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Quan T, Li R, Gao T. The Intestinal Macrophage-Intestinal Stem Cell Axis in Inflammatory Bowel Diseases: From Pathogenesis to Therapy. Int J Mol Sci 2025; 26:2855. [PMID: 40243444 PMCID: PMC11988290 DOI: 10.3390/ijms26072855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 03/19/2025] [Accepted: 03/19/2025] [Indexed: 04/18/2025] Open
Abstract
The gut plays a crucial role in digestion and immunity, so its balance is essential to overall health. This balance relies on dynamic interactions between intestinal epithelial cells, immune cells, and crypt stem cells. Inflammatory bowel disease (IBD), which consists of ulcerative colitis and Crohn's disease, is a chronic relapsing inflammatory disease of the gastrointestinal tract closely related to immune dysfunction. Stem cells, known for their ability to self-renew and differentiate, play an important role in repairing damaged intestinal epithelium and maintaining homeostasis in vivo. Macrophages are key gatekeepers of intestinal immune homeostasis and have a significant impact on IBD. Current research has focused on the link between epithelial cells and stem cells, but interactions with macrophages, which have been recognized as attractive targets for the development of new therapeutic approaches to disease, have been less explored. Recently, the developing field of immunometabolism has reinforced that metabolic reprogramming is a key determinant of macrophage function and subsequent disease progression. The aim of this review is to explore the role of the macrophage-stem cell axis in the maintenance of intestinal homeostasis and to summarize potential approaches to treating IBD by manipulating the cellular metabolism of macrophages, as well as the main opportunities and challenges faced. In summary, our overview provides a framework for understanding the critical role of macrophage immunometabolism in maintaining gut health and potential therapeutic targets.
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Affiliation(s)
| | | | - Ting Gao
- College of Veterinary Medicine, China Agricultural University, Beijing 100083, China; (T.Q.); (R.L.)
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2
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Yue N, Zhao H, Hu P, Zhang Y, Tian C, Kong C, Mai Z, Huang L, Luo Q, Wei D, Shi R, Tang S, Nie Y, Liang Y, Yao J, Wang L, Li D. Real-world of Limosilactobacillus reuteri in mitigation of acute experimental colitis. J Nanobiotechnology 2025; 23:65. [PMID: 39891249 PMCID: PMC11783912 DOI: 10.1186/s12951-025-03158-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Accepted: 01/22/2025] [Indexed: 02/03/2025] Open
Abstract
Probiotics have been proposed as a potential strategy for managing ulcerative colitis (UC). However, the underlying mechanisms mediating microbiota-host crosstalk remain largely elusive. Here, we report that Limosilactobacillus reuteri (L. reuteri), as a probiotic, secretes cytoplasmic membrane vesicles (CMVs) that communicate with host cells, alter host physiology, and alleviate dextran sulfate sodium (DSS)-induced colitis. First, L. reuteri-CMVs selectively promoted the proliferation of the beneficial bacterium Akkermansia muciniphila (AKK) by upregulating the expression of glycosidases (beta-N-acetylhexosaminidase and alpha-N-acetylglucosaminidase) involved in glycan degradation and metabolic pathways and restored the disrupted gut microbiota balance. Second, L. reuteri-CMVs were taken up by intestinal epithelial cells (IECs), elevated the expression of ZO-1, E-cadherin (Cdh1), and Occludin (Ocln), decreased intestinal permeability, and exerted protective effects on epithelial tight junction functionality. RNA sequencing analysis demonstrated that L. reuteri-CMVs repaired intestinal barrier by activating the HIF-1 signaling pathway and upregulating HMOX1 expression. Third, L. reuteri-CMVs increased the population of double positive (DP) CD4+CD8+ T cells in the intestinal epithelial layer, suppressing gut inflammation and maintaining gut mucosal homeostasis. Finally, L. reuteri-CMVs exhibited satisfactory stability and safety in the gastrointestinal tract and specifically targeted the desired sites in colitis mice. Collectively, these findings shed light on how L. reuteri interact with the host in colitis, and provide new insights into potential strategies for alleviating colitis.
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Affiliation(s)
- Ningning Yue
- Department of Gastroenterology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, 518020, China
| | - Hailan Zhao
- Department of Gastroenterology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, 518020, China
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, 510630, China
| | - Peng Hu
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China
| | - Yuan Zhang
- Department of Medical Administration, Huizhou Institute of Occupational Diseases Control and Prevention, Huizhou, Guangdong, 516008, China
| | - Chengmei Tian
- Department of Emergency, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, 518020, China
| | - Chen Kong
- Department of Gastroenterology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, 518020, China
| | - Zhiliang Mai
- Department of Gastroenterology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, 518020, China
| | - Longbin Huang
- Department of Gastroenterology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, 518020, China
| | - Qianjun Luo
- Department of Endocrine, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, Guangdong, 518067, China
| | - Daoru Wei
- Department of Rehabilitation, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, 518020, China
| | - Ruiyue Shi
- Department of Gastroenterology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, 518020, China
| | - Shaohui Tang
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, 510630, China
| | - Yuqiang Nie
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, China
| | - Yujie Liang
- Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, Guangdong, 518020, China.
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, 518020, China.
- Department of Gastroenterology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, 518020, China.
| | - Lisheng Wang
- Department of Gastroenterology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, 518020, China.
- Department of Gastroenterology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, 518020, China.
| | - Defeng Li
- Department of Gastroenterology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, 518020, China.
- Department of Gastroenterology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, 518020, China.
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3
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Zhang J, Jia C, Dong J, Wu J, Liu M, Zhang H, Zhao C. The role of sodium butyrate in modulating growth, intestinal health, and antimicrobial efficacy in turbot (Scophthalmus maximus L.) fed high soy diets. Sci Rep 2024; 14:32033. [PMID: 39739006 PMCID: PMC11685986 DOI: 10.1038/s41598-024-83704-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 12/17/2024] [Indexed: 01/02/2025] Open
Abstract
Butyrate is one of the most abundant short-chain fatty acids (SCFAs), which are important metabolites of dietary fiber by fermentation of gut commensals, and has been shown to be vital in maintaining host health. The present study mainly investigated how sodium butyrate (NaB) supplementation in the diet with high proportion of soybean meal (SBM) affected turbot. Four experimental diets were formulated: (1) fish meal (FM) based diet (control group), (2) SBM protein replacing 45% FM protein in the diet (high SBM group), (3) 0.2% NaB supplementation in the high SBM diet (high SBM + 0.2% NaB group), and (4) 0.5% NaB supplementation in the high SBM diet (high SBM + 0.5% NaB group). The fish were fed four different diets for 8 weeks. The results showed that the high SBM diet significantly suppressed growth performance, induced typical enteritis symptoms and decreased resistance to bacterial infection. However, inclusion of 0.2% and 0.5% NaB in the high SBM diet both effectively increased the growth performance of turbot. Meanwhile, dietary NaB protected the intestinal morphology, and regulated the gene expression of inflammatory cytokines to relieve the inflammation of turbot, such as TNFα, IL-1β, NFκB and IL-10. Moreover, supplementation with NaB in the high SBM diet activated HIF-1α/IL-22/Lysozyme signaling pathway to against Edwardsiella tarda (E. tarda) infection, especially 0.5% NaB supplementation exerted more effectively to defence bacterial infection under inflammatory state. In conclusion, dietary NaB significantly promoted growth and gut health of turbot. Besides, it enhanced the resistance of fish to bacterial infection, especially dietary 0.5% NaB supplementation.
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Affiliation(s)
- Jinjin Zhang
- Weifang University of Science and Technology, Jinguang Road No. 1299, Weifang City, Shandong Province, China.
| | - Cuijing Jia
- Weifang University of Science and Technology, Jinguang Road No. 1299, Weifang City, Shandong Province, China
| | - Jinping Dong
- Weifang University of Science and Technology, Jinguang Road No. 1299, Weifang City, Shandong Province, China
| | - Jingliang Wu
- Weifang University of Science and Technology, Jinguang Road No. 1299, Weifang City, Shandong Province, China
| | - Minggang Liu
- Weifang University of Science and Technology, Jinguang Road No. 1299, Weifang City, Shandong Province, China
| | - Hansong Zhang
- Weifang University of Science and Technology, Jinguang Road No. 1299, Weifang City, Shandong Province, China
| | - Chengshuo Zhao
- Weifang University of Science and Technology, Jinguang Road No. 1299, Weifang City, Shandong Province, China
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Biscu F, Zouzaf A, Cicia D, Pridans C, Matteoli G. Innate immunity champions: The diverse functions of macrophages. Eur J Immunol 2024; 54:e2451139. [PMID: 39308210 DOI: 10.1002/eji.202451139] [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: 06/27/2024] [Revised: 09/03/2024] [Accepted: 09/05/2024] [Indexed: 12/11/2024]
Abstract
Macrophages are instrumental in maintaining tissue homeostasis, modulating inflammation, and driving regeneration. The advent of omics techniques has led to the identification of numerous tissue-specific macrophage subtypes, thereby introducing the concept of the "macrophage niche". This paradigm underscores the ability of macrophages to adapt their functions based on environmental cues, such as tissue-specific signals. This adaptability is closely linked to their metabolic states, which are crucial for their function and role in health and disease. Macrophage metabolism is central to their ability to switch between proinflammatory and anti-inflammatory states. In this regard, environmental factors, including the extracellular matrix, cellular interactions, and microbial metabolites, profoundly influence macrophage behavior. Moreover, diet and gut microbiota significantly impact macrophage function, with nutrients and microbial metabolites influencing their activity and contributing to conditions like inflammatory bowel disease. Targeting specific macrophage functions and their metabolic processes is leading to the development of novel treatments for a range of chronic inflammatory conditions. The exploration of macrophage biology enriches our understanding of immune regulation and holds the promise of innovative approaches to managing diseases marked by inflammation and immune dysfunction, offering a frontier for scientific and clinical advancement.
