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Tuffs C, Dupovac M, Richter K, Holten S, Schaschinger T, Marg O, Poljo A, Tasdemir AN, Harnoss JM, Billeter A, Schneider M, Strowitzki MJ. Genetic Loss of HIF-Prolyl-Hydroxylase 1, but Not Pharmacological Inhibition, Mitigates Hepatic Fibrosis. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:480-493. [PMID: 39566823 DOI: 10.1016/j.ajpath.2024.10.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 10/09/2024] [Accepted: 10/16/2024] [Indexed: 11/22/2024]
Abstract
Liver fibrosis is characterized by excessive deposition of extracellular matrix due to chronic inflammation of the liver. Hepatic stellate cells (HSCs) become activated and produce increased amounts of extracellular matrix. Loss of HIF-prolyl-hydroxylase 1 (PHD1) attenuates HSC activation and fibrotic tissue remodeling in a murine model of biliary liver fibrosis. Herein, the protective effect of PHD1 deficiency (PHD1-/-) in an additional (toxic) model of liver fibrosis was validated and the effect of dimethyloxalylglycine (DMOG), a pan-HIF-prolyl-hydroxylase inhibitor, on the development of liver fibrosis, was evaluated. Liver fibrosis was induced utilizing carbon tetrachloride in wild-type (WT) and PHD1-/- mice treated with either vehicle or DMOG. To assess fibrosis development, expression of profibrotic genes in the livers was analyzed by Sirius red staining. When compared with WT mice, PHD1-/- mice developed less-severe liver fibrosis. DMOG treatment did not prevent this liver fibrosis. PHD1-/- mice had fewer α-SMA+ cells and less macrophage infiltration compared with WT mice. Expression of profibrogenic and proinflammatory genes was reduced in livers from carbon tetrachloride-exposed PHD1-/- mice. In vitro analyses of PHD1-deficient human HSCs revealed attenuated mRNA levels of profibrotic genes, as well as impaired migration and invasion. Although PHD1 deficiency attenuated activation of HSCs, pharmacologic PHD inhibition did not ameliorate fibrosis development. These data indicate that selective PHD1 inhibitors could prove effective in preventing and treating liver fibrosis.
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Affiliation(s)
- Christopher Tuffs
- Department of General, Visceral, and Transplantation Surgery, Heidelberg University, Heidelberg, Germany; Department of General, Visceral, Thoracic, and Transplantation Surgery, University of Giessen, Giessen, Germany
| | - Mareen Dupovac
- Department of General, Visceral, and Transplantation Surgery, Heidelberg University, Heidelberg, Germany
| | - Katrin Richter
- Department of General, Visceral, Thoracic, and Transplantation Surgery, University of Giessen, Giessen, Germany; Department of Natural Sciences, Bonn-Rhein-Sieg University of Applied Sciences, Rheinbach, Germany
| | - Sophia Holten
- Department of General, Visceral, and Transplantation Surgery, Heidelberg University, Heidelberg, Germany
| | - Thomas Schaschinger
- Department of General, Visceral, and Transplantation Surgery, Heidelberg University, Heidelberg, Germany
| | - Oliver Marg
- Department of General, Visceral, Thoracic, and Transplantation Surgery, University of Giessen, Giessen, Germany
| | - Adisa Poljo
- Clarunis University Digestive Healthcare Center Basel, Basel, Switzerland
| | - Ayse Nur Tasdemir
- Department of General, Visceral, and Transplantation Surgery, Heidelberg University, Heidelberg, Germany
| | - Jonathan M Harnoss
- Department of General, Visceral, and Transplantation Surgery, Heidelberg University, Heidelberg, Germany; Department of General, Visceral, Thoracic, and Transplantation Surgery, University of Giessen, Giessen, Germany
| | - Adrian Billeter
- Clarunis University Digestive Healthcare Center Basel, Basel, Switzerland
| | - Martin Schneider
- Department of General, Visceral, and Transplantation Surgery, Heidelberg University, Heidelberg, Germany; Department of General, Visceral, Thoracic, and Transplantation Surgery, University of Giessen, Giessen, Germany
| | - Moritz J Strowitzki
- Department of General, Visceral, and Transplantation Surgery, Heidelberg University, Heidelberg, Germany; Department of General, Visceral, Thoracic, and Transplantation Surgery, University of Giessen, Giessen, Germany.
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Xie Y, Ma Y, Xu L, Liu H, Ge W, Wu B, Duan H, Zhang H, Fu Y, Xu H, Sun Y, Han Z, Zhu Y. Inhibition of Angiogenesis and Effect on Inflammatory Bowel Disease of Ginsenoside Rg3-Loaded Thermosensitive Hydrogel. Pharmaceutics 2024; 16:1243. [PMID: 39458575 PMCID: PMC11509886 DOI: 10.3390/pharmaceutics16101243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 09/10/2024] [Accepted: 09/11/2024] [Indexed: 10/28/2024] Open
Abstract
Background: Inflammatory bowel disease (IBD), characterized by chronic inflammation of the digestive tract, involves angiogenesis as a key pathogenic mechanism. Ginsenoside Rg3, derived from the traditional Chinese herb ginseng, is recognized for its anti-angiogenic properties but is limited by low oral bioavailability. This necessitates the development of an alternative delivery system to improve its therapeutic effectiveness. Methods: Pluronic F-127 (F127) and Pluronic F-68 (F68) were used to construct Rg3-loaded thermosensitive hydrogel Gel-Rg3. Meanwhile, a series of physicochemical properties were determined. Then the safety and pharmacological activity of Gel-Rg3 were evaluated in vitro and in vivo using human umbilical vein endothelial cells (HUVECs) and colitis mouse model, in order to initially validate the potential of Gel-Rg3 for the treatment of IBD. Results: We engineered a rectally administrable, thermosensitive Gel-Rg3 hydrogel using F127 and F68, which forms at body temperature, enhancing Rg3's intestinal retention and slowly releasing the drug. In vitro, Gel-Rg3 demonstrated superior anti-angiogenic activity by inhibiting HUVEC proliferation, migration, and tube formation. It also proved safer and better suited for IBD's delicate intestinal environment than unformulated Rg3. In vivo assessments confirmed increased intestinal adhesion and anti-angiogenic efficacy. Conclusions: The Gel-Rg3 hydrogel shows promise for IBD therapy by effectively inhibiting angiogenesis via rectal delivery, overcoming Rg3's bioavailability limitations with improved safety and efficacy. This study provides new inspiration and data support for the design of treatment strategies for IBD.
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Affiliation(s)
- Yiqiong Xie
- Department of Pharmacy, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210008, China; (Y.X.); (L.X.); (W.G.)
| | - Ying Ma
- Jiangsu Institute for Food and Drug Control, Nanjing 210008, China;
| | - Lu Xu
- Department of Pharmacy, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210008, China; (Y.X.); (L.X.); (W.G.)
| | - Hongwen Liu
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China;
| | - Weihong Ge
- Department of Pharmacy, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210008, China; (Y.X.); (L.X.); (W.G.)
- Nanjing Medical Center for Clinical Pharmacy, Nanjing 210008, China;
| | - Baojuan Wu
- Division of Breast Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China;
| | - Hongjue Duan
- Nanjing Medical Center for Clinical Pharmacy, Nanjing 210008, China;
| | - Hongmei Zhang
- Division of Breast Surgery, Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210008, China; (H.Z.); (Y.F.)
| | - Yuping Fu
- Division of Breast Surgery, Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210008, China; (H.Z.); (Y.F.)
| | - Hang Xu
- School of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Macau SAR, China;
- Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Yuxiang Sun
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou 225001, China;
| | - Zhou Han
- Department of Pharmacy, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210008, China; (Y.X.); (L.X.); (W.G.)
- Nanjing Medical Center for Clinical Pharmacy, Nanjing 210008, China;
| | - Yun Zhu
- Department of Pharmacy, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210008, China; (Y.X.); (L.X.); (W.G.)
- Nanjing Medical Center for Clinical Pharmacy, Nanjing 210008, China;
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Germeys C, Vandoorne T, Davie K, Poovathingal S, Heeren K, Vermeire W, Nami F, Moisse M, Quaegebeur A, Sierksma A, Rué L, Sicart A, Eykens C, De Cock L, De Strooper B, Carmeliet P, Van Damme P, De Bock K, Van Den Bosch L. Targeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response. Cell Rep 2024; 43:114719. [PMID: 39255062 DOI: 10.1016/j.celrep.2024.114719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 07/08/2024] [Accepted: 08/20/2024] [Indexed: 09/12/2024] Open
Abstract
Neuroinflammation and dysregulated energy metabolism are linked to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The egl-9 family hypoxia-inducible factor (EGLN) enzymes, also known as prolyl hydroxylase domain (PHD) enzymes, are metabolic sensors regulating cellular inflammation and metabolism. Using an oligonucleotide-based and a genetic approach, we showed that the downregulation of Egln2 protected motor neurons and mitigated the ALS phenotype in two zebrafish models and a mouse model of ALS. Single-nucleus RNA sequencing of the murine spinal cord revealed that the loss of EGLN2 induced an astrocyte-specific downregulation of interferon-stimulated genes, mediated via the stimulator of interferon genes (STING) protein. In addition, we found that the genetic deletion of EGLN2 restored this interferon response in patient induced pluripotent stem cell (iPSC)-derived astrocytes, confirming the link between EGLN2 and astrocytic interferon signaling. In conclusion, we identified EGLN2 as a motor neuron protective target normalizing the astrocytic interferon-dependent inflammatory axis in vivo, as well as in patient-derived cells.
