxo-C12 increased paracellular permeability and decreased occludin and tricellulin signal at bicellular and tricellular TJ, respectively, 3-oxo-C12:2 modified neither permeability nor TJ integrity. Whereas 3-oxo-C12 potentiated the hyperpermeability induced by cytokines, 3-oxo-C12:2 attenuated their deleterious effects on occludin and tricellulin, and maintained their interaction with their partner ZO-1. In addition, 3-oxo-C12:2 limited the cytokine-induced ubiquitination of occludin and tricellulin, suggesting that this AHL prevented their endocytosis. In conclusion, the role of 3-oxo-C12:2 in maintaining TJ integrity under inflammatory conditions identifies this new AHL as a potential beneficial actor of host–microbiota interactions in IBD.
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Affiliation(s)
- Doriane Aguanno
- Centre de Recherche Saint-Antoine, Sorbonne Université, INSERM , Paris, France.,EPHE, PSL University , Paris, France
| | - Garance Coquant
- Centre de Recherche Saint-Antoine, Sorbonne Université, INSERM , Paris, France
| | - Barbara G Postal
- Centre de Recherche Saint-Antoine, Sorbonne Université, INSERM , Paris, France.,Université de Paris, Centre De Recherche sur l'Inflammation, INSERM UMR 1149 , Paris, France.,Biology and Genetics of Bacterial Cell Wall Unit, Pasteur Institute , Paris, France
| | - Céline Osinski
- Sorbonne Université, INSERM, Nutrition and obesities: systemic approaches , Paris, France
| | - Margaux Wieckowski
- Centre de Recherche Saint-Antoine, Sorbonne Université, INSERM , Paris, France.,EPHE, PSL University , Paris, France
| | - Daniel Stockholm
- Centre de Recherche Saint-Antoine, Sorbonne Université, INSERM , Paris, France.,EPHE, PSL University , Paris, France
| | - Jean-Pierre Grill
- Centre de Recherche Saint-Antoine, Sorbonne Université, INSERM , Paris, France
| | - Véronique Carrière
- Centre de Recherche Saint-Antoine, Sorbonne Université, INSERM , Paris, France
| | - Philippe Seksik
- Centre de Recherche Saint-Antoine, Sorbonne Université, INSERM , Paris, France.,Département De Gastroentérologie Et Nutrition , Paris, France
| | - Sophie Thenet
- Centre de Recherche Saint-Antoine, Sorbonne Université, INSERM , Paris, France.,EPHE, PSL University , Paris, France
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Heat stress effect on the intestinal epithelial function of broilers fed methionine supplementation. Livest Sci 2020. [DOI: 10.1016/j.livsci.2020.104152] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Yuan X, Chen J, Grauer JA, Xu Q, Van Brunt LA, Helms JA. The Junctional Epithelium Is Maintained by a Stem Cell Population. J Dent Res 2020; 100:209-216. [PMID: 32985318 DOI: 10.1177/0022034520960125] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
The most fundamental function of an epithelial tissue is to act as a barrier, regulating interactions between the external environment and the body. This barrier function typically requires a contiguous cell layer but since teeth penetrate the oral epithelium, a modified barrier has evolved, called the junctional epithelium (JE). In health, the JE attaches to the tooth, sealing the inside of the body against oral micro-organisms. Breakdown of the JE barrier results in periodontal ligament (PDL) disintegration, alveolar bone resorption, and ultimately tooth loss. Using lineage tracing and DNA pulse-chase analyses, we identified an anatomical location in the JE that supported both fast- and slow-cycling Wnt-responsive stem cells that contributed to self-renewal of the tissue. Stem cells produced daughter cells with an extraordinarily high rate of turnover that maintained JE integrity for 1.4 y in mice. Blocking cell proliferation via a chemotherapeutic agent 5-fluorouracil (5-Fu) eliminated fast-cycling stem cells, which caused JE degeneration, PDL destruction, and bone resorption. Upon removal of 5-Fu, slow-cycling stem cells regenerated both the structure and barrier function of the JE. Taken together, our studies identified a stem cell population in the JE and have potential clinical implications for prevention and treatment of periodontitis.
