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1
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Marín-López AG, Macias-Velez RDJ, Jarero-Basulto JJ, Rivera-Cervantes MC. Evidence of a hormetic-like cytoprotective effect by erythropoietin in the SH-SY5Y cell model of oxygen-glucose deprivation. Neuroscience 2025; 577:114-122. [PMID: 40368234 DOI: 10.1016/j.neuroscience.2025.05.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 05/01/2025] [Accepted: 05/11/2025] [Indexed: 05/16/2025]
Abstract
Erythropoietin is recognized as a neuroprotective agent for the brain and it has been suggested that may have a biphasic hormetic-like response, with low to intermediate doses providing greater cytoprotective benefits, whereas high doses have been associated with undesirable side effects related to its systemic application; however, it is unknown whether this occurs in brain and what mechanisms could be implicated. This study investigated the potential hormetic effects of recombinant human erythropoietin (rhEPO) on SH-SY5Y cells subjected to oxygen and glucose deprivation (OGD) and reoxygenation (reox) injury. We developed an in vitro protocol to investigate the rhEPO's hormetic effect under conditions similar to ischemic stroke. Cell vitality assays were conducted, and the gene and protein expression of EPO, erythropoietin receptor (EPOR), β-common receptor (βcR), and Bcl-xL were analyzed. We found that all evaluated doses of rhEPO exhibited a cytoprotective effect on cells treated during the 24 h reox period. Notably, the intermediate 50 IU/mL dose showed significantly higher cell vitality than the high 100 IU/mL dose (p < 0.05), suggesting a potential hormetic-like effect. Interestingly, both EPO and EPOR mRNA levels increased after OGD, followed by an increase in EPOR protein levels after the reox period. However, no changes were observed in EPOR or Bcl-xL mRNA expression after 4 and 8 h of rhEPO treatment during reox. Finally, βcR mRNA expression was not detected in any group. While further research is needed, these results suggest that rhEPO treatment may exert a hormetic-like effect and offer cytoprotection against ischemic stroke-like injury.
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Affiliation(s)
- Alejandra Guadalupe Marín-López
- Cellular Neurobiology Laboratory, Cell and Molecular Department, CUCBA, University of Guadalajara, 45220 Zapopan, Jalisco, Mexico
| | - Rafael de Jesús Macias-Velez
- Cellular Neurobiology Laboratory, Cell and Molecular Department, CUCBA, University of Guadalajara, 45220 Zapopan, Jalisco, Mexico
| | - José Jaime Jarero-Basulto
- Cellular Neurobiology Laboratory, Cell and Molecular Department, CUCBA, University of Guadalajara, 45220 Zapopan, Jalisco, Mexico
| | - Martha Catalina Rivera-Cervantes
- Cellular Neurobiology Laboratory, Cell and Molecular Department, CUCBA, University of Guadalajara, 45220 Zapopan, Jalisco, Mexico.
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Fang T, Ma C, Yang B, Zhao M, Sun L, Zheng N. Roxadustat improves diabetic myocardial injury by upregulating HIF-1α/UCP2 against oxidative stress. Cardiovasc Diabetol 2025; 24:67. [PMID: 39920720 PMCID: PMC11806548 DOI: 10.1186/s12933-025-02601-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 01/17/2025] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND Diabetes mellitus (DM), characterized by hyperglycemia, is intricately linked with cardiovascular complications. Hyperglycemia induces oxidative stress, compromising mitochondria energy metabolism disturbances, leading to cardiomyocyte hypoxia and dysregulation of hypoxia-inducible factor-1α (HIF-1α), thereby exacerbating diabetic myocardial injury. Roxadustat (FG-4592), as an inhibitor of HIF-PHD, reduces HIF-1α degradation and regulates the transcription and function of downstream target genes. This study explores the protective effect of FG-4592 on the diabetic myocardium and further investigates the specific mechanisms responsible for this action. METHODS We established diabetic myocardial injury mice and high glucose-induced rat cardiomyocyte models, administered FG-4592 pretreatment to clarify the protective effects and related mechanisms of FG-4592 on diabetic myocardial injury by detecting changes in oxidative stress, mitochondrial function, and related pathways. RESULTS FG-4592 demonstrated cardioprotective effects in diabetic mice by regulating mitochondrial structure and function, as well as maintaining oxidative stress balance in the myocardium. It stabilized HIF-1α, activated UCP2, and enhanced the PI3K/AKT/Nrf2 pathway, reducing mitochondrial superoxide production, improving mitochondrial respiratory potential, and modulating oxidative stress markers in high glucose-induced cardiomyocytes. CONCLUSIONS FG-4592 exerts protective effects against diabetic myocardial injury by reducing oxidative stress. The mechanism is linked with the upregulation of HIF-1α and UCP2, which subsequently activate the PI3K/AKT/Nrf2 signaling pathway.