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Affiliation(s)
- Christine Germeys
- KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium
| | - Tijs Vandoorne
- KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium
| | - Kristofer Davie
- VIB-KU Leuven, Center for Brain & Disease Research Technologies, Single Cell Bioinformatics Unit, 3000 Leuven, Belgium
| | - Suresh Poovathingal
- VIB-KU Leuven, Center for Brain & Disease Research Technologies, Single Cell Microfluidics & Analytics Unit, 3000 Leuven, Belgium; VIB, Center for AI & Computational Biology (VIB.AI), 3000 Leuven, Belgium
| | - Kara Heeren
- KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium
| | - Wendy Vermeire
- KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium
| | - FatemehArefeh Nami
- KU Leuven - University of Leuven, Department of Development and Regeneration, Stem Cell Institute Leuven (SCIL), 3000 Leuven, Belgium
| | - Matthieu Moisse
- KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium
| | - Annelies Quaegebeur
- University of Cambridge, Department of Clinical Neurosciences, CB2 2PY Cambridge, UK; Cambridge University Hospitals, Department of Histopathology, CB2 0QQ Cambridge, UK
| | - Annerieke Sierksma
- KU Leuven - University of Leuven, Department of Neurosciences, Research Group Molecular Neurobiology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory for the Research of Neurodegenerative Diseases, 3000 Leuven, Belgium
| | - Laura Rué
- KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium
| | - Adrià Sicart
- KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium
| | - Caroline Eykens
- KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium
| | - Lenja De Cock
- KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium
| | - Bart De Strooper
- KU Leuven - University of Leuven, Department of Neurosciences, Research Group Molecular Neurobiology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory for the Research of Neurodegenerative Diseases, 3000 Leuven, Belgium; Dementia Research Institute, University College London, WC1E 6BT London, UK
| | - Peter Carmeliet
- KU Leuven - University of Leuven, Department of Oncology and Leuven Cancer Institute (LKI), Laboratory of Angiogenesis and Vascular Metabolism, 3000 Leuven, Belgium; VIB, Center for Cancer Biology, Laboratory of Angiogenesis and Vascular Metabolism, 3000 Leuven, Belgium; Khalifa University of Science and Technology, Center for Biotechnology, Abu Dhabi, United Arab Emirates
| | - Philip Van Damme
- KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium; University Hospitals Leuven, Department of Neurology, 3000 Leuven, Belgium
| | - Katrien De Bock
- ETH Zürich, Department of Health Sciences and Technology, 8092 Zürich, Switzerland
| | - Ludo Van Den Bosch
- KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium.
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Jucht AE, Scholz CC. PHD1-3 oxygen sensors in vivo-lessons learned from gene deletions. Pflugers Arch 2024; 476:1307-1337. [PMID: 38509356 PMCID: PMC11310289 DOI: 10.1007/s00424-024-02944-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 03/02/2024] [Accepted: 03/07/2024] [Indexed: 03/22/2024]
Abstract
Oxygen sensors enable cells to adapt to limited oxygen availability (hypoxia), affecting various cellular and tissue responses. Prolyl-4-hydroxylase domain 1-3 (PHD1-3; also called Egln1-3, HIF-P4H 1-3, HIF-PH 1-3) proteins belong to the Fe2+- and 2-oxoglutarate-dependent dioxygenase superfamily and utilise molecular oxygen (O2) alongside 2-oxoglutarate as co-substrate to hydroxylate two proline residues of α subunits of the dimeric hypoxia inducible factor (HIF) transcription factor. PHD1-3-mediated hydroxylation of HIF-α leads to its degradation and inactivation. Recently, various PHD inhibitors (PHI) have entered the clinics for treatment of renal anaemia. Pre-clinical analyses indicate that PHI treatment may also be beneficial in numerous other hypoxia-associated diseases. Nonetheless, the underlying molecular mechanisms of the observed protective effects of PHIs are only partly understood, currently hindering their translation into the clinics. Moreover, the PHI-mediated increase of Epo levels is not beneficial in all hypoxia-associated diseases and PHD-selective inhibition may be advantageous. Here, we summarise the current knowledge about the relevance and function of each of the three PHD isoforms in vivo, based on the deletion or RNA interference-mediated knockdown of each single corresponding gene in rodents. This information is crucial for our understanding of the physiological relevance and function of the PHDs as well as for elucidating their individual impact on hypoxia-associated diseases. Furthermore, this knowledge highlights which diseases may best be targeted by PHD isoform-selective inhibitors in case such pharmacologic substances become available.
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Affiliation(s)
- Agnieszka E Jucht
- Institute of Physiology, University of Zurich, Zurich, 8057, Switzerland
| | - Carsten C Scholz
- Institute of Physiology, University Medicine Greifswald, Friedrich-Ludwig-Jahn-Str. 15a, 17475, Greifswald, Germany.
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Yang MJ, Zhang YN, Qiao Z, Xu RY, Chen SM, Hu P, Yu HL, Pan Y, Cao J. An investigation into the HIF-dependent intestinal barrier protective mechanism of Qingchang Wenzhong decoction in ulcerative colitis management. JOURNAL OF ETHNOPHARMACOLOGY 2024; 325:117807. [PMID: 38280661 DOI: 10.1016/j.jep.2024.117807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 01/15/2024] [Accepted: 01/19/2024] [Indexed: 01/29/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ulcerative colitis (UC) is a chronic, non-specific inflammatory disease affecting the colon and rectum with an etiology that remains elusive. Traditional Chinese medicine (TCM) has been widely used on long-term UC treatment to better maintain the efficacy than traditional aminosalicylic acid or glucocorticosteroids and to ease financial burden of patients. Qingchang Wenzhong Decoction (QCWZD) is a modern TCM decoction with established clinical efficacy but the mechanism of its protection on intestinal barrier function remains unclear. AIM OF THE STUDY Current findings highlight that the activation of the hypoxia inducible factor (HIF) pathway can facilitate the repair of intestinal epithelium barrier. This study is to investigate the protective effects of QCWZD and its HIF-targeted ingredients on hypoxia-dependent intestinal barrier. METHODS The mice model of UC was induced by dextran sulfate sodium (DSS). Disease activity index (DAI) and histopathology scores and colon length were used to measure the severity of colitis. The DAO activity in serum and protein expression of tight junction (TJ) proteins were detected to explore the function of intestinal barrier. The protein levels of HIF-1α and its downstream gene heme oxygenase-1 (HO-1) were measured as well. HIF-targeted active ingredients in QCWZD were selected by network pharmacology and molecular docking. Protective effects of six constituents on HIF-related anti-oxidative and barrier protective pathway were evaluated by lipopolysaccharide (LPS)-induced HT29 and RAW264.7 cells, through the measurement of the production of ROS and mRNA level of pro-inflammatory cytokines. HIF-1α knockdown was carried out to explore the correlation of protection effects with HIF-related pathway of the active ingredients. RESULTS QCWZD effectively alleviated colitis induced by DSS and demonstrated a protective effect on intestinal barrier function by upregulating HIF-related pathways. Six specific ingredients in QCWZD, targeting HIF, successfully reduced the production of cellular ROS and proinflammatory cytokines in LPS-induced cells. It is noteworthy that the barrier protection provided by these molecules is intricately linked with the HIF-related pathway. CONCLUSIONS This study elucidates the HIF-related molecular mechanism of QCWZD in protecting the function of the epithelial barrier. Six compounds targeting the activation of the HIF-dependent pathway were demonstrated to unveil a novel therapeutic approach for managing UC.
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Affiliation(s)
- Meng-Juan Yang
- School of pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China
| | - Yi-Nuo Zhang
- School of pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China
| | - Zhi Qiao
- School of pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China
| | - Rui-Ying Xu
- School of pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China
| | - Si-Min Chen
- School of pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China
| | - Po Hu
- School of pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China
| | - Hong-Li Yu
- School of pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China
| | - Yang Pan
- School of pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China.
| | - Jing Cao
- School of pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China.
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Yuan X, Ruan W, Bobrow B, Carmeliet P, Eltzschig HK. Targeting hypoxia-inducible factors: therapeutic opportunities and challenges. Nat Rev Drug Discov 2024; 23:175-200. [PMID: 38123660 DOI: 10.1038/s41573-023-00848-6] [Citation(s) in RCA: 52] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/06/2023] [Indexed: 12/23/2023]
Abstract
Hypoxia-inducible factors (HIFs) are highly conserved transcription factors that are crucial for adaptation of metazoans to limited oxygen availability. Recently, HIF activation and inhibition have emerged as therapeutic targets in various human diseases. Pharmacologically desirable effects of HIF activation include erythropoiesis stimulation, cellular metabolism optimization during hypoxia and adaptive responses during ischaemia and inflammation. By contrast, HIF inhibition has been explored as a therapy for various cancers, retinal neovascularization and pulmonary hypertension. This Review discusses the biochemical mechanisms that control HIF stabilization and the molecular strategies that can be exploited pharmacologically to activate or inhibit HIFs. In addition, we examine medical conditions that benefit from targeting HIFs, the potential side effects of HIF activation or inhibition and future challenges in this field.
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Affiliation(s)
- Xiaoyi Yuan
- Department of Anaesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
| | - Wei Ruan
- Department of Anaesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- Department of Anaesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Bentley Bobrow
- Department of Emergency Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Peter Carmeliet
- Laboratory of Angiogenesis & Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, KU Leuven, Leuven, Belgium
- Laboratory of Angiogenesis & Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Holger K Eltzschig
- Department of Anaesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
- Outcomes Research Consortium, Cleveland, OH, USA.
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Solanki S, Shah YM. Hypoxia-Induced Signaling in Gut and Liver Pathobiology. ANNUAL REVIEW OF PATHOLOGY 2024; 19:291-317. [PMID: 37832943 DOI: 10.1146/annurev-pathmechdis-051122-094743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2023]
Abstract
Oxygen (O2) is essential for cellular metabolism and biochemical reactions. When the demand for O2 exceeds the supply, hypoxia occurs. Hypoxia-inducible factors (HIFs) are essential to activate adaptive and survival responses following hypoxic stress. In the gut (intestines) and liver, the presence of oxygen gradients or physiologic hypoxia is necessary to maintain normal homeostasis. While physiologic hypoxia is beneficial and aids in normal functions, pathological hypoxia is harmful as it exacerbates inflammatory responses and tissue dysfunction and is a hallmark of many cancers. In this review, we discuss the role of gut and liver hypoxia-induced signaling, primarily focusing on HIFs, in the physiology and pathobiology of gut and liver diseases. Additionally, we examine the function of HIFs in various cell types during gut and liver diseases, beyond intestinal epithelial and hepatocyte HIFs. This review highlights the importance of understanding hypoxia-induced signaling in the pathogenesis of gut and liver diseases and emphasizes the potential of HIFs as therapeutic targets.