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Affiliation(s)
- Francesca Biscu
- Laboratory of Mucosal Immunology, Department of Chronic Diseases, Metabolism, and Ageing (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom
| | - Anissa Zouzaf
- Laboratory of Mucosal Immunology, Department of Chronic Diseases, Metabolism, and Ageing (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Donatella Cicia
- Laboratory of Mucosal Immunology, Department of Chronic Diseases, Metabolism, and Ageing (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Clare Pridans
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom
| | - Gianluca Matteoli
- Laboratory of Mucosal Immunology, Department of Chronic Diseases, Metabolism, and Ageing (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
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5
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Kang GS, Kim YE, Oh HR, Jo HJ, Bok S, Jeon YK, Cheon GJ, Roh TY, Chang YT, Park DJ, Ahn GO. Hypoxia-inducible factor-1α-deficient adipose-tissue macrophages produce the heat to mediate lipolysis of white adipose tissue through uncoupling protein-1. Lab Anim Res 2024; 40:37. [PMID: 39473019 PMCID: PMC11523771 DOI: 10.1186/s42826-024-00224-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 10/17/2024] [Accepted: 10/22/2024] [Indexed: 11/02/2024] Open
Abstract
BACKGROUND Uncoupling protein 1 (UCP1) is a proton uncoupler located across the mitochondrial membrane generally involved in thermogenesis of brown adipose tissues. Although UCP1 is known to be strongly expressed in brown adipocytes, recent evidence suggest that white adipocytes can also express UCP1 under certain circumstances such as cold- or β-adrenergic receptor-stimulation, allowing them to acquire brown adipocyte-like features thereby becoming 'beige' adipocytes. RESULTS In this study, we report that UCP1 can be expressed in adipose-tissue macrophages (ATM) lacking functional hypoxia-inducible factor-1 (HIF-1) and this does not require cold- nor β-adrenergic receptor activation. By using myeloid-specific Hif-1α knockout (KO) mice, we observed that these mice were protected from diet-induced obesity and exhibited an improved thermogenic tolerance upon cold challenge. ATM isolated from white adipose tissues (WAT) of these mice fed with high fat diet exhibited significantly higher M2-polarization, decreased glycolysis, increased mitochondrial functions and acetyl-CoA levels, along with increased expression of Ucp1, peroxisome proliferator activated receptor-gamma co-activator-1a, and others involved in histone acetylation. Consistent with the increased Ucp1 gene expression, these ATM produced a significant amount of heat mediating lipolysis of co-cultured adipocytes liberating free fatty acid. Treating ATM with acetate, a substrate for acetyl-CoA synthesis was able to boost the heat production in wild-type or Hif-1α-deficient but not UCP1-deficient macrophages, indicating that UCP1 was necessary for the heat production in macrophages. Lastly, we observed a significant inverse correlation between the number of UCP1-expressing ATM in WAT and the body mass index of human individuals. CONCLUSIONS UCP1-expressing ATM produce the heat to mediate lipolysis of adipocytes, indicating that this can be a novel strategy to treat and prevent diet-induced obesity.
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Affiliation(s)
- Gi-Sue Kang
- College of Veterinary Medicine, Seoul National University, Seoul, 08826, Korea
| | - Young-Eun Kim
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Korea
| | - Ho Rim Oh
- Department of Nuclear Medicine, College of Medicine, Seoul National University, Seoul, 03080, Korea
| | - Hye-Ju Jo
- College of Veterinary Medicine, Seoul National University, Seoul, 08826, Korea
| | - Seoyeon Bok
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Korea
| | - Yoon Kyung Jeon
- Department of Pathology, College of Medicine, Seoul National University, Seoul, 03080, Korea
| | - Gi Jeong Cheon
- Department of Nuclear Medicine, College of Medicine, Seoul National University, Seoul, 03080, Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, Korea
- College of Medicine, Cancer Research Institute, Seoul National University, Seoul, 03080, Korea
| | - Tae-Young Roh
- Department of Life Sciences, Ewha Womans University, Seoul, 03760, Korea
| | | | - Do Joong Park
- Department of Surgery, College of Medicine, Seoul National University, Seoul, 03080, Korea
| | - G-One Ahn
- College of Veterinary Medicine, Seoul National University, Seoul, 08826, Korea.
- College of Medicine, Cancer Research Institute, Seoul National University, Seoul, 03080, Korea.
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6
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Ma X, Li M, Wang X, Xu H, Jiang L, Wu F, Wei L, Qi G, Zhang D. Dihydromyricetin ameliorates experimental ulcerative colitis by inhibiting neutrophil extracellular traps formation via the HIF-1α/VEGFA signaling pathway. Int Immunopharmacol 2024; 138:112572. [PMID: 38955027 DOI: 10.1016/j.intimp.2024.112572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 06/24/2024] [Accepted: 06/24/2024] [Indexed: 07/04/2024]
Abstract
Dihydromyricetin (DHM), which has various biological functions, possesses therapeutic potential for ulcerative colitis (UC). Neutrophil extracellular traps (NETs) and their components play a crucial role in several pathological processes in UC. However, whether DHM alleviates UC by regulating NETs remains unclear. Mice with dextran sulfate sodium (DSS)-induced acute colitis were treated with DHM at different concentrations, and the severity of colitis was evaluated by assessing body weight, colon length, histological scores, cytokine production, and epithelial barrier integrity. To quantify and visualize NETs, the expression of cell free-DNA (cf-DNA) in serum and Cit-H3 in colonic tissue was analyzed via western blotting and immunofluorescence analysis. HL-60 cells and mouse bone marrow-derived neutrophils (BMDNs) were used to evaluate the effects of DHM on NETs in vitro. NETs were treated with DHM at varying concentrations or DNase I and used to repair the intestinal epithelial barrier in a Caco-2/HIEC-6 cell monolayer model. Furthermore, the genes targeted by DHM through neutrophils for alleviating UC were identified by screening online databases, and the results of network pharmacological analysis were verified via western blotting and quantitative real-time polymerase chain reaction. DHM alleviated DSS-induced colitis in mice by reversing weight loss, increased DAI score, colon length shortening, enhanced spleen index, colonic pathological damage, cytokine production, and epithelial barrier loss in a dose-dependent manner. In addition, it inhibited the formation of NETs both in vivo and in vitro. Based on the results of network pharmacological analysis, DHM may target HIF-1α and VEGFA through neutrophils to alleviate UC. Treatment with PMA increased the expression of HIF-1α and VEGFA in D-HL-60 cells and BMDNs, whereas treatment with DHM or DNase I reversed this effect. Treatment with DMOG, an inhibitor of HIF prolyl hydroxylase (HIF-PH), counteracted the suppressive effects of DHM on NETs formation in D-HL-60 cells and BMDNs. Accordingly, it partially counteracted the protective effects of DHM on the intestinal epithelial barrier in Caco-2 and HIEC-6 cells. These results indicated that DHM alleviated DSS-induced UC by regulating NETs formation via the HIF-1α/VEGFA signaling pathway, suggesting that DHM is a promising therapeutic candidate for UC.
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Affiliation(s)
- Xueni Ma
- Key Laboratory of Digestive Diseases, Lanzhou University Second Hospital, Lanzhou, China; The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Muyang Li
- Key Laboratory of Digestive Diseases, Lanzhou University Second Hospital, Lanzhou, China; The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Xiaochun Wang
- Key Laboratory of Digestive Diseases, Lanzhou University Second Hospital, Lanzhou, China; Department of Gastroenterology, Gansu Provincial Hospital, Lanzhou, China
| | - Huimei Xu
- Key Laboratory of Digestive Diseases, Lanzhou University Second Hospital, Lanzhou, China; The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Luxia Jiang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China; Department of Cardiac Surgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Fanqi Wu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China; Department of Respiratory, Lanzhou University Second Hospital, Lanzhou, China
| | - Lina Wei
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, China
| | - Guoqing Qi
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, China
| | - Dekui Zhang
- Key Laboratory of Digestive Diseases, Lanzhou University Second Hospital, Lanzhou, China; Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, China.
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7
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Xin R. Inflammatory Gene Panel Guiding the Study of Genetics in Inflammatory Bowel Disease. Mol Diagn Ther 2024; 28:389-401. [PMID: 38635139 DOI: 10.1007/s40291-024-00709-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2024] [Indexed: 04/19/2024]
Abstract
Inflammatory bowel disease (IBD) is a complex disease that develops through a sequence of molecular events that are still poorly defined. This process is driven by a multitude of context-dependent genes that play different roles based on their environment. The complexity and multi-faceted nature of these genes make it difficult to study the genetic basis of IBD. The goal of this article is to review the key genes in the pathophysiology of IBD and highlight new technology that can be used in further research. This paper examines Nanostring RNA probe technology, which uses tissue analyzed without the use of enzymes, transcription, or amplification. Nanostring offers several panels of genes to test, including an inflammation panel of 234 genes. This article analyzes this panel and reviews the literature for each gene's effect in IBD for use as a framework to review the pathophysiology of the disease. The panel was narrowed to 26 genes with significant evidence of mechanistic potential in IBD, which were then categorized into specific areas of pathogenesis. These include gut barrier breakdown, inappropriate recognition of commensal bacteria, immune cell activation, proinflammatory cytokine release, and subsequent impairment of the anti-inflammatory response. The eventual goal of this paper is the creation of a customized panel of IBD genes that can be used to better understand the genetic mechanism of IBD and aid in the development of future therapies in IBD.
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Affiliation(s)
- Ryan Xin
- Columbia University Irving Medical Center, 177 Fort Washington Avenue, New York, NY, 10032, USA.