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MESH Headings
- Animals
- Oxidative Stress/drug effects
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/complications
- Diabetes Mellitus, Experimental/pathology
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Male
- Up-Regulation
- Uncoupling Protein 2/metabolism
- Uncoupling Protein 2/genetics
- Diabetic Cardiomyopathies/metabolism
- Diabetic Cardiomyopathies/prevention & control
- Diabetic Cardiomyopathies/pathology
- Glycine/analogs & derivatives
- Glycine/pharmacology
- Mice, Inbred C57BL
- Signal Transduction/drug effects
- Isoquinolines/pharmacology
- Mitochondria, Heart/drug effects
- Mitochondria, Heart/metabolism
- Mitochondria, Heart/pathology
- Rats, Sprague-Dawley
- Rats
- Mice
- NF-E2-Related Factor 2/metabolism
- Proto-Oncogene Proteins c-akt/metabolism
- Antioxidants/pharmacology
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Affiliation(s)
- Tingting Fang
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning, China
| | - Congcong Ma
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning, China
| | - Bingyun Yang
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning, China
| | - Meiyu Zhao
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning, China
| | - Luning Sun
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning, China.
| | - Ningning Zheng
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning, China.
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Mori H, Hwang H, Goto K. Inter-individual variation in SpO 2 during endurance exercise in hypoxia does not correlate with endocrine and angiogenic growth factor responses. Physiol Rep 2025; 13:e70221. [PMID: 39924721 PMCID: PMC11807840 DOI: 10.14814/phy2.70221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 12/25/2024] [Accepted: 01/16/2025] [Indexed: 02/11/2025] Open
Abstract
The present study determined the relationship between inter-individual variation in arterial O2 saturation (SpO2) and exercise-induced endocrine and angiogenic growth factor responses under hypoxia. Sixteen healthy men completed two trials on separate days: 60 min of cycling at 65% of maximal oxygen uptake (VO2max) followed by a 60-min rest period, under either normoxia (FiO2 = 20.9%, NOR) or hypoxia (FiO2 = 14.5%, HYP). Serum growth hormone (GH), cortisol, and vascular endothelial growth factor (VEGF) concentrations were determined before, immediately after, and at 60 min after exercise. SpO2 and heart rate were continuously measured during exercise. In the HYP trial, the average SpO2 during exercise varied by >10% among all participants (77.5%-88.2%). However, the ΔSpO2 (Δ = HYP-NOR) did not correlate significantly with exercise-induced changes in serum ΔGH (r = 0.205, p = 0.446), Δcortisol (r = 0.059, p = 0.828), and ΔVEGF (r = -0.004, p = 0.989). Moreover, no significant correlations were observed between the absolute SpO2 value and exercise-induced responses in these blood variables in the HYP trial. Inter-individual variation in SpO2 did not modify exercise-induced endocrine (GH, cortisol) or angiogenic growth factor (VEGF) responses to endurance exercise in hypoxia.
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Affiliation(s)
- Hisashi Mori
- School of Human Science and EnvironmentUniversity of HyogoHimejiHyogoJapan
- Faculty of Sport and Health ScienceRitsumeikan UniversityKusatsuShigaJapan
| | - Hyejung Hwang
- Faculty of Sport and Health ScienceRitsumeikan UniversityKusatsuShigaJapan
- Physical Activity and Performance InstituteKonkuk UniversitySeoulRepublic of Korea
| | - Kazushige Goto
- Faculty of Sport and Health ScienceRitsumeikan UniversityKusatsuShigaJapan
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Çalışkan H, Koçak S, Güneş E. Epoetin alfa has a potent anxiolytic effect on naive female rats. BMC Pharmacol Toxicol 2025; 26:18. [PMID: 39876022 PMCID: PMC11773716 DOI: 10.1186/s40360-025-00845-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 01/17/2025] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND Epoetin alfa is a derivative of the erythropoietin hormone. This study aims to investigate the epoetin alfa effect on anxiety-like behaviors. METHODS Adult female Wistar Albino rats were divided into Control (n = 8), 1000 U Epoetien alfa, and 2000 U Epoetien alpha. Epoetin alfa was administered intraperitoneally once a week for 4 weeks. The animals were then subjected to open field test, elevated plus maze, light-dark box, and the behaviors were video recorded. RESULTS Epoetin alfa significantly reduced anxiety-like behaviors in both low- and high-dose groups in a dose-independent manner. This anxiolytic effect was seen in all three anxiety tests. Further, exploratory behaviors such as unsupported rearing and head-dipping behaviors increased with the application of Epoetin alfa. This protocol did not alter locomotor activity. CONCLUSION The present study found beneficial effects of epoetin alfa on behaviors. Further studies on the effect of derivatives of erythropoietin hormone on anxiety-like behaviors are needed.