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Affiliation(s)
- Sumeet Solanki
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA;
| | - Yatrik M Shah
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA;
- University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
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De Kock I, Bos S, Delrue L, Van Welden S, Bunyard P, Hindryckx P, De Vos M, Villeirs G, Laukens D. MRI texture analysis of T2-weighted images is preferred over magnetization transfer imaging for readily longitudinal quantification of gut fibrosis. Eur Radiol 2023; 33:5943-5952. [PMID: 37071162 DOI: 10.1007/s00330-023-09624-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 02/10/2023] [Accepted: 02/17/2023] [Indexed: 04/19/2023]
Abstract
OBJECTIVES To investigate the value of magnetization transfer (MT) MRI and texture analysis (TA) of T2-weighted MR images (T2WI) in the assessment of intestinal fibrosis in a mouse model. METHODS Chronic colitis was induced in mice by cyclic administration of dextran sodium sulphate (DSS) resulting in chronic inflammation and progressive bowel fibrosis. Mice underwent 7-T MR imaging at various time points. Bowel wall MT ratio (MTR) and textural features (skewness, kurtosis, entropy), extracted by a filtration histogram technique, were correlated with histopathology. Performance of both techniques were validated using antifibrotic therapy. Finally, a retrospective study was conducted in five patients with Crohn's disease (CD) who underwent bowel surgery. RESULTS MTR and texture entropy correlated with histopathological fibrosis (r = .85 and .81, respectively). Entropy was superior to MTR for monitoring bowel fibrosis in the presence of coexisting inflammation (linear regression R2 = .93 versus R2 = .01). Furthermore, texture entropy was able to assess antifibrotic therapy response (placebo mice versus treated mice at endpoint scan; Δmean = 0.128, p < .0001). An increase in entropy was indicative of fibrosis accumulation in human CD strictures (inflammation: 1.29; mixed strictures: 1.4 and 1.48; fibrosis: 1.73 and 1.9). CONCLUSION MT imaging and TA of T2WI can both noninvasively detect established intestinal fibrosis in a mouse model. However, TA is especially useful for the longitudinal quantification of fibrosis in mixed inflammatory-fibrotic tissue, as well as for antifibrotic treatment response evaluation. This accessible post-processing technique merits further validation as the benefits for clinical practice as well as antifibrotic trial design would be numerous. KEY POINTS • Magnetization transfer MRI and texture analysis of T2-weighted MR images can detect established bowel fibrosis in an animal model of gut fibrosis. • Texture entropy is able to identify and monitor bowel fibrosis progression in an inflammatory context and can assess the response to antifibrotic treatment. • A proof-of-concept study in five patients with Crohn's disease suggests that texture entropy can detect and grade fibrosis in human intestinal strictures.
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Affiliation(s)
- Isabelle De Kock
- Department of Radiology and Medical Imaging, Ghent University Hospital, Ghent, Belgium
| | - Simon Bos
- Department of Internal Medicine and Pediatrics, Ghent University, Corneel Heymanslaan 10, 0MRB2, B-9000, Ghent, Belgium
- VIB Center for Inflammation Research, Ghent, Belgium
| | - Louke Delrue
- Department of Radiology and Medical Imaging, Ghent University Hospital, Ghent, Belgium
| | - Sophie Van Welden
- Department of Internal Medicine and Pediatrics, Ghent University, Corneel Heymanslaan 10, 0MRB2, B-9000, Ghent, Belgium
- VIB Center for Inflammation Research, Ghent, Belgium
| | | | - Pieter Hindryckx
- Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium
| | - Martine De Vos
- Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium
| | - Geert Villeirs
- Department of Radiology and Medical Imaging, Ghent University Hospital, Ghent, Belgium
| | - Debby Laukens
- Department of Internal Medicine and Pediatrics, Ghent University, Corneel Heymanslaan 10, 0MRB2, B-9000, Ghent, Belgium.
- VIB Center for Inflammation Research, Ghent, Belgium.
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9
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Sun Q, Lu Z, Ma L, Xue D, Liu C, Ye C, Huang W, Dang Y, Li F. Integrin β6 deficiency protects mice from experimental colitis and colitis-associated carcinoma by altering macrophage polarization. Front Oncol 2023; 13:1190229. [PMID: 37223685 PMCID: PMC10200923 DOI: 10.3389/fonc.2023.1190229] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 04/17/2023] [Indexed: 05/25/2023] Open
Abstract
Background Given the key role of integrins in maintaining intestinal homeostasis, anti-integrin biologics in inflammatory bowel disease (IBD) are being investigated in full swing. However, the unsatisfactory efficacy and safety of current anti-integrin biologics in clinical trials limit their widespread use in clinic. Therefore, it is particularly important to find a target that is highly and specifically expressed in the intestinal epithelium of patients with IBD. Methods The function of integrin αvβ6 in IBD and colitis-associated carcinoma (CAC) with the underlying mechanisms has been less studied. In the present study, we detected the level of integrin β6 within inflammation including colitis tissues in human and mouse. To investigate the role of integrin β6 in IBD and CAC, integrin β6 deficient mice were hence generated based on the construction of colitis and CAC model. Results We noted that integrin β6 was significantly upregulated in inflammatory epithelium of patients with IBD. Integrin β6 deletion not only reduced infiltration of pro-inflammatory cytokines, but also attenuated disruption of tight junctions between colonic epithelial cells. Meanwhile, lack of integrin β6 affected macrophage infiltration in mice with colitis. This study further revealed that lack of integrin β6 could inhibit tumorigenesis and tumor progression in CAC model by influencing macrophage polarization, which was also involved in attenuating the degree of intestinal symptoms and inflammatory responses in mice suffering from colitis. Conclusions The present research provides a potentially new perspective and option for the treatment of IBD and CAC.
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Affiliation(s)
- Qi Sun
- Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Zhihua Lu
- Department of General Surgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China
| | - Lei Ma
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Dong Xue
- Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Chang Liu
- Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Changchun Ye
- Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Wenbo Huang
- Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yueyan Dang
- Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Fanni Li
- Department of Talent Highland, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
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10
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Dal-Fabbro R, Swanson WB, Capalbo LC, Sasaki H, Bottino MC. Next-generation biomaterials for dental pulp tissue immunomodulation. Dent Mater 2023; 39:333-349. [PMID: 36894414 PMCID: PMC11034777 DOI: 10.1016/j.dental.2023.03.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 02/24/2023] [Accepted: 03/03/2023] [Indexed: 03/09/2023]
Abstract
OBJECTIVES The current standard for treating irreversibly damaged dental pulp is root canal therapy, which involves complete removal and debridement of the pulp space and filling with an inert biomaterial. A regenerative approach to treating diseased dental pulp may allow for complete healing of the native tooth structure and enhance the long-term outcome of once-necrotic teeth. The aim of this paper is, therefore, to highlight the current state of dental pulp tissue engineering and immunomodulatory biomaterials properties, identifying exciting opportunities for their synergy in developing next-generation biomaterials-driven technologies. METHODS An overview of the inflammatory process focusing on immune responses of the dental pulp, followed by periapical and periodontal tissue inflammation are elaborated. Then, the most recent advances in treating infection-induced inflammatory oral diseases, focusing on biocompatible materials with immunomodulatory properties are discussed. Of note, we highlight some of the most used modifications in biomaterials' surface, or content/drug incorporation focused on immunomodulation based on an extensive literature search over the last decade. RESULTS We provide the readers with a critical summary of recent advances in immunomodulation related to pulpal, periapical, and periodontal diseases while bringing light to tissue engineering strategies focusing on healing and regenerating multiple tissue types. SIGNIFICANCE Significant advances have been made in developing biomaterials that take advantage of the host's immune system to guide a specific regenerative outcome. Biomaterials that efficiently and predictably modulate cells in the dental pulp complex hold significant clinical promise for improving standards of care compared to endodontic root canal therapy.
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Affiliation(s)
- Renan Dal-Fabbro
- Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
| | - W Benton Swanson
- Department of Biologic and Materials Science, Division of Prosthodontics, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
| | - Leticia C Capalbo
- Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
| | - Hajime Sasaki
- Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
| | - Marco C Bottino
- Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, MI, USA; Department of Biomedical Engineering, College of Engineering, University of Michigan, Ann Arbor, MI, USA.
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11
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Hypoxia and Intestinal Inflammation: Common Molecular Mechanisms and Signaling Pathways. Int J Mol Sci 2023; 24:ijms24032425. [PMID: 36768744 PMCID: PMC9917195 DOI: 10.3390/ijms24032425] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/21/2023] [Accepted: 01/24/2023] [Indexed: 01/28/2023] Open
Abstract
The gastrointestinal tract (GI) has a unique oxygenation profile. It should be noted that the state of hypoxia can be characteristic of both normal and pathological conditions. Hypoxia-inducible factors (HIF) play a key role in mediating the response to hypoxia, and they are tightly regulated by a group of enzymes called HIF prolyl hydroxylases (PHD). In this review, we discuss the involvement of inflammation hypoxia and signaling pathways in the pathogenesis of inflammatory bowel disease (IBD) and elaborate in detail on the role of HIF in multiple immune reactions during intestinal inflammation. We emphasize the critical influence of tissue microenvironment and highlight the existence of overlapping functions and immune responses mediated by the same molecular mechanisms. Finally, we also provide an update on the development of corresponding therapeutic approaches that would be useful for treatment or prophylaxis of inflammatory bowel disease.
