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Clyne M, Ó Cróinín T. Pathogenicity and virulence of Helicobacter pylori: A paradigm of chronic infection. Virulence 2025; 16:2438735. [PMID: 39725863 DOI: 10.1080/21505594.2024.2438735] [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: 05/13/2024] [Revised: 11/18/2024] [Accepted: 12/02/2024] [Indexed: 12/28/2024] Open
Abstract
Infection with Helicobacter pylori is one of the most common infections of mankind. Infection typically occurs in childhood and persists for the lifetime of the host unless eradicated with antimicrobials. The organism colonizes the stomach and causes gastritis. Most infected individuals are asymptomatic, but infection also causes gastric and duodenal ulceration, and gastric cancer. H. pylori possesses an arsenal of virulence factors, including a potent urease enzyme for protection from acid, flagella that mediate motility, an abundance of outer membrane proteins that can mediate attachment, several immunomodulatory proteins, and an ability to adapt to specific conditions in individual human stomachs. The presence of a type 4 secretion system that injects effector molecules into gastric cells and subverts host cell signalling is associated with virulence. In this review we discuss the interplay of H. pylori colonization and virulence factors with host and environmental factors to determine disease outcome in infected individuals.
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Affiliation(s)
- Marguerite Clyne
- School of Medicine, University College Dublin, Dublin, Ireland
- The Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
| | - Tadhg Ó Cróinín
- The Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
- School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
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Huang CW, Liu SY, Bhattarai BP, Lee TY, Chang HT, Lin HC, Weng HM, Huang HH, Lin JS, Lee JW. Live Multi-Strain Probiotics Enhance Growth Performance by Regulating Intestinal Morphology and Microbiome Population in Weaning Piglets. Microorganisms 2024; 12:2334. [PMID: 39597723 PMCID: PMC11596860 DOI: 10.3390/microorganisms12112334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 11/12/2024] [Accepted: 11/14/2024] [Indexed: 11/29/2024] Open
Abstract
The effects of different forms of multi-strain probiotics on weaning piglets are limitedly addressed. Thus, this study investigated the effects of live or inanimate multi-strain probiotics comprising Lactobacillus plantarum, Streptococcus thermophilus, and Bacillus subtilis on growth performance, intestinal morphology, fecal microbiota, short-chain fatty acids, and intestinal gene expression of weaning piglets. A total of 160 weaning piglets (4 weeks old) were randomly allocated into four treatments (CON: basal diet; AB: basal diet with 110 ppm and 66 ppm colistin in the weaning and nursery phases, respectively; LP: basal diet with 2.0 × 109 CFU/kg live probiotics; and IP: basal diet with 2.0 × 109 CFU/kg inanimate probiotics). Piglets fed with LP had significantly lower FCR compared to those of the CON and IP groups in week 4 to week 8 (p < 0.05). Moreover, the LP group had significantly higher villus height (VH) compared with AB at week 6, lower crypt depth (CD) compared with IP, and higher VH/CD ratio compared to other treatments at week 10 (p < 0.05), which indicate healthier intestinal morphology. Probiotic treatments (LP and IP) increased Bifidobacterium population compared to CON at week 6 and lowered Enterobacteriaceae at week 6 and week 10 (p < 0.05). Regarding gene expressions of intestinal integrity, LP showed significantly higher TFF3 expression compared with CON and AB at week 6 and compared with other treatments in jejunum at week 10 (p < 0.05). IP treatment had significantly higher MUC2 expression compared to other treatments at week 6 and week 10 (p < 0.05). Overall, live multi-strain probiotics improved growth efficiency by enhancing gut integrity and microbiome balance, making them a potential antibiotic alternative to ameliorate weaning stress and promote productive performance in weaning piglets.
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Affiliation(s)
- Chao-Wei Huang
- Department of Tropical Agriculture and International Cooperation, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan; (C.-W.H.); (S.-Y.L.); (B.P.B.)
| | - Shi-Yong Liu
- Department of Tropical Agriculture and International Cooperation, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan; (C.-W.H.); (S.-Y.L.); (B.P.B.)
| | - Bishnu Prasad Bhattarai
- Department of Tropical Agriculture and International Cooperation, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan; (C.-W.H.); (S.-Y.L.); (B.P.B.)
| | - Ting-Yu Lee
- SYNBIO TECH Inc., Kaohsiung 821011, Taiwan; (T.-Y.L.); (H.-T.C.); (H.-C.L.); (H.-M.W.); (H.-H.H.); (J.-S.L.)
| | - Hsiao-Tung Chang
- SYNBIO TECH Inc., Kaohsiung 821011, Taiwan; (T.-Y.L.); (H.-T.C.); (H.-C.L.); (H.-M.W.); (H.-H.H.); (J.-S.L.)
| | - Hsiao-Ching Lin
- SYNBIO TECH Inc., Kaohsiung 821011, Taiwan; (T.-Y.L.); (H.-T.C.); (H.-C.L.); (H.-M.W.); (H.-H.H.); (J.-S.L.)
| | - Hsiu-Ming Weng
- SYNBIO TECH Inc., Kaohsiung 821011, Taiwan; (T.-Y.L.); (H.-T.C.); (H.-C.L.); (H.-M.W.); (H.-H.H.); (J.-S.L.)
| | - Hsin-Hsuan Huang
- SYNBIO TECH Inc., Kaohsiung 821011, Taiwan; (T.-Y.L.); (H.-T.C.); (H.-C.L.); (H.-M.W.); (H.-H.H.); (J.-S.L.)
| | - Jin-Seng Lin
- SYNBIO TECH Inc., Kaohsiung 821011, Taiwan; (T.-Y.L.); (H.-T.C.); (H.-C.L.); (H.-M.W.); (H.-H.H.); (J.-S.L.)
| | - Jai-Wei Lee
- Department of Tropical Agriculture and International Cooperation, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan; (C.-W.H.); (S.-Y.L.); (B.P.B.)
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Peiffer AL, Dugan AE, Kiessling LL. Soluble Human Lectins at the Host-Microbe Interface. Annu Rev Biochem 2024; 93:565-601. [PMID: 38640018 PMCID: PMC11296910 DOI: 10.1146/annurev-biochem-062917-012322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/21/2024]
Abstract
Human lectins are integral to maintaining microbial homeostasis on the skin, in the blood, and at mucosal barriers. These proteins can recognize microbial glycans and inform the host about its microbial status. In accordance with their roles, their production can vary with tissue type. They also can have unique structural and biochemical properties, and they can influence microbial colonization at sites proximal and distal to their tissue of origin. In line with their classification as innate immune proteins, soluble lectins have long been studied in the context of acute infectious disease, but only recently have we begun to appreciate their roles in maintaining commensal microbial communities (i.e., the human microbiota). This review provides an overview of soluble lectins that operate at host-microbe interfaces, their glycan recognition properties, and their roles in physiological and pathological mechanisms.
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Affiliation(s)
- Amanda L Peiffer
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA;
| | - A E Dugan
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA;
| | - L L Kiessling
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA;
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Yamaguchi J, Kokuryo T, Yokoyama Y, Oishi S, Sunagawa M, Mizuno T, Onoe S, Watanabe N, Ogura A, Ebata T. Trefoil factor 1 suppresses stemness and enhances chemosensitivity of pancreatic cancer. Cancer Med 2024; 13:e7395. [PMID: 38872370 PMCID: PMC11176577 DOI: 10.1002/cam4.7395] [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: 11/12/2023] [Revised: 05/30/2024] [Accepted: 06/06/2024] [Indexed: 06/15/2024] Open
Abstract
BACKGROUND AND AIMS Pancreatic cancer is one of the most lethal malignancies, partly due to resistance to conventional chemotherapy. The chemoresistance of malignant tumors is associated with epithelial-mesenchymal transition (EMT) and the stemness of cancer cells. The aim of this study is to investigate the availability and functional mechanisms of trefoil factor family 1 (TFF1), a tumor-suppressive protein in pancreatic carcinogenesis, to treat pancreatic cancer. METHODS To investigate the role of endogenous TFF1 in human and mice, specimens of human pancreatic cancer and genetically engineered mouse model of pancreatic cancer (KPC/TFF1KO; Pdx1-Cre/LSL-KRASG12D/LSL-p53R172H/TFF1-/-) were analyzed by immunohistochemistry (IHC). To explore the efficacy of extracellular administration of TFF1, recombinant and chemically synthesized TFF1 were administered to pancreatic cancer cell lines, a xenograft mouse model and a transgenic mouse model. RESULTS The deficiency of TFF1 was associated with increased EMT of cancer cells in mouse models of pancreatic cancer, KPC. The expression of TFF1 in cancer cells was associated with better survival rate of the patients who underwent chemotherapy, and loss of TFF1 deteriorated the benefit of gemcitabine in KPC mice. Extracellular administration of TFF1 inhibited gemcitabine-induced EMT, Wnt pathway activation and cancer stemness, eventually increased apoptosis of pancreatic cancer cells in vitro. In vivo, combined treatment of gemcitabine and subcutaneous administration of TFF1 arrested tumor growth in xenograft mouse model and resulted in the better survival of KPC mice by inhibiting EMT and cancer stemness. CONCLUSION These results indicate that TFF1 can contribute to establishing a novel strategy to treat pancreatic cancer patients by enhancing chemosensitivity.
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Affiliation(s)
- Junpei Yamaguchi
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Toshio Kokuryo
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yukihiro Yokoyama
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shunsuke Oishi
- Institute of Transformative Bio-Molecules, Nagoya University, Nagoya, Japan
| | - Masaki Sunagawa
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takashi Mizuno
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shunsuke Onoe
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Nobuyuki Watanabe
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Atsushi Ogura
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tomoki Ebata
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Yu S, Xie J, Guo Q, Yan X, Wang Y, Leng T, Li L, Zhou J, Zhang W, Su X. Clostridium butyricum isolated from giant panda can attenuate dextran sodium sulfate-induced colitis in mice. Front Microbiol 2024; 15:1361945. [PMID: 38646621 PMCID: PMC11027743 DOI: 10.3389/fmicb.2024.1361945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 03/14/2024] [Indexed: 04/23/2024] Open
Abstract
Objective Probiotics are beneficial to the intestinal barrier, but few studies have investigated probiotics from giant pandas. This study aims to explore the preventive effects of giant panda-derived Clostridium butyricum on dextran sodium sulfate (DSS)-induced colitis in mice. Methods Clostridium butyricum was administered to mice 14 days before administering DSS treatment to induce enteritis. Results Clostridium butyricum B14 could more effectively prevent colitis in mice than C. butyricum B13. C. butyricum B14 protected the mouse colon by decreasing the histology index and serum interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels, which improved intestinal inflammation-related symptoms. In addition, the treatment led to the regulation of the expression of Tifa, Igkv12-89, and Nr1d1, which in turn inhibited immune pathways. The expression of Muc4, Lama3, Cldn4, Cldn3, Ocln, Zo1, Zo2, and Snai is related the intestinal mucosal barrier. 16S sequencing shows that the C. butyricum B14 significantly increased the abundance of certain intestinal probiotics. Overall, C. butyricum B14 exerted a preventive effect on colitis in mice by inhibiting immune responses, enhancing the intestinal barrier and increasing the abundance of probiotic species. Thus, C. butyricum B14 administration helps regulate the balance of the intestinal microecology. It can suppress immune pathways and enhance barrier-protective proteins.
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Affiliation(s)
- Shuran Yu
- College of Life Science, Southwest Forestry University, Kunming, China
- Sichuan Key Laboratory of Conservation Biology for Endangered Wildlife, Chengdu Research Base of Giant Panda Breeding, Chengdu, China
- College of Life Science and Biotechnology, Mianyang Normal University, Mianyang, China
| | - Junjin Xie
- Sichuan Key Laboratory of Conservation Biology for Endangered Wildlife, Chengdu Research Base of Giant Panda Breeding, Chengdu, China
| | - Qiang Guo
- College of Biodiversity Conservation, Southwest Forestry University, Kunming, China
| | - Xia Yan
- Sichuan Key Laboratory of Conservation Biology for Endangered Wildlife, Chengdu Research Base of Giant Panda Breeding, Chengdu, China
| | - Yuxiang Wang
- College of Life Science, Southwest Forestry University, Kunming, China
| | - Tangjian Leng
- College of Life Science, Southwest Forestry University, Kunming, China
| | - Lin Li
- Sichuan Key Laboratory of Conservation Biology for Endangered Wildlife, Chengdu Research Base of Giant Panda Breeding, Chengdu, China
| | - Jielong Zhou
- College of Life Science, Southwest Forestry University, Kunming, China
| | - Wenping Zhang
- College of Life Science and Biotechnology, Mianyang Normal University, Mianyang, China
| | - Xiaoyan Su
- Sichuan Key Laboratory of Conservation Biology for Endangered Wildlife, Chengdu Research Base of Giant Panda Breeding, Chengdu, China
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Childs CJ, Holloway EM, Sweet CW, Tsai YH, Wu A, Vallie A, Eiken MK, Capeling MM, Zwick RK, Palikuqi B, Trentesaux C, Wu JH, Pellón-Cardenas O, Zhang CJ, Glass I, Loebel C, Yu Q, Camp JG, Sexton JZ, Klein OD, Verzi MP, Spence JR. EPIREGULIN creates a developmental niche for spatially organized human intestinal enteroids. JCI Insight 2023; 8:e165566. [PMID: 36821371 PMCID: PMC10070114 DOI: 10.1172/jci.insight.165566] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 02/07/2023] [Indexed: 02/24/2023] Open
Abstract
Epithelial organoids derived from intestinal tissue, called enteroids, recapitulate many aspects of the organ in vitro and can be used for biological discovery, personalized medicine, and drug development. Here, we interrogated the cell signaling environment within the developing human intestine to identify niche cues that may be important for epithelial development and homeostasis. We identified an EGF family member, EPIREGULIN (EREG), which is robustly expressed in the developing human crypt. Enteroids generated from the developing human intestine grown in standard culture conditions, which contain EGF, are dominated by stem and progenitor cells and feature little differentiation and no spatial organization. Our results demonstrate that EREG can replace EGF in vitro, and EREG leads to spatially resolved enteroids that feature budded and proliferative crypt domains and a differentiated villus-like central lumen. Multiomic (transcriptome plus epigenome) profiling of native crypts, EGF-grown enteroids, and EREG-grown enteroids showed that EGF enteroids have an altered chromatin landscape that is dependent on EGF concentration, downregulate the master intestinal transcription factor CDX2, and ectopically express stomach genes, a phenomenon that is reversible. This is in contrast to EREG-grown enteroids, which remain intestine like in culture. Thus, EREG creates a homeostatic intestinal niche in vitro, enabling interrogation of stem cell function, cellular differentiation, and disease modeling.