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Affiliation(s)
- Hasan Çalışkan
- Department of Physiology, Balıkesir University Medicine Faculty, Balıkesir, Turkey.
| | - Seda Koçak
- Department of Physiology, Kırşehir Ahi Evran University Medicine Faculty, Kırşehir, Turkey
| | - Emel Güneş
- Department of Physiology, Ankara University Medicine Faculty, Ankara, Turkey
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Pauzaite T, Nathan JA. A closer look at the role of deubiquitinating enzymes in the Hypoxia Inducible Factor pathway. Biochem Soc Trans 2024; 52:2253-2265. [PMID: 39584532 PMCID: PMC11668284 DOI: 10.1042/bst20230861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 10/31/2024] [Accepted: 11/01/2024] [Indexed: 11/26/2024]
Abstract
Hypoxia Inducible transcription Factors (HIFs) are central to the metazoan oxygen-sensing response. Under low oxygen conditions (hypoxia), HIFs are stabilised and govern an adaptive transcriptional programme to cope with prolonged oxygen starvation. However, when oxygen is present, HIFs are continuously degraded by the proteasome in a process involving prolyl hydroxylation and subsequent ubiquitination by the Von Hippel Lindau (VHL) E3 ligase. The essential nature of VHL in the HIF response is well established but the role of other enzymes involved in ubiquitination is less clear. Deubiquitinating enzymes (DUBs) counteract ubiquitination and provide an important regulatory aspect to many signalling pathways involving ubiquitination. In this review, we look at the complex network of ubiquitination and deubiquitination in controlling HIF signalling in normal and low oxygen tensions. We discuss the relative importance of DUBs in opposing VHL, and explore roles of DUBs more broadly in hypoxia, in both VHL and HIF independent contexts. We also consider the catalytic and non-catalytic roles of DUBs, and elaborate on the potential benefits and challenges of inhibiting these enzymes for therapeutic use.
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Affiliation(s)
- Tekle Pauzaite
- Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah, Biomedical Centre, Department of Medicine, University of Cambridge, Cambridge CB2 0AW, U.K
| | - James A. Nathan
- Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah, Biomedical Centre, Department of Medicine, University of Cambridge, Cambridge CB2 0AW, U.K
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Pruitt L, Abbott RK. Hypoxia-adenosinergic regulation of B cell responses. Front Immunol 2024; 15:1478506. [PMID: 39559353 PMCID: PMC11570280 DOI: 10.3389/fimmu.2024.1478506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 10/15/2024] [Indexed: 11/20/2024] Open
Abstract
Hypoxic microenvironments induce widespread metabolic changes that have been shown to be critical in regulating innate and adaptive immune responses. Hypoxia-induced changes include the generation of extracellular adenosine followed by subsequent signaling through adenosine receptors on immune cells. This evolutionarily conserved "hypoxia-adenosinergic" pathway of hypoxia → extracellular adenosine → adenosine receptor signaling has been shown to be critical in limiting and redirecting T cell responses including in tumor microenvironments and the gut mucosa. However, the question of whether hypoxic microenvironments are involved in the development of B cell responses has remained unexplored until recently. The discovery that germinal centers (GC), the anatomic site in which B cells undergo secondary diversification and affinity maturation, develop a hypoxic microenvironment has sparked new interest in how this evolutionarily conserved pathway affects antibody responses. In this review we will summarize what is known about hypoxia-adenosinergic microenvironments in lymphocyte development and ongoing immune responses. Specific focus will be placed on new developments regarding the role of the hypoxia-adenosinergic pathway in regulating GC development and humoral immunity.
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Affiliation(s)
| | - Robert K. Abbott
- Department of Pathology, University of Texas Medical Branch,
Galveston, TX, United States
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7
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Schönberger T, Jakobs M, Friedel AL, Hörbelt-Grünheidt T, Tebbe B, Witzke O, Schedlowski M, Fandrey J. Exposure to normobaric hypoxia shapes the acute inflammatory response in human whole blood cells in vivo. Pflugers Arch 2024; 476:1369-1381. [PMID: 38714572 PMCID: PMC11310243 DOI: 10.1007/s00424-024-02969-2] [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: 03/25/2024] [Revised: 04/26/2024] [Accepted: 04/29/2024] [Indexed: 05/10/2024]
Abstract
Cells of the immune defence, especially leukocytes, often have to perform their function in tissue areas that are characterized by oxygen deficiency, so-called hypoxia. Physiological hypoxia significantly affects leukocyte function and controls the innate and adaptive immune response mainly through transcriptional gene regulation via the hypoxia-inducible factors (HIFs). Multiple pathogens including components of bacteria, such as lipopolysaccharides (LPS) trigger the activation of leukocytes. HIF pathway activation enables immune cells to adapt to both hypoxic environments in physiological and inflammatory settings and modulates immune cell responses through metabolism changes and crosstalk with other immune-relevant signalling pathways. To study the mutual influence of both processes in vivo, we used a human endotoxemia model, challenging participants with an intravenous LPS injection post or prior to a 4-h stay in a hypoxic chamber with normobaric hypoxia of 10.5% oxygen. We analysed changes in gene expression in whole blood cells and determined inflammatory markers to unveil the crosstalk between both processes. Our investigations showed differentially altered gene expression patterns of HIF and target genes upon in vivo treatment with LPS and hypoxia. Further, we found evidence for effects of hypoxic priming upon inflammation in combination with immunomodulatory effects in whole blood cells in vivo. Our work elucidates the complex interplay of hypoxic and inflammatory HIF regulation in human immune cells and offers new perspectives for further clinical research.