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Lun J, Zhang H, Guo J, Yu M, Fang J. Hypoxia inducible factor prolyl hydroxylases in inflammatory bowel disease. Front Pharmacol 2023; 14:1045997. [PMID: 37201028 PMCID: PMC10187758 DOI: 10.3389/fphar.2023.1045997] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 04/18/2023] [Indexed: 05/20/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic disease that is characterized by intestinal inflammation. Epithelial damage and loss of intestinal barrier function are believed to be the hallmark pathologies of the disease. In IBD, the resident and infiltrating immune cells consume much oxygen, rendering the inflamed intestinal mucosa hypoxic. In hypoxia, the hypoxia-inducible factor (HIF) is induced to cope with the lack of oxygen and protect intestinal barrier. Protein stability of HIF is tightly controlled by prolyl hydroxylases (PHDs). Stabilization of HIF through inhibition of PHDs is appearing as a new strategy of IBD treatment. Studies have shown that PHD-targeting is beneficial to the treatment of IBD. In this Review, we summarize the current understanding of the role of HIF and PHDs in IBD and discuss the therapeutic potential of targeting PHD-HIF pathway for IBD treatment.
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Affiliation(s)
- Jie Lun
- Department of Oncology, Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hongwei Zhang
- Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, China
| | - Jing Guo
- Department of Oncology, Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Mengchao Yu
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China
| | - Jing Fang
- Department of Oncology, Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
- *Correspondence: Jing Fang,
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Kennel KB, Burmeister J, Radhakrishnan P, Giese NA, Giese T, Salfenmoser M, Gebhardt JM, Strowitzki MJ, Taylor CT, Wielockx B, Schneider M, Harnoss JM. The HIF-prolyl hydroxylases have distinct and nonredundant roles in colitis-associated cancer. JCI Insight 2022; 7:153337. [PMID: 36509284 DOI: 10.1172/jci.insight.153337] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 10/11/2022] [Indexed: 11/22/2022] Open
Abstract
Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease (IBD). HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) control cellular adaptation to hypoxia and are considered promising therapeutic targets in IBD. However, their relevance in the pathogenesis of CAC remains elusive. We induced CAC in Phd1-/-, Phd2+/-, Phd3-/-, and WT mice with azoxymethane (AOM) and dextran sodium sulfate (DSS). Phd1-/- mice were protected against chronic colitis and displayed diminished CAC growth compared with WT mice. In Phd3-/- mice, colitis activity and CAC growth remained unaltered. In Phd2+/- mice, colitis activity was unaffected, but CAC growth was aggravated. Mechanistically, Phd2 deficiency (i) increased the number of tumor-associated macrophages in AOM/DSS-induced tumors, (ii) promoted the expression of EGFR ligand epiregulin in macrophages, and (iii) augmented the signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2 signaling, which at least in part contributed to aggravated tumor cell proliferation in colitis-associated tumors. Consistently, Phd2 deficiency in hematopoietic (Vav:Cre-Phd2fl/fl) but not in intestinal epithelial cells (Villin:Cre-Phd2fl/fl) increased CAC growth. In conclusion, the 3 different PHD isoenzymes have distinct and nonredundant effects, promoting (PHD1), diminishing (PHD2), or neutral (PHD3), on CAC growth.
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Affiliation(s)
- Kilian B Kennel
- Department of General, Visceral and Transplantation Surgery and
| | | | | | | | - Thomas Giese
- Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | | | | | | | - Cormac T Taylor
- School of Medicine, Systems Biology Ireland, and the Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Ben Wielockx
- Institute for Clinical Chemistry and Laboratory Medicine, Dresden University of Technology, Dresden, Germany
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14
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De Galan C, De Vos M, Hindryckx P, Laukens D, Van Welden S. Long-Term Environmental Hypoxia Exposure and Haematopoietic Prolyl Hydroxylase-1 Deletion Do Not Impact Experimental Crohn's Like Ileitis. BIOLOGY 2021; 10:biology10090887. [PMID: 34571764 PMCID: PMC8464968 DOI: 10.3390/biology10090887] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 08/23/2021] [Accepted: 09/03/2021] [Indexed: 11/16/2022]
Abstract
Simple Summary Hypoxia-induced signalling represents an important contributor to inflammatory bowel disease (IBD) pathophysiology. However, available data solely focus on colonic inflammation while the primary disease location in Crohn’s disease patients is the terminal ileum. Therefore, we explored the effects of environmental hypoxia and immune cell-specific deletion of oxygen sensor prolyl hydroxylase (PHD) 1 in a Crohn’s like ileitis mouse model. Five-week-old TNF∆ARE/+ mice and wildtype (WT) littermates were housed in normoxia (21% O2) or hypoxia (8% O2) for 10 weeks. Although environmental hypoxia increased both systemic as ileal markers of hypoxia, the body weight evolution in both WT and TNF∆ARE/+ mice was not affected. Interestingly, hypoxia did increase circulatory monocytes, ileal mononuclear phagocytes and proinflammatory cytokine expression in WT mice. However, no histological or inflammatory gene expression differences in the ileum could be identified between TNF∆ARE/+ mice housed in hypoxia versus normoxia nor between TNF∆ARE/+ and WT mice with additional loss of immune cell-specific Phd1 expression. This is the first study showing that long-term environmental hypoxia or haematopoietic Phd1-deletion does not impact experimental ileitis. Therefore, it strongly questions whether targeting hypoxia-induced signalling via currently available PHD inhibitors would exert an immune suppressive effect in IBD patients with ileal inflammation. Abstract Environmental hypoxia and hypoxia-induced signalling in the gut influence inflammatory bowel disease pathogenesis, however data is limited to colitis. Hence, we investigated the effect of environmental hypoxia and immune cell-specific deletion of oxygen sensor prolyl hydroxylase (PHD) 1 in a Crohn’s like ileitis mouse model. Therefore, 5-week-old C57/BL6 TNF∆ARE/+ mice and wildtype (WT) littermates were housed in normoxia (21% O2) or hypoxia (8% O2) for 10 weeks. Systemic inflammation was assessed by haematology. Distal ileal hypoxia was evaluated by pimonidazole staining. The ileitis degree was scored on histology, characterized via qPCR and validated in haematopoietic Phd1-deficient TNF∆ARE/+ mice. Our results demonstrated that hypoxia did not impact body weight evolution in WT and TNF∆ARE/+ mice. Hypoxia increased red blood cell count, haemoglobin, haematocrit and increased pimonidazole intensity in the ileum. Interestingly, hypoxia evoked an increase in circulatory monocytes, ileal mononuclear phagocytes and proinflammatory cytokine expression in WT mice. Despite these alterations, no histological or ileal gene expression differences could be identified between TNF∆ARE/+ mice housed in hypoxia versus normoxia nor between haematopoietic Phd1-deficient TNF∆ARE/+ and their WT counterparts. Therefore, we demonstrated for the first time that long-term environmental hypoxia or haematopoietic Phd1-deletion does not impact experimental ileitis development.
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Affiliation(s)
- Cara De Galan
- Department of Internal Medicine and Paediatrics, Ghent University, 9000 Ghent, Belgium; (C.D.G.); (M.D.V.); (P.H.); (D.L.)
- Ghent Gut Inflammation Group (GGIG), Ghent University, 9000 Ghent, Belgium
- VIB Centre for Inflammation Research, 9000 Ghent, Belgium
| | - Martine De Vos
- Department of Internal Medicine and Paediatrics, Ghent University, 9000 Ghent, Belgium; (C.D.G.); (M.D.V.); (P.H.); (D.L.)
- Ghent Gut Inflammation Group (GGIG), Ghent University, 9000 Ghent, Belgium
| | - Pieter Hindryckx
- Department of Internal Medicine and Paediatrics, Ghent University, 9000 Ghent, Belgium; (C.D.G.); (M.D.V.); (P.H.); (D.L.)
- Department of Gastroenterology, Ghent University Hospital, 9000 Ghent, Belgium
| | - Debby Laukens
- Department of Internal Medicine and Paediatrics, Ghent University, 9000 Ghent, Belgium; (C.D.G.); (M.D.V.); (P.H.); (D.L.)
- Ghent Gut Inflammation Group (GGIG), Ghent University, 9000 Ghent, Belgium
- VIB Centre for Inflammation Research, 9000 Ghent, Belgium
| | - Sophie Van Welden
- Department of Internal Medicine and Paediatrics, Ghent University, 9000 Ghent, Belgium; (C.D.G.); (M.D.V.); (P.H.); (D.L.)
- Ghent Gut Inflammation Group (GGIG), Ghent University, 9000 Ghent, Belgium
- VIB Centre for Inflammation Research, 9000 Ghent, Belgium
- Correspondence: ; Tel.: +32-9-332-58-30
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15
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Zhou HC, Xin-Yan Yan, Yu WW, Liang XQ, Du XY, Liu ZC, Long JP, Zhao GH, Liu HB. Lactic acid in macrophage polarization: The significant role in inflammation and cancer. Int Rev Immunol 2021; 41:4-18. [PMID: 34304685 DOI: 10.1080/08830185.2021.1955876] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Metabolite lactic acid has always been regarded as a metabolic by-product rather than a bioactive molecule. Recently, this view has changed since it was discovered that lactic acid can be used as a signal molecule and has novel signal transduction functions both intracellular and extracellular, which can regulate key functions in the immune system. In recent years, more and more evidence has shown that lactic acid is closely related to the metabolism and polarization of macrophages. During inflammation, lactic acid is a regulator of macrophage metabolism, and it can prevent excessive inflammatory responses; In malignant tumors, lactic acid produced by tumor tissues promotes the polarization of tumor-associated macrophages, which in turn promotes tumor progression. In this review, we examined the relationship between lactic acid and macrophage metabolism. We further discussed how lactic acid plays a role in maintaining the homeostasis of macrophages, as well as the biology of macrophage polarization and the M1/M2 imbalance in human diseases. Potential methods to target lactic acid in the treatment of inflammation and cancer will also be discussed so as to provide new strategies for the treatment of diseases.