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Affiliation(s)
- Charlie J. Childs
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
| | - Emily M. Holloway
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Caden W. Sweet
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, and
| | - Yu-Hwai Tsai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, and
| | - Angeline Wu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, and
| | - Abigail Vallie
- Graduate Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Madeline K. Eiken
- Department of Biomedical Engineering, University of Michigan Medical School and University of Michigan College of Engineering, Ann Arbor, Michigan, USA
| | - Meghan M. Capeling
- Department of Biomedical Engineering, University of Michigan Medical School and University of Michigan College of Engineering, Ann Arbor, Michigan, USA
| | - Rachel K. Zwick
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, San Francisco, California, USA
| | - Brisa Palikuqi
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, San Francisco, California, USA
| | - Coralie Trentesaux
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, San Francisco, California, USA
| | - Joshua H. Wu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, and
| | - Oscar Pellón-Cardenas
- New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
| | - Charles J. Zhang
- Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Ian Glass
- Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA
| | - Claudia Loebel
- Department of Biomedical Engineering, University of Michigan Medical School and University of Michigan College of Engineering, Ann Arbor, Michigan, USA
- Department of Materials Science and Engineering, University of Michigan College of Engineering, Ann Arbor, Michigan, USA
| | - Qianhui Yu
- Roche Institute for Translational Bioengineering (ITB), Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
- Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland
| | - J. Gray Camp
- Roche Institute for Translational Bioengineering (ITB), Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
- Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland
| | - Jonathan Z. Sexton
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, and
- Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Ophir D. Klein
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, San Francisco, California, USA
| | - Michael P. Verzi
- New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
| | - Jason R. Spence
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, and
- Graduate Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA
- Department of Biomedical Engineering, University of Michigan Medical School and University of Michigan College of Engineering, Ann Arbor, Michigan, USA
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Qu H, Zong Q, Wang H, Wu S, Cai D, Bao W. C/EBPα Epigenetically Modulates TFF1 Expression via mC-6 Methylation in the Jejunum Inflammation Induced by a Porcine Coronavirus. Front Immunol 2022; 13:881289. [PMID: 35693767 PMCID: PMC9174463 DOI: 10.3389/fimmu.2022.881289] [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: 03/23/2022] [Accepted: 04/26/2022] [Indexed: 11/20/2022] Open
Abstract
Porcine epidemic diarrhea virus (PEDV) is an emerging coronavirus which causes acute diarrhea and destroys gastrointestinal barrier function in neonatal pigs. Trefoil factor 1 (TFF1) is a protective peptide for maintaining the integrity of gastrointestinal mucosa and reducing intestinal inflammation. However, its role in protecting intestinal epithelium against PEDV infection is still unclear. In this study, we discovered that TFF1 expression was activated in the jejunum of pigs with PEDV infection and TFF1 is required for the growth of porcine intestinal epithelial cells. For instance, inhibited cell proliferation and cell arrest were observed when TFF1 is genetically knocked-out using CRISPR-Cas9. Additionally, TFF1 depletion increased viral copy number and PEDV titer, along with the elevated genes involved in antiviral and inflammatory cytokines. The decreased TFF1 mRNA expression is in line with hypermethylation on the gene promoter. Notably, the strong interactions of protein-DNA complexes containing CCAAT motif significantly increased C/EBPα accessibility, whereas hypermethylation of mC-6 loci decreased C/EBPα binding occupancies in TFF1 promoter. Overall, our findings show that PEDV triggers the C/EBPα-mediated epigenetic regulation of TFF1 in intestine epithelium and facilitates host resistance to PEDV and other Coronavirus infections.
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Affiliation(s)
- Huan Qu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Qiufang Zong
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Haifei Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety, Yangzhou University, Yangzhou, China
| | - Shenglong Wu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety, Yangzhou University, Yangzhou, China
| | - Demin Cai
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety, Yangzhou University, Yangzhou, China
| | - Wenbin Bao
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety, Yangzhou University, Yangzhou, China
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Yoo CY, Son HU, Kim SK, Kim SO, Lee SH. Improved Image Analysis for Measuring Gastric Ulcer Index in Animal Models and Clinical Diagnostic Data. Diagnostics (Basel) 2022; 12:1233. [PMID: 35626388 PMCID: PMC9139872 DOI: 10.3390/diagnostics12051233] [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: 04/25/2022] [Accepted: 05/11/2022] [Indexed: 02/05/2023] Open
Abstract
Gastric ulcers are one of the most common gastrointestinal diseases. In this study, as an attempt to reduce the minimal error in clinical observations during the diagnosis of gastric ulcers, the applicability of improved ImageJ analysis (IA) was investigated by comparing the results of animal experiments and clinical data. As a result, IA exhibited a significantly improved potential for determining the ulcer index (UI) of clinical data sheets compared to those rated directly by conventional clinical observation (CCO). This indicated that IA enhanced the reproducibility of the measurement of gastric UI using a Bland-Altman plot, resulting in a reduced deviation of each UI value. In addition, it was confirmed that errors in gastric UI decisions can be reduced by adjusting RGB values in diagnostic clinical data (i.e., adjusting to 100 is relatively better than adjusting to 50 or 200). Together, these results suggest that the new enhanced IA could be compatible with novel applications for measuring and evaluating gastric ulcers in clinical settings, meaning that the developed method could be used not only as an auxiliary tool for CCO, but also as a pipeline for ulcer diagnosis.
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Affiliation(s)
- Chi-Yeol Yoo
- Department of Food Science and Biotechnology, Graduate School of Kyungpook National University, Daegu 41566, Korea; (C.-Y.Y.); (H.-U.S.)
| | - Hyeong-U Son
- Department of Food Science and Biotechnology, Graduate School of Kyungpook National University, Daegu 41566, Korea; (C.-Y.Y.); (H.-U.S.)
| | - Sung-kook Kim
- Department of Gastroenterology & Hepatology, Kyungpook National University Hospital, Daegu 41944, Korea;
| | - Si-Oh Kim
- Department of Anesthesiology, Kyungpook National University Chilgok Hospital, Daegu 41404, Korea;
| | - Sang-Han Lee
- Department of Food Science and Biotechnology, Graduate School of Kyungpook National University, Daegu 41566, Korea; (C.-Y.Y.); (H.-U.S.)
- Department of Gastroenterology & Hepatology, Kyungpook National University Hospital, Daegu 41944, Korea;
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9
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Kang Y, Park H, Choe BH, Kang B. The Role and Function of Mucins and Its Relationship to Inflammatory Bowel Disease. Front Med (Lausanne) 2022; 9:848344. [PMID: 35602503 PMCID: PMC9120656 DOI: 10.3389/fmed.2022.848344] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 04/15/2022] [Indexed: 02/06/2023] Open
Abstract
Mucus is present throughout the gastrointestinal tract and is essential for regulating gut microbiota homeostasis and preventing disease by protecting the gastrointestinal barrier from microorganisms, pathogens and toxins or other irritants. Mucin (MUC)-2 is a secreted protein produced by epithelial goblet cells as the main component of mucus. Defects in the gastrointestinal tract, such as inflammation and ulcers, cause damage to the mucus barrier, which can worsen mucus quality and reduce mucus production. Therefore, we would like to review the characteristics of MUC2 and its role in intestinal disorders and highlight the importance of further studies. We also investigated whether the role of MUC2 differs between children and adults, ulcerative colitis (UC) and Crohn's disease (CD).
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Affiliation(s)
- Youra Kang
- Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Hyeonjeong Park
- Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Byung-Ho Choe
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Ben Kang
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, South Korea
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10
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Yang Y, Lin Z, Lin Q, Bei W, Guo J. Pathological and therapeutic roles of bioactive peptide trefoil factor 3 in diverse diseases: recent progress and perspective. Cell Death Dis 2022; 13:62. [PMID: 35039476 PMCID: PMC8763889 DOI: 10.1038/s41419-022-04504-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 12/23/2021] [Accepted: 12/30/2021] [Indexed: 12/16/2022]
Abstract
Trefoil factor 3 (TFF3) is the last small-molecule peptide found in the trefoil factor family, which is mainly secreted by intestinal goblet cells and exerts mucosal repair effect in the gastrointestinal tract. Emerging evidence indicated that the TFF3 expression profile and biological effects changed significantly in pathological states such as cancer, colitis, gastric ulcer, diabetes mellitus, non-alcoholic fatty liver disease, and nervous system disease. More importantly, mucosal protection would no longer be the only effect of TFF3, it gradually exhibits carcinogenic activity and potential regulatory effect of nervous and endocrine systems, but the inner mechanisms remain unclear. Understanding the molecular function of TFF3 in specific diseases might provide a new insight for the clinical development of novel therapeutic strategies. This review provides an up-to-date overview of the pathological effects of TFF3 in different disease and discusses the binding proteins, signaling pathways, and clinical application.
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Affiliation(s)
- Yiqi Yang
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Science and Technology Building, 280 Waihuan East Road, Guangzhou Higher Education Mega, Guangzhou, China
| | - Ziyang Lin
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Science and Technology Building, 280 Waihuan East Road, Guangzhou Higher Education Mega, Guangzhou, China
| | - Quanyou Lin
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Science and Technology Building, 280 Waihuan East Road, Guangzhou Higher Education Mega, Guangzhou, China
| | - Weijian Bei
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Science and Technology Building, 280 Waihuan East Road, Guangzhou Higher Education Mega, Guangzhou, China
| | - Jiao Guo
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Science and Technology Building, 280 Waihuan East Road, Guangzhou Higher Education Mega, Guangzhou, China.
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11
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Sugiyama M, Machida N, Yasunaga A, Terai N, Fukasawa H, Ono HK, Kobayashi R, Nishiyama K, Hashimoto O, Kurusu S, Yoshioka K. Vaginal mucus in mice: developmental and gene expression features of epithelial mucous cells during pregnancy†. Biol Reprod 2021; 105:1272-1282. [PMID: 34416757 DOI: 10.1093/biolre/ioab157] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 07/12/2021] [Accepted: 08/16/2021] [Indexed: 01/18/2023] Open
Abstract
The vagina is the site of copulation and serves as the birth canal. It also provides protection against external pathogens. In mice, due to the absence of cervical glands, the vaginal epithelium is the main producer of vaginal mucus. The development and differentiation of vaginal epithelium-constituting cells and the molecular characteristics of vaginal mucus have not been thoroughly examined. Here, we characterized vaginal mucous cell development and the expression of mucus-related factors in pregnant mice. The vaginal mucous epithelium layer thickened and became multilayered after Day 12 of pregnancy and secreted increasing amounts of mucus until early postpartum. Using histochemistry and transmission electron microscopy, we found supra-basal mucous cells as probable candidates for precursor cells. In vaginal mucous cells, the expression of TFF1, a stabilizer of mucus, was high, and some members of mucins and antimicrobial peptides (MUC5B and DEFB1) were expressed in a stage-dependent manner. In summary, this study presents the partial characterization of vaginal epithelial mucous cell lineage and expression of genes encoding several peptide substances that may affect vaginal tissue homeostasis and mucosal immunity during pregnancy and parturition.
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Affiliation(s)
- Makoto Sugiyama
- Faculty of Veterinary Medicine, Kitasato University School of Veterinary Medicine, Towada, Japan
| | - Nao Machida
- Faculty of Veterinary Medicine, Kitasato University School of Veterinary Medicine, Towada, Japan
| | - Arata Yasunaga
- Faculty of Veterinary Medicine, Kitasato University School of Veterinary Medicine, Towada, Japan.,Department of Animal Science, Kitasato University School of Veterinary Medicine, Towada, Japan
| | - Nanako Terai
- Faculty of Veterinary Medicine, Kitasato University School of Veterinary Medicine, Towada, Japan
| | - Hanae Fukasawa
- Faculty of Veterinary Medicine, Kitasato University School of Veterinary Medicine, Towada, Japan
| | - Hisaya K Ono
- Faculty of Veterinary Medicine, Kitasato University School of Veterinary Medicine, Towada, Japan
| | - Ryosuke Kobayashi
- Laboratory of Genome Science, Biological Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Keita Nishiyama
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
| | - Osamu Hashimoto
- Faculty of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama, Japan
| | - Shiro Kurusu
- Faculty of Veterinary Medicine, Kitasato University School of Veterinary Medicine, Towada, Japan
| | - Kazuki Yoshioka
- Faculty of Veterinary Medicine, Kitasato University School of Veterinary Medicine, Towada, Japan
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12
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Adewale B, Heintz JR, Pastore CF, Rossi HL, Hung LY, Rahman N, Bethony J, Diemert D, Babatunde JA, Herbert DR. Parasitic helminth infections in humans modulate Trefoil Factor levels in a manner dependent on the species of parasite and age of the host. PLoS Negl Trop Dis 2021; 15:e0009550. [PMID: 34662329 PMCID: PMC8553090 DOI: 10.1371/journal.pntd.0009550] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 10/28/2021] [Accepted: 10/07/2021] [Indexed: 11/19/2022] Open
Abstract
Helminth infections, including hookworms and Schistosomes, can cause severe disability and death. Infection management and control would benefit from identification of biomarkers for early detection and prognosis. While animal models suggest that Trefoil Factor Family proteins (TFF2 and TFF3) and interleukin-33 (IL-33) -driven type 2 immune responses are critical mediators of tissue repair and worm clearance in the context of hookworm infection, very little is known about how they are modulated in the context of human helminth infection. We measured TFF2, TFF3, and IL-33 levels in serum from patients in Brazil infected with Hookworm and/or Schistosomes, and compared them to endemic and non-endemic controls. TFF2 was specifically elevated by Hookworm infection in females, not Schistosoma or co-infection. This elevation was correlated with age, but not worm burden. TFF3 was elevated by Schistosoma infection and found to be generally higher in females. IL-33 was not significantly altered by infection. To determine if this might apply more broadly to other species or regions, we measured TFFs and cytokine levels (IFNγ, TNFα, IL-33, IL-13, IL-1β, IL-17A, IL-22, and IL-10) in both the serum and urine of Nigerian school children infected with S. haematobium. We found that serum levels of TFF2 and 3 were reduced by infection, likely in an age dependent manner. In the serum, only IL-10 and IL-13 were significantly increased, while in urine IFN-γ, TNF-α, IL-13, IL-1β, IL-22, and IL-10 were significantly increased in by infection. Taken together, these data support a role for TFF proteins in human helminth infection. Billions of people are infected with parasitic helminths across the globe, especially in resource poor regions. These infections can result in severe developmental delay, disability, and death. Adequate management of helminth infection would benefit from the identification of host biomarkers in easily obtained samples (e.g. serum or urine) that correlate to infection state. Our goal was to determine if specific proteins involved in tissue repair and immune modulation are altered by infection with specific helminth species in Brazil (hookworm and S. mansoni species of blood fluke) or Nigeria (S. haematobium species of blood fluke). One of these proteins, Trefoil Factor 2 (TFF2), was elevated in the serum of hookworm infected women from Brazil, while another, TFF3 is higher in women than men, but also increased by S. mansoni blood fluke infection. In contrast, both TFFs were decreased in the serum of Nigerian children infected by S. haematobium, while many pro-inflammatory cytokines were increased in the urine, where the eggs emerge from host tissue.