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Affiliation(s)
- Tina Schönberger
- Institute of Physiology, University Duisburg-Essen, University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany.
| | - Marie Jakobs
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, 45147, Essen, Germany
| | - Anna-Lena Friedel
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, 45147, Essen, Germany
| | - Tina Hörbelt-Grünheidt
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, 45147, Essen, Germany
| | - Bastian Tebbe
- Institute of Physiology, University Duisburg-Essen, University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany
- Department of Nephrology, University Hospital Essen, 45147, Essen, Germany
| | - Oliver Witzke
- Department of Infectious Diseases, West German Centre of Infectious Diseases, University Hospital Essen, 45147, Essen, Germany
| | - Manfred Schedlowski
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, 45147, Essen, Germany
- Department of Clinical Neuroscience, Osher Center for Integrative Medicine, Karolinska Institutet, 171 77, Stockholm, Sweden
| | - Joachim Fandrey
- Institute of Physiology, University Duisburg-Essen, University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany
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Stepien BK, Wielockx B. From Vessels to Neurons-The Role of Hypoxia Pathway Proteins in Embryonic Neurogenesis. Cells 2024; 13:621. [PMID: 38607059 PMCID: PMC11012138 DOI: 10.3390/cells13070621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 03/20/2024] [Accepted: 03/26/2024] [Indexed: 04/13/2024] Open
Abstract
Embryonic neurogenesis can be defined as a period of prenatal development during which divisions of neural stem and progenitor cells give rise to neurons. In the central nervous system of most mammals, including humans, the majority of neocortical neurogenesis occurs before birth. It is a highly spatiotemporally organized process whose perturbations lead to cortical malformations and dysfunctions underlying neurological and psychiatric pathologies, and in which oxygen availability plays a critical role. In case of deprived oxygen conditions, known as hypoxia, the hypoxia-inducible factor (HIF) signaling pathway is activated, resulting in the selective expression of a group of genes that regulate homeostatic adaptations, including cell differentiation and survival, metabolism and angiogenesis. While a physiological degree of hypoxia is essential for proper brain development, imbalanced oxygen levels can adversely affect this process, as observed in common obstetrical pathologies such as prematurity. This review comprehensively explores and discusses the current body of knowledge regarding the role of hypoxia and the HIF pathway in embryonic neurogenesis of the mammalian cortex. Additionally, it highlights existing gaps in our understanding, presents unanswered questions, and provides avenues for future research.
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Affiliation(s)
- Barbara K. Stepien
- Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, 01307 Dresden, Germany
| | - Ben Wielockx
- Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, 01307 Dresden, Germany
- Experimental Centre, Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, Germany
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Sun N, Wang Z, Zhu X, Tan S, Song R, Shi W, Han L, Yu Q. Potential Effects of NO-Induced Hypoxia-Inducible Factor-1α on Yak Meat Tenderness during Post-Mortem Aging. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:5944-5954. [PMID: 38466638 DOI: 10.1021/acs.jafc.4c00332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/13/2024]
Abstract
The objective of this study was to investigate the mechanism underlying nitric oxide (NO)-induced hypoxia-inducible factor-1α (HIF-1α) and its impact on yak muscle tenderness during post-mortem aging. The Longissimus thoracis et lumborum (LTL) muscle of yak were incubated at 4 °C for 0, 3, 6, 9, 12, 24, and 72 h after treatment with 0.9% saline, NO activator, or a combination of the NO activator and an HIF-1α inhibitor. Results indicated that elevated NO levels could increase HIF-1α transcription to achieve stable expression of HIF-1α protein (P < 0.05). Additionally, elevated NO triggered HIF-1α S-nitrosylation, which further upregulated the activity of key glycolytic enzymes, increased glycogen consumption, accelerated lactic acid accumulation, and decreased pH (P < 0.05). These processes eventually improved the tenderness of yak muscle during post-mortem aging (P < 0.05). The results demonstrated that NO-induced activation of HIF-1α S-nitrosylation enhanced glycolysis during post-mortem aging and provided a possible pathway for improving meat tenderness.
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Affiliation(s)
- Nan Sun
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou 730070, Gansu, China
| | - Zhuo Wang
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou 730070, Gansu, China
| | - Xijin Zhu
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou 730070, Gansu, China
| | - Siyi Tan
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou 730070, Gansu, China
| | - Rende Song
- Yushu Tibetan Autonomous Prefecture Animal Husbandry and Veterinary Workstation, Yushu 815000, Qinghai, China
| | - Wenying Shi
- Qinghai Kekexili Food Co., Ltd., Xining 815000, Qinghai, China
| | - Ling Han
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou 730070, Gansu, China
| | - Qunli Yu
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou 730070, Gansu, China
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Fang T, Ma C, Zhang Z, Sun L, Zheng N. Roxadustat, a HIF-PHD inhibitor with exploitable potential on diabetes-related complications. Front Pharmacol 2023; 14:1088288. [PMID: 36843948 PMCID: PMC9950780 DOI: 10.3389/fphar.2023.1088288] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 01/26/2023] [Indexed: 02/12/2023] Open
Abstract
Diabetes mellitus (DM) is a group of metabolic diseases caused by absolute or relative deficiency of insulin secretion and characterized by chronic hyperglycemia. Its complications affect almost every tissue of the body, usually leading to blindness, renal failure, amputation, etc. and in the final stage, it mostly develops into cardiac failure, which is the main reason why diabetes mellitus manifests itself as a high clinical lethality. The pathogenesis of diabetes mellitus and its complications involves various pathological processes including excessive production of mitochondrial reactive oxygen species (ROS) and metabolic imbalance. Hypoxia-inducible Factor (HIF) signaling pathway plays an important role in both of the above processes. Roxadustat is an activator of Hypoxia-inducible Factor-1α, which increases the transcriptional activity of Hypoxia-inducible Factor-1α by inhibiting hypoxia-inducible factor prolyl hydroxylase (HIF-PHD). Roxadustat showed regulatory effects on maintaining metabolic stability in the hypoxic state of the body by activating many downstream signaling pathways such as vascular endothelial growth factor (VEGF), glucose transporter protein-1 (GLUT1), lactate dehydrogenase (LDHA), etc. This review summarizes the current research findings of roxadustat on the diseases of cardiomyopathy, nephropathy, retinal damage and impaired wound healing, which also occur at different stages of diabetes and greatly contribute to the damage caused by diabetes to the organism. We attempts to uncover a more comprehensive picture of the therapeutic effects of roxadustat, and inform its expanding research about diabetic complications treatment.