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Affiliation(s)
- Hai-Cun Zhou
- Department of Breast Surgery, Gansu Maternal and Child Health Care Hospital, Lanzhou, Gansu Province, P. R. China.,Key Laboratory of Stem Cells and Gene Drugs of Gansu Province, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou, P.R. China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, P.R.China
| | - Xin-Yan Yan
- Department of Breast Surgery, Gansu Maternal and Child Health Care Hospital, Lanzhou, Gansu Province, P. R. China
| | - Wen-Wen Yu
- Key Laboratory of Stem Cells and Gene Drugs of Gansu Province, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou, P.R. China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, P.R.China
| | - Xiao-Qin Liang
- Key Laboratory of Stem Cells and Gene Drugs of Gansu Province, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou, P.R. China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, P.R.China
| | - Xiao-Yan Du
- Department of Breast Surgery, Gansu Maternal and Child Health Care Hospital, Lanzhou, Gansu Province, P. R. China
| | - Zhi-Chang Liu
- Key Laboratory of Stem Cells and Gene Drugs of Gansu Province, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou, P.R. China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, P.R.China
| | - Jian-Ping Long
- Department of Breast Surgery, Gansu Maternal and Child Health Care Hospital, Lanzhou, Gansu Province, P. R. China
| | - Guang-Hui Zhao
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, P. R. China
| | - Hong-Bin Liu
- Key Laboratory of Stem Cells and Gene Drugs of Gansu Province, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou, P.R. China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, P.R.China
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16
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Liu ZQ, Shang LL, Ge SH. Immunomodulatory effect of dimethyloxallyl glycine/nanosilicates-loaded fibrous structure on periodontal bone remodeling. J Dent Sci 2021; 16:937-947. [PMID: 34141108 PMCID: PMC8189879 DOI: 10.1016/j.jds.2020.10.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/23/2020] [Accepted: 10/25/2020] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND/PURPOSE Relieving immuno-inflammatory responses is the prerequisite step for treating periodontitis. The angiogenic small molecule, dimethyloxalylglycine (DMOG), and osteoinductive inorganic nanomaterial, nanosilicate (nSi) have a powerful effect on bone regeneration, whereas the roles in osteoimmunomodulation have not been totally uncovered. Our study aimed to explore the immunomodulatory effect of DMOG/nSi-loaded fibrous membranes on periodontal bone remodeling. MATERIALS AND METHODS The fibrous membranes were prepared by incorporating DMOG and nSi into poly (lactic-co-glycolic acid) (PLGA) with electrospinning. The morphology features, surface chemical property and biocompatibility of DMOG/nSi-PLGA fibrous membranes were characterized. Thereafter, the fibrous membranes were implanted into rat periodontal defects, bone remodeling potential and immunomodulatory effect were evaluated by micro-computed tomography (micro-CT), histological evaluation and immunohistochemical analysis. RESULTS DMOG/nSi-PLGA membranes possessed favorable physicochemical properties and biocompatibility. After the fibrous membranes implanted into periodontal defects, DMOG/nSi-PLGA membranes could relieve immuno-inflammatory responses of the defects (reduction of inflammatory cell infiltration, CD40L and CD11b-positive cells), increased CD206-positive M2 macrophages, and eventually facilitated periodontal bone regeneration. CONCLUSION DMOG/nSi-PLGA fibrous membranes exert protective effects during periodontal bone defect repairing, and steer immune response towards bone regeneration. Consequently, DMOG/nSi-PLGA fibrous membranes may serve as a promising scaffold in periodontal tissue engineering.
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Affiliation(s)
- Zi-Qi Liu
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No. 44-1, Wenhua Road West, Jinan, Shandong, 250012, China
| | - Ling-Ling Shang
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No. 44-1, Wenhua Road West, Jinan, Shandong, 250012, China
| | - Shao-Hua Ge
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No. 44-1, Wenhua Road West, Jinan, Shandong, 250012, China
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17
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Bhattacharya S, Shrimali NM, Mohammad G, Koul PA, Prchal JT, Guchhait P. Gain-of-function Tibetan PHD2 D4E;C127S variant suppresses monocyte function: A lesson in inflammatory response to inspired hypoxia. EBioMedicine 2021; 68:103418. [PMID: 34102396 PMCID: PMC8190441 DOI: 10.1016/j.ebiom.2021.103418] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 04/01/2021] [Accepted: 05/14/2021] [Indexed: 12/30/2022] Open
Abstract
Background We have previously described an evolutionarily selected Tibetan prolyl hydroxylase-2 (PHD2D4E;C127S) variant that degrades the hypoxia-inducible factor (HIFα) more efficiently and protects these highlanders from hypoxia-triggered elevation in haemoglobin concentration. High altitude is known to cause acute mountain sickness (AMS) and high-altitude pulmonary edema (HAPE) in a section of rapidly ascending non-acclimatised lowlanders. These morbidities are often accompanied by inflammatory response and exposure to hypobaric hypoxia is presumed to be the principal causative agent. We have investigated whether PHD2D4E;C127S variant is associated with prevention of hypoxia-mediated inflammatory milieu in Tibetan highlanders and therefore identify a potential target to regulate inflammation. Methods We genotyped the Tibetans using DNA isolated from whole blood. Thereafter immunophenotying was performed on PBMCs from homozygous PHD2D4E;C127S and PHD2WT individuals using flow cytometry. RNA isolated from these individuals was used to evaluate the peripheral level of important transcripts associated with immune as well as hypoxia response employing the nCounter technology. The ex-vivo findings were validated by generating monocytic cell lines (U937 cell line) expressing PHD2D4E;C127S and PHD2WT variants post depletion of endogenous PHD2. We had also collected whole blood samples from healthy travellers and travellers afflicted with AMS and HAPE to evaluate the significance of our ex-vivo and in vitro findings. Hereafter, we also attempted to resolve hypoxia-triggered inflammation in vitro as well as in vivo by augmenting the function of PHD2 using alpha-ketoglutarate (αKG), a co-factor of PHD2. Findings We report that homozygous PHD2D4E;C127S highlanders harbour less inflammatory and patrolling monocytes in circulation as compared to Tibetan PHD2WT highlanders. In response to in vitro hypoxia, secretion of IL6 and IL1β from PHD2D4E;C127S monocytes, and their chemotactic response compared to the PHD2WT are compromised, corresponding to the down-modulated expression of related signalling molecules RELA, JUN, STAT1, ATF2 and CXCR4. We verified these functional outcomes in monocytic U937 cell line engineered to express PHD2D4E;C127S and confirmed the down-modulation of the signalling molecules at protein level under hypoxia. In contrast, non-Tibetan sojourners with AMS and HAPE at high altitude (3,600 m above sea level) displayed significant increase in these inflammatory parameters. Our data henceforth underline the role of gain-of-function of PHD2 as the rate limiting factor to harness hyper-activation of monocytes in hypoxic environment. Therefore upon pre-treatment with αKG, we observed diminished inflammatory response of monocytes in vitro and reduction in leukocyte infiltration to the lungs in mice exposed to normobaric hypoxia. Interpretation Our report suggests that gain-of-function PHD2 D4E;C127S variant can therefore protect against inflammation elicited by hypobaric hypoxia. Augmentation of PHD2 activity therefore may be an important method to alleviate inflammatory response to inspired hypoxia. Funding This study is supported by the Department of Biotechnology, Government of India.
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Affiliation(s)
- Sulagna Bhattacharya
- Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, India; School of Biotechnology, Kalinga Institute of Industrial Technology, Orissa, India
| | - Nishith M Shrimali
- Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, India
| | | | - Parvaiz A Koul
- Department of Internal and Pulmonary Medicine, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, India
| | - Josef T Prchal
- Department of Medicine, University of Utah School of Medicine & Huntsman Cancer Center and George E. Wahlin Veteran's Administration Medical Center, Salt Lake City, UT, USA
| | - Prasenjit Guchhait
- Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, India.
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18
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Dengler F, Sova S, Salo AM, Mäki JM, Koivunen P, Myllyharju J. Expression and Roles of Individual HIF Prolyl 4-Hydroxylase Isoenzymes in the Regulation of the Hypoxia Response Pathway along the Murine Gastrointestinal Epithelium. Int J Mol Sci 2021; 22:4038. [PMID: 33919829 PMCID: PMC8070794 DOI: 10.3390/ijms22084038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/07/2021] [Accepted: 04/11/2021] [Indexed: 12/11/2022] Open
Abstract
The HIF prolyl 4-hydroxylases (HIF-P4H) control hypoxia-inducible factor (HIF), a powerful mechanism regulating cellular adaptation to decreased oxygenation. The gastrointestinal epithelium subsists in "physiological hypoxia" and should therefore have an especially well-designed control over this adaptation. Thus, we assessed the absolute mRNA expression levels of the HIF pathway components, Hif1a, HIF2a, Hif-p4h-1, 2 and 3 and factor inhibiting HIF (Fih1) in murine jejunum, caecum and colon epithelium using droplet digital PCR. We found a higher expression of all these genes towards the distal end of the gastrointestinal tract. We detected mRNA for Hif-p4h-1, 2 and 3 in all parts of the gastrointestinal tract. Hif-p4h-2 had significantly higher expression levels compared to Hif-p4h-1 and 3 in colon and caecum epithelium. To test the roles each HIF-P4H isoform plays in the gut epithelium, we measured the gene expression of classical HIF target genes in Hif-p4h-1-/-, Hif-p4h-2 hypomorph and Hif-p4h-3-/- mice. Only Hif-p4h-2 hypomorphism led to an upregulation of HIF target genes, confirming a predominant role of HIF-P4H-2. However, the abundance of Hif-p4h-1 and 3 expression in the gastrointestinal epithelium implies that these isoforms may have specific functions as well. Thus, the development of selective inhibitors might be useful for diverging therapeutic needs.
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Affiliation(s)
- Franziska Dengler
- Unit of Physiology, Pathophysiology and Experimental Endocrinology, University of Veterinary Medicine, 1210 Vienna, Austria
- Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90220 Oulu, Finland; (S.S.); (A.M.S.); (J.M.M.); (P.K.); (J.M.)
- Institute of Veterinary Physiology, University of Leipzig, 04103 Leipzig, Germany
| | - Sofia Sova
- Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90220 Oulu, Finland; (S.S.); (A.M.S.); (J.M.M.); (P.K.); (J.M.)
| | - Antti M. Salo
- Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90220 Oulu, Finland; (S.S.); (A.M.S.); (J.M.M.); (P.K.); (J.M.)
| | - Joni M. Mäki
- Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90220 Oulu, Finland; (S.S.); (A.M.S.); (J.M.M.); (P.K.); (J.M.)
| | - Peppi Koivunen
- Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90220 Oulu, Finland; (S.S.); (A.M.S.); (J.M.M.); (P.K.); (J.M.)
| | - Johanna Myllyharju
- Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90220 Oulu, Finland; (S.S.); (A.M.S.); (J.M.M.); (P.K.); (J.M.)