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8
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Xiao J, Guo X, Wang Z. Crosstalk between hypoxia-inducible factor-1α and short-chain fatty acids in inflammatory bowel disease: key clues toward unraveling the mystery. Front Immunol 2024; 15:1385907. [PMID: 38605960 PMCID: PMC11007100 DOI: 10.3389/fimmu.2024.1385907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 03/19/2024] [Indexed: 04/13/2024] Open
Abstract
The human intestinal tract constitutes a complex ecosystem, made up of countless gut microbiota, metabolites, and immune cells, with hypoxia being a fundamental environmental characteristic of this ecology. Under normal physiological conditions, a delicate balance exists among these complex "residents", with disruptions potentially leading to inflammatory bowel disease (IBD). The core pathology of IBD features a disrupted intestinal epithelial barrier, alongside evident immune and microecological disturbances. Central to these interconnected networks is hypoxia-inducible factor-1α (HIF-1α), which is a key regulator in gut cells for adapting to hypoxic conditions and maintaining gut homeostasis. Short-chain fatty acids (SCFAs), as pivotal gut metabolites, serve as vital mediators between the host and microbiota, and significantly influence intestinal ecosystem. Recent years have seen a surge in research on the roles and therapeutic potential of HIF-1α and SCFAs in IBD independently, yet reviews on HIF-1α-mediated SCFAs regulation of IBD under hypoxic conditions are scarce. This article summarizes evidence of the interplay and regulatory relationship between SCFAs and HIF-1α in IBD, pivotal for elucidating the disease's pathogenesis and offering promising therapeutic strategies.
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Affiliation(s)
- Jinyin Xiao
- Graduate School, Hunan University of Traditional Chinese Medicine, Changsha, China
- Department of Anorectal, the Second Affiliated Hospital of Hunan University of Traditional Chinese Medicine, Changsha, China
| | - Xiajun Guo
- Department of Geriatric, the First People’s Hospital of Xiangtan City, Xiangtan, China
| | - Zhenquan Wang
- Department of Anorectal, the Second Affiliated Hospital of Hunan University of Traditional Chinese Medicine, Changsha, China
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9
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Long XQ, Liu MZ, Liu ZH, Xia LZ, Lu SP, Xu XP, Wu MH. Bile acids and their receptors: Potential therapeutic targets in inflammatory bowel disease. World J Gastroenterol 2023; 29:4252-4270. [PMID: 37545642 PMCID: PMC10401658 DOI: 10.3748/wjg.v29.i27.4252] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 05/19/2023] [Accepted: 06/21/2023] [Indexed: 07/13/2023] Open
Abstract
Chronic and recurrent inflammatory disorders of the gastrointestinal tract caused by a complex interplay between genetics and intestinal dysbiosis are called inflammatory bowel disease. As a result of the interaction between the liver and the gut microbiota, bile acids are an atypical class of steroids produced in mammals and traditionally known for their function in food absorption. With the development of genomics and metabolomics, more and more data suggest that the pathophysiological mechanisms of inflammatory bowel disease are regulated by bile acids and their receptors. Bile acids operate as signalling molecules by activating a variety of bile acid receptors that impact intestinal flora, epithelial barrier function, and intestinal immunology. Inflammatory bowel disease can be treated in new ways by using these potential molecules. This paper mainly discusses the increasing function of bile acids and their receptors in inflammatory bowel disease and their prospective therapeutic applications. In addition, we explore bile acid metabolism and the interaction of bile acids and the gut microbiota.
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Affiliation(s)
- Xiong-Quan Long
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Ming-Zhu Liu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Zi-Hao Liu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Lv-Zhou Xia
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Shi-Peng Lu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Xiao-Ping Xu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
| | - Ming-Hao Wu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha 410005, Hunan Province, China
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10
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Schwarz J, Rühle J, Stephan K, Dietz S, Geißert J, Schoppmeier U, Frick JS, Hudalla H, Lajqi T, Poets CF, Gille C, Köstlin-Gille N. HIF-1α targeted deletion in myeloid cells decreases MDSC accumulation and alters microbiome in neonatal mice. Eur J Immunol 2023; 53:e2250144. [PMID: 37044112 DOI: 10.1002/eji.202250144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 04/01/2023] [Accepted: 04/11/2023] [Indexed: 04/14/2023]
Abstract
The newborn's immune system is faced with the challenge of having to learn quickly to fight off infectious agents, but tolerating the colonization of the body surfaces with commensals without reacting with an excessive inflammatory response. Myeloid-derived suppressor cells (MDSC) are innate immune cells with suppressive activity on other immune cells that regulate fetal-maternal tolerance during pregnancy and control intestinal inflammation in neonates. Until now, nothing is known about the role of MDSC in microbiome establishment. One of the transcription factors regulating MDSC homeostasis is the hypoxia-inducible factor 1α (HIF-1α). We investigated the impact of HIF-1α on MDSC accumulation and microbiome establishment during the neonatal period in a mouse model with targeted deletion of HIF-1α in myeloid cells (Hif1a loxP/loxP LysMCre+). We show that in contrast to wildtype mice, where an extensive expansion of MDSC was observed, MDSC expansion in neonatal Hif1a loxP/loxP LysMCre+ mice was dramatically reduced both systemically and locally in the intestine. This was accompanied by an altered microbiome composition and intestinal T-cell homeostasis. Our results point toward a role of MDSC in inflammation regulation in the context of microbiome establishment and thus reveal a new aspect of the biological role of MDSC during the neonatal period.
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Affiliation(s)
- Julian Schwarz
- Tuebingen University Children's Hospital, Department of Neonatology, Tuebingen, Germany
| | - Jessica Rühle
- Tuebingen University Children's Hospital, Department of Neonatology, Tuebingen, Germany
| | - Kevin Stephan
- Tuebingen University Children's Hospital, Department of Neonatology, Tuebingen, Germany
| | - Stefanie Dietz
- Tuebingen University Children's Hospital, Department of Neonatology, Tuebingen, Germany
- Heidelberg University Children's Hospital, Department of Neonatology, Heidelberg, Germany
| | - Janina Geißert
- Institute for Medical Microbiology and Hygiene, University Hospital Tuebingen, Tuebingen, Germany
- NGS-Competence Center Tuebingen, Institute for Medical Microbiology and Hygiene, University Hospital Tuebingen, Tuebingen, Germany
| | - Ulrich Schoppmeier
- Institute for Medical Microbiology and Hygiene, University Hospital Tuebingen, Tuebingen, Germany
| | - Julia S Frick
- Institute for Medical Microbiology and Hygiene, University Hospital Tuebingen, Tuebingen, Germany
- MVZ Laboratory Ludwigsburg GbR, Germany
| | - Hannes Hudalla
- Heidelberg University Children's Hospital, Department of Neonatology, Heidelberg, Germany
| | - Trim Lajqi
- Heidelberg University Children's Hospital, Department of Neonatology, Heidelberg, Germany
| | - Christian F Poets
- Tuebingen University Children's Hospital, Department of Neonatology, Tuebingen, Germany
| | - Christian Gille
- Heidelberg University Children's Hospital, Department of Neonatology, Heidelberg, Germany
| | - Natascha Köstlin-Gille
- Tuebingen University Children's Hospital, Department of Neonatology, Tuebingen, Germany
- Heidelberg University Children's Hospital, Department of Neonatology, Heidelberg, Germany
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11
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Abstract
Inflammatory bowel disease (IBD) is an idiopathic disease of disordered chronic inflammation in the intestines that affects many people across the world. While the disease is still being better characterized, greater progress has been made in understanding the many components that intersect in the disease. Among these components are the many pieces that compose the intestinal epithelial barrier, the various cytokines and immune cells, and the population of microbes that reside in the intestinal lumen. Since their discovery, the hypoxia-inducible factors (HIFs) have been found to play an expansive role in physiology as well as diseases such as inflammation due to their role in oxygen sensing-related gene transcription, and metabolic control. Making use of existing and developing paradigms in the immuno-gastroenterology of IBD, we summarized that hypoxic signaling plays as another component in the status and progression of IBD, which may include possible functions at the origins of inflammatory dysregulation. © 2023 American Physiological Society. Compr Physiol 13:4767-4783, 2023.
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Affiliation(s)
- Michael Morales
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Xiang Xue
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
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12
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Hegarty LM, Jones GR, Bain CC. Macrophages in intestinal homeostasis and inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2023:10.1038/s41575-023-00769-0. [PMID: 37069320 DOI: 10.1038/s41575-023-00769-0] [Citation(s) in RCA: 118] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/13/2023] [Indexed: 04/19/2023]
Abstract
Macrophages are essential for the maintenance of intestinal homeostasis, yet appear to be drivers of inflammation in the context of inflammatory bowel disease (IBD). How these peacekeepers become powerful aggressors in IBD is still unclear, but technological advances have revolutionized our understanding of many facets of their biology. In this Review, we discuss the progress made in understanding the heterogeneity of intestinal macrophages, the functions they perform in gut health and how the environment and origin can control the differentiation and longevity of these cells. We describe how these processes might change in the context of chronic inflammation and how aberrant macrophage behaviour contributes to IBD pathology, and discuss how therapeutic approaches might target dysregulated macrophages to dampen inflammation and promote mucosal healing. Finally, we set out key areas in the field of intestinal macrophage biology for which further investigation is warranted.
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Affiliation(s)
- Lizi M Hegarty
- Centre for Inflammation Research, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh BioQuarter, Queen's Medical Research Institute, Edinburgh, UK
| | - Gareth-Rhys Jones
- Centre for Inflammation Research, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh BioQuarter, Queen's Medical Research Institute, Edinburgh, UK
| | - Calum C Bain
- Centre for Inflammation Research, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh BioQuarter, Queen's Medical Research Institute, Edinburgh, UK.