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Affiliation(s)
- Tingting Fang
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, Liaoning, China
| | - Congcong Ma
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, Liaoning, China
| | - Zhanming Zhang
- Pharmaceutical Sciences, China Medical University-The Queen’s University of Belfast Joint College, Shenyang, Liaoning, China
| | - Luning Sun
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, Liaoning, China
| | - Ningning Zheng
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, Liaoning, China,*Correspondence: Ningning Zheng,
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11
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Zhu X, Jiang L, Wei X, Long M, Du Y. Roxadustat: Not just for anemia. Front Pharmacol 2022; 13:971795. [PMID: 36105189 PMCID: PMC9465375 DOI: 10.3389/fphar.2022.971795] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 08/12/2022] [Indexed: 11/13/2022] Open
Abstract
Roxadustat is a recently approved hypoxia-inducible factor prolyl hydroxylase inhibitor that has demonstrated favorable safety and efficacy in the treatment of renal anemia. Recent studies found it also has potential for the treatment of other hypoxia-related diseases. Although clinical studies have not yet found significant adverse or off-target effects of roxadustat, clinicians must be vigilant about these possible effects. Hypoxia-inducible factor regulates the expression of many genes and physiological processes in response to a decreased level of oxygen, but its role in the pathogenesis of different diseases is complex and controversial. In addition to increasing the expression of hypoxia-inducible factor, roxadustat also has some effects that may be HIF-independent, indicating some potential off-target effects. This article reviews the pharmacological characteristics of roxadustat, its current status in the treatment of renal anemia, and its possible effects on other pathological mechanisms.
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Affiliation(s)
- Xiaoyu Zhu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Lili Jiang
- Physical Examination Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xuejiao Wei
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Mengtuan Long
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yujun Du
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, China
- *Correspondence: Yujun Du,
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Khafagi AT, Yehia MA, Helmy AK, Hassan W, Abdelhakim N. Effect of Erythropoietin-stimulating agent on uremic neuropathy in hemodialysis patients: a single-center open-label prospective study. THE EGYPTIAN JOURNAL OF NEUROLOGY, PSYCHIATRY AND NEUROSURGERY 2022. [DOI: 10.1186/s41983-022-00477-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Uremic neuropathy is a distal sensorimotor polyneuropathy caused by uremic toxins; its severity is correlated with the degree of renal insufficiency. Erythropoietin (EPO) and erythropoietin receptors (EpoR) are produced in the peripheral nervous system. This is a single-center open-label prospective study was designed to investigate the possible effect of erythropoietin-stimulating agents (ESAs) on uremic neuropathy. Twenty-four newly diagnosed end-stage kidney disease (ESKD) patients were selected, clinical assessment, laboratory, and neurophysiological study were done at 1 and follow-up after 3 months. Patients were divided into two groups (group A received ESA and group B did not receive ESA).
Results
Eighteen patients completed the study, eight patients (44.4%) did not have symptoms but had electrophysiological findings of neuropathy (subclinical neuropathy). After 3 months of hemodialysis, patients in group A showed improvement of some electrophysiological features (ulnar MNCV; P = 0.016).
Conclusions
The use of ESA may improve uremic neuropathy in patients with newly diagnosed ESKD who have been started on hemodialysis.