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19
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Strowitzki MJ, Kimmer G, Wehrmann J, Ritter AS, Radhakrishnan P, Opitz VM, Tuffs C, Biller M, Kugler J, Keppler U, Harnoss JM, Klose J, Schmidt T, Blanco A, Taylor CT, Schneider M. Inhibition of HIF-prolyl hydroxylases improves healing of intestinal anastomoses. JCI Insight 2021; 6:139191. [PMID: 33784253 PMCID: PMC8119215 DOI: 10.1172/jci.insight.139191] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 03/24/2021] [Indexed: 12/15/2022] Open
Abstract
Anastomotic leakage (AL) accounts for a major part of in-house mortality in patients undergoing colorectal surgery. Local ischemia and abdominal sepsis are common risk factors contributing to AL and are characterized by upregulation of the hypoxia-inducible factor (HIF) pathway. The HIF pathway is critically regulated by HIF-prolyl hydroxylases (PHDs). Here, we investigated the significance of PHDs and the effects of pharmacologic PHD inhibition (PHI) during anastomotic healing. Ischemic or septic colonic anastomoses were created in mice by ligation of mesenteric vessels or lipopolysaccharide-induced abdominal sepsis, respectively. Genetic PHD deficiency (Phd1-/-, Phd2+/-, and Phd3-/-) or PHI were applied to manipulate PHD activity. Pharmacologic PHI and genetic PHD2 haplodeficiency (Phd2+/-) significantly improved healing of ischemic or septic colonic anastomoses, as indicated by increased bursting pressure and reduced AL rates. Only Phd2+/- (but not PHI or Phd1-/-) protected from sepsis-related mortality. Mechanistically, PHI and Phd2+/- induced immunomodulatory (M2) polarization of macrophages, resulting in increased collagen content and attenuated inflammation-driven immune cell recruitment. We conclude that PHI improves healing of colonic anastomoses in ischemic or septic conditions by Phd2+/--mediated M2 polarization of macrophages, conferring a favorable microenvironment for anastomotic healing. Patients with critically perfused colorectal anastomosis or abdominal sepsis could benefit from pharmacologic PHI.
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Affiliation(s)
- Moritz J Strowitzki
- Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany.,School of Medicine and Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin, Ireland
| | - Gwendolyn Kimmer
- Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany
| | - Julian Wehrmann
- Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany
| | - Alina S Ritter
- Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany
| | - Praveen Radhakrishnan
- Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany
| | - Vanessa M Opitz
- Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany
| | - Christopher Tuffs
- Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany
| | - Marvin Biller
- Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany
| | - Julia Kugler
- School of Medicine and Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin, Ireland
| | - Ulrich Keppler
- Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany.,Department of Anaesthesiology, Heidelberg University, Heidelberg, Germany
| | - Jonathan M Harnoss
- Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany
| | - Johannes Klose
- Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany
| | - Thomas Schmidt
- Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany
| | - Alfonso Blanco
- Flow Cytometry Core Technology. Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin, Ireland
| | - Cormac T Taylor
- School of Medicine and Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin, Ireland
| | - Martin Schneider
- Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany
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20
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Du Y, Rong L, Cong Y, Shen L, Zhang N, Wang B. Macrophage polarization: an effective approach to targeted therapy of inflammatory bowel disease. Expert Opin Ther Targets 2021; 25:191-209. [PMID: 33682588 DOI: 10.1080/14728222.2021.1901079] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Introduction: Inflammatory bowel disease (IBD) is a systemic disease with immune abnormalities that can affect the entire digestive tract. A high percentage of patients with IBD are unresponsive to current pharmacological agents, hence the need exists for novel therapeutic approaches. There is compelling evidence that macrophage polarization plays a key role in the remission of IBD patients and that it could open up future treatment options for patients.Areas covered: This paper highlights the crucial role of macrophage polarization in IBD. The authors shed light on the phenotype and function of macrophages and potential drug targets for polarization regulation. Existing approaches for regulating macrophage polarization are discussed and potential solutions for safety concerns are considered. We performed a literature search on the IBD and macrophage polarization mainly published in PubMed January 2010-July 2020.Expert opinion: Evidence indicates that there are fewer M2 macrophages and a high proportion of M1 macrophages in the intestinal tissues of individuals who are non- responsive to treatment. Regulating macrophage polarization is a potential novel targeted option for IBD treatment. Improved mechanistic insights are required to uncover more precise and effective targets for skewing macrophages into a proper phenotype.
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Affiliation(s)
- Yaoyao Du
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lan Rong
- Department of Digestive Diseases, Huashan Hospital Affiliated to Fudan University, Shanghai, China
| | - Yuanhua Cong
- Center for Pharmaceutics Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai, China
| | - Lan Shen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ning Zhang
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Bing Wang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Center for Pharmaceutics Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai, China
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21
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MyD88 in myofibroblasts enhances colitis-associated tumorigenesis via promoting macrophage M2 polarization. Cell Rep 2021; 34:108724. [PMID: 33535045 DOI: 10.1016/j.celrep.2021.108724] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 11/20/2020] [Accepted: 01/13/2021] [Indexed: 12/24/2022] Open
Abstract
The signal adaptor MyD88, an essential component of TLR signaling, plays an important role in gut-microbiome interactions. However, its contribution to colitis-associated cancer (CAC) is still controversial. Far less is known about the specific effects of MyD88 signaling in myofibroblasts in CAC development. Here, we used a CAC mouse model in which MyD88 was selectively depleted in myofibroblasts. Myofibroblast MyD88-deficient mice are resistant to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced tumorigenesis, as evidenced by the decrease in the number and sizes of tumors. MyD88 deficiency in myofibroblasts attenuates intestinal epithelial cell (IEC) proliferation after acute DSS-induced colitis. Furthermore, MyD88 signaling in myofibroblasts increases the secretion of osteopontin (OPN), which promotes macrophage M2 polarization through binding to αvβ3 and CD44, leading to activation of the STAT3/PPARγ pathway. Thus, MyD88 signaling in myofibroblasts crucially contributes to colorectal cancer development and provides a promising therapeutic target for the prevention of colitis-associated carcinogenesis.
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22
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Abstract
The disease course of autoimmune diseases such as rheumatoid arthritis is altered during pregnancy, and a similar modulatory role of pregnancy on inflammatory bowel disease (IBD) has been proposed. Hormonal, immunological, and microbial changes occurring during normal pregnancy may interact with the pathophysiology of IBD. IBD consists of Crohn's disease and ulcerative colitis, and because of genetic, immunological, and microbial differences between these disease entities, they may react differently during pregnancy and should be described separately. This review will address the pregnancy-induced physiological changes and their potential effect on the disease course of ulcerative colitis and Crohn's disease, with emphasis on the modulation of epithelial barrier function and immune profiles by pregnancy hormones, microbial changes, and microchimerism.
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23
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Harnoss JM, Gebhardt JM, Radhakrishnan P, Leowardi C, Burmeister J, Halligan DN, Yuan S, Kennel KB, Strowitzki MJ, Schaible A, Lasitschka F, Taylor CT, Schneider M. Prolyl Hydroxylase Inhibition Mitigates Pouchitis. Inflamm Bowel Dis 2020; 26:192-205. [PMID: 31618435 DOI: 10.1093/ibd/izz218] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Pouchitis is the most common long-term complication after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) or familial adenomatous polyposis (FAP), which can eventually progress to pouch failure, necessitating permanent stoma construction. Hypoxia-inducible transcription factor prolyl hydroxylase-containing enzymes (PHD1, PHD2, and PHD3) are molecular oxygen sensors that control adaptive gene expression through hypoxia-inducible factor (HIF). Emerging evidence supports PHDs as being therapeutic targets in intestinal inflammation. However, pharmacological inhibition of PHDs has not been validated as a treatment strategy in pouchitis. METHODS PHD1-3 mRNA and protein expression were analyzed in mucosal pouch and prepouch ileal patient biopsies. After establishment of a preclinical IPAA model in rats, the impact of the pan-PHD small-molecule inhibitor dimethyloxalylglycine (DMOG) on dextran sulfate sodium (DSS)-induced pouchitis was studied. Clinical and molecular parameters were investigated. RESULTS PHD1, but not PHD2 or PHD3, was overexpressed in pouchitis in biopsies of patients with IPAA for UC but not FAP. In addition, PHD1 expression correlated with disease activity. DMOG treatment profoundly mitigated DSS-induced pouchitis in a rodent IPAA model. Mechanistically, DMOG restored intestinal epithelial barrier function by induction of tight junction proteins zona occludens-1 and claudin-1 and alleviation of intestinal epithelial cell apoptosis, thus attenuating pouch inflammation. CONCLUSIONS Together, these results establish a strong therapeutic rationale for targeting PHD1 with small-molecule inhibitors in pouchitis after IPAA for UC.