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13
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Suau R, Garcia A, Bernal C, Llaves M, Schiering K, Jou-Ollé E, Pertegaz A, Garcia-Jaraquemada A, Bartolí R, Lorén V, Vergara P, Mañosa M, Domènech E, Manyé J. Response Variability to Drug Testing in Two Models of Chemically Induced Colitis. Int J Mol Sci 2023; 24:ijms24076424. [PMID: 37047397 PMCID: PMC10094987 DOI: 10.3390/ijms24076424] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 03/23/2023] [Accepted: 03/27/2023] [Indexed: 04/14/2023] Open
Abstract
The lack of knowledge regarding the pathogenesis of IBD is a challenge for the development of more effective and safer therapies. Although in vivo preclinical approaches are critical for drug testing, none of the existing models accurately reproduce human IBD. Factors that influence the intra-individual response to drugs have barely been described. With this in mind, our aim was to compare the anti-inflammatory efficacy of a new molecule (MTADV) to that of corticosteroids in TNBS and DSS-induced colitis mice of both sexes in order to clarify further the response mechanism involved and the variability between sexes. The drugs were administered preventively and therapeutically, and real-time bioluminescence was performed for the in vivo time-course colitis monitoring. Morphometric data were also collected, and colonic cytokines and acute plasma phase proteins were analyzed by qRT-PCR and ELISA, respectively-bioluminescence images correlated with inflammatory markers. In the TNBS model, dexamethasone worked better in females, while MTADV improved inflammation in males. In DSS-colitis, both therapies worked similarly. Based on the molecular profiles, interaction networks were constructed to pinpoint the drivers of therapeutic response that were highly dependent on the sex. In conclusion, our results suggest the importance of considering sex in IBD preclinical drug screening.
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Affiliation(s)
- Roger Suau
- IBD Research Group, Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
| | - Anna Garcia
- IBD Research Group, Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain
| | - Carla Bernal
- Laboratory of Genetic Metabolic Diseases, Faculty of Biosciences, National University of San Marcos, Lima 15088, Peru
| | - Mariona Llaves
- IBD Research Group, Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain
| | - Katharina Schiering
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, 30625 Hannover, Germany
| | - Eva Jou-Ollé
- IBD Research Group, Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain
| | - Alex Pertegaz
- IBD Research Group, Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain
| | | | - Ramon Bartolí
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
- Hepatology Unit IGTP, 08916 Badalona, Spain
| | - Violeta Lorén
- IBD Research Group, Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
| | - Patri Vergara
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
- Department of Physiology, Faculty of Veterinary, Autonomous University of Barcelona, 08193 Bellaterra, Spain
| | - Míriam Mañosa
- IBD Research Group, Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
- Gastroenterology Department, Germans Trias i Pujol University Hospital, 08916 Badalona, Spain
| | - Eugeni Domènech
- IBD Research Group, Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
- Gastroenterology Department, Germans Trias i Pujol University Hospital, 08916 Badalona, Spain
| | - Josep Manyé
- IBD Research Group, Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
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14
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Dong Y, Yang Q, Niu R, Zhang Z, Huang Y, Bi Y, Liu G. Modulation of tumor‐associated macrophages in colitis‐associated colorectal cancer. J Cell Physiol 2022; 237:4443-4459. [DOI: 10.1002/jcp.30906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 10/11/2022] [Accepted: 10/13/2022] [Indexed: 11/10/2022]
Affiliation(s)
- Yingjie Dong
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences Beijing Normal University Beijing China
| | - Qiuli Yang
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences Beijing Normal University Beijing China
| | - Ruiying Niu
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences Beijing Normal University Beijing China
| | - Zhiyuan Zhang
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences Beijing Normal University Beijing China
| | - Yijin Huang
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences Beijing Normal University Beijing China
| | - Yujing Bi
- State Key Laboratory of Pathogen and Biosecurity Beijing Institute of Microbiology and Epidemiology Beijing China
| | - Guangwei Liu
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences Beijing Normal University Beijing China
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15
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Cheng J, Sun Y, He J, Wang Z, Li W, Wang R. The mechanism of colon tissue damage mediated by HIF-1α/NF-κB/STAT1 in high-altitude environment. Front Physiol 2022; 13:933659. [PMID: 36164339 PMCID: PMC9508275 DOI: 10.3389/fphys.2022.933659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 08/08/2022] [Indexed: 11/25/2022] Open
Abstract
The high-altitude environment damages the intestinal mucosal barrier, leading to a high incidence of intestinal diseases and seriously affects the working ability of people at high altitude. However, how high altitude induces intestinal mucosal barrier injury has not been well defined. The purpose of this study was to investigate the mechanism of colonic tissue injury induced by the influence of the high-altitude environment on the colonic microenvironment. Forty-eight SPF C57BL/6J mice were randomly divided into four groups: the control group and three other that were high-altitude exposure groups (Yushu, Qinghai; elevation: 4,010 m; 12 h, 24 h, 48 h). First, HE staining was used to observe the effect of the high-altitude environment on colon histomorphology of mice. The protein expression levels of claudin-1, occludin, and ZO-1 were analyzed by molecular biological methods. We found that altitude caused inflammatory damage to colon tissue. Intestinal hypoxia was measured with the hypoxic probe pimonidazole (PMDZ). Interestingly, we observed a decrease in the concentration of oxygen in the microenvironment in the colonic lumen. We sought to explore the mechanism of colonic mucosal barrier damage at different times when entering high altitude. The expression levels of hypoxia-inducible factors: HIF-1α, STAT1, and NF-κB and of inflammatory factors: IFN-γ, TNF-α, and IL-6 were significantly increased. This work highlights that the high-altitude environment leads to a reduction in the concentration of oxygen in the microenvironment of the colonic lumen, which disrupts the colonic mucosal barrier and ultimately induces and exacerbates intestinal injury.
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Affiliation(s)
- Junfei Cheng
- Lanzhou University School of Pharmacy, Lanzhou, Gansu, China
- The Logistics Support Force of Chinese People’s Liberation Army Pharmacy Department, Lanzhou, Gansu, China
| | - Yuemei Sun
- The Logistics Support Force of Chinese People’s Liberation Army Pharmacy Department, Lanzhou, Gansu, China
| | - Jiaxin He
- Lanzhou University School of Pharmacy, Lanzhou, Gansu, China
- The Logistics Support Force of Chinese People’s Liberation Army Pharmacy Department, Lanzhou, Gansu, China
| | - Zihan Wang
- The Logistics Support Force of Chinese People’s Liberation Army Pharmacy Department, Lanzhou, Gansu, China
| | - Wenbin Li
- The Logistics Support Force of Chinese People’s Liberation Army Pharmacy Department, Lanzhou, Gansu, China
- *Correspondence: Wenbin Li, Rong Wang,
| | - Rong Wang
- Lanzhou University School of Pharmacy, Lanzhou, Gansu, China
- The Logistics Support Force of Chinese People’s Liberation Army Pharmacy Department, Lanzhou, Gansu, China
- *Correspondence: Wenbin Li, Rong Wang,
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16
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Li P, Shi DP, Jin T, Tang D, Wang W, Wang LH. MTA1 aggravates experimental colitis in mice by promoting transcription factor HIF1A and up-regulating AQP4 expression. Cell Death Discov 2022; 8:298. [PMID: 35764613 PMCID: PMC9240051 DOI: 10.1038/s41420-022-01052-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 11/11/2021] [Accepted: 11/22/2021] [Indexed: 12/15/2022] Open
Abstract
Experimental colitis can persist as a chronic disease, accompanied with an underlying risk of development into colorectal cancer. Metastasis-associated protein 1 (MTA1), as a chromatin modifier, exerts notable association with multiple diseases, including colitis. The current study aims to investigate the mechanism of MTA1/HIF1A/AQP4 axis in experimental colitis in mice. First, experimental colitis mouse models were established using dextran sulfate sodium (DSS) and in vitro colonic epithelial cells FHC inflammation models were with lipopolysaccharide (LPS) for determination of MTA1 and HIF1A expressions. It was found that MTA1 and HIF1A were both highly-expressed in experimental colitis samples. Results of dual-luciferase reporter gene assay and ChIP assay further revealed that MTA1 activated HIF1A, and subsequently induced AQP4 transcription to up-regulate AQP4 in experimental colitis. Following loss- and gain-function, the effects of MTA1/HIF1A/AQP4 axis on apoptosis and viability of colon epithelial cells were detected by a combination of TUNEL staining and flow cytometry, and CCK-8 assay. It was observed that silencing of MAT1 in the FHC and NCM460 cells reduced IL-1β and TNF-α expressions induced by LPS. Meanwhile, AQP4 promoted LPS-induced inflammation, and exacerbated apoptosis of colon epithelial cells and augmented experimental colitis development in mice. In vivo experiments further verified that TGN-020 treatment effectively alleviated DSS-induced experimental colitis in mice and diminished apoptosis of colon epithelial cells. Altogether, MTA1 may promote AQP4 transcription by activating HIF1A, thus exacerbating DSS-induced experimental colitis in mice, which provides a novel direction for the treatment of experimental colitis.
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Affiliation(s)
- Ping Li
- Department of General Surgery, Huaian Tumor Hospital & Huaian Hospital of Huaian City, Huaian, 223200, P. R. China
- Department of Central Laboratory, Huaian Tumor Hospital & Huaian Hospital of Huaian City, Huaian, 223200, P. R. China
- Department of Experimental Surgery-Cancer Metastasis, Medical Faculty Mannheim, Ruprecht Karls University, Mannheim, 68167, Germany
| | - Dong-Ping Shi
- Department of Central Laboratory, Huaian Tumor Hospital & Huaian Hospital of Huaian City, Huaian, 223200, P. R. China
| | - Tao Jin
- Department of Central Laboratory, Huaian Tumor Hospital & Huaian Hospital of Huaian City, Huaian, 223200, P. R. China
| | - Dong Tang
- Department of General Surgery, General Surgery Institute of Yangzhou, Northern Jiangsu People's Hospital, Clinical Medical College, Yangzhou University, Yangzhou, 225001, P. R. China
| | - Wei Wang
- Department of General Surgery, General Surgery Institute of Yangzhou, Northern Jiangsu People's Hospital, Clinical Medical College, Yangzhou University, Yangzhou, 225001, P. R. China
| | - Liu-Hua Wang
- Department of General Surgery, General Surgery Institute of Yangzhou, Northern Jiangsu People's Hospital, Clinical Medical College, Yangzhou University, Yangzhou, 225001, P. R. China.