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Maniego J, Pesko B, Hincks P, Taylor P, Stewart G, Proudman C, Scarth J, Ryder E. Direct sequence confirmation of qPCR products for gene doping assay validation in horses. Drug Test Anal 2022; 14:1017-1025. [PMID: 34994083 DOI: 10.1002/dta.3219] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 12/15/2021] [Accepted: 12/22/2021] [Indexed: 11/11/2022]
Abstract
The misuse of gene therapy by the introduction of transgenes via plasmid or viral vectors as a doping agent is an increasing concern in human and animal sports, not only in consideration to fair competition but also potential detrimental effects to welfare. Doping events can be detected by PCR amplification of a transgene-specific region of DNA. The quantitative nature of real time qPCR makes it particularly suited to confirmatory investigations where precise limits of detection can be calculated. To fully validate a qPCR experiment, it is highly desirable to confirm the identity of the amplicon. Although post-PCR techniques such as melt curve and fragment size analysis can provide strong evidence that the amplicon is as expected, sequence identity confirmation may be beneficial as part of regulatory proceedings. We present here our investigation into two alternative processes for the direct assessment of qPCR products for five genes using next-generation sequencing: ligation of sequence-ready adapters to qPCR products, and qPCR assays performed with primers tailed with Illumina flow cell binding sites. To fully test the robustness of the techniques at concentrations required for gene doping detection, we also calculated a putative limit of detection for the assays. Both ligated adapters and tailed primers were successful in producing sequence data for the qPCR products without further amplification. Ligated adapters are preferred, however, as they do not require re-optimisation of existing qPCR assays.
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Affiliation(s)
- Jillian Maniego
- Sport and Specialised Analytical Services, LGC, Newmarket Road, Fordham, Cambridgeshire, UK
| | - Bogusia Pesko
- Sport and Specialised Analytical Services, LGC, Newmarket Road, Fordham, Cambridgeshire, UK
| | - Pamela Hincks
- Sport and Specialised Analytical Services, LGC, Newmarket Road, Fordham, Cambridgeshire, UK
| | - Polly Taylor
- Sport and Specialised Analytical Services, LGC, Newmarket Road, Fordham, Cambridgeshire, UK
| | - Graham Stewart
- School of Biosciences and Medicine, University of Surrey, Guildford, Surrey
| | | | - James Scarth
- Sport and Specialised Analytical Services, LGC, Newmarket Road, Fordham, Cambridgeshire, UK
| | - Edward Ryder
- Sport and Specialised Analytical Services, LGC, Newmarket Road, Fordham, Cambridgeshire, UK
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14
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Shen XY, Gao ZK, Han Y, Yuan M, Guo YS, Bi X. Activation and Role of Astrocytes in Ischemic Stroke. Front Cell Neurosci 2021; 15:755955. [PMID: 34867201 PMCID: PMC8635513 DOI: 10.3389/fncel.2021.755955] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 10/22/2021] [Indexed: 12/21/2022] Open
Abstract
Ischemic stroke refers to the disorder of blood supply of local brain tissue caused by various reasons. It has high morbidity and mortality worldwide. Astrocytes are the most abundant glial cells in the central nervous system (CNS). They are responsible for the homeostasis, nutrition, and protection of the CNS and play an essential role in many nervous system diseases’ physiological and pathological processes. After stroke injury, astrocytes are activated and play a protective role through the heterogeneous and gradual changes of their gene expression, morphology, proliferation, and function, that is, reactive astrocytes. However, the position of reactive astrocytes has always been a controversial topic. Many studies have shown that reactive astrocytes are a double-edged sword with both beneficial and harmful effects. It is worth noting that their different spatial and temporal expression determines astrocytes’ various functions. Here, we comprehensively review the different roles and mechanisms of astrocytes after ischemic stroke. In addition, the intracellular mechanism of astrocyte activation has also been involved. More importantly, due to the complex cascade reaction and action mechanism after ischemic stroke, the role of astrocytes is still difficult to define. Still, there is no doubt that astrocytes are one of the critical factors mediating the deterioration or improvement of ischemic stroke.
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Affiliation(s)
- Xin-Ya Shen
- Graduate School of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhen-Kun Gao
- Graduate School of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu Han
- Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China
| | - Mei Yuan
- Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China
| | - Yi-Sha Guo
- Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China
| | - Xia Bi
- Department of Rehabilitation Medicine, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
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15
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Wish JB, Eckardt KU, Kovesdy CP, Fishbane S, Spinowitz BS, Berns JS. Hypoxia-Inducible Factor Stabilization as an Emerging Therapy for CKD-Related Anemia: Report From a Scientific Workshop Sponsored by the National Kidney Foundation. Am J Kidney Dis 2021; 78:709-718. [PMID: 34332007 DOI: 10.1053/j.ajkd.2021.06.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 06/01/2021] [Indexed: 12/16/2022]
Abstract
The National Kidney Foundation convened an interdisciplinary international workshop in March 2019 to discuss the potential role of a new class of agents for the treatment of anemia in patients with chronic kidney disease (CKD): the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs). International experts with expertise in physiology, biochemistry, structural chemistry, translational medicine and clinical management of anemia participated. Participants reviewed the unmet needs of current anemia treatment, the biology of hypoxia-inducible factor, the pharmacology of prolyl hydroxylase inhibitors, and the results of phase 2 clinical trials of HIF-PHIs among patients with both non-dialysis dependent and dialysis-dependent CKD. The results of key phase 3 clinical trials of HIF-PHIs in the public domain as of this writing are also presented in this article although they appeared after the workshop was completed. Participants in the workshop developed a number of recommendations for further examination of HIF-PHIs which are summarized in this article and include long-term safety issues, potential benefits, and practical considerations for implementation including patient and provider education.