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Affiliation(s)
- Jonathan M Harnoss
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Jasper M Gebhardt
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Praveen Radhakrishnan
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Christine Leowardi
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Julius Burmeister
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Doug N Halligan
- School of Medicine, Systems Biology Ireland and the Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Shuai Yuan
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Kilian B Kennel
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Moritz J Strowitzki
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.,School of Medicine, Systems Biology Ireland and the Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Anja Schaible
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Felix Lasitschka
- Institute of Pathology, University of Heidelberg, Heidelberg, Germany
| | - Cormac T Taylor
- School of Medicine, Systems Biology Ireland and the Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Martin Schneider
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
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24
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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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25
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Tsuda S, Carreras J, Kikuti YY, Nakae H, Dekiden-Monma M, Imai J, Tsuruya K, Nakamura J, Tsukune Y, Uchida T, Matsushima M, Roncador G, Suzuki T, Nakamura N, Mine T. Prediction of steroid demand in the treatment of patients with ulcerative colitis by immunohistochemical analysis of the mucosal microenvironment and immune checkpoint: role of macrophages and regulatory markers in disease severity. Pathol Int 2019; 69:260-271. [PMID: 30990953 DOI: 10.1111/pin.12794] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 02/24/2019] [Indexed: 12/11/2022]
Abstract
We aimed to characterize the mucosal immune microenvironment and immune checkpoint of Ulcerative colitis (UC) by immunohistochemistry with correlation to prognosis: requirement of second-line steroid-therapy within the 2-years after diagnosis (SR). A series of 72 cases included 56 UC, 43 non-SR (with first-line treatment 5-ASA) and 13 SR, 11 infectious colitis and 5 normal colonic biopsies. Normal mucosa was characterized by low infiltrates but high BTLA and TNFRSF14. Compared to normal, UC had increased pan-immune-markers of CD3, CD8, FOXP3, PD-1, CD68, CD16, CD163, PTX3 and CD11C but had decreased BTLA (P < 0.05); by GSEA analysis comparable results were found in an independent UC gene-expression-data set (GSE38713). Compared to infectious, UC had higher CD4, CD8, PTX3 and CD11C but lower BTLA (P < 0.05). Compared to non-SR, SR had lower FOXP3 + Tregs (Odds-Ratio = 0.114, P = 0.002), PD-1 (OR = 0.176, P = 0.002) and CD163/CD68 M2-ratio (OR, 0.019, P = 0.019) but higher CD68 + pan-macrophages (OR = 6.034, P = 0.002). Higher Baron endoscopic and Geboes histologic disease activity scores also correlated with SR. In summary, UC was characterized by increased pan-immune-markers, normal TNFRSF14 and low BTLA. SR had increased CD68 + pan-macrophages but lower immune inhibitors of FOXP3 + Tregs, PD-1 and CD163/CD68 M2-macrophage ratio. In conclusion, alterations of the immune homeostasis mechanisms are relevant in the UC pathogenesis and steroid-requiring situation.
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Affiliation(s)
- Shingo Tsuda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Joaquim Carreras
- Department of Pathology, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Yara Y Kikuti
- Department of Pathology, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Hirohiko Nakae
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Makiko Dekiden-Monma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Jin Imai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Kota Tsuruya
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Jun Nakamura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Yoko Tsukune
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Tetsufumi Uchida
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Masashi Matsushima
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Giovanna Roncador
- Monoclonal Antibodies Core Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Takayoshi Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Naoya Nakamura
- Department of Pathology, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Tetsuya Mine
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
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26
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Shang L, Wang T, Tong D, Kang W, Liang Q, Ge S. Prolyl hydroxylases positively regulated LPS-induced inflammation in human gingival fibroblasts via TLR4/MyD88-mediated AKT/NF-κB and MAPK pathways. Cell Prolif 2018; 51:e12516. [PMID: 30091492 PMCID: PMC6528886 DOI: 10.1111/cpr.12516] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 07/17/2018] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVES Prolyl hydroxylases (PHDs) play essential roles in oxygen-sensing system, whereas the effects of PHDs on inflammation have not been totally uncovered. Our study aimed to investigate the role of PHDs in lipopolysaccharide (LPS)-induced inflammation of human gingival fibroblasts (HGFs) and clarify the potential mechanisms. MATERIALS AND METHODS A pan hydroxylase inhibitor, dimethyloxallyl glycine (DMOG), and RNA interference were used to explore the role of PHDs in inflammation. Cytotoxic effect of DMOG was determined by cell-counting kit-8 and flow cytometry respectively. The secretion levels of IL-6 and IL-8 were assessed by ELISA. The mRNA levels of inflammatory cytokines, Toll-like receptor (TLR) 4 and MyD88 were evaluated by quantitative real-time PCR. The activation of NF-κB, mitogen-activated protein kinase (MAPK) and PI3K/AKT pathways were detected by western blot and the nuclear translocation of NF-κB p65 was examined by immunofluorescence. Downregulation of PHD1 and PHD2 was performed with siRNA transfection. RESULTS Dimethyloxallyl glycine inhibited LPS-induced inflammatory cytokine, TLR4 and MyD88 expression in gene level and the elevated secretion of IL-6 and IL-8 was also downregulated. Additionally, LPS-induced activation of NF-κB, MAPK and AKT pathways was abolished by DMOG treatment. Importantly, LPS-induced inflammatory cytokine expression was merely suppressed by PHD2 knockdown. CONCLUSIONS Prolyl hydroxylases acted as a positive regulator in LPS-induced inflammation of HGFs via TLR4/MyD88-mediated NF-κB, MAPK and AKT signalling pathways and PHD2 among three isoforms was principally responsible for the effects.
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Affiliation(s)
- Lingling Shang
- Shandong Provincial Key Laboratory of Oral Tissue RegenerationSchool of Stomatology, Shandong UniversityShandong, JinanChina
- Department of PeriodontologySchool of Stomatology, Shandong UniversityShandong, JinanChina
| | - Ting Wang
- Shandong Provincial Key Laboratory of Oral Tissue RegenerationSchool of Stomatology, Shandong UniversityShandong, JinanChina
- Department of PeriodontologySchool of Stomatology, Shandong UniversityShandong, JinanChina
| | - Dongdong Tong
- Department of Oral maxillofacial SurgerySchool of Stomatology, Shandong UniversityShandong, JinanChina
| | - Wenyan Kang
- Shandong Provincial Key Laboratory of Oral Tissue RegenerationSchool of Stomatology, Shandong UniversityShandong, JinanChina
- Department of PeriodontologySchool of Stomatology, Shandong UniversityShandong, JinanChina
| | - Qianyu Liang
- Shandong Provincial Key Laboratory of Oral Tissue RegenerationSchool of Stomatology, Shandong UniversityShandong, JinanChina
- Department of PeriodontologySchool of Stomatology, Shandong UniversityShandong, JinanChina
| | - Shaohua Ge
- Shandong Provincial Key Laboratory of Oral Tissue RegenerationSchool of Stomatology, Shandong UniversityShandong, JinanChina
- Department of PeriodontologySchool of Stomatology, Shandong UniversityShandong, JinanChina
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27
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Watts ER, Walmsley SR. Inflammation and Hypoxia: HIF and PHD Isoform Selectivity. Trends Mol Med 2018; 25:33-46. [PMID: 30442494 DOI: 10.1016/j.molmed.2018.10.006] [Citation(s) in RCA: 163] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 10/16/2018] [Accepted: 10/17/2018] [Indexed: 12/16/2022]
Abstract
Cells sense and respond to hypoxia through the activity of the transcription factor HIF (hypoxia-inducible factor) and its regulatory hydroxylases, the prolyl hydroxylase domain enzymes (PHDs). Multiple isoforms of HIFs and PHDs exist, and isoform-selective roles have been identified in the context of the inflammatory environment, which is itself frequently hypoxic. Recent advances in the field have highlighted the complexity of this system, particularly with regards to the cell and context-specific activity of HIFs and PHDs. Because novel therapeutic agents which regulate this pathway are nearing the clinic, understanding the role of HIFs and PHDs in inflammation outcomes is an essential step in avoiding off-target effects and, crucially, in developing new anti-inflammatory strategies.
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Affiliation(s)
- Emily R Watts
- The University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Sarah R Walmsley
- The University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
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28
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Kennel KB, Burmeister J, Schneider M, Taylor CT. The PHD1 oxygen sensor in health and disease. J Physiol 2018; 596:3899-3913. [PMID: 29435987 DOI: 10.1113/jp275327] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 01/31/2018] [Indexed: 12/13/2022] Open
Abstract
The hypoxia-inducible factor (HIF) co-ordinates the adaptive transcriptional response to hypoxia in metazoan cells. The hypoxic sensitivity of HIF is conferred by a family of oxygen-sensing enzymes termed HIF hydroxylases. This family consists of three prolyl hydroxylases (PHD1-3) and a single asparagine hydroxylase termed factor inhibiting HIF (FIH). It has recently become clear that HIF hydroxylases are functionally non-redundant and have discrete but overlapping physiological roles. Furthermore, altered abundance or activity of these enzymes is associated with a number of pathologies. Pharmacological HIF-hydroxylase inhibitors have recently proven to be both tolerated and therapeutically effective in patients. In this review, we focus on the physiology, pathophysiology and therapeutic potential of the PHD1 isoform, which has recently been implicated in diseases including inflammatory bowel disease, ischaemia and cancer.
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Affiliation(s)
- Kilian B Kennel
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Julius Burmeister
- 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
| | - Cormac T Taylor
- UCD Conway Institute & School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland
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Panax notoginseng Promotes Repair of Colonic Microvascular Injury in Sprague-Dawley Rats with Experimental Colitis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:4386571. [PMID: 29785192 PMCID: PMC5896412 DOI: 10.1155/2018/4386571] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Revised: 12/20/2017] [Accepted: 12/27/2017] [Indexed: 12/17/2022]
Abstract
To investigate the therapeutic effects of PN on intestinal inflammation and microvascular injury and its mechanisms, dextran sodium sulfate- (DSS-) or iodoacetamide- (IA-) induced rat colitis models were used. After colitis model was established, PN was orally administered for 7 days at daily dosage of 1.0 g/kg. Obvious colonic inflammation and mucosal injuries and microvessels were observed in DSS- and IA-induced colitis groups. DAI scores, serum concentrations of VEGFA121, VEGFA165, VEGFA165/VEGFA121, IL-6, and TNF-α, and expression of Rap1GAP and TSP1 proteins in the colon were significantly higher while serum concentrations of IL-4 and IL-10 and MVD in colon were significantly lower in the colitis model groups than in the normal control group. PN promoted repair of colonic mucosal injury and microvessels, attenuated inflammation, and decreased DAI scores in rats with colitis. PN also decreased the serum concentrations of VEGFA121, VEGFA165, VEGFA165/VEGFA121, IL-6, and TNF-α and increased the serum concentrations of IL-4 and IL-10, with the expression of Rap1GAP and TSP1 proteins in colonic mucosa being downregulated. The constituents of PN were identified with HPLC-DAD. To sum up, PN could promote repair of injuries of colonic mucosa and microvessels via downregulating VEGFA isoforms and inhibiting Rap1GAP/TSP1 signaling pathway.