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Affiliation(s)
- X Yuan
- Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, Stanford University, Palo Alto, CA, USA
| | - J Chen
- Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, Stanford University, Palo Alto, CA, USA.,State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - J A Grauer
- Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, Stanford University, Palo Alto, CA, USA.,Dr. Gerald Niznick College of Dentistry, University of Manitoba, Winnipeg, MB, Canada
| | - Q Xu
- Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, Stanford University, Palo Alto, CA, USA.,Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - L A Van Brunt
- Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, Stanford University, Palo Alto, CA, USA
| | - J A Helms
- Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, Stanford University, Palo Alto, CA, USA
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Couto MR, Gonçalves P, Magro F, Martel F. Microbiota-derived butyrate regulates intestinal inflammation: Focus on inflammatory bowel disease. Pharmacol Res 2020; 159:104947. [DOI: 10.1016/j.phrs.2020.104947] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/04/2020] [Accepted: 05/19/2020] [Indexed: 12/12/2022]
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Fredericks J, Senapati S, Wannemuehler MJ. Cytotoxic effects of manganese oxide nanoparticles in combination with microbial components on intestinal epithelial cells. F1000Res 2020. [DOI: 10.12688/f1000research.25238.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background: Manganese oxide has been shown to cause toxicity and is associated with occupational-related disease (e.g., welders). With the goal to improve several biomedical areas, manganese oxide nanoparticles (MnO NP) are being considered for use in drug delivery and magnetic resonance imaging (MRI) to obtain high resolution anatomical images of tumors and gastrointestinal (GI) inflammation. Regardless of whether it is intentional or unintentional ingestion, the GI tract has been shown to be the primary route of entry for metal nanoparticles including MnO NP. However, studies assessing toxicity of MnO NP for intestinal epithelial cells (IECs) are virtually nonexistent. Methods: Given the proximity to the GI lumen, assessing the effects of nanoparticles on IECs in the presence of bacterial components presents a more holistic model of exposure. Therefore, we examined the effects of MnO NP alone and MnO NP in combination with Escherichia coli LF82 bacterial lysate on selected functions of MODE-K cells, a murine intestinal epithelial cell line. Data were analyzed using one-way ANOVA. Differences with p < 0.05 were considered significant. Results: Results showed MnO NP plus E. coli LF82 lysate added to MODE-K cells severely inhibited monolayer scratch wound healing, enhanced the secretion of interleukin 6 (IL-6), and induced mitochondrial dysfunction. Conclusions: Overall, our findings show that toxicity of MnO NP deleteriously affected MODE-K cells and demonstrated the necessity to integrate other environmental factors, such as microbial components and/or inflammatory cytokines, into studies assessing effects of nanoparticles on mucosal epithelia.
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50
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Vitamin D regulates claudin-2 and claudin-4 expression in active ulcerative colitis by p-Stat-6 and Smad-7 signaling. Int J Colorectal Dis 2020; 35:1231-1242. [PMID: 32314188 DOI: 10.1007/s00384-020-03576-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/04/2020] [Indexed: 02/04/2023]
Abstract
PURPOSE The tight junctions (TJ) responsible for the integrity of the intestinal barrier are altered in patients with inflammatory bowel disease (IBD), but the physiopathological mechanisms that lead to this alteration are not yet clear. The aim of this study was to determine whether vitamin D, which regulates the integrity of the epithelial barrier by expressing TJ proteins, reduces claudin-2 (Cl-2) levels by inhibiting Stat-6 phosphorylation and whether it increases claudin-4 (Cl-4) levels by blocking Smad-7 activity. METHODS Biopsies were obtained from inflamed and non-inflamed tracts of the right side colon (caecum or ascending colon) from the same patient with active UC. All the patients were affected by a recent flare-up of ulcerative rectocolitis (RCU), with no previous biologic or immunosuppressive therapy, and all the biopsies were obtained before any treatments. The biopsies were cultured in the presence or not of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). We also used T84 cells as an in vitro model to perform transfection experiments with Stat-6 and Smad-7. RESULTS Our results indicate that 1,25(OH)2D3 is able to regulate CL-2 and CL-4 protein levels, which are increased and reduced in the intestinal mucosa of UC patients, respectively. In the biopsies obtained from UC patients 1,25(OH)2D3 reduces Cl-2 levels by blocking Stat-6 phosphorylation and increases Cl-4 levels by blocking Smad-7 activity. T84 cells, transfected with siRNA of Stat-6 and Smad-7, showed reduced Cl-2 levels and increased Cl-4 levels, confirming that 1,25(OH)2D3 regulates Cl-2 and Cl-4 by decreasing p-Stat-6 and Smad-7 levels. CONCLUSIONS Our results indicate that the effects of vitamin D on Cl-2 and Cl-4 are mediated by p-Stat-6 and Smad-7 signal, respectively. The study suggests that vitamin D administration to UC patients could be a useful therapeutic intervention, given that vitamin D deficiency is found in these patients.
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