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17
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Ma Y, Ling S, Li Y, Hu M, Kong B, Huang P, Liu H. Loss of Heterozygosity for KrasG12D Promotes Malignant Phenotype of Pancreatic Ductal Adenocarcinoma by Activating HIF-2α-c-Myc-Regulated Glutamine Metabolism. Int J Mol Sci 2022; 23:6697. [PMID: 35743139 PMCID: PMC9224498 DOI: 10.3390/ijms23126697] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 06/09/2022] [Accepted: 06/12/2022] [Indexed: 01/27/2023] Open
Abstract
Loss of heterozygosity (LOH) for KRAS, in which a wild-type KRAS allele is progressively lost, promotes invasive and migratory abilities of pancreatic ductal adenocarcinoma (PDAC) cells and tissues. Moreover, the occurrence of KrasG12D-LOH activates nonclassical glutamine metabolism, which is related to the malignant behavior of PDAC cells. Herein, we aim to demonstrate the regulatory link between hypoxia-inducible factor-2α (HIF-2α) and glutamine metabolism that mediates malignant phenotypes in KrasG12D-LOH PDAC cells. HIF-2α-shRNA knockdown lentivirus transfection and metabolite analysis were performed in KrasG12D-LOH and KrasG12D cell lines, respectively. Cell proliferation, migration, and invasion were examined using Cell Counting Kit-8, colony formation, and Transwell assays. Cell cycle phase and apoptosis were determined using flow cytometry. Western blotting and real-time quantitative PCR were also performed. Additionally, a subcutaneous xenograft mouse model was established. LOH stimulated HIF-2α activity and transactivated c-Myc, which has a central regulatory effect on glutamine metabolism independent of hypoxia. Meanwhile, HIF-2α silencing repressed KrasG12D-LOH PDAC cell proliferation, invasion, and migration. HIF-2α knockdown inhibited glutamine uptake and GOT1 expression via a c-Myc-dependent pathway. Collectively, KrasG12D-LOH can activate HIF-2α to regulate c-Myc-mediated glutamine metabolism and promote malignant phenotypes. Moreover, targeting HIF-2α-c-Myc regulated nonclassical glutamine metabolism, providing a new therapeutic perspective for KrasG12D-LOH PDAC.
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Affiliation(s)
- Yu Ma
- Department of Pathology, Xuzhou Medical University, Xuzhou 221004, China;
| | - Sunkai Ling
- School of Medicine, Southeast University, Nanjing 210009, China; (S.L.); (Y.L.); (M.H.); (P.H.)
| | - Yuan Li
- School of Medicine, Southeast University, Nanjing 210009, China; (S.L.); (Y.L.); (M.H.); (P.H.)
| | - Mingyue Hu
- School of Medicine, Southeast University, Nanjing 210009, China; (S.L.); (Y.L.); (M.H.); (P.H.)
| | - Bo Kong
- Department of Surgery, Klinikumrechts der Isar, School of Medicine, Technical University of Munich (TUM), 81675 Munich, Germany;
| | - Peilin Huang
- School of Medicine, Southeast University, Nanjing 210009, China; (S.L.); (Y.L.); (M.H.); (P.H.)
| | - Hui Liu
- Department of Pathology, Xuzhou Medical University, Xuzhou 221004, China;
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18
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Knyazev E, Maltseva D, Raygorodskaya M, Shkurnikov M. HIF-Dependent NFATC1 Activation Upregulates ITGA5 and PLAUR in Intestinal Epithelium in Inflammatory Bowel Disease. Front Genet 2021; 12:791640. [PMID: 34858489 PMCID: PMC8632048 DOI: 10.3389/fgene.2021.791640] [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: 10/08/2021] [Accepted: 10/27/2021] [Indexed: 12/11/2022] Open
Abstract
Intestinal epithelial cells exist in physiological hypoxia, leading to hypoxia-inducible factor (HIF) activation and supporting barrier function and cell metabolism of the intestinal epithelium. In contrast, pathological hypoxia is a common feature of some chronic disorders, including inflammatory bowel disease (IBD). This work was aimed at studying HIF-associated changes in the intestinal epithelium in IBD. In the first step, a list of genes responding to chemical activation of hypoxia was obtained in an in vitro intestinal cell model with RNA sequencing. Cobalt (II) chloride and oxyquinoline treatment of both undifferentiated and differentiated Caco-2 cells activate the HIF-signaling pathway according to gene set enrichment analysis. The core gene set responding to chemical hypoxia stimulation in the intestinal model included 115 upregulated and 69 downregulated genes. Of this set, protein product was detected for 32 genes, and fold changes in proteome and RNA sequencing significantly correlate. Analysis of publicly available RNA sequencing set of the intestinal epithelial cells of patients with IBD confirmed HIF-1 signaling pathway activation in sigmoid colon of patients with ulcerative colitis and terminal ileum of patients with Crohn's disease. Of the core gene set from the gut hypoxia model, expression activation of ITGA5 and PLAUR genes encoding integrin α5 and urokinase-type plasminogen activator receptor (uPAR) was detected in IBD specimens. The interaction of these molecules can activate cell migration and regenerative processes in the epithelium. Transcription factor analysis with the previously developed miRGTF tool revealed the possible role of HIF1A and NFATC1 in the regulation of ITGA5 and PLAUR gene expression. Detected genes can serve as markers of IBD progression and intestinal hypoxia.
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Affiliation(s)
- Evgeny Knyazev
- Laboratory of Microfluidic Technologies for Biomedicine, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia
| | - Diana Maltseva
- Faculty of Biology and Biotechnology, National Research University Higher School of Economics (HSE), Moscow, Russia
| | - Maria Raygorodskaya
- Laboratory of Microfluidic Technologies for Biomedicine, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia
| | - Maxim Shkurnikov
- Laboratory of Microfluidic Technologies for Biomedicine, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia.,Faculty of Biology and Biotechnology, National Research University Higher School of Economics (HSE), Moscow, Russia.,National Center of Medical Radiological Research, P. Hertsen Moscow Oncology Research Institute, Moscow, Russia
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19
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Pral LP, Fachi JL, Corrêa RO, Colonna M, Vinolo MAR. Hypoxia and HIF-1 as key regulators of gut microbiota and host interactions. Trends Immunol 2021; 42:604-621. [PMID: 34171295 DOI: 10.1016/j.it.2021.05.004] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/05/2021] [Accepted: 05/07/2021] [Indexed: 12/11/2022]
Abstract
Oxygen (O2) availability is a key factor regulating microbiota composition and the homeostatic function of cells in the intestinal mucosa of vertebrates. Microbiota-derived metabolites increase O2 consumption by intestinal epithelial cells (IECs), reducing its availability in the gut and leading to hypoxia. This physiological hypoxia activates cellular hypoxic sensors that adapt the metabolism and function of IECs and mucosa-resident cells, such as type-3 innate lymphoid cells (ILC3s). In this review, we discuss recent evidence suggesting that the intricate and multidirectional interactions among the microbiota, hypoxia/hypoxic sensors, and mammalian host cells (IECs and ILC3s) determine how the intestinal barrier and host-microbiota-pathogens connections are molded. Understanding these interactions might provide new treatment possibilities for dysbiosis, as well as certain inflammatory and infectious diseases.
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Affiliation(s)
- Laís P Pral
- Laboratory of Immunoinflammation, Department of Genetics and Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - José L Fachi
- Laboratory of Immunoinflammation, Department of Genetics and Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil; Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA
| | - Renan O Corrêa
- Laboratory of Immunoinflammation, Department of Genetics and Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Marco Colonna
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA.
| | - Marco A R Vinolo
- Laboratory of Immunoinflammation, Department of Genetics and Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil; Experimental Medicine Research Cluster, Campinas, Brazil; Obesity and Comorbidities Research Center (OCRC), University of Campinas, Campinas, Brazil.
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20
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Xue G, Gao R, Liu Z, Xu N, Cao Y, Zhao B, Du J. Vitamin D/VDR signaling inhibits colitis by suppressing HIF-1α activation in colonic epithelial cells. Am J Physiol Gastrointest Liver Physiol 2021; 320:G837-G846. [PMID: 33759562 DOI: 10.1152/ajpgi.00061.2021] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Vitamin D/vitamin D receptor (VDR) signaling is reported to have a protective effect on the onset or progression of inflammatory bowel diseases (IBD), and hypoxia-inducible factor 1α (HIF-1α) activation is demonstrated to be closely associated with chemical-induced colitis. However, the association between vitamin D/VDR signaling and HIF-1α on IBD development remains a mystery. Here, we showed that HIF-1α expression was largely increased in the colonic epithelial cells of diseased tissues from patients with ulcerative colitis (UC). Consistently, HIF-1α activation was also improved in colonic epithelial cells upon TNFα treatment in a NF-κB pathway-dependent manner. HIF-1α inhibitors treatments ameliorated 2,4,6-trinitrobenzenesulfonic acid (TNBS)- or dextran sulfate sodium (DSS)-induced colitis in animal models. In cell or colitis animal models, vitamin D/VDR signaling suppressed HIF-1α overexpression in colonic epithelial cells via regulating NF-κB pathway, resulting in the inhibition of IFNγ and IL-1β overproductions in these cells. Collectively, these data suggest that vitamin D/VDR signaling relieves colitis development in animal models, at least in part, by suppressing HIF-1α expression in colonic epithelial cells.NEW & NOTEWORTHY This study demonstrates vitamin D/VDR signaling inhibits colitis by suppressing HIF-1α activation in colonic epithelial cells. Since the effect of vitamin D/VDR signaling is only apparent on patients who seem to be vitamin D deficient, the benefits of vitamin D supplementation in patients who are not vitamin D deficient need to be proven.