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Affiliation(s)
- Babatunde Adewale
- Public Health Department, Nigerian Institute of Medical Research, Yaba, Lagos, Nigeria
| | - Jonathan R. Heintz
- University of Pennsylvania, Perlman School of Medicine Biostatistics Analysis Center, Philadelphia, Pennsylvania, United States of America
| | - Christopher F. Pastore
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States of Amerca
| | - Heather L. Rossi
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States of Amerca
| | - Li-Yin Hung
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States of Amerca
- Department of Medicine, Division of Experimental Medicine, University of California, San Francisco, San Francisco, California, United States of Amerca
| | - Nurudeen Rahman
- Public Health Department, Nigerian Institute of Medical Research, Yaba, Lagos, Nigeria
| | - Jeff Bethony
- Department of Microbiology, Immunology & Tropical Medicine, George Washington University Medical Center, Washington, District of Columbia, United States of Amerca
| | - David Diemert
- Department of Microbiology, Immunology & Tropical Medicine, George Washington University Medical Center, Washington, District of Columbia, United States of Amerca
| | - James Ayorinde Babatunde
- Department of Biochemistry & Nutrition, Nigerian Institute of Medical Research, Yaba, Lagos, Nigeria
| | - De’Broski R. Herbert
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States of Amerca
- Department of Medicine, Division of Experimental Medicine, University of California, San Francisco, San Francisco, California, United States of Amerca
- * E-mail:
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13
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Ray P, Nancarrow DJ, Ferrer-Torres D, Wang Z, San Martinho M, Hinton T, Wu JH, Wu A, Turgeon DK, Hammer MA, Dame MK, Lawrence TS, O'Brien PJ, Spence JR, Beer DG, Ray D. UBCH5 Family Members Differentially Impact Stabilization of Mutant p53 via RNF128 Iso1 During Barrett's Progression to Esophageal Adenocarcinoma. Cell Mol Gastroenterol Hepatol 2021; 13:129-149. [PMID: 34416429 PMCID: PMC8593620 DOI: 10.1016/j.jcmgh.2021.08.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 08/05/2021] [Accepted: 08/10/2021] [Indexed: 12/10/2022]
Abstract
BACKGROUND & AIMS TP53 mutations underlie Barrett's esophagus (BE) progression to dysplasia and cancer. During BE progression, the ubiquitin ligase (E3) RNF128/GRAIL switches expression from isoform 2 (Iso2) to Iso1, stabilizing mutant p53. However, the ubiquitin-conjugating enzyme (E2) that partners with Iso1 to stabilize mutant p53 is unknown. METHODS Single-cell RNA sequencing of paired normal esophagus and BE tissues identified candidate E2s, further investigated in expression data from BE to esophageal adenocarcinoma (EAC) progression samples. Biochemical and cellular studies helped clarify the role of RNF128-E2 on mutant p53 stability. RESULTS The UBE2D family member 2D3 (UBCH5C) is the most abundant E2 in normal esophagus. However, during BE to EAC progression, loss of UBE2D3 copy number and reduced expression of RNF128 Iso2 were noted, 2 known p53 degraders. In contrast, expression of UBE2D1 (UBCH5A) and RNF128 Iso1 in dysplastic BE and EAC forms an inactive E2-E3 complex, stabilizing mutant p53. To destabilize mutant p53, we targeted RNF128 Iso1 either by mutating asparagine (N48, 59, and 101) residues to block glycosylation to facilitate β-TrCP1-mediated degradation or by mutating proline (P54 and 105) residues to restore p53 polyubiquitinating ability. In addition, either loss of UBCH5A catalytic activity, or disruption of the Iso1-UBCH5A interaction promoted Iso1 loss. Consequently, overexpression of either catalytically dead or Iso1-binding-deficient UBCH5A mutants destabilized Iso1 to degrade mutant p53, thus compromising the clonogenic survival of mutant p53-dependent BE cells. CONCLUSIONS Loss of RNF128 Iso2-UBCH5C and persistence of the Iso1-UBCH5A complex favors mutant p53 stability to promote BE cell survival. Therefore, targeting of Iso1-UBCH5A may provide a novel therapeutic strategy to prevent BE progression.
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Affiliation(s)
- Paramita Ray
- Department of Radiation Oncology, Ann Arbor, Michigan
| | | | | | | | | | - Tonaye Hinton
- Department of Radiation Oncology, Ann Arbor, Michigan
| | - Joshua H Wu
- Department of Internal Medicine, Ann Arbor, Michigan
| | - Angeline Wu
- Department of Internal Medicine, Ann Arbor, Michigan
| | | | - Max A Hammer
- Department of Internal Medicine, Ann Arbor, Michigan
| | | | | | | | - Jason R Spence
- Department of Internal Medicine, Ann Arbor, Michigan; Department of Cell and Developmental Biology, Ann Arbor, Michigan; Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - David G Beer
- Department of Radiation Oncology, Ann Arbor, Michigan; Department of Surgery, Ann Arbor, Michigan
| | - Dipankar Ray
- Department of Radiation Oncology, Ann Arbor, Michigan.
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14
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Braga Emidio N, Meli R, Tran HNT, Baik H, Morisset-Lopez S, Elliott AG, Blaskovich MAT, Spiller S, Beck-Sickinger AG, Schroeder CI, Muttenthaler M. Chemical Synthesis of TFF3 Reveals Novel Mechanistic Insights and a Gut-Stable Metabolite. J Med Chem 2021; 64:9484-9495. [PMID: 34142550 PMCID: PMC8273887 DOI: 10.1021/acs.jmedchem.1c00767] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Indexed: 01/07/2023]
Abstract
TFF3 regulates essential gastro- and neuroprotective functions, but its molecular mode of action remains poorly understood. Synthetic intractability and lack of reliable bioassays and validated receptors are bottlenecks for mechanistic and structure-activity relationship studies. Here, we report the chemical synthesis of TFF3 and its homodimer via native chemical ligation followed by oxidative folding. Correct folding was confirmed by NMR and circular dichroism, and TFF3 and its homodimer were not cytotoxic or hemolytic. TFF3, its homodimer, and the trefoil domain (TFF310-50) were susceptible to gastrointestinal degradation, revealing a gut-stable metabolite (TFF37-54; t1/2 > 24 h) that retained its trefoil structure and antiapoptotic bioactivity. We tried to validate the putative TFF3 receptors CXCR4 and LINGO2, but neither TFF3 nor its homodimer displayed any activity up to 10 μM. The discovery of a gut-stable bioactive metabolite and reliable synthetic accessibility to TFF3 and its analogues are cornerstones for future molecular probe development and structure-activity relationship studies.
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Affiliation(s)
- Nayara Braga Emidio
- Institute
for Molecular Bioscience, The University
of Queensland, Brisbane, QLD 4072, Australia
| | - Rajeshwari Meli
- Institute
of Biological Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria
| | - Hue N. T. Tran
- Institute
for Molecular Bioscience, The University
of Queensland, Brisbane, QLD 4072, Australia
| | - Hayeon Baik
- Institute
of Biological Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria
| | - Séverine Morisset-Lopez
- Centre
de Biophysique Moléculaire, CNRS, Unité Propre de Recherche
4301, Université d’Orléans, Orleans 45071, France
| | - Alysha G. Elliott
- Institute
for Molecular Bioscience, The University
of Queensland, Brisbane, QLD 4072, Australia
| | - Mark A. T. Blaskovich
- Institute
for Molecular Bioscience, The University
of Queensland, Brisbane, QLD 4072, Australia
| | - Sabrina Spiller
- Institute
of Biochemistry, Faculty of Life Sciences, Leipzig University, Leipzig 04103, Germany
| | | | - Christina I. Schroeder
- Institute
for Molecular Bioscience, The University
of Queensland, Brisbane, QLD 4072, Australia
- Center
for Cancer Research, National Cancer Institute,
National Institutes of Health, Frederick, Maryland 21702, United States
| | - Markus Muttenthaler
- Institute
for Molecular Bioscience, The University
of Queensland, Brisbane, QLD 4072, Australia
- Institute
of Biological Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria
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15
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Zullo KM, Douglas B, Maloney NM, Ji Y, Wei Y, Herbine K, Cohen R, Pastore C, Cramer Z, Wang X, Wei W, Somsouk M, Hung LY, Lengner C, Kohanski MH, Cohen NA, Herbert DR. LINGO3 regulates mucosal tissue regeneration and promotes TFF2 dependent recovery from colitis. Scand J Gastroenterol 2021; 56:791-805. [PMID: 33941035 PMCID: PMC8647134 DOI: 10.1080/00365521.2021.1917650] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Aim: Recovery of damaged mucosal surfaces following inflammatory insult requires diverse regenerative mechanisms that remain poorly defined. Previously, we demonstrated that the reparative actions of Trefoil Factor 3 (TFF3) depend upon the enigmatic receptor, leucine rich repeat and immunoglobulin-like domain containing nogo receptor 2 (LINGO2). This study examined the related orphan receptor LINGO3 in the context of intestinal tissue damage to determine whether LINGO family members are generally important for mucosal wound healing and maintenance of the intestinal stem cell (ISC) compartment needed for turnover of mucosal epithelium.Methods and Results: We find that LINGO3 is broadly expressed on human enterocytes and sparsely on discrete cells within the crypt niche, that contains ISCs. Loss of function studies indicate that LINGO3 is involved in recovery of normal intestinal architecture following dextran sodium sulfate (DSS)-induced colitis, and that LINGO3 is needed for therapeutic action of the long acting TFF2 fusion protein (TFF2-Fc), including a number of signaling pathways critical for cell proliferation and wound repair. LINGO3-TFF2 protein-protein interactions were relatively weak however and LINGO3 was only partially responsible for TFF2 induced MAPK signaling suggesting additional un-identified components of a receptor complex. However, deficiency in either TFF2 or LINGO3 abrogated budding/growth of intestinal organoids and reduced expression of the intestinal ISC gene leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), indicating homologous roles for these proteins in tissue regeneration, possibly via regulation of ISCs in the crypt niche.Conclusion: We propose that LINGO3 serves a previously unappreciated role in promoting mucosal wound healing.
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Affiliation(s)
- Kelly M. Zullo
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
| | - Bonnie Douglas
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
| | - Nicole M. Maloney
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
| | - Yingbiao Ji
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
| | - Yun Wei
- Department of Medicine, Division of Experimental Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Karl Herbine
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
| | - Rachel Cohen
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
| | - Christopher Pastore
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
| | - Zvi Cramer
- Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
| | - Xin Wang
- Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
| | - Wenjie Wei
- Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19147
| | - Ma Somsouk
- Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Li Yin Hung
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104,Department of Medicine, Division of Experimental Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Christopher Lengner
- Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
| | - Michael H. Kohanski
- Department of Otorhinolaryngology—Head and Neck Surgery, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104,The Corporal Michael J. Crescenz VA Medical Center Surgical Service, Philadelphia, PA 19104
| | - Noam A. Cohen
- Department of Otorhinolaryngology—Head and Neck Surgery, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104,The Corporal Michael J. Crescenz VA Medical Center Surgical Service, Philadelphia, PA 19104,Monell Chemical Senses Center, Philadelphia, PA 19104
| | - De’Broski R. Herbert
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104,Department of Medicine, Division of Experimental Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
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16
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Lee DY, Song MY, Kim EH. Trefoil Factor 1 Suppresses Epithelial-mesenchymal Transition through Inhibition of TGF-beta Signaling in Gastric Cancer Cells. J Cancer Prev 2021; 26:137-144. [PMID: 34258252 PMCID: PMC8249209 DOI: 10.15430/jcp.2021.26.2.137] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/19/2021] [Accepted: 06/21/2021] [Indexed: 01/22/2023] Open
Abstract
Gastric cancer is a malignancy with high incidence and mortality worldwide. In gastric cancer, epithelial-mesenchymal transition (EMT) and metastasis further increase the mortality rate. Trefoil factor 1 (TFF1) has been reported as a protective factor in the gastric mucosa. In this study, TFF1 inhibited the migration and invasive capability of gastric cancer cells. Elevated TFF1 levels induced the expression of E-cadherin, the epithelial marker, and reduced the expression of N-cadherin, vimentin, Snail, Twist, Zinc finger E-box binding homeobox (ZEB) 1 and ZEB2, well-known repressors of E-cadherin expression. In addition, the expression of matrix metalloproteinase (MMP)-2, MMP-7 and MMP-9, which are major markers of cancer metastasis, was suppressed by TFF1. Upregulation of TFF1 inhibited TGF-β, a major signaling for EMT induction, and the phosphorylation of Smad2/3 activated by TGF-β in AGS cells. In conclusion, TFF1 inhibits EMT through suppression of TGF-β signaling in AGS cells, which might be used in therapeutic strategies for reducing metastatic potential and invasiveness of these cells.