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Jia X, Wang B, Yao Q, Li Q, Zhang J. Variations in CD14 Gene Are Associated With Autoimmune Thyroid Diseases in the Chinese Population. Front Endocrinol (Lausanne) 2018; 9:811. [PMID: 30700980 PMCID: PMC6343429 DOI: 10.3389/fendo.2018.00811] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Accepted: 12/24/2018] [Indexed: 12/12/2022] Open
Abstract
Autoimmune thyroid diseases (AITDs) are chronic organ-specific autoimmune diseases and mainly include Graves' disease (GD) and Hashimoto's thyroiditis (HT). CD14 is an important component of the immune system as a receptor for gram-negative lipopolysaccharide (LPS). The genetic polymorphisms of CD14 have been confirmed to be associated with a variety of autoimmune diseases. However, its relationship with AITDs is still unclear. The study was aimed to determine whether four single nucleotide polymorphisms (rs2915863, rs2569190, rs2569192, and rs2563298) of CD14 are associated with AITDs and its subgroups of GD and HT. The results showed significant association of rs2915863 and rs2569190 with GD. The frequencies of rs2915863 genotypes and T allele in patients with GD differed significantly from their controls (P = 0.007 and P = 0.021, respectively). For rs2569190, frequencies of genotypes and G allele in GD patients also showed positive P-values (P = 0.038 and P = 0.027, respectively). The correlations between these two loci and GD are more pronounced in female GD patients and patients with a family history. In genetic model analysis, the allele model, recessive model, and homozygous model of rs2569190 and rs2915863 embodied strong correlations with GD after the adjusting of age and gender (P = 0.014, P = 0.015, P = 0.009, and P = 0.014, P = 0.001, P = 0.006, respectively). However, these four sites are not related to HT. We firstly discovered the relationship between CD14 gene polymorphism and GD, and the results indicate that CD14 is an important risk locus for AITD and its SNPs may contribute to host's genetic predisposition to GD.
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Affiliation(s)
- Xi Jia
- Department of Endocrinology, Jinshan Hospital of Fudan University, Shanghai, China
| | - Bing Wang
- Department of Endocrinology, Jinshan Hospital of Fudan University, Shanghai, China
| | - Qiuming Yao
- Department of Endocrinology, Jinshan Hospital of Fudan University, Shanghai, China
| | - Qian Li
- Department of Endocrinology, Jinshan Hospital of Fudan University, Shanghai, China
| | - Jinan Zhang
- Department of Endocrinology, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
- *Correspondence: Jinan Zhang
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31
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Wang Y, Mao Y, Zhang J, Shi G, Cheng L, Lin Y, Li Y, Zhang X, Zhang Y, Chen X, Deng J, Su X, Dai L, Yang Y, Zhang S, Yu D, Wei Y, Deng H. IL-35 recombinant protein reverses inflammatory bowel disease and psoriasis through regulation of inflammatory cytokines and immune cells. J Cell Mol Med 2017; 22:1014-1025. [PMID: 29193791 PMCID: PMC5783847 DOI: 10.1111/jcmm.13428] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 09/22/2017] [Indexed: 02/05/2023] Open
Abstract
Interleukin‐35 (IL‐35), a member of the IL‐12 family, functions as a new anti‐inflammatory factor involved in arthritis, psoriasis, inflammatory bowel disease (IBD) and other immune diseases. Although IL‐35 can significantly prevent the development of inflammation in many diseases, there have been no early studies accounting for the role of IL‐35 recombinant protein in IBD and psoriasis. In this study, we assessed the therapeutic potential of IL‐35 recombinant protein in three well‐known mouse models: the dextransulfate sodium (DSS)‐induced colitis mouse model, the keratin14 (K14)‐vascular endothelial growth factor A (VEGF‐A)‐transgenic (Tg) psoriasis mouse model and the imiquimod (IMQ)‐induced psoriasis mouse model. Our results indicated that IL‐35 recombinant protein can slow down the pathologic process in DSS‐induced acute colitis mouse model by decreasing the infiltrations of macrophages, CD4+T and CD8+T cells and by promoting the infiltration of Treg cells. Further analysis demonstrated that IL‐35 recombinant protein may regulate inflammation through promoting the secretion of IL‐10 and inhibiting the expression of pro‐inflammatory cytokines such as IL‐6, TNF‐α and IL‐17 in acute colitis model. In addition, lower dose of IL‐35 recombinant protein could achieve long‐term treatment effects as TNF‐α monoclonal antibody did in the psoriasis mouse. In summary, the remarkable therapeutic effects of IL‐35 recombinant protein in acute colitis and psoriasis mouse models indicated that IL‐35 recombinant protein had a variety of anti‐inflammatory effects and was expected to become an effective candidate drug for the treatment of inflammatory diseases.
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Affiliation(s)
- Yuan Wang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Ying Mao
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Junfeng Zhang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Gang Shi
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Lin Cheng
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Lin
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yiming Li
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaomei Zhang
- Laboratory Animal Center, Sichuan University, Chengdu, China
| | - Yujing Zhang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaolei Chen
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Jie Deng
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaolan Su
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Lei Dai
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Yang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Shuang Zhang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Dechao Yu
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yuquan Wei
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Hongxin Deng
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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32
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Brown E, Taylor CT. Hypoxia-sensitive pathways in intestinal inflammation. J Physiol 2017; 596:2985-2989. [PMID: 29114885 DOI: 10.1113/jp274350] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 10/24/2017] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a common chronic intestinal disorder characterised by a loss of epithelial barrier function leading to the unregulated movement of luminal antigenic material into mucosal tissue with resultant inflammation. In IBD, multiple components of the inflammatory response lead to tissue hypoxia. Mucosal hypoxia leads to the inactivation of prolyl hydroxylase domain-containing (PHD) enzymes, which in turn leads to the stabilisation of the hypoxia-inducible factor (HIF), which induces the expression of barrier protective genes. Furthermore, pharmacological hydroxylase inhibition has been shown to be protective in colitis, at least in part through enhancing intestinal epithelial barrier function through HIF-1-dependent barrier-protective gene expression. Therefore, targeting hypoxia-sensitive pathways represents a new and promising therapeutic approach in IBD.
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Affiliation(s)
- Eric Brown
- UCD Conway Institute & School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland
| | - Cormac T Taylor
- UCD Conway Institute & School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland
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33
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Chen H, Shi H, Liu Y, Ren X, He S, Chang X, Yin Y. Activation of corticotropin-releasing factor receptor 1 aggravates dextran sodium sulphate-induced colitis in mice by promoting M1 macrophage polarization. Mol Med Rep 2017; 17:234-242. [PMID: 29115460 PMCID: PMC5780132 DOI: 10.3892/mmr.2017.7909] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 09/19/2017] [Indexed: 12/27/2022] Open
Abstract
The corticotropin-releasing factor (CRF) family is involved in modulating gastrointestinal motility, sensitivity and inflammation. CRF signalling exerts an important role in inflammatory bowel disease (IBD), predominantly by activating CRF receptors. The aim of the present study was to investigate the function of CRF receptor 1 (CRF-R1) in the development of mucosal inflammation induced by dextran sulphate sodium (DSS) and the underlying mechanism. Consecutive administration of CRF or CP154526 was used to activate or block the CRF-R1 in DSS-treated mice. Colonic inflammation was evaluated by determining the Disease Activity Index (DAI) and histology score. CRF-R1 expression was proportional to the DAI, the histology score and the number of macrophages. Activation of CRF-R1 aggravated mucosal inflammation by activating nuclear factor (NF)-κB and subsequently increasing the expression levels of tumour necrosis factor (TNF)-α and interleukin (IL)-6. Inhibition of CRF-R1 decreased the expression level of CRF-R1, macrophage infiltration, NF-κB activation, and TNF-α and IL-6 expression levels, ultimately alleviating the mucosal inflammation. Thus, CRF-R1 expression was proportional to the severity of DSS-induced colitis. Activation of CRF-R1 increased the DAI and histological scores of the colons from DSS-treated mice by promoting M1 macrophage polarization, demonstrated as increased NF-κB activation, and TNF-α and IL-6 release. These results provide evidence of the pro-inflammatory role of CRF-R1 in a DSS-induced ulcerative colitis (UC) model and a possible underlying mechanism, which may facilitate the elucidation of potential treatment approaches for UC.
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Affiliation(s)
- Hong Chen
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Haitao Shi
- Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Yaping Liu
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xiaoyang Ren
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Shuixiang He
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xinming Chang
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yan Yin
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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Van Welden S, Selfridge AC, Hindryckx P. Intestinal hypoxia and hypoxia-induced signalling as therapeutic targets for IBD. Nat Rev Gastroenterol Hepatol 2017; 14:596-611. [PMID: 28853446 DOI: 10.1038/nrgastro.2017.101] [Citation(s) in RCA: 91] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Tissue hypoxia occurs when local oxygen demand exceeds oxygen supply. In chronic inflammatory conditions such as IBD, the increased oxygen demand by resident and gut-infiltrating immune cells coupled with vascular dysfunction brings about a marked reduction in mucosal oxygen concentrations. To counter the hypoxic challenge and ensure their survival, mucosal cells induce adaptive responses, including the activation of hypoxia-inducible factors (HIFs) and modulation of nuclear factor-κB (NF-κB). Both pathways are tightly regulated by oxygen-sensitive prolyl hydroxylases (PHDs), which therefore represent promising therapeutic targets for IBD. In this Review, we discuss the involvement of mucosal hypoxia and hypoxia-induced signalling in the pathogenesis of IBD and elaborate in detail on the role of HIFs, NF-κB and PHDs in different cell types during intestinal inflammation. We also provide an update on the development of PHD inhibitors and discuss their therapeutic potential in IBD.
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Affiliation(s)
- Sophie Van Welden
- Department of Gastroenterology, Ghent University, De Pintelaan 185, 1K12-E, 9000 Ghent, Belgium
| | - Andrew C Selfridge
- Robarts Clinical Trials West, 4350 Executive Drive 210, San Diego, California 92121, USA
| | - Pieter Hindryckx
- Department of Gastroenterology, Ghent University, De Pintelaan 185, 1K12-E, 9000 Ghent, Belgium
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