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Affiliation(s)
- Gang Xue
- Department of Gastroenterology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Ruifang Gao
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China
| | - Zhuanzhuan Liu
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China
| | - Na Xu
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China
| | - Yong Cao
- Department of Gastroenterology, Division of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Bin Zhao
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China
| | - Jie Du
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China.,Institute of Biomedical Research, Shanxi Medical University, Taiyuan, Shanxi, China
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21
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Zhang J, Zhang H, Liu M, Lan Y, Sun H, Mai K, Wan M. Short-Chain Fatty Acids Promote Intracellular Bactericidal Activity in Head Kidney Macrophages From Turbot ( Scophthalmus maximus L.) via Hypoxia Inducible Factor-1α. Front Immunol 2021; 11:615536. [PMID: 33424870 PMCID: PMC7785818 DOI: 10.3389/fimmu.2020.615536] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 11/18/2020] [Indexed: 12/14/2022] Open
Abstract
Short-chain fatty acids (SCFAs) are mainly produced by microbiota through the fermentation of carbohydrates in the intestine. Acetate, propionate, and butyrate are the most abundant SCFA metabolites and have been shown to be important in the maintenance of host health. In this study, head kidney macrophages (HKMs) were isolated and cultured from turbots. We found that the antibacterial activity of HKMs was increased after these cells were incubated with sodium butyrate, sodium propionate or sodium acetate. Interestingly, our results showed that all three SCFAs enhanced the expression of hypoxia inducible factor-1 α (HIF-1α) in HKMs, and further study confirmed that butyrate augmented the oxygen consumption of these cells. Moreover, HIF-1α inhibition diminished the butyrate-promoted intracellular bacterial killing activity of macrophages, and SCFAs also raised the gene expression and activity of lysozymes in HKMs via HIF-1α signaling. In addition, our results suggested that butyrate induced HIF-1α expression and the bactericidal activity of HKMs through histone deacetylase inhibition, while G protein-coupled receptors did not contribute to this effect. Finally, we demonstrated that butyrate induced a similar response in the murine macrophage cell line RAW264.7. In conclusion, our results demonstrated that SCFAs promoted HIF-1α expression via histone deacetylase inhibition, leading to the enhanced production of antibacterial effectors and increased bacterial killing of macrophages.
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Affiliation(s)
- Jinjin Zhang
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture & Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao, China
| | - Hui Zhang
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture & Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao, China
| | - Miao Liu
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture & Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao, China
| | - Yawen Lan
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture & Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao, China
| | - Huiyuan Sun
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture & Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao, China
| | - Kangsen Mai
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture & Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao, China.,Pilot National Laboratory of Marine Science and Technology, Qingdao, China
| | - Min Wan
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture & Key Laboratory of Mariculture, Ministry of Education, College of Fisheries, Ocean University of China, Qingdao, China.,Pilot National Laboratory of Marine Science and Technology, Qingdao, China
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22
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Synthesis and evaluation of HIF-1α inhibitory activities of novel panaxadiol derivatives. Bioorg Med Chem Lett 2020; 30:127652. [PMID: 33130293 DOI: 10.1016/j.bmcl.2020.127652] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 10/22/2020] [Accepted: 10/24/2020] [Indexed: 12/23/2022]
Abstract
Hypoxia-inducible factor 1α (HIF-1α) is a known regulator of tumor cell proliferation, migration, and angiogenesis. The presence of a high concentration of HIF-1α is positively correlated with the severity of cancer. Therefore, the inhibition of this pathway represents an important therapeutic target for the treatment of various types of cancer. Here, we designed and synthesized 30 panaxadiol (PD) derivatives and evaluated their inhibitory activities against HIF-1α transcription. Of these, compound 3l exhibited the most promising inhibitory activity (IC50 = 3.7 µM) and showed significantly decreased cytotoxicity compared with PD. Compound 9e exhibited the strongest cytotoxic effect and may be considered for further preclinical development.
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23
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Torretta S, Scagliola A, Ricci L, Mainini F, Di Marco S, Cuccovillo I, Kajaste-Rudnitski A, Sumpton D, Ryan KM, Cardaci S. D-mannose suppresses macrophage IL-1β production. Nat Commun 2020; 11:6343. [PMID: 33311467 PMCID: PMC7733482 DOI: 10.1038/s41467-020-20164-6] [Citation(s) in RCA: 144] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 11/13/2020] [Indexed: 01/01/2023] Open
Abstract
D-mannose is a monosaccharide approximately a hundred times less abundant than glucose in human blood. Previous studies demonstrated that supraphysiological levels of D-mannose inhibit tumour growth and stimulate regulatory T cell differentiation. It is not known whether D-mannose metabolism affects the function of non-proliferative cells, such as inflammatory macrophages. Here, we show that D-mannose suppresses LPS-induced macrophage activation by impairing IL-1β production. In vivo, mannose administration improves survival in a mouse model of LPS-induced endotoxemia as well as decreases progression in a mouse model of DSS-induced colitis. Phosphomannose isomerase controls response of LPS-activated macrophages to D-mannose, which impairs glucose metabolism by raising intracellular mannose-6-phosphate levels. Such alterations result in the suppression of succinate-mediated HIF-1α activation, imposing a consequent reduction of LPS-induced Il1b expression. Disclosing an unrecognized metabolic hijack of macrophage activation, our study points towards safe D-mannose utilization as an effective intervention against inflammatory conditions.
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Affiliation(s)
- Simone Torretta
- Cancer Metabolism Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy
| | - Alessandra Scagliola
- Cancer Metabolism Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy
| | - Luisa Ricci
- Cancer Metabolism Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy
| | - Francesco Mainini
- Cancer Metabolism Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy
| | - Sabrina Di Marco
- Cancer Metabolism Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy
| | - Ivan Cuccovillo
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy
| | - Anna Kajaste-Rudnitski
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy
| | | | | | - Simone Cardaci
- Cancer Metabolism Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy.
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24
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Kerber EL, Padberg C, Koll N, Schuetzhold V, Fandrey J, Winning S. The Importance of Hypoxia-Inducible Factors (HIF-1 and HIF-2) for the Pathophysiology of Inflammatory Bowel Disease. Int J Mol Sci 2020; 21:ijms21228551. [PMID: 33202783 PMCID: PMC7697655 DOI: 10.3390/ijms21228551] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/09/2020] [Accepted: 11/10/2020] [Indexed: 12/20/2022] Open
Abstract
(1) Background: Hypoxia is a common feature of inflammation when hypoxia inducible factors (HIFs) adapt cells to conditions of low oxygen tension and inflammation. We studied the role of HIF-1 and HIF-2 in cells of the myeloid lineage in a mouse model of acute colitis. (2) Methods: Mice with and without a conditional knockout for either Hif-1a or Hif-2a or Hif-1a and Hif-2a in cells of the myeloid lineage were treated with 2.5% dextran sodium sulfate (DSS) for 6 days to induce an acute colitis. We analyzed the course of inflammation with respect to macroscopic (disease activity index) and microscopic (histology score and immunohistochemical staining of immune cells) parameters and quantified the mRNA expression of cytokines and chemokines in the colon and the mesenteric lymph nodes. (3) Results: A conditional knockout of myeloid Hif-1a ameliorated whereas the knockout of Hif-2a aggravated murine DSS colitis by increased recruitment of neutrophils to deeper layers of the colon. This led to higher expression of Il6, Ifng, Cd11c, Cd4, and Cd8 in the colon but also induced anti-inflammatory mediators such as Foxp3 and Il10. A conditional knockout of Hif-1a and Hif-2a did not show any differences compared to wildtype mice. (4) Conclusions: Myeloid HIF-1α and HIF-2α play opposing roles in acute DSS colitis. Thus, not only a cell type specific, but also the isoform specific modulation of HIFs needs to be addressed in attempts to modify HIF for therapeutic purposes.
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25
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Kling L, Schreiber A, Eckardt KU, Kettritz R. Hypoxia-inducible factors not only regulate but also are myeloid-cell treatment targets. J Leukoc Biol 2020; 110:61-75. [PMID: 33070368 DOI: 10.1002/jlb.4ri0820-535r] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 09/30/2020] [Accepted: 09/30/2020] [Indexed: 12/19/2022] Open
Abstract
Hypoxia describes limited oxygen availability at the cellular level. Myeloid cells are exposed to hypoxia at various bodily sites and even contribute to hypoxia by consuming large amounts of oxygen during respiratory burst. Hypoxia-inducible factors (HIFs) are ubiquitously expressed heterodimeric transcription factors, composed of an oxygen-dependent α and a constitutive β subunit. The stability of HIF-1α and HIF-2α is regulated by oxygen-sensing prolyl-hydroxylases (PHD). HIF-1α and HIF-2α modify the innate immune response and are context dependent. We provide a historic perspective of HIF discovery, discuss the molecular components of the HIF pathway, and how HIF-dependent mechanisms modify myeloid cell functions. HIFs enable myeloid-cell adaptation to hypoxia by up-regulating anaerobic glycolysis. In addition to effects on metabolism, HIFs control chemotaxis, phagocytosis, degranulation, oxidative burst, and apoptosis. HIF-1α enables efficient infection defense by myeloid cells. HIF-2α delays inflammation resolution and decreases antitumor effects by promoting tumor-associated myeloid-cell hibernation. PHDs not only control HIF degradation, but also regulate the crosstalk between innate and adaptive immune cells thereby suppressing autoimmunity. HIF-modifying pharmacologic compounds are entering clinical practice. Current indications include renal anemia and certain cancers. Beneficial and adverse effects on myeloid cells should be considered and could possibly lead to drug repurposing for inflammatory disorders.