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Affiliation(s)
- Da-Young Lee
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, Korea
| | - Moon-Young Song
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, Korea
| | - Eun-Hee Kim
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, Korea
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17
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Humulene Inhibits Acute Gastric Mucosal Injury by Enhancing Mucosal Integrity. Antioxidants (Basel) 2021; 10:antiox10050761. [PMID: 34064830 PMCID: PMC8150829 DOI: 10.3390/antiox10050761] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/30/2021] [Accepted: 05/07/2021] [Indexed: 12/17/2022] Open
Abstract
This study was designed to determine whether α-humulene, a major constituent in many plants used in fragrances, has a protective role against gastric injury in vivo and in vitro. A rat model of hydrochloric acid (HCl)/ethanol-induced gastritis and human mast cells (HMC-1) were used to investigate the mucosal protective effect of α-humulene. α-Humulene significantly inhibited gastric lesions in HCl/ethanol-induced acute gastritis and decreased gastric acid secretion pyloric ligation-induced gastric ulcers in vivo. In addition, α-humulene reduced the amount of reactive oxygen species and malondialdehyde through upregulation of prostaglandin E2 (PGE2) and superoxide dismutase (SOD). In HMC-1 cells, α-humulene decreased intracellular calcium and increased intracellular cyclic adenosine monophosphate (cAMP) levels, resulting in low histamine levels. α-Humulene also reduced the expression levels of cytokine genes such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF) by downregulating nuclear factor-κB (NF-κB) nuclear translocation. Finally, α-humulene upregulated the expression levels of mucin 5AC (Muc5ac), Muc6, trefoil factor 1 (Tff1), trefoil factor 2 (Tff2), and polymeric immunoglobulin receptor (pigr). α-Humulene may attenuate HCl/ethanol-induced gastritis by inhibiting histamine release and NF-κB activation and stimulating antioxidants and mucosal protective factors, particularly Muc5ac and Muc6. Therefore, these data suggest that α-humulene is a potential drug candidate for the treatment of stress-induced or alcoholic gastritis.
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18
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Zhou Y, Ji X, Chen J, Fu Y, Huang J, Guo R, Zhou J, Cen J, Zhang Q, Chu A, Huang Y, Xu C, Wang F. Short-chain fatty acid butyrate: A novel shield against chronic gastric ulcer. Exp Ther Med 2021; 21:329. [PMID: 33732302 PMCID: PMC7903393 DOI: 10.3892/etm.2021.9760] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Accepted: 12/14/2020] [Indexed: 01/16/2023] Open
Abstract
Butyrate is one of the most abundant short-chain fatty acids produced by intestinal bacteria. In the present study, the action of butyrate on chronic gastric mucosa lesions was investigated, as well as its underlying mechanism in mice. Male mice from the Institute of Cancer Research were randomly divided into three groups: Sham, model and butyrate groups. Butyrate was administered intragastrically for 7 days to butyrate group mice following the establishment of a gastric ulcer model. Hematoxylin and eosin staining, immunohistochemical analysis, enzyme-linked immunosorbent assay and quantitative polymerase chain reaction were used to determine the therapeutic effects and molecular mechanism of butyrate treatment. The findings demonstrated that butyrate induced a marked shift in superoxide dismutase and catalase activities, along with a decrease in malondialdehyde levels, thereby attenuating oxidative stress. Furthermore, butyrate decreased the levels of pro-inflammatory cytokines interleukin-1β, tumour necrosis factor-α and leukotriene B4, which helped combat inflammatory responses. Moreover, butyrate treatment exerted remarkable positive influences that mediate an increase in 6-keto-PGF-1α (a degradation product of prostacyclin), trefoil factor 2, MUC5AC and fibroblast growth factor-7 levels to promote gastric mucosal repair. The expression of specific receptor GPR109A for butyrate was upregulated, with no significant difference noted in the expression of GPR43 or GPR41. Overall, the present findings revealed that butyrate exerted therapeutic effects by upregulating mucosal repair factors and stimulating protective responses against oxidation and inflammation. GPR109A may be the key receptor for butyrate therapy.
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Affiliation(s)
- Yan Zhou
- Wenzhou Key Laboratory of Sanitary Microbiology, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Xiawei Ji
- Department of Pathophysiology, School of Basic Medical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Jiajing Chen
- Department of Pathophysiology, School of Basic Medical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Yaoyang Fu
- Department of Pathophysiology, School of Basic Medical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Juewei Huang
- Department of Pathophysiology, School of Basic Medical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Rui Guo
- Department of Pathophysiology, School of Basic Medical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Jinhui Zhou
- Department of Pathophysiology, School of Basic Medical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Jianke Cen
- Department of Pathophysiology, School of Basic Medical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Qihao Zhang
- Department of Pathophysiology, School of Basic Medical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Anne Chu
- Department of Pathophysiology, School of Basic Medical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Yingpeng Huang
- Department of General Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Changlong Xu
- Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Fangyan Wang
- Department of Pathophysiology, School of Basic Medical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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19
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Issaka Salia O, Mitchell DM. Bioinformatic analysis and functional predictions of selected regeneration-associated transcripts expressed by zebrafish microglia. BMC Genomics 2020; 21:870. [PMID: 33287696 PMCID: PMC7720500 DOI: 10.1186/s12864-020-07273-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Unlike mammals, zebrafish have a remarkable capacity to regenerate a variety of tissues, including central nervous system tissue. The function of macrophages in tissue regeneration is of great interest, as macrophages respond and participate in the landscape of events that occur following tissue injury in all vertebrate species examined. Understanding macrophage populations in regenerating tissue (such as in zebrafish) may inform strategies that aim to regenerate tissue in humans. We recently published an RNA-seq experiment that identified genes enriched in microglia/macrophages in regenerating zebrafish retinas. Interestingly, a small number of transcripts differentially expressed by retinal microglia/macrophages during retinal regeneration did not have predicted orthologs in human or mouse. We reasoned that at least some of these genes could be functionally important for tissue regeneration, but most of these genes have not been studied experimentally and their functions are largely unknown. To reveal their possible functions, we performed a variety of bioinformatic analyses aimed at identifying the presence of functional protein domains as well as orthologous relationships to other species. RESULTS Our analyses identified putative functional domains in predicted proteins for a number of selected genes. For example, we confidently predict kinase function for one gene, cytokine/chemokine function for another, and carbohydrate enzymatic function for a third. Predicted orthologs were identified for some, but not all, genes in species with described regenerative capacity, and functional domains were consistent with identified orthologs. Comparison to other published gene expression datasets suggest that at least some of these genes could be important in regenerative responses in zebrafish and not necessarily in response to microbial infection. CONCLUSIONS This work reveals previously undescribed putative function of several genes implicated in regulating tissue regeneration. This will inform future work to experimentally determine the function of these genes in vivo, and how these genes may be involved in microglia/macrophage roles in tissue regeneration.
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Affiliation(s)
- Ousseini Issaka Salia
- Department of Biological Sciences, University of Idaho, Moscow, ID, USA.,Institute for Modeling Collaboration and Innovation (IMCI), University of Idaho, Moscow, ID, USA.,Present affiliation: Kellog Biological Station and Department of Plant Biology, Michigan State University, 3700 East Gull Lake Drive, Hickory Corners, MI, 49060, USA
| | - Diana M Mitchell
- Department of Biological Sciences, University of Idaho, Moscow, ID, USA.
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20
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Ghanemi A, Yoshioka M, St-Amand J. Trefoil Factor Family Member 2 (TFF2) as an Inflammatory-Induced and Anti-Inflammatory Tissue Repair Factor. Animals (Basel) 2020; 10:ani10091646. [PMID: 32937753 PMCID: PMC7552208 DOI: 10.3390/ani10091646] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 09/06/2020] [Accepted: 09/11/2020] [Indexed: 12/13/2022] Open
Abstract
Trefoil factor family member 2 (TFF2) is known for its involvement in mucosal repair. Whereas it is overexpressed during inflammatory processes, adding TFF2 leads to an anti-inflammatory effect that would contribute to create the microenvironment required for tissue repair. These properties present TFF2 with a homeostatic pattern during inflammatory processes as illustrated by selected examples.
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Affiliation(s)
- Abdelaziz Ghanemi
- Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec, QC G1V 0A6, Canada;
- Endocrinology and Nephrology Axis, Functional Genomics Laboratory, CHU de Québec-Université Laval Research Center, Québec, QC G1V 4G2, Canada;
| | - Mayumi Yoshioka
- Endocrinology and Nephrology Axis, Functional Genomics Laboratory, CHU de Québec-Université Laval Research Center, Québec, QC G1V 4G2, Canada;
| | - Jonny St-Amand
- Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec, QC G1V 0A6, Canada;
- Endocrinology and Nephrology Axis, Functional Genomics Laboratory, CHU de Québec-Université Laval Research Center, Québec, QC G1V 4G2, Canada;
- Correspondence: ; Tel.: +1-(418)-654-2296; Fax: +1-(418)-654-2761
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21
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Engevik MA, Banks LD, Engevik KA, Chang-Graham AL, Perry JL, Hutchinson DS, Ajami NJ, Petrosino JF, Hyser JM. Rotavirus infection induces glycan availability to promote ileum-specific changes in the microbiome aiding rotavirus virulence. Gut Microbes 2020; 11:1324-1347. [PMID: 32404017 PMCID: PMC7524290 DOI: 10.1080/19490976.2020.1754714] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Multiple studies have identified changes within the gut microbiome in response to diarrheal-inducing bacterial pathogens. However, examination of the microbiome in response to viral pathogens remains understudied. Compounding this, many studies use fecal samples to assess microbiome composition; which may not accurately mirror changes within the small intestine, the primary site for most enteric virus infections. As a result, the functional significance of small intestinal microbiome shifts during infection is not well defined. To address these gaps, rotavirus-infected neonatal mice were examined for changes in bacterial community dynamics, host gene expression, and tissue recovery during infection. Profiling bacterial communities using 16S rRNA sequencing suggested significant and distinct changes in ileal communities in response to rotavirus infection, with no significant changes for other gastrointestinal (GI) compartments. At 1-d post-infection, we observed a loss in Lactobacillus species from the ileum, but an increase in Bacteroides and Akkermansia, both of which exhibit mucin-digesting capabilities. Concomitant with the bacterial community shifts, we observed a loss of mucin-filled goblet cells in the small intestine at d 1, with recovery occurring by d 3. Rotavirus infection of mucin-producing cell lines and human intestinal enteroids (HIEs) stimulated release of stored mucin granules, similar to in vivo findings. In vitro, incubation of mucins with Bacteroides or Akkermansia members resulted in significant glycan degradation, which altered the binding capacity of rotavirus in silico and in vitro. Taken together, these data suggest that the response to and recovery from rotavirus-diarrhea is unique between sub-compartments of the GI tract and may be influenced by mucin-degrading microbes.
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Affiliation(s)
- Melinda A. Engevik
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA,Department of Pathology, Texas Children’s Hospital, Houston, TX, USA
| | - Lori D. Banks
- Alkek Center for Metagenomic and Microbiome Research, Baylor College of Medicine, Houston, TX, USA,Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Kristen A. Engevik
- Alkek Center for Metagenomic and Microbiome Research, Baylor College of Medicine, Houston, TX, USA,Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Alexandra L. Chang-Graham
- Alkek Center for Metagenomic and Microbiome Research, Baylor College of Medicine, Houston, TX, USA,Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Jacob L. Perry
- Alkek Center for Metagenomic and Microbiome Research, Baylor College of Medicine, Houston, TX, USA,Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Diane S. Hutchinson
- Alkek Center for Metagenomic and Microbiome Research, Baylor College of Medicine, Houston, TX, USA,Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Nadim J. Ajami
- Alkek Center for Metagenomic and Microbiome Research, Baylor College of Medicine, Houston, TX, USA,Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Joseph F. Petrosino
- Alkek Center for Metagenomic and Microbiome Research, Baylor College of Medicine, Houston, TX, USA,Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Joseph M. Hyser
- Alkek Center for Metagenomic and Microbiome Research, Baylor College of Medicine, Houston, TX, USA,Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA,CONTACT Joseph M. Hyser 1 Baylor Plaza, HoustonTX77030, USA
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22
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Braga Emidio N, Brierley SM, Schroeder CI, Muttenthaler M. Structure, Function, and Therapeutic Potential of the Trefoil Factor Family in the Gastrointestinal Tract. ACS Pharmacol Transl Sci 2020; 3:583-597. [PMID: 32832864 DOI: 10.1021/acsptsci.0c00023] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Indexed: 12/20/2022]
Abstract
Trefoil factor family peptides (TFF1, TFF2, and TFF3) are key players in protecting, maintaining, and repairing the gastrointestinal tract. Accordingly, they have the therapeutic potential to treat and prevent a variety of gastrointestinal disorders associated with mucosal damage. TFF peptides share a conserved motif, including three disulfide bonds that stabilize a well-defined three-loop-structure reminiscent of a trefoil. Although multiple functions have been described for TFF peptides, their mechanisms at the molecular level remain poorly understood. This review presents the status quo of TFF research relating to gastrointestinal disorders. Putative TFF receptors and protein partners are described and critically evaluated. The therapeutic potential of these peptides in gastrointestinal disorders where altered mucosal biology plays a crucial role in the underlying etiology is discussed. Finally, areas of investigation that require further research are addressed. Thus, this review provides a comprehensive update on TFF literature as well as guidance toward future research to better understand this peptide family and its therapeutic potential for the treatment of gastrointestinal disorders.