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Affiliation(s)
- Jay B Wish
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
| | - Kai-Uwe Eckardt
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Csaba P Kovesdy
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Steven Fishbane
- Department of Medicine, Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY, USA
| | - Bruce S Spinowitz
- Department of Medicine, New York Hospital Queens, Cornell University Medical Center, Queens, NY, USA
| | - Jeffrey S Berns
- Department of Medicine, Perelman School of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
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16
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Tomc J, Debeljak N. Molecular Insights into the Oxygen-Sensing Pathway and Erythropoietin Expression Regulation in Erythropoiesis. Int J Mol Sci 2021; 22:ijms22137074. [PMID: 34209205 PMCID: PMC8269393 DOI: 10.3390/ijms22137074] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/25/2021] [Accepted: 06/26/2021] [Indexed: 02/07/2023] Open
Abstract
Erythropoiesis is regulated by several factors, including the oxygen-sensing pathway as the main regulator of erythropoietin (EPO) synthesis in the kidney. The release of EPO from the kidney and its binding to the EPO receptor (EPOR) on erythrocyte progenitor cells in the bone marrow results in increased erythropoiesis. Any imbalance in these homeostatic mechanisms can lead to dysregulated erythropoiesis and hematological disorders. For example, mutations in genes encoding key players of oxygen-sensing pathway and regulation of EPO production (HIF-EPO pathway), namely VHL, EGLN, EPAS1 and EPO, are well known causative factors that contribute to the development of erythrocytosis. We aimed to investigate additional molecular mechanisms involved in the HIF-EPO pathway that correlate with erythropoiesis. To this end, we conducted an extensive literature search and used several in silico tools. We identified genes encoding transcription factors and proteins that control transcriptional activation or repression; genes encoding kinases, deacetylases, methyltransferases, conjugating enzymes, protein ligases, and proteases involved in post-translational modifications; and genes encoding nuclear transport receptors that regulate nuclear transport. All these genes may modulate the stability or activity of HIF2α and its partners in the HIF-EPO pathway, thus affecting EPO synthesis. The theoretical information we provide in this work can be a valuable tool for a better understanding of one of the most important regulatory pathways in the process of erythropoiesis. This knowledge is necessary to discover the causative factors that may contribute to the development of hematological diseases and improve current diagnostic and treatment solutions in this regard.
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Affiliation(s)
- Jana Tomc
- Medical Centre for Molecular Biology, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia;
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Nataša Debeljak
- Medical Centre for Molecular Biology, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia;
- Correspondence: ; Tel.: +386-1-543-7645
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17
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Xu Y, Kong X, Li J, Cui T, Wei Y, Xu J, Zhu Y, Zhu X. Mild Hypoxia Enhances the Expression of HIF and VEGF and Triggers the Response to Injury in Rat Kidneys. Front Physiol 2021; 12:690496. [PMID: 34248676 PMCID: PMC8267573 DOI: 10.3389/fphys.2021.690496] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 06/07/2021] [Indexed: 11/17/2022] Open
Abstract
Background Hypoxia contributes to a cascade of inflammatory response mechanisms in kidneys that result in the development of renal interstitial fibrosis and subsequent chronic renal failure. Nonetheless, the kidney possesses a self-protection mechanism under a certain degree of hypoxia and this mechanism its adaptation to hypoxia. As the hypoxia-inducible factor (HIF)–vascular endothelial growth factor (VEGF) axis is a key pathway for neovascularization, the activation of this axis is a target for renal hypoxia therapies. Methods Sprague–Dawley rats were exposed to normobaric hypoxia and subdivided into three groups, namely group A (21% O2), group B (10% O2), and group C (7% O2). Renal tissue samples were processed and analyzed to determine pathological morphological changes, the expression of HIF, VEGF, inflammation factor and vascular density. Results We found that as the duration of hypoxia increased, destructive changes in the kidney tissues became more severe in group C (7% O2). In contrast, the increased duration of hypoxia did not exacerbate kidney damage in group B (10% O2). As the hypoxia was prolonged and the degree of hypoxia increased, the expression of HIF-1α increased gradually. As hypoxia time increased, the expression of VEGF increased gradually, but VEGF expression in group B (10% O2) was the highest. Group C (7% O2) had higher levels of IL-6, IL-10, and TNF-alpha. Additionally, the highest vascular density was observed in group B. Conclusion These findings suggest that activating the HIF–VEGF signaling pathway to regulate angiogenesis after infliction of hypoxic kidney injury may provide clues for the development of novel CKD treatments.