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Affiliation(s)
- Lovis Kling
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Adrian Schreiber
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.,Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max Delbrueck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Kai-Uwe Eckardt
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Ralph Kettritz
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.,Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max Delbrueck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
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26
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Banfield E, Fulton W, Burd I, Kovler ML, Sodhi CP, Hackam DJ. The role of in utero endotoxin exposure in the development of inflammatory bowel disease in mice. Am J Reprod Immunol 2020; 84:e13302. [PMID: 32662549 PMCID: PMC7722031 DOI: 10.1111/aji.13302] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 06/30/2020] [Accepted: 07/09/2020] [Indexed: 01/03/2023] Open
Abstract
PROBLEM Although early environmental influences are thought to influence the development of inflammatory bowel disease (IBD), little is known about the role of the in utero environment on subsequent IBD risk. We hypothesized that prenatal exposure to bacterial lipopolysaccharide (LPS) could modify the subsequent development of dextran sulfate sodium (DSS)-induced ulcerative colitis in adulthood by influencing the associated cellular and immune response. METHOD OF STUDY To test this hypothesis, we exposed developing mice in utero to LPS or saline (PBS) at E17.5, and then induced colitis at 5 weeks. We then assessed colitis severity and effects on the microbiome. In order to define the developmental impact of any potential LPS effect, we also exposed 1-week-old mice to either LPS or saline before inducing colitis at 5 weeks. RESULTS Mice that had been exposed to LPS but not saline in utero were protected from subsequent colitis development, and their intestinal barrier integrity and tight junction expression distribution were similar to that of control mice that were not exposed to DSS. By contrast, mice exposed to either LPS or saline at day 7 of life all developed severe colitis upon subsequent DSS exposure. CONCLUSION These results identify an informative time window during fetal development during which exposure to an otherwise pro-inflammatory agent like LPS protects against an inflammatory disease in adulthood.
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Affiliation(s)
- Emilyn Banfield
- Department of Human Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - William Fulton
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Irina Burd
- Division of Maternal Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Mark L Kovler
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Chhinder P Sodhi
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - David J Hackam
- Department of Human Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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27
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Yin J, Zhou C, Yang K, Ren Y, Qiu Y, Xu P, Xiao W, Yang H. Mutual regulation between butyrate and hypoxia-inducible factor-1α in epithelial cell promotes expression of tight junction proteins. Cell Biol Int 2020; 44:1405-1414. [PMID: 32129567 DOI: 10.1002/cbin.11336] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 03/01/2020] [Indexed: 01/16/2023]
Abstract
Inflammatory bowel disease is a kind of multi-aetiological chronic disease that is driven by multidimensional factors. Hypoxia-inducible factor-1α (HIF-1α) plays an important role in anti-inflammatory and cellular responses to hypoxia. Previous studies have found that B or T-cell-specific HIF-1α knock out mice exhibit severe colonic inflammation. However, we know very little about other functions of HIF-1α in intestinal epithelial cells (IECs). In our study, HIF-1αΔIEC mice were used to study the function of HIF-1α in IECs. HIF-1α was knocked down in Caco-2 cells by transfection with a small interfering (si) RNA. Immunohistochemical staining and western blotting were used to detect the expression of zonula occluden-1 (ZO-1) and Occludin. The content of colon was harvested for high-performance liquid chromatography analysis to examine the levels of butyrate in the gut. Our research found that HIF-1α played a protective role in dextran sulphate sodium-induced colitis, which was partly due to its regulation of tight junction (TJ) protein expression. Further study revealed that HIF-1α mediated TJ proteins levels by moderating the content of butyrate. Moreover, we found that butyrate regulated TJ protein expression, which is dependent on HIF-1α. These results indicated that there is a mutual regulatory mechanism between butyrate and HIF-1α, which has an important role in the maintenance of barrier function of the gastrointestinal tract.
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Affiliation(s)
- Jiuheng Yin
- Department of General Surgery, Xinqiao Hospital, Army Military Medical University, Chongqing, 400037, China
| | - Chao Zhou
- Department of General Surgery, Xinqiao Hospital, Army Military Medical University, Chongqing, 400037, China
| | - Kunqiu Yang
- Department of General Surgery, Sixth Medical Center of PLA General Hospital, Beijing, 100048, China
| | - Yanbei Ren
- Department of General Surgery, Xinqiao Hospital, Army Military Medical University, Chongqing, 400037, China
| | - Yuan Qiu
- Department of General Surgery, Xinqiao Hospital, Army Military Medical University, Chongqing, 400037, China
| | - Pengyuan Xu
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China
| | - Weidong Xiao
- Department of General Surgery, Xinqiao Hospital, Army Military Medical University, Chongqing, 400037, China
| | - Hua Yang
- Department of General Surgery, Xinqiao Hospital, Army Military Medical University, Chongqing, 400037, China
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28
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Zhou X, Liu H, Zhang J, Mu J, Zalan Z, Hegyi F, Takács K, Zhao X, Du M. Protective effect of Lactobacillus fermentum CQPC04 on dextran sulfate sodium–induced colitis in mice is associated with modulation of the nuclear factor-κB signaling pathway. J Dairy Sci 2019; 102:9570-9585. [DOI: 10.3168/jds.2019-16840] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 07/10/2019] [Indexed: 12/16/2022]
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29
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Strowitzki MJ, Ritter AS, Kimmer G, Schneider M. Hypoxia-adaptive pathways: A pharmacological target in fibrotic disease? Pharmacol Res 2019; 147:104364. [PMID: 31376431 DOI: 10.1016/j.phrs.2019.104364] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 07/19/2019] [Accepted: 07/19/2019] [Indexed: 02/07/2023]
Abstract
Wound healing responses are physiological reactions to injuries and share common characteristics and phases independently of the injured organ or tissue. A major hallmark of wound healing responses is the formation of extra-cellular matrix (ECM), mainly consisting of collagen fibers, to restore the initial organ architecture and function. Overshooting wound healing responses result in unphysiological accumulation of ECM and collagen deposition, a process called fibrosis. Importantly, hypoxia (oxygen demand exceeds supply) plays a significant role during wound healing responses and fibrotic diseases. Under hypoxic conditions, cells activate a gene program, including the stabilization of hypoxia-inducible factors (HIFs), which induces the expression of HIF target genes counteracting hypoxia. In contrast, in normoxia, so-called HIF-prolyl hydroxylases (PHDs) oxygen-dependently hydroxylate HIF-α, which marks it for proteasomal degradation. Importantly, PHDs can be pharmacologically inhibited (PHI) by so-called PHD inhibitors. There is mounting evidence that the HIF-pathway is continuously up-regulated during the development of tissue fibrosis, and that pharmacological (HIFI) or genetic inhibition of HIF can prevent organ fibrosis. By contrast, initial (short-term) activation of the HIF pathway via PHI during wound healing seems to be beneficial in several models of inflammation or acute organ injury. Thus, timing and duration of PHI and HIFI treatment seem to be crucial. In this review, we will highlight the role of hypoxia-adaptive pathways during wound healing responses and development of fibrotic disease. Moreover, we will discuss whether PHI and HIFI might be a promising treatment option in fibrotic disease, and consider putative pitfalls that might result from this approach.
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Affiliation(s)
- Moritz J Strowitzki
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Alina S Ritter
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Gwendolyn Kimmer
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Martin Schneider
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
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30
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Rohwer N, Jumpertz S, Erdem M, Egners A, Warzecha KT, Fragoulis A, Kühl AA, Kramann R, Neuss S, Rudolph I, Endermann T, Zasada C, Apostolova I, Gerling M, Kempa S, Hughes R, Lewis CE, Brenner W, Malinowski MB, Stockmann M, Schomburg L, Faller W, Sansom OJ, Tacke F, Morkel M, Cramer T. Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis. Oncogene 2019; 38:5670-5685. [PMID: 31043706 DOI: 10.1038/s41388-019-0816-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 03/25/2019] [Accepted: 03/26/2019] [Indexed: 01/20/2023]
Abstract
The hypoxia-inducible transcription factor HIF-1 is appreciated as a promising target for cancer therapy. However, conditional deletion of HIF-1 and HIF-1 target genes in cells of the tumor microenvironment can result in accelerated tumor growth, calling for a detailed characterization of the cellular context to fully comprehend HIF-1's role in tumorigenesis. We dissected cell type-specific functions of HIF-1 for intestinal tumorigenesis by lineage-restricted deletion of the Hif1a locus. Intestinal epithelial cell-specific Hif1a loss reduced activation of Wnt/β-catenin, tumor-specific metabolism and inflammation, significantly inhibiting tumor growth. Deletion of Hif1a in myeloid cells reduced the expression of fibroblast-activating factors in tumor-associated macrophages resulting in decreased abundance of tumor-associated fibroblasts (TAF) and robustly reduced tumor formation. Interestingly, hypoxia was detectable only sparsely and without spatial association with HIF-1α, arguing for an importance of hypoxia-independent, i.e., non-canonical, HIF-1 stabilization for intestinal tumorigenesis that has not been previously appreciated. This adds a further layer of complexity to the regulation of HIF-1 and suggests that hypoxia and HIF-1α stabilization can be uncoupled in cancer. Collectively, our data show that HIF-1 is a pivotal pro-tumorigenic factor for intestinal tumor formation, controlling key oncogenic programs in both the epithelial tumor compartment and the tumor microenvironment.