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Affiliation(s)
- Nayara Braga Emidio
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Stuart M Brierley
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medicial Research Insittitue (FHMRI), Flinders University, Bedford Park, South Australia 5042, Australia.,Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia 5000, Australia.,Discipline of Medicine, University of Adelaide, Adelaide, South Australia 5000, Australia
| | - Christina I Schroeder
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.,National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States
| | - Markus Muttenthaler
- Institute of Biological Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria.,Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
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23
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Cho SH, Lee KM, Kim CH, Kim SS. Construction of a Lectin-Glycan Interaction Network from Enterohemorrhagic Escherichia coli Strains by Multi-omics Analysis. Int J Mol Sci 2020; 21:2681. [PMID: 32290560 PMCID: PMC7215717 DOI: 10.3390/ijms21082681] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 04/04/2020] [Accepted: 04/07/2020] [Indexed: 11/17/2022] Open
Abstract
Enterohemorrhagic Escherichia coli (EHEC) causes hemorrhagic colitis and hemolytic uremic syndrome. EHEC infection begins with bacterial adherence to the host intestine via lectin-like adhesins that bind to the intestinal wall. However, EHEC-related lectin-glycan interactions (LGIs) remain unknown. Here, we conducted a genome-wide investigation of putative adhesins to construct an LGI network. We performed microarray-based transcriptomic and proteomic analyses with E. coli EDL933. Using PSORTb-based analysis, potential outer-membrane-embedded adhesins were predicted from the annotated genes of 318 strains. Predicted proteins were classified using TMHMM v2.0, SignalP v5.0, and LipoP v1.0. Functional and protein-protein interaction analyses were performed using InterProScan and String databases, respectively. Structural information of lectin candidate proteins was predicted using Iterative Threading ASSEmbly Refinement (I-TASSER) and Spatial Epitope Prediction of Protein Antigens (SEPPA) tools based on 3D structure and B-cell epitopes. Pathway analysis returned 42,227 Gene Ontology terms; we then selected 2585 lectin candidate proteins by multi-omics analysis and performed homology modeling and B-cell epitope analysis. We predicted a total of 24,400 outer-membrane-embedded proteins from the genome of 318 strains and integrated multi-omics information into the genomic information of the proteins. Our integrated multi-omics data will provide a useful resource for the construction of LGI networks of E. coli.
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Affiliation(s)
- Seung-Hak Cho
- Division of Bacterial Disease Research, Center for Infectious Disease Research, Korea National Institute of Health, Cheongju, Chungchungbuk-do 28160, Korea; (S.-H.C.); (K.M.L.)
| | - Kang Mo Lee
- Division of Bacterial Disease Research, Center for Infectious Disease Research, Korea National Institute of Health, Cheongju, Chungchungbuk-do 28160, Korea; (S.-H.C.); (K.M.L.)
| | - Cheorl-Ho Kim
- Glycobiology Unit, Department of Biological Science, Sungkyunkwan University and Samsung Advanced Institute for Health Science and Technology (SAIHST), Suwon, Gyeonggi-do 16419, Korea
| | - Sung Soon Kim
- Division of Bacterial Disease Research, Center for Infectious Disease Research, Korea National Institute of Health, Cheongju, Chungchungbuk-do 28160, Korea; (S.-H.C.); (K.M.L.)
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24
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Josenhans C, Müthing J, Elling L, Bartfeld S, Schmidt H. How bacterial pathogens of the gastrointestinal tract use the mucosal glyco-code to harness mucus and microbiota: New ways to study an ancient bag of tricks. Int J Med Microbiol 2020; 310:151392. [DOI: 10.1016/j.ijmm.2020.151392] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 11/28/2019] [Accepted: 12/06/2019] [Indexed: 12/13/2022] Open
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25
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Meditskou S, Grekou A, Toskas A, Papamitsou T, Miliaras D. Pyloric and foveolar type metaplasia are important diagnostic features in Crohn's disease that are frequently missed in routine pathology. Histol Histopathol 2019; 35:553-558. [PMID: 31538655 DOI: 10.14670/hh-18-167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Pyloric type metaplasia (PYME) as evidence of chronic mucosal damage, is one of the main histopathological findings for diagnosing Crohn's Disease (CD) in terminal ileum biopsies, according to the latest guidelines but still frequently underdiagnosed in routine pathology. Foveolar metaplasia (FOME) changes in mucosa, another aspect of the chronic post -inflammatory Ulcer Associated Cell Lineage (UACL), have only been reported in a few cases. However, their clinical significance has not been investigated in depth except in pouchitis. The aim of this study was to investigate the importance of meticulous study of terminal ileum biopsies for the recognition of PYME/FOME as an adjunct finding helpful for the diagnosis of CD. In the present study, two experienced gastrointestinal pathologists, have reviewed 105 terminal ileum biopsies from 105 patients with CD, using a protocol of 15 sections on average per biopsy. In 21% (22/105) of cases PYME was recognized and in 4% (4/105) FOME was also present. PYME/FOME had not been detected in 83% of these cases in the original reports. FOME was also identified in terminal ileum biopsies, a feature not reported previously in CD. Conclusively, PYME/FOME can be easily missed in terminal ileum biopsies from patients with suspected or known CD unless a meticulous study of the histologic material is carried out combined with awareness of the pathologist about its importance.
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Affiliation(s)
- Soultana Meditskou
- Laboratory of Histology - Embryology, Aristotle University of Thessaloniki, Thessaloniki, Greece.,"Istodiagnostiki" Histopathology Laboratory, Thessaloniki, Greece
| | - Alexandra Grekou
- "Istodiagnostiki" Histopathology Laboratory, Thessaloniki, Greece
| | - Alexandros Toskas
- Laboratory of Histology - Embryology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Theodora Papamitsou
- Laboratory of Histology - Embryology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Dimosthenis Miliaras
- Laboratory of Histology - Embryology, Aristotle University of Thessaloniki, Thessaloniki, Greece
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26
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Basmaciyan L, Bon F, Paradis T, Lapaquette P, Dalle F. " Candida Albicans Interactions With The Host: Crossing The Intestinal Epithelial Barrier". Tissue Barriers 2019; 7:1612661. [PMID: 31189436 PMCID: PMC6619947 DOI: 10.1080/21688370.2019.1612661] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 04/24/2019] [Accepted: 04/24/2019] [Indexed: 02/08/2023] Open
Abstract
Formerly a commensal organism of the mucosal surfaces of most healthy individuals, Candida albicans is an opportunistic pathogen that causes infections ranging from superficial to the more life-threatening disseminated infections, especially in the ever-growing population of vulnerable patients in the hospital setting. In these situations, the fungus takes advantage of its host following a disturbance in the host defense system and/or the mucosal microbiota. Overwhelming evidence suggests that the gastrointestinal tract is the main source of disseminated C. albicans infections. Major risk factors for disseminated candidiasis include damage to the mucosal intestinal barrier, immune dysfunction, and dysbiosis of the resident microbiota. A better understanding of C. albicans' interaction with the intestinal epithelial barrier will be useful for designing future therapies to avoid systemic candidiasis. In this review, we provide an overview of the current knowledge regarding the mechanisms of pathogenicity that allow the fungus to reach and translocate the gut barrier.
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Affiliation(s)
- Louise Basmaciyan
- Laboratoire de Parasitologie-Mycologie, Plateforme de Biologie Hospitalo-Universitaire Gérard Mack, Dijon France
- UMR PAM Univ Bourgogne Franche-Comté - AgroSup Dijon - Equipe Vin, Aliment, Microbiologie, Stress, Dijon, France
| | - Fabienne Bon
- UMR PAM Univ Bourgogne Franche-Comté - AgroSup Dijon - Equipe Vin, Aliment, Microbiologie, Stress, Dijon, France
| | - Tracy Paradis
- UMR PAM Univ Bourgogne Franche-Comté - AgroSup Dijon - Equipe Vin, Aliment, Microbiologie, Stress, Dijon, France
| | - Pierre Lapaquette
- UMR PAM Univ Bourgogne Franche-Comté - AgroSup Dijon - Equipe Vin, Aliment, Microbiologie, Stress, Dijon, France
| | - Frédéric Dalle
- Laboratoire de Parasitologie-Mycologie, Plateforme de Biologie Hospitalo-Universitaire Gérard Mack, Dijon France
- UMR PAM Univ Bourgogne Franche-Comté - AgroSup Dijon - Equipe Vin, Aliment, Microbiologie, Stress, Dijon, France
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27
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Fabisiak A, Bartoszek A, Kardas G, Fabisiak N, Fichna J. Possible application of trefoil factor family peptides in gastroesophageal reflux and Barrett's esophagus. Peptides 2019; 115:27-31. [PMID: 30831146 DOI: 10.1016/j.peptides.2019.02.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 02/16/2019] [Accepted: 02/24/2019] [Indexed: 12/14/2022]
Abstract
Gastroesophageal reflux disease (GERD) is a chronic disorder of the digestive tract characterised mainly by a heartburn. Being one of the most common gastrointestinal diseases, the prevalence of GERD reaches up to 25.9% in Europe. Barrett's esophagus (BE) is an acquired condition characterized by the replacement of the normal stratified squamous epithelium with metaplastic columnar epithelium. BE is believed to develop mainly from chronic GERD and is the most important risk factor of esophageal adenocarcinoma. Despite the availability of drugs such as proton pomp inhibitors and antacids, GERD is still a burden to local economy and impairs health-related quality of life in patients. Also, the endoscopic surveillance in patients with BE is burdensome and expensive what drives the need for biomarker of intestinal metaplasia and dysplasia. Trefoil factor family (TFF), consisting of TFF1, TFF2 and TFF3 peptides is gaining more and more attention due to its unique biochemical features and numerous functions. In this review the role of TFF1, TFF2 and TFF3 as potential treatment option and/or biomarker in the upper GI tract is discussed with particular focus on GERD and BE.
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Affiliation(s)
- Adam Fabisiak
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland; Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Poland
| | - Adrian Bartoszek
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Grzegorz Kardas
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Natalia Fabisiak
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland; Department of Gastroenterology, Faculty of Military Medicine, Medical University of Lodz, Poland
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
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28
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Thorsvik S, van Beelen Granlund A, Svendsen TD, Bakke I, Røyset ES, Flo TH, Damås JK, Østvik AE, Bruland T, Sandvik AK. Ulcer-associated cell lineage expresses genes involved in regeneration and is hallmarked by high neutrophil gelatinase-associated lipocalin (NGAL) levels. J Pathol 2019; 248:316-325. [PMID: 30746716 PMCID: PMC6618036 DOI: 10.1002/path.5258] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 01/13/2019] [Accepted: 02/07/2019] [Indexed: 01/16/2023]
Abstract
Neutrophil gelatinase-associated lipocalin (NGAL), also known as Lipocalin 2, is an antimicrobial protein, encoded by the gene LCN2, strongly upregulated in inflammatory bowel disease (IBD) and a promising biomarker for IBD. Here we demonstrate that NGAL is highly expressed in all parts of pyloric metaplasia, also known as the ulcer-associated cell lineage (UACL), a metaplastic cell lineage suggested to play a role in wound healing in Crohn's disease (CD). We further show NGAL expression in regenerative intestinal crypts and in undifferentiated patient-derived colonoids. This indicates that NGAL is important in the tissue regeneration process. The remarkable overexpression of NGAL in UACL led us to explore the pathobiology of these cells by transcriptome-wide RNA sequencing. This study is, to our knowledge, the first to characterize the UACL at this level. Biopsies with UACL and inflamed non-UACL epithelium from the terminal ileum of CD patients and epithelium from healthy controls were laser capture microdissected for RNA sequencing. Among the 180 genes differentially expressed between UACL and control epithelium, the ten most-upregulated genes specific for UACL were MUC5AC, PGC, MUC6, MUC5B, LCN2, POU2AF1, MUC1, SDC3, IGFBP5, and SLC7A5. PDX1 was among the most upregulated in both UACL and inflamed non-UACL epithelium. Immunohistochemistry and iDisco 3D visualization was used to characterize UACL histo-morphologically, and to validate protein expression of 11 selected differentially expressed genes. Among these genes, LCN2, NOTCH2, PHLDA1, IGFBP5, SDC3, BPIFB1, and RCN1 have previously not been linked to UACL. Gene expression results were analyzed for functional implications using MetaCore, showing that differentially expressed genes are enriched for genes involved in cell migration and motility, and for biomarkers of gastrointestinal neoplasia. These results support a role for UACL as part of the reepithelialization process during and after destructive intestinal inflammation. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Silje Thorsvik
- Centre of Molecular Inflammation Research, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Gastroenterology and Hepatology, St Olav's University Hospital, Trondheim, Norway
| | - Atle van Beelen Granlund
- Centre of Molecular Inflammation Research, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
| | - Tarjei D Svendsen
- Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
| | - Ingunn Bakke
- Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.,Clinic of Medicine, St Olav's University Hospital, Trondheim, Norway
| | - Elin S Røyset
- Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Pathology, St Olav's University Hospital, Trondheim, Norway
| | - Trude H Flo
- Centre of Molecular Inflammation Research, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
| | - Jan K Damås
- Centre of Molecular Inflammation Research, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Infectious Diseases, St Olav's University Hospital, Trondheim, Norway
| | - Ann E Østvik
- Centre of Molecular Inflammation Research, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Gastroenterology and Hepatology, St Olav's University Hospital, Trondheim, Norway
| | - Torunn Bruland
- Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.,Clinic of Medicine, St Olav's University Hospital, Trondheim, Norway
| | - Arne K Sandvik
- Centre of Molecular Inflammation Research, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Gastroenterology and Hepatology, St Olav's University Hospital, Trondheim, Norway
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29
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Abstract
Mucins are large glycoproteins that are ubiquitous in the animal kingdom. Mucins coat the surfaces of many cell types and can be secreted to form mucus gels that assume important physiological roles in many animals. Our growing understanding of the structure and function of mucin molecules and their functionalities has sparked interest in investigating the use of mucins as building blocks for innovative functional biomaterials. These pioneering studies have explored how new biomaterials can benefit from the barrier properties, hydration and lubrication properties, unique chemical diversity, and bioactivities of mucins. Owing to their multifunctionality, mucins have been used in a wide variety of applications, including as antifouling coatings, as selective filters, and artificial tears and saliva, as basis for cosmetics, as drug delivery materials, and as natural detergents. In this review, we summarize the current knowledge regarding key mucin properties and survey how they have been put to use. We offer a vision for how mucins could be used in the near future and what challenges await the field before biomaterials made of mucins and mucin-mimics can be translated into commercial products.
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Affiliation(s)
- Georgia Petrou
- School of Engineering Sciences in Chemistry, Biotechnology and Health, Department of Chemistry, Kungliga Tekniska Hogskolan, Stockholm, Sweden.