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Affiliation(s)
- Nadine Rohwer
- Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Sandra Jumpertz
- Molecular Tumor Biology, Department of General Visceral and Transplantation Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Merve Erdem
- Molecular Tumor Biology, Department of General Visceral and Transplantation Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Antje Egners
- Molecular Tumor Biology, Department of General Visceral and Transplantation Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Klaudia T Warzecha
- Medicine III, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Athanassios Fragoulis
- Molecular Tumor Biology, Department of General Visceral and Transplantation Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Anja A Kühl
- Research Center Immunosciences, Charité Universitätsmedizin Berlin, Hindenburgdamm 30, 12200, Berlin, Germany
| | - Rafael Kramann
- Medicine II, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Sabine Neuss
- Pathology, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Ines Rudolph
- Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Tobias Endermann
- Experimental Endocrinology, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Christin Zasada
- Max-Delbrück-Centrum, Robert-Rössle-Straße 10, 13125, Berlin, Germany
| | - Ivayla Apostolova
- Nuclear Medicine, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Marco Gerling
- Biosciences and Nutrition, Karolinska Institutet, Alfred Nobels Allé 8, 17177, Stockholm, Sweden
| | - Stefan Kempa
- Max-Delbrück-Centrum, Robert-Rössle-Straße 10, 13125, Berlin, Germany
| | - Russell Hughes
- Oncology and Metabolism, University of Sheffield Medical School, Sheffield, S10 2RX, UK
| | - Claire E Lewis
- Oncology and Metabolism, University of Sheffield Medical School, Sheffield, S10 2RX, UK
| | - Winfried Brenner
- Nuclear Medicine, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Maciej B Malinowski
- Surgery, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
- Department for General Visceral, Vascular, and Pediatric Surgery, Saarland University Hospital, Homburg, Germany
| | - Martin Stockmann
- Surgery, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Lutz Schomburg
- Experimental Endocrinology, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - William Faller
- Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK
- The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Owen J Sansom
- Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK
| | - Frank Tacke
- Medicine III, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Markus Morkel
- Institute for Pathology, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Thorsten Cramer
- Molecular Tumor Biology, Department of General Visceral and Transplantation Surgery, RWTH University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany.
- NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.
- ESCAM-European Surgery Center Aachen Maastricht, Aachen, Germany.
- ESCAM-European Surgery Center Aachen Maastricht, Maastricht, The Netherlands.
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31
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Sheng Z, Lu W, Zuo Z, Wang D, Zuo P, Yao Y, Ma G. MicroRNA-7b attenuates ischemia/reperfusion-induced H9C2 cardiomyocyte apoptosis via the hypoxia inducible factor-1/p-p38 pathway. J Cell Biochem 2018; 120:9947-9955. [PMID: 30548297 DOI: 10.1002/jcb.28277] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 10/24/2018] [Indexed: 12/30/2022]
Abstract
OBJECTIVE MicroRNAs (miRNAs) have been shown to play crucial roles in the occurrence, development, and treatment of many cardiovascular diseases. Coronary heart disease (CAD)-related miRNAs are still a growing research area. miR-7b was reported to be downregulated in acute myocardial infarction (AMI) myocardium tissues. However, it remains largely unknown whether miR-7b is involved in the pathogenesis and progression of the AMI ischemia/reperfusion (I/R) injury. METHODS Male C57BL/6 J mice and H9C2 cells were used as models in this study. Masson staining, real-time polymerase chain reaction, Western blot analysis, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling immunofluorescence staining assays were performed to detect the related indicators in the study. SPSS 17.0 software was used to calculate the experimental data. RESULTS The results showed that miR-7b expression is downregulated after I/R in mice, and miR-7b could inhibit apoptosis in I/R-induced H9C2 cells via upregulating hypoxia-inducible factor 1a (HIF1a). The inhibitory effect of miR-7b on I/R-induced apoptosis in H9C2 cells was blocked by HIF1a silencing. In addition, our data suggested that the p-P38 pathway may be involved in the role of miR-7 in I/R-induced H9C2 cell apoptosis. CONCLUSION We confirmed that the overexpression of miR-7b inhibits I/R-induced apoptosis in H9C2 cells by targeting the HIF1a/p-P38 pathway. Our findings not only demonstrate the potential role of miR-7b in attenuating I/R-induced apoptosis but also provide a new insight into the better prevention of the I/R injury by mediating HIF-1 and p-P38.
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Affiliation(s)
- Zulong Sheng
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China
| | - Wenbin Lu
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China
| | - Zhi Zuo
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China
| | - Dong Wang
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China
| | - Pengfei Zuo
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China
| | - Yuyu Yao
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China
| | - Genshan Ma
- Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, China
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32
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Lin N, Shay JES, Xie H, Lee DSM, Skuli N, Tang Q, Zhou Z, Azzam A, Meng H, Wang H, FitzGerald GA, Simon MC. Myeloid Cell Hypoxia-Inducible Factors Promote Resolution of Inflammation in Experimental Colitis. Front Immunol 2018; 9:2565. [PMID: 30455703 PMCID: PMC6230677 DOI: 10.3389/fimmu.2018.02565] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2018] [Accepted: 10/17/2018] [Indexed: 12/23/2022] Open
Abstract
Colonic tissues in Inflammatory Bowel Disease (IBD) patients exhibit oxygen deprivation and activation of hypoxia-inducible factor 1α and 2α (HIF-1α and HIF-2α), which mediate cellular adaptation to hypoxic stress. Notably, macrophages and neutrophils accumulate preferentially in hypoxic regions of the inflamed colon, suggesting that myeloid cell functions in colitis are HIF-dependent. By depleting ARNT (the obligate heterodimeric binding partner for both HIFα subunits) in a murine model, we demonstrate here that myeloid HIF signaling promotes the resolution of acute colitis. Specifically, myeloid pan-HIF deficiency exacerbates infiltration of pro-inflammatory neutrophils and Ly6C+ monocytic cells into diseased tissue. Myeloid HIF ablation also hinders macrophage functional conversion to a protective, pro-resolving phenotype, and elevates gut serum amyloid A levels during the resolution phase of colitis. Therefore, myeloid cell HIF signaling is required for efficient resolution of inflammatory damage in colitis, implicating serum amyloid A in this process.
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Affiliation(s)
- Nan Lin
- Perelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, United States.,Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Jessica E S Shay
- Perelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, United States
| | - Hong Xie
- Perelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, United States.,Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - David S M Lee
- Perelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, United States.,Genomics and Computational Biology Graduate Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Nicolas Skuli
- Perelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, United States
| | - Qiaosi Tang
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, United States.,Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, United States
| | - Zilu Zhou
- Genomics and Computational Biology Graduate Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Andrew Azzam
- Perelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, United States
| | - Hu Meng
- Perelman School of Medicine, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, United States
| | - Haichao Wang
- Department of Emergency Medicine, North Shore University Hospital, Manhasset, NY, United States.,The Feinstein Institute for Medical Research, Manhasset, NY, United States
| | - Garret A FitzGerald
- Perelman School of Medicine, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, United States
| | - M Celeste Simon
- Perelman School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, United States.,Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
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33
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Zhou H, Zhang HJ, Guan L, Zhang YN, Li Y, Sun MJ. Mechanism and therapeutic effects of Saccharomyces boulardii on experimental colitis in mice. Mol Med Rep 2018; 18:5652-5662. [PMID: 30387820 PMCID: PMC6236308 DOI: 10.3892/mmr.2018.9612] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 10/10/2018] [Indexed: 12/26/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a type of chronic inflammatory disturbance that affects a number of individuals worldwide; the precise mechanism is unclear and treatment is frequently insufficient to maintain patients in remission. Saccharomyces boulardii is a thermophilic, non‑pathogenic yeast that may be administered for prophylaxis and treatment of a variety of diarrheal diseases. Recent clinical studies have demonstrated that it may have a role in IBD; however, the mechanism of action is unclear. The hypoxia‑inducible factors (HIFs) are ubiquitously expressed regulators of cellular adaptation to hypoxia and are central to the adaptive and inflammatory responses of cells of the intestinal mucosa in patients with IBD. The present study aimed to investigate the effects of S. boulardii on dextran sulfate sodium (DSS)‑induced colitis in mice and the effects of S. boulardii on HIFs. Mice were divided into five groups (n=10 mice/group): i) Control; ii) DSS; iii) S. boulardii (Sb) + DSS; iv) normal saline (NS) + DSS; and v) Sb. For 14 consecutive days, mice from the Sb+DSS and Sb groups were given S. boulardii suspension in saline (150 mg/kg/day; final volume 0.2 ml) by oral gavage. The NS+DSS group received the same volume of NS by gavage. The Control mice received water only. From day 8 to day 14, 3.5% DSS was added to the drinking water of the DSS, Sb+DSS and NS+DSS groups to induce acute colitis. Body weight decreased and disease activity index and histological score increased in mice with DSS‑induced colitis. Oral administration of S. boulardii reduced DSS‑induced weight loss, ameliorated the histological damage and protected the colon barrier in mice with DSS‑induced colitis. The expression of HIF‑1α and HIF‑2α in colon tissues was measured by reverse transcription‑quantitative polymerase chain reaction, immunoblotting and immunohistochemistry. The increase in HIFs in the colon induced by DSS was significantly inhibited by S. boulardii treatment. The expression levels of several epithelial‑mesenchymal transition (EMT) markers and of vascular endothelial growth factor (VEGF) that are regulated by HIFs were measured. S. boulardii reduced EMT and decreased expression of VEGF that was induced by DSS treatment. These results indicated that treatment with S. boulardii ameliorated DSS‑induced colitis, partly through downregulation of HIF‑1α and HIF‑2α.
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Affiliation(s)
- Huan Zhou
- Department of Gastroenterology and Endoscopy, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 11000, P.R. China
| | - Hui-Jing Zhang
- Department of Gastroenterology and Endoscopy, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 11000, P.R. China
| | - Lin Guan
- Department of Gastroenterology and Endoscopy, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 11000, P.R. China
| | - Yi-Ning Zhang
- Department of Gastroenterology and Endoscopy, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 11000, P.R. China
| | - Yue Li
- Department of Gastroenterology and Endoscopy, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 11000, P.R. China
| | - Ming-Jun Sun
- Department of Gastroenterology and Endoscopy, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 11000, P.R. China
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