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30
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Yamaguchi J, Yokoyama Y, Kokuryo T, Ebata T, Enomoto A, Nagino M. Trefoil factor 1 inhibits epithelial-mesenchymal transition of pancreatic intraepithelial neoplasm. J Clin Invest 2018; 128:3619-3629. [PMID: 29809170 DOI: 10.1172/jci97755] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 05/24/2018] [Indexed: 12/30/2022] Open
Abstract
The tumor-suppressive role of trefoil factor family (TFF) members in gastric carcinogenesis has been suggested, but their significance and mechanisms in other digestive diseases remain elusive. To clarify the role of TFF1 in pancreatic carcinogenesis, we performed IHC on human samples, transfected siRNA against TFF1 into pancreatic cancer cell lines, and employed mouse models in which PanIN development and loss of TFF1 occur simultaneously. In human samples, the expression of TFF1 was specifically observed in pancreatic intraepithelial neoplasm (PanIN), but was frequently lost in the invasive component of pancreatic ductal adenocarcinoma (PDAC). When the expression of TFF1 was suppressed in vitro, pancreatic cancer cell lines showed enhanced invasive ability and features of epithelial-mesenchymal transition (EMT), including upregulated Snail expression. TFF1 expression was also observed in PanIN lesions of Pdx-1 Cre; LSL-KRASG12D (KC) mice, a model of pancreatic cancer, and loss of TFF1 in these mice resulted in the expansion of PanIN lesions, an EMT phenotype in PanIN cells, and an accumulation of cancer-associated fibroblasts (CAFs), eventually resulting in the development of invasive adenocarcinoma. This study indicates that the acquisition of TFF1 expression is an early event in pancreatic carcinogenesis and that TFF1 might act as a tumor suppressor to prevent EMT and the invasive transformation of PanIN.
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Affiliation(s)
| | | | - Toshio Kokuryo
- Division of Surgical Oncology, Department of Surgery, and
| | - Tomoki Ebata
- Division of Surgical Oncology, Department of Surgery, and
| | - Atsushi Enomoto
- Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Masato Nagino
- Division of Surgical Oncology, Department of Surgery, and
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Phytic acid improves intestinal mucosal barrier damage and reduces serum levels of proinflammatory cytokines in a 1,2-dimethylhydrazine-induced rat colorectal cancer model. Br J Nutr 2018; 120:121-130. [DOI: 10.1017/s0007114518001290] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
AbstractPhytic acid (PA) has been demonstrated to have a potent anticarcinogenic activity against colorectal cancer (CRC). Defects of the intestinal mucosal barrier and inflammation processes are involved in the development and progression of CRC. In the present study, we evaluated the effect of PA on the intestinal mucosal barrier and proinflammatory cytokines. After a 1-week acclimatisation period, sixty Wistar male rats were divided into the following five groups, with twelve rats per group: the control group (CG), model group (MG), low-PA-dose group (0·25 g/kg per d), middle-PA-dose group (0·5 g/kg per d), and high-PA-dose group (1 g/kg per d). 1,2-Dimethylhydrazine (DMH) at a dosage of 30 mg/kg of body weight was injected weekly to induce CRC for 18 weeks. We examined the expression of genes related to the intestinal mucosal barrier in the model. The results demonstrated that tumour incidence was decreased following PA treatment. The mRNA and protein expression of mucin 2 (MUC2), trefoil factor 3 (TFF3) and E-cadherin in the MG were significantly lower than those in the CG (P<0·05). The mRNA and protein expression of claudin-1 in the MG were significantly higher than those in the CG (P<0·05). PA elevated the mRNA and protein expression of MUC2, TFF3 and E-cadherin, and diminished the mRNA and protein expression of claudin-1. Furthermore, PA decreased serum levels of proinflammatory cytokines, which included TNF-α, IL-1β and IL-6. In conclusion, this study suggests that PA has favourable effects on the intestinal mucosal barrier and may reduce serum proinflammatory cytokine levels.
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Binding of Helicobacter pylori to Human Gastric Mucins Correlates with Binding of TFF1. Microorganisms 2018; 6:microorganisms6020044. [PMID: 29783620 PMCID: PMC6027488 DOI: 10.3390/microorganisms6020044] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 04/23/2018] [Accepted: 05/01/2018] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori binds to the gastric mucin, MUC5AC, and to trefoil factor, TFF1, which has been shown to interact with gastric mucin. We examined the interactions of TFF1 and H. pylori with purified gastrointestinal mucins from different animal species and from humans printed on a microarray platform to investigate whether TFF1 may play a role in locating H. pylori in gastric mucus. TFF1 bound almost exclusively to human gastric mucins and did not interact with human colonic mucins. There was a strong correlation between binding of TFF1 and H. pylori to human gastric mucins, and between binding of both TFF1 and H. pylori to gastric mucins with that of Griffonia simplicifolia lectin-II, which is specific for terminal non-reducing α- or β-linked N-acetyl-d-glucosamine. These results suggest that TFF1 may help to locate H. pylori in a discrete layer of gastric mucus and hence restrain their interactions with epithelial cells.
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Sáenz JB, Mills JC. Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer. Nat Rev Gastroenterol Hepatol 2018; 15:257-273. [PMID: 29463907 PMCID: PMC6016373 DOI: 10.1038/nrgastro.2018.5] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Subjected to countless daily injuries, the stomach still functions as a remarkably efficient digestive organ and microbial filter. In this Review, we follow the lead of the earliest gastroenterologists who were fascinated by the antiseptic and digestive powers of gastric secretions. We propose that it is easiest to understand how the stomach responds to injury by stressing the central role of the most important gastric secretion, acid. The stomach follows two basic patterns of adaptation. The superficial response is a pattern whereby the surface epithelial cells migrate and rapidly proliferate to repair erosions induced by acid or other irritants. The stomach can also adapt through a glandular response when the source of acid is lost or compromised (that is, the process of oxyntic atrophy). We primarily review the mechanisms governing the glandular response, which is characterized by a metaplastic change in cellular differentiation known as spasmolytic polypeptide-expressing metaplasia (SPEM). We propose that the stomach, like other organs, exhibits marked cellular plasticity: the glandular response involves reprogramming mature cells to serve as auxiliary stem cells that replace lost cells. Unfortunately, such plasticity might mean that the gastric epithelium undergoes cycles of differentiation and de-differentiation that increase the risk of accumulating cancer-predisposing mutations.
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Affiliation(s)
- José B. Sáenz
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine
| | - Jason C. Mills
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine
- Department of Developmental Biology, Washington University School of Medicine
- Department of Pathology and Immunology, Washington University School of Medicine
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Hu J, Shi Y, Wang C, Wan H, Wu D, Wang H, Peng X. Role of intestinal trefoil factor in protecting intestinal epithelial cells from burn-induced injury. Sci Rep 2018; 8:3201. [PMID: 29453360 PMCID: PMC5816625 DOI: 10.1038/s41598-018-21282-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 01/30/2018] [Indexed: 12/19/2022] Open
Abstract
Although intestinal trefoil factor (ITF) can alleviate the burn-induced intestinal mucosa injury, the underlying mechanisms remains elusive. In this study, we investigated if ITF alters glutamine transport on the brush border membrane vesicles (BBMVs) of the intestines in Sprague-Dawley rats inflicted with 30% TBSA and the underlying mechanisms. We found that ITF significantly stimulated intestinal glutamine transport in burned rats. Mechanistically, ITF enhanced autophagy, reduces endoplasmic reticulum stress (ERS), and alleviates the impaired PDI, ASCT2, and B0AT1 in IECs and BBMVs after burn injury likely through AMPK activation. Therefore, ITF may protect intestinal epithelial cells from burn-induced injury through improving glutamine transport by alleviating ERS.
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Affiliation(s)
- Jianhong Hu
- Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing, 400038, China
| | - Yan Shi
- Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing, 400038, China
| | - Chao Wang
- Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing, 400038, China
| | - Hanxing Wan
- Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing, 400038, China
| | - Dan Wu
- Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing, 400038, China
| | - Hongyu Wang
- Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing, 400038, China
| | - Xi Peng
- Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing, 400038, China.
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Comprehensive Evaluation of TFF3 Promoter Hypomethylation and Molecular Biomarker Potential for Prostate Cancer Diagnosis and Prognosis. Int J Mol Sci 2017; 18:ijms18092017. [PMID: 28930171 PMCID: PMC5618665 DOI: 10.3390/ijms18092017] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 09/08/2017] [Accepted: 09/13/2017] [Indexed: 01/03/2023] Open
Abstract
Overdiagnosis and overtreatment of clinically insignificant tumors remains a major problem in prostate cancer (PC) due to suboptimal diagnostic and prognostic tools. Thus, novel biomarkers are urgently needed. In this study, we investigated the biomarker potential of Trefoil factor 3 (TFF3) promoter methylation and RNA expression levels for PC. Initially, by quantitative methylation specific PCR (qMSP) analysis of a large radical prostatectomy (RP) cohort (n = 292), we found that the TFF3 promoter was significantly hypomethylated in PC compared to non-malignant (NM) prostate tissue samples (p < 0.001) with an AUC (area under the curve) of 0.908 by receiver operating characteristics (ROC) curve analysis. Moreover, significant TFF3 promoter hypomethylation (p ≤ 0.010) as well as overexpression (p < 0.001) was found in PC samples from another large independent patient sample set (498 PC vs. 67 NM) analyzed by Illumina 450K DNA methylation arrays and/or RNA sequencing. TFF3 promoter methylation and transcriptional expression levels were inversely correlated, suggesting that epigenetic mechanisms contribute to the regulation of gene activity. Furthermore, low TFF3 expression was significantly associated with high ERG, ETS transcription factor (ERG) expression (p < 0.001), as well as with high Gleason score (p < 0.001), advanced pathological T-stage (p < 0.001), and prostate-specific antigen (PSA) recurrence after RP (p = 0.013; univariate Cox regression analysis). There were no significant associations between TFF3 promoter methylation levels, ERG status, or PSA recurrence in these RP cohorts. In conclusion, our results demonstrated diagnostic biomarker potential of TFF3 promoter hypomethylation for PC as well as prognostic biomarker potential of TFF3 RNA expression. To the best of our knowledge, this is the most comprehensive study of TFF3 promoter methylation and transcriptional expression in PC to date.
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Colgan SP, Campbell EL. Oxygen metabolism and innate immune responses in the gut. J Appl Physiol (1985) 2017; 123:1321-1327. [PMID: 28705991 DOI: 10.1152/japplphysiol.00113.2017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 06/27/2017] [Accepted: 07/06/2017] [Indexed: 01/02/2023] Open
Abstract
Epithelial cells of the mucosa provide a first line of defense to prevent the inappropriate translocation of luminal antigens, and therefore contribute significantly to nonspecific innate immunity. In the gastrointestinal (GI) tract, barrier is provided by multiple components of the mucosa, including mucus production, epithelial junctional complexes, and the production of antimicrobial molecules. In recent years, it is better appreciated that tissue oxygen metabolism is key to homeostasis in the mucosa. The intestine, for example, maintains a low baseline Po2 level due to high rates of metabolism, countercurrent blood flow, and the presence of a steep oxygen gradient across the luminal aspect of tissue surface. As a result, hypoxia and hypoxia-inducible factor (HIF)-dependent signaling exists even in the healthy, unperturbed intestinal mucosa. In a number of examples, HIF has been demonstrated both to promote barrier function during homeostasis and to promote resolution of active inflammation. Hypoxia-elicited factors that contribute to innate responses in the mucosa include the transcriptional regulation of mucin genes, junction proteins, and autophagic flux. Here, we review current literature related to hypoxia and innate immunity in health and during mucosal inflammation.
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Affiliation(s)
- Sean P Colgan
- Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, Colorado; and
| | - Eric L Campbell
- Centre for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom
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Woodfint RM, Chen PR, Ahn J, Suh Y, Hwang S, Lee SS, Lee K. Identification of the MUC2 Promoter as a Strong Promoter for Intestinal Gene Expression through Generation of Transgenic Quail Expressing GFP in Gut Epithelial Cells. Int J Mol Sci 2017; 18:ijms18010196. [PMID: 28106824 PMCID: PMC5297827 DOI: 10.3390/ijms18010196] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 01/10/2017] [Accepted: 01/12/2017] [Indexed: 01/23/2023] Open
Abstract
Identification of tissue- and stage-specific gene promoters is valuable for delineating the functional roles of specific genes in genetically engineered animals. Here, through the comparison of gene expression in different tissues by analysis of a microarray database, the intestinal specificity of mucin 2 (MUC2) expression was identified in mice and humans, and further confirmed in chickens by RT-PCR (reverse transcription-PCR) analysis. An analysis of cis-acting elements in avian MUC2 gene promoters revealed conservation of binding sites, within a 2.9 kb proximal promoter region, for transcription factors such as caudal type homeobox 2 (CDX2), GATA binding protein 4 (GATA4), hepatocyte nuclear factor 4 α (HNF4A), and transcription factor 4 (TCF4) that are important for maintaining intestinal homeostasis and functional integrity. By generating transgenic quail, we demonstrated that the 2.9 kb chicken MUC2 promoter could drive green fluorescent protein (GFP) reporter expression exclusively in the small intestine, large intestine, and ceca. Fluorescence image analysis further revealed GFP expression in intestine epithelial cells. The GFP expression was barely detectable in the embryonic intestine, but increased during post-hatch development. The spatiotemporal expression pattern of the reporter gene confirmed that the 2.9 kb MUC2 promoter could retain the regulatory element to drive expression of target genes in intestinal tissues after hatching. This new transgene expression system, using the MUC2 promoter, will provide a new method of overexpressing target genes to study gene function in the avian intestine.
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Affiliation(s)
- Rachel M Woodfint
- Department of Animal Sciences, The Ohio State University, Columbus, OH 43210, USA.
| | - Paula R Chen
- Department of Animal Sciences, The Ohio State University, Columbus, OH 43210, USA.
| | - Jinsoo Ahn
- Department of Animal Sciences, The Ohio State University, Columbus, OH 43210, USA.
| | - Yeunsu Suh
- Department of Animal Sciences, The Ohio State University, Columbus, OH 43210, USA.
| | - Seongsoo Hwang
- Animal Biotechnology Division, National Institute of Animal Science, RDA, Wanju-gun, Jeonbuk 55365, Korea.
| | - Sang Suk Lee
- Department of Animal Science and Technology, Sunchon National University, Suncheon 57922, Korea.
| | - Kichoon Lee
- Department of Animal Sciences, The Ohio State University, Columbus, OH 43210, USA.
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Abstract
Trefoil factor (TFF) peptides, with a 40-amino acid motif and including six conserved cysteine residues that form intramolecular disulfide bonds, are a family of mucin-associated secretory molecules mediating many physiological roles that maintain and restore gastrointestinal (GI) mucosal homeostasis. TFF peptides play important roles in response to GI mucosal injury and inflammation. In response to acute GI mucosal injury, TFF peptides accelerate cell migration to seal the damaged area from luminal contents, whereas chronic inflammation leads to increased TFF expression to prevent further progression of disease. Although much evidence supports the physiological significance of TFF peptides in mucosal defenses, the molecular and cellular mechanisms of TFF peptides in the GI epithelium remain largely unknown. In this review, we summarize the functional roles of TFF1, 2, and 3 and illustrate their action mechanisms, focusing on defense mechanisms in the GI tract.
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Affiliation(s)
- Eitaro Aihara
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267;
| | - Kristen A Engevik
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267;
| | - Marshall H Montrose
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267;
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Khaidakov M, Lai KK, Roudachevski D, Sargsyan J, Goyne HE, Pai RK, Lamps LW, Hagedorn CH. Gastric Proteins MUC5AC and TFF1 as Potential Diagnostic Markers of Colonic Sessile Serrated Adenomas/Polyps. Am J Clin Pathol 2016; 146:530-537. [PMID: 28430953 PMCID: PMC5377921 DOI: 10.1093/ajcp/aqw142] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES A subset of colon cancers originates from sessile serrated adenomas/polyps (SSA/Ps). Our goal was to identify markers for SSA/Ps that could aid in distinguishing them from hyperplastic polyps (HPs). METHODS We performed immunostaining for gastric proteins MUC5AC and TFF1 in formalin-fixed, paraffin-embedded (FFPE) samples of HPs (n = 47), SSA/Ps (n = 37), and normal colon (n = 30). RESULTS Control mucosa expressed only trace amounts of MUC5AC and TFF1. HPs exhibited an 11.3- and 11.4-fold increase in MUC5AC and TFF1 expression confined to the upper segments of the crypts near the luminal surface of the polyps. SSA/Ps displayed on average 1.6-fold (MUC5AC, P < .008) and 1.4-fold (TFF1, P < .03) higher signal intensity for these markers than HPs, with a dramatic coexpression of MUC5AC and TFF1 typically occupying the entire length of the crypt. Immunoperoxidase results were similar to immunofluorescence staining for both MUC5AC and TFF1. CONCLUSIONS Our results suggest that the analysis of expression of MUC5AC and TFF1 may be useful for differentiating SSA/Ps from HPs. We also suggest the possibility that crypt morphology may be at least partly due to overproduction of highly viscous gastric mucins and that these proteins may play a role in the serrated pathway to colon carcinogenesis.
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Affiliation(s)
- Magomed Khaidakov
- From the Department of Medicine
- Central Arkansas Veterans Healthcare System, Little Rock
| | - Keith K. Lai
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock
| | | | | | - Hannah E. Goyne
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock
| | - Rish K. Pai
- Department of Pathology, Mayo Clinic, Scottsdale, AZ
| | - Laura W. Lamps
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock
| | - Curt H. Hagedorn
- From the Department of Medicine
- Central Arkansas Veterans Healthcare System, Little Rock
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Glover LE, Lee JS, Colgan SP. Oxygen metabolism and barrier regulation in the intestinal mucosa. J Clin Invest 2016; 126:3680-3688. [PMID: 27500494 DOI: 10.1172/jci84429] [Citation(s) in RCA: 113] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Mucosal surfaces are lined by epithelial cells and provide an important barrier to the flux of antigens from the outside. This barrier is provided at a number of levels, including epithelial junctional complexes, mucus production, and mucosa-derived antimicrobials. Tissue metabolism is central to the maintenance of homeostasis in the mucosa. In the intestine, for example, baseline pO2 levels are uniquely low due to counter-current blood flow and the presence of large numbers of bacteria. As such, hypoxia and HIF signaling predominates normal intestinal metabolism and barrier regulation during both homeostasis and active inflammation. Contributing factors that elicit important adaptive responses within the mucosa include the transcriptional regulation of tight junction proteins, metabolic regulation of barrier components, and changes in autophagic flux. Here, we review recent literature around the topic of hypoxia and barrier function in health and during disease.
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Yoshida S, Yamamoto H, Tetsui T, Kobayakawa Y, Hatano R, Mukaisho KI, Hattori T, Sugihara H, Asano S. Effects of ezrin knockdown on the structure of gastric glandular epithelia. J Physiol Sci 2016; 66:53-65. [PMID: 26329936 PMCID: PMC10717290 DOI: 10.1007/s12576-015-0393-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 08/18/2015] [Indexed: 10/23/2022]
Abstract
Ezrin, an adaptor protein that cross-links plasma membrane-associated proteins with the actin cytoskeleton, is concentrated on apical surfaces of epithelial cells, especially in microvilli of the small intestine and stomach. In the stomach, ezrin is predominantly expressed on the apical canalicular membrane of parietal cells. Transgenic ezrin knockdown mice in which the expression level of ezrin was reduced to <7% compared with the wild-type suffered from achlorhydria because of impairment of membrane fusion between tubulovesicles and apical membranes. We observed, for the first time, hypergastrinemia and foveolar hyperplasia in the gastric fundic region of the knockdown mice. Dilation of fundic glands was observed, the percentage of parietal and chief cells was reduced, and that of mucous-secreting cells was increased. The parietal cells of knockdown mice contained dilated tubulovesicles and abnormal mitochondria, and subsets of these cells contained abnormal vacuoles and multilamellar structures. Therefore, lack of ezrin not only causes achlorhydria and hypergastrinemia but also changes the structure of gastric glands, with severe perturbation of the secretory membranes of parietal cells.
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Affiliation(s)
- Saori Yoshida
- Department of Molecular Physiology, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga, 525-8577, Japan
| | - Hiroto Yamamoto
- Department of Molecular Physiology, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga, 525-8577, Japan
- Department of Pathology, Shiga University of Medical Sciences, Seta Tsukinowa-cho, Otsu, Shiga, 520-2192, Japan
| | - Takahito Tetsui
- Department of Molecular Physiology, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga, 525-8577, Japan
| | - Yuka Kobayakawa
- Department of Molecular Physiology, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga, 525-8577, Japan
| | - Ryo Hatano
- Department of Molecular Physiology, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga, 525-8577, Japan
| | - Ken-ichi Mukaisho
- Department of Pathology, Shiga University of Medical Sciences, Seta Tsukinowa-cho, Otsu, Shiga, 520-2192, Japan
| | - Takanori Hattori
- Department of Pathology, Shiga University of Medical Sciences, Seta Tsukinowa-cho, Otsu, Shiga, 520-2192, Japan
| | - Hiroyuki Sugihara
- Department of Pathology, Shiga University of Medical Sciences, Seta Tsukinowa-cho, Otsu, Shiga, 520-2192, Japan
| | - Shinji Asano
- Department of Molecular Physiology, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga, 525-8577, Japan.
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Zheng L, Kelly CJ, Colgan SP. Physiologic hypoxia and oxygen homeostasis in the healthy intestine. A Review in the Theme: Cellular Responses to Hypoxia. Am J Physiol Cell Physiol 2015; 309:C350-60. [PMID: 26179603 DOI: 10.1152/ajpcell.00191.2015] [Citation(s) in RCA: 327] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In recent years, the intestinal mucosa has proven to be an intriguing organ to study tissue oxygenation. The highly vascularized lamina propria juxtaposed to an anaerobic lumen containing trillions of metabolically active microbes results in one of the most austere tissue microenvironments in the body. Studies to date have determined that a healthy mucosa contains a steep oxygen gradient along the length of the intestine and from the lumen to the serosa. Advances in technology have allowed multiple independent measures and indicate that, in the healthy mucosa of the small and large intestine, the lumen-apposed epithelia experience Po2 conditions of <10 mmHg, so-called physiologic hypoxia. This unique physiology results from a combination of factors, including countercurrent exchange blood flow, fluctuating oxygen demands, epithelial metabolism, and oxygen diffusion into the lumen. Such conditions result in the activation of a number of hypoxia-related signaling processes, including stabilization of the transcription factor hypoxia-inducible factor. Here, we review the principles of mucosal oxygen delivery, metabolism, and end-point functional responses that result from this unique oxygenation profile.
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Affiliation(s)
- Leon Zheng
- Department of Medicine and Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, Colorado
| | - Caleb J Kelly
- Department of Medicine and Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, Colorado
| | - Sean P Colgan
- Department of Medicine and Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, Colorado
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Heterogeneous Nuclear Ribonucleoprotein A1 Improves the Intestinal Injury by Regulating Apoptosis Through Trefoil Factor 2 in Mice with Anti-CD3-induced Enteritis. Inflamm Bowel Dis 2015; 21:1541-52. [PMID: 25901972 DOI: 10.1097/mib.0000000000000401] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND The role of hnRNP A1 in the onset of intestinal inflammation remains unclear. This study investigated the function of hnRNP A1 in mice enteritis models. METHODS C57Bl6/J mice were intraperitoneally injected with anti-CD3 antibodies to develop enteritis. In the DSS-induced colitis group, the mice were allowed free access to 3% DSS solution in their drinking water for 5 days. 3H-mannitol flux and complementary DNA array tests were used to assess the intestinal barrier function and messenger RNA (mRNA) expression, respectively. Real-time PCR was performed after immunoprecipitation with anti-hnRNP antibodies to determine the specific mRNA binding of hnRNP A1. RESULTS The hnRNP A1 expression was increased in the intestine of the mouse at 24 hours after treatment with anti-CD3 antibodies and 5 days after starting DSS administration. Small interfering RNA (siRNA) against hnRNP A1 exacerbated the intestinal injuries in both models. According to the microarray analysis, trefoil factor 2 (TFF2) was identified as a candidate molecule targeted by hnRNP A1 in the anti-CD3 antibody-induced enteritis group. Moreover, the binding between hnRNP A1 and TFF2 mRNA significantly increased in the enteritis mice, and the administration of siRNA against either hnRNP A1 or TFF2 exacerbated the degree of intestinal injury. In the DSS-induced colitis group, treatment with the siRNA of hnRNP A1 worsened the intestinal injury, while the expression of TFF3 did not change. CONCLUSIONS hnRNP A1 improves intestinal injury in anti-CD3 antibody-induced enteritis mice through the upregulation of TFF2, which regulates apoptosis and enhances epithelial restoration, whereas this molecule ameliorates DSS-induced colitis through a different pathway.
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Yamaguchi J, Liss AS, Sontheimer A, Mino-Kenudson M, Castillo CFD, Warshaw AL, Thayer SP. Pancreatic duct glands (PDGs) are a progenitor compartment responsible for pancreatic ductal epithelial repair. Stem Cell Res 2015; 15:190-202. [PMID: 26100232 DOI: 10.1016/j.scr.2015.05.006] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 04/13/2015] [Accepted: 05/11/2015] [Indexed: 12/11/2022] Open
Abstract
Pancreatic duct glands (PDGs) have molecular features known to mark stem cell niches, but their function remains to be determined. To investigate the role of PDGs as a progenitor niche, PDGs were analyzed in both humans and mice. Cells were characterized by immunohistochemistry and microarray analysis. In vivo proliferative activity and migration of PDG cells were evaluated using a BrdU tag-and-chase strategy in a mouse model of pancreatitis. In vitro migration assays were used to determine the role of trefoil factor (TFF) -1 and 2 in cell migration. Proliferative activity in the pancreatic epithelium in response to inflammatory injury is identified principally within the PDG compartment. These proliferating cells then migrate out of the PDG compartment to populate the pancreatic duct. Most of the pancreatic epithelial migration occurs within 5days and relies, in part, on TFF-1 and -2. After migration, PDG cells lose their PDG-specific markers and gain a more mature pancreatic ductal phenotype. Expression analysis of the PDG epithelium reveals enrichment of embryonic and stem cell pathways. These results suggest that PDGs are an epithelial progenitor compartment that gives rise to mature differentiated progeny that migrate to the pancreatic duct. Thus PDGs are a progenitor niche important for pancreatic epithelial regeneration.
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Affiliation(s)
- Junpei Yamaguchi
- Andrew L. Warshaw Institute for Pancreatic Cancer Research, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Andrew S Liss
- Andrew L. Warshaw Institute for Pancreatic Cancer Research, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Alexandra Sontheimer
- Andrew L. Warshaw Institute for Pancreatic Cancer Research, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Mari Mino-Kenudson
- Andrew L. Warshaw Institute for Pancreatic Cancer Research, Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Carlos Fernández-Del Castillo
- Andrew L. Warshaw Institute for Pancreatic Cancer Research, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Andrew L Warshaw
- Andrew L. Warshaw Institute for Pancreatic Cancer Research, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Sarah P Thayer
- Andrew L. Warshaw Institute for Pancreatic Cancer Research, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA; The University of Nebraska Medical Center (UNMC) Department of Surgery, Division of Surgical Oncology, Omaha, NE, USA.
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45
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Dunn LJ, Jankowski JA, Griffin SM. Trefoil Factor Expression in a Human Model of the Early Stages of Barrett's Esophagus. Dig Dis Sci 2015; 60:1187-94. [PMID: 25424203 DOI: 10.1007/s10620-014-3440-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Accepted: 11/14/2014] [Indexed: 12/22/2022]
Abstract
BACKGROUND Trefoil proteins are believed to have an important role in mucosal protection and repair in the gastrointestinal tract. They are well recognized in Barrett's esophagus and considered a potential biomarker for the condition. Metaplasia occurring in the esophageal remnant after esophagectomy is a human model for the early stages of development of Barrett's esophagus. AIMS To assess expression of trefoil proteins in post-esophagectomy columnar epithelium and to use trefoils as a molecular tool to understand regenerative mucosa in the esophagus. METHODS Patients with columnar metaplasia in the esophageal remnant were recruited from a large esophago-gastric cancer center. Trefoil factor expression was determined using immunohistochemical techniques. RESULTS Samples were obtained from 37 patients. TFF1 and TFF2 were expressed by all samples in a similar pattern to that described in studies of sporadic Barrett's esophagus. TFF3 was less widely expressed and was significantly associated with time elapsed between surgery and endoscopy. Median time from surgery to endoscopy was 8.1 years for patients with TFF3 expression versus 3.4 years for those without (p = 0.004). CONCLUSIONS Widespread expression of trefoils in this environment suggests that these proteins have an important role in development of Barrett's metaplasia. TFF3 expression may be absent in the early stages of metaplasia and may represent more established columnar epithelium. Biopsy samples from post-esophagectomy patients provide a valuable resource to study the early stages of Barrett's esophagus.
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Affiliation(s)
- Lorna J Dunn
- Northern Oesophago-Gastric Cancer Unit, Royal Victoria Infirmary, Queen Victoria Road, Newcastle-upon-Tyne, NE1 4LP, UK,
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46
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Judd LM, Chalinor HV, Walduck A, Pavlic DI, Däbritz J, Dubeykovskaya Z, Wang TC, Menheniott TR, Giraud AS. TFF2 deficiency exacerbates weight loss and alters immune cell and cytokine profiles in DSS colitis, and this cannot be rescued by wild-type bone marrow. Am J Physiol Gastrointest Liver Physiol 2015; 308:G12-24. [PMID: 25324506 PMCID: PMC9925116 DOI: 10.1152/ajpgi.00172.2014] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The trefoil factor TFF2 is a member of a tripartite family of small proteins that is produced by the stomach and the colon. Recombinant TFF2, when applied intrarectally in a rodent model of hapten colitis, hastens mucosal healing and reduces inflammatory indexes. Additionally, TFF2 is expressed in immune organs, supporting a potential immunomodulatory and reparative role in the bowel. In this study we confirm that TFF2 is expressed in the colon and is specifically enriched in epithelial cells relative to colonic leukocytes. TFF2-deficient, but not TFF1-deficient, mice exhibit a more severe response to acute or chronic dextran sulfate (DSS)-induced colitis that correlates with a 50% loss of expression of TFF3, the principal colonic trefoil. In addition, the response to acute colitis is associated with altered expression of IL-6 and IL-33, but not other inflammatory cytokines. While TFF2 can reduce macrophage responsiveness and block inflammatory cell recruitment to the colon, the major role in limiting the susceptibility to acute colitis appears to be maintenance of barrier function. Bone marrow transfer experiments demonstrate that leukocyte expression of TFF2 is not sufficient for prevention of colitis induction but, rather, that the gastrointestinal epithelium is the primary source of TFF2. Together, these findings illustrate that epithelial TFF2 is an important endogenous regulator of gut mucosal homeostasis that can modulate immune and epithelial compartments. Because of its extreme stability, even in the corrosive gut lumen, TFF2 is an attractive candidate as an oral therapeutic scaffold for future drug development in the treatment of inflammatory bowel disease.
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Affiliation(s)
- Louise M. Judd
- 1Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia
| | - Heather V. Chalinor
- 1Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia
| | | | - Daniel I. Pavlic
- 1Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia
| | - Jan Däbritz
- 1Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia
| | - Zinaida Dubeykovskaya
- 3Department of Medicine and Irving Cancer Research Centre, Columbia University, New York, New York
| | - Timothy C. Wang
- 3Department of Medicine and Irving Cancer Research Centre, Columbia University, New York, New York
| | - Trevelyan R. Menheniott
- 1Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia
| | - Andrew S. Giraud
- 1Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia
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47
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Corfield AP. Mucins: A biologically relevant glycan barrier in mucosal protection. Biochim Biophys Acta Gen Subj 2015; 1850:236-52. [PMID: 24821013 DOI: 10.1016/j.bbagen.2014.05.003] [Citation(s) in RCA: 377] [Impact Index Per Article: 37.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 04/05/2014] [Accepted: 05/02/2014] [Indexed: 02/08/2023]
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48
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Hensel KO, Boland V, Postberg J, Zilbauer M, Heuschkel R, Vogel S, Gödde D, Wirth S, Jenke AC. Differential expression of mucosal trefoil factors and mucins in pediatric inflammatory bowel diseases. Sci Rep 2014; 4:7343. [PMID: 25475414 PMCID: PMC4256710 DOI: 10.1038/srep07343] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Accepted: 11/18/2014] [Indexed: 02/06/2023] Open
Abstract
In the intestinal mucosa trefoil factors (TFF) and mucins (Muc) - primarily produced by goblet cells - are thought to play a major role in providing barrier function during infection and inflammation. To investigate their role in pediatric Crohn's disease (CD) and ulcerative colitis (UC) we obtained mucosal biopsies of children with CD, UC and healthy controls and analyzed genetic expression. Levels of TFF2 mRNA were lower in inflamed mucosal samples (terminal ileum (TI) and duodenum) of children with CD, but higher in non-inflamed mucosal samples when compared to healthy controls (p < 0.05). Similarly, TFF2 levels in the TI were significantly lower in inflamed UC tissue. Adjustment for goblet cell density revealed slightly less marked, yet significantly different gene expression in IBD and controls. Furthermore, TI expression of TFF2 and Muc2 was inversely correlated with interleukin-8 expression in CD (p = 0.027). In Summary, our data demonstrate significant changes in Muc and TFF mRNA expression in pediatric patients with IBD suggesting a role in mucosal healing. Further studies are needed to elucidate a potential use as biomarkers for disease progression.
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Affiliation(s)
- Kai O Hensel
- Department of Pediatrics, HELIOS Medical Center Wuppertal, Faculty of Health, Witten/Herdecke University, Germany
| | - Veronika Boland
- Department of Pediatrics, HELIOS Medical Center Wuppertal, Faculty of Health, Witten/Herdecke University, Germany
| | - Jan Postberg
- Department of Pediatrics, HELIOS Medical Center Wuppertal, Faculty of Health, Witten/Herdecke University, Germany
| | - Matthias Zilbauer
- 1] Department of Pediatric Gastroenterology, Hepatology and Nutrition, Addenbrooke's Hospital, Cambridge, UK [2] University Department of Pediatrics, University of Cambridge, Cambridge, UK
| | - Robert Heuschkel
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Addenbrooke's Hospital, Cambridge, UK
| | - Silvia Vogel
- Department of Pathology, HELIOS Medical Center Wuppertal, Faculty of Health, Witten/Herdecke University, Germany
| | - Daniel Gödde
- Department of Pathology, HELIOS Medical Center Wuppertal, Faculty of Health, Witten/Herdecke University, Germany
| | - Stefan Wirth
- Department of Pediatrics, HELIOS Medical Center Wuppertal, Faculty of Health, Witten/Herdecke University, Germany
| | - Andreas C Jenke
- Department of Pediatrics, HELIOS Medical Center Wuppertal, Faculty of Health, Witten/Herdecke University, Germany
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49
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Lavery DL, Nicholson AM, Poulsom R, Jeffery R, Hussain A, Gay LJ, Jankowski JA, Zeki SS, Barr H, Harrison R, Going J, Kadirkamanathan S, Davis P, Underwood T, Novelli MR, Rodriguez-Justo M, Shepherd N, Jansen M, Wright NA, McDonald SAC. The stem cell organisation, and the proliferative and gene expression profile of Barrett's epithelium, replicates pyloric-type gastric glands. Gut 2014; 63:1854-63. [PMID: 24550372 PMCID: PMC4251192 DOI: 10.1136/gutjnl-2013-306508] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 01/20/2014] [Accepted: 01/21/2014] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Barrett's oesophagus shows appearances described as 'intestinal metaplasia', in structures called 'crypts' but do not typically display crypt architecture. Here, we investigate their relationship to gastric glands. METHODS Cell proliferation and migration within Barrett's glands was assessed by Ki67 and iododeoxyuridine (IdU) labelling. Expression of mucin core proteins (MUC), trefoil family factor (TFF) peptides and LGR5 mRNA was determined by immunohistochemistry or by in situ hybridisation, and clonality was elucidated using mitochondrial DNA (mtDNA) mutations combined with mucin histochemistry. RESULTS Proliferation predominantly occurs in the middle of Barrett's glands, diminishing towards the surface and the base: IdU dynamics demonstrate bidirectional migration, similar to gastric glands. Distribution of MUC5AC, TFF1, MUC6 and TFF2 in Barrett's mirrors pyloric glands and is preserved in Barrett's dysplasia. MUC2-positive goblet cells are localised above the neck in Barrett's glands, and TFF3 is concentrated in the same region. LGR5 mRNA is detected in the middle of Barrett's glands suggesting a stem cell niche in this locale, similar to that in the gastric pylorus, and distinct from gastric intestinal metaplasia. Gastric and intestinal cell lineages within Barrett's glands are clonal, indicating derivation from a single stem cell. CONCLUSIONS Barrett's shows the proliferative and stem cell architecture, and pattern of gene expression of pyloric gastric glands, maintained by stem cells showing gastric and intestinal differentiation: neutral drift may suggest that intestinal differentiation advances with time, a concept critical for the understanding of the origin and development of Barrett's oesophagus.
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Affiliation(s)
- Danielle L Lavery
- Epithelial Stem Cell Group, Centre for Tumour Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Anna M Nicholson
- Stem Cell Biology of the Intestine Laboratory, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK
| | - Richard Poulsom
- Centre for Digestive Diseases, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Rosemary Jeffery
- Centre for Digestive Diseases, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Alia Hussain
- Epithelial Stem Cell Group, Centre for Tumour Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Laura J Gay
- Epithelial Stem Cell Group, Centre for Tumour Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Janusz A Jankowski
- Centre for Digestive Diseases, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Sebastian S Zeki
- Epithelial Stem Cell Group, Centre for Tumour Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Hugh Barr
- Department of Surgery, Gloucestershire Royal Hospital, Gloucestershire Royal Hospital, Gloucester, UK
| | - Rebecca Harrison
- Department of Pathology, University Hospitals Leicester, Leicester, UK
| | - James Going
- University of Glasgow, Institute of Cancer Sciences, Glasgow, UK
| | | | - Peter Davis
- Mid Essex Hospital Services NHS Trust, Broomfield Hospital, Chelmsford, UK
| | | | - Marco R Novelli
- Department of Histopathology, University College London, London, UK
| | | | - Neil Shepherd
- Gloucestershire Cellular Pathology Laboratory, Cheltenham General Hospital, Cheltenham, UK
| | - Marnix Jansen
- Department of Pathology, Academic Medical Center (AMC), Amsterdam, The Netherlands
| | - Nicholas A Wright
- Epithelial Stem Cell Group, Centre for Tumour Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Stuart A C McDonald
- Epithelial Stem Cell Group, Centre for Tumour Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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50
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Spenlé C, Lefebvre O, Lacroute J, Méchine-Neuville A, Barreau F, Blottière HM, Duclos B, Arnold C, Hussenet T, Hemmerlé J, Gullberg D, Kedinger M, Sorokin L, Orend G, Simon-Assmann P. The laminin response in inflammatory bowel disease: protection or malignancy? PLoS One 2014; 9:e111336. [PMID: 25347196 PMCID: PMC4210184 DOI: 10.1371/journal.pone.0111336] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 09/23/2014] [Indexed: 02/07/2023] Open
Abstract
Laminins (LM), basement membrane molecules and mediators of epithelial-stromal communication, are crucial in tissue homeostasis. Inflammatory Bowel Diseases (IBD) are multifactorial pathologies where the microenvironment and in particular LM play an important yet poorly understood role in tissue maintenance, and in cancer progression which represents an inherent risk of IBD. Here we showed first that in human IBD colonic samples and in murine colitis the LMα1 and LMα5 chains are specifically and ectopically overexpressed with a concomitant nuclear p53 accumulation. Linked to this observation, we provided a mechanism showing that p53 induces LMα1 expression at the promoter level by ChIP analysis and this was confirmed by knockdown in cell transfection experiments. To mimic the human disease, we induced colitis and colitis-associated cancer by chemical treatment (DSS) combined or not with a carcinogen (AOM) in transgenic mice overexpressing LMα1 or LMα5 specifically in the intestine. We demonstrated that high LMα1 or LMα5 expression decreased susceptibility towards experimentally DSS-induced colon inflammation as assessed by histological scoring and decrease of pro-inflammatory cytokines. Yet in a pro-oncogenic context, we showed that LM would favor tumorigenesis as revealed by enhanced tumor lesion formation in both LM transgenic mice. Altogether, our results showed that nuclear p53 and associated overexpression of LMα1 and LMα5 protect tissue from inflammation. But in a mutation setting, the same LM molecules favor progression of IBD into colitis-associated cancer. Our transgenic mice represent attractive new models to acquire knowledge about the paradoxical effect of LM that mediate either tissue reparation or cancer according to the microenvironment. In the early phases of IBD, reinforcing basement membrane stability/organization could be a promising therapeutic approach.
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Affiliation(s)
- Caroline Spenlé
- Inserm U1109, MNT3 team, Strasbourg, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Olivier Lefebvre
- Inserm U1109, MNT3 team, Strasbourg, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Joël Lacroute
- Inserm U1109, MNT3 team, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Department of Gastroenterology, CHRU Hautepierre, Strasbourg, France
| | | | | | - Hervé M Blottière
- INRA, UMR1319, Jouy-en-Josas, France; AgroParisTech, UMR Micalis, Jouy-en-Josas, France
| | - Bernard Duclos
- Department of Gastroenterology, CHRU Hautepierre, Strasbourg, France
| | - Christiane Arnold
- Inserm U1109, MNT3 team, Strasbourg, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Thomas Hussenet
- Inserm U1109, MNT3 team, Strasbourg, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Joseph Hemmerlé
- Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France; Inserm U1121, Strasbourg, France
| | - Donald Gullberg
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Michèle Kedinger
- Inserm U1109, MNT3 team, Strasbourg, France; Université de Strasbourg, Strasbourg, France
| | - Lydia Sorokin
- Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany
| | - Gertraud Orend
- Inserm U1109, MNT3 team, Strasbourg, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Patricia Simon-Assmann
- Inserm U1109, MNT3 team, Strasbourg, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
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