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Affiliation(s)
- Yaya Xu
- Department of Pediatric Critical Care Medicine, Xinhua Hospital, Affiliated to the Medical School of Shanghai Jiao Tong University, Shanghai, China
| | - Xiangmei Kong
- Department of Pediatric Critical Care Medicine, Xinhua Hospital, Affiliated to the Medical School of Shanghai Jiao Tong University, Shanghai, China
| | - Jiru Li
- Department of Pediatric Critical Care Medicine, Xinhua Hospital, Affiliated to the Medical School of Shanghai Jiao Tong University, Shanghai, China
| | - Tiantian Cui
- Department of Pediatric Critical Care Medicine, Xinhua Hospital, Affiliated to the Medical School of Shanghai Jiao Tong University, Shanghai, China
| | - Yifan Wei
- Department of Pediatric Critical Care Medicine, Xinhua Hospital, Affiliated to the Medical School of Shanghai Jiao Tong University, Shanghai, China
| | - Jiayue Xu
- Department of Pediatric Critical Care Medicine, Xinhua Hospital, Affiliated to the Medical School of Shanghai Jiao Tong University, Shanghai, China
| | - Yueniu Zhu
- Department of Pediatric Critical Care Medicine, Xinhua Hospital, Affiliated to the Medical School of Shanghai Jiao Tong University, Shanghai, China
| | - Xiaodong Zhu
- Department of Pediatric Critical Care Medicine, Xinhua Hospital, Affiliated to the Medical School of Shanghai Jiao Tong University, Shanghai, China
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Ma X, Shi Y. Whether erythropoietin can be a neuroprotective agent against premature brain injury: cellular mechanisms and clinical efficacy. Curr Neuropharmacol 2021; 20:611-629. [PMID: 34030616 DOI: 10.2174/1570159x19666210524154519] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 04/27/2021] [Accepted: 05/08/2021] [Indexed: 11/22/2022] Open
Abstract
Preterm infants are at high risk of brain injury. With more understanding of the preterm brain injury's pathogenesis, neuroscientists are looking for more effective methods to prevent and treat it, among which erythropoietin (Epo) is considered as a prime candidate. This review tries to clarify the possible mechanisms of Epo in preterm neuroprotection and summarize updated evidence considering Epo as a pharmacological neuroprotective strategy in animal models and clinical trials. To date, various animal models have validated that Epo is an anti-apoptotic, anti-inflammatory, anti-oxidant, anti-excitotoxic, neurogenetic, erythropoietic, angiogenetic, and neurotrophic agent, thus preventing preterm brain injury. However, although the scientific rationale and preclinical data for Epo's neuroprotective effect are promising, when translated to bedside, the results vary in different studies, especially in its long-term efficacy. Based on existing evidence, it is still too early to recommend Epo as the standard treatment for preterm brain injury.
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Affiliation(s)
- Xueling Ma
- Department of Neonatology, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing 400014, China
| | - Yuan Shi
- Department of Neonatology, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing 400014, China
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19
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Ways into Understanding HIF Inhibition. Cancers (Basel) 2021; 13:cancers13010159. [PMID: 33466454 PMCID: PMC7796500 DOI: 10.3390/cancers13010159] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 12/29/2020] [Accepted: 12/31/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Cancer cells adapt to hypoxia, survive, and grow. To that aim, they engage hypoxia-inducible pathways. These pathways are under intense investigation in search of new therapies to interfere with signaling components to kill cancer cells. Nowadays, new technologies enable more in-depth studies of hypoxia-induced signaling including protein–protein interaction and transcriptional processes, as well as the mode of action of different inhibitors. In this review, we give insight into useful techniques for studying the components of the hypoxia-inducible pathway and current inhibitors. Abstract Hypoxia is a key characteristic of tumor tissue. Cancer cells adapt to low oxygen by activating hypoxia-inducible factors (HIFs), ensuring their survival and continued growth despite this hostile environment. Therefore, the inhibition of HIFs and their target genes is a promising and emerging field of cancer research. Several drug candidates target protein–protein interactions or transcription mechanisms of the HIF pathway in order to interfere with activation of this pathway, which is deregulated in a wide range of solid and liquid cancers. Although some inhibitors are already in clinical trials, open questions remain with respect to their modes of action. New imaging technologies using luminescent and fluorescent methods or nanobodies to complement widely used approaches such as chromatin immunoprecipitation may help to answer some of these questions. In this review, we aim to summarize current inhibitor classes targeting the HIF pathway and to provide an overview of in vitro and in vivo techniques that could improve the understanding of inhibitor mechanisms. Unravelling the distinct principles regarding how inhibitors work is an indispensable step for efficient clinical applications and safety of anticancer compounds.
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20
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Effects of Dietary L-Carnitine Supplementation on Platelets and Erythrogram of Dairy Cows with Special Emphasis on Parturition. DAIRY 2020. [DOI: 10.3390/dairy2010001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
During late gestation and early lactation, many proliferative processes and metabolic adaptions are involved in homeorhesis. An adjusted supply of oxygen is a precondition for an optimized cellular energy metabolism whereby erythrocytes play a central role. Endogenous L-carnitine modulates the mitochondrial fatty acid utilization for generating adenosine triphosphate (ATP). As it might be insufficient around calving due to increased need, L-carnitine supplementation is frequently recommended. Thus, the present study addressed the interplay between the red hemogram, platelets, oxidative stress indices, and L-carnitine supplementation of dairy cows around calving. German Holstein cows were assigned to a control (n = 30) and an L-carnitine group (n = 29, 25 g of rumen-protected L-carnitine per cow and per day), and blood samples were taken from day 42 ante partum (ap) until day 110 postpartum (pp), with a higher sampling frequency during the first three days pp. The time courses of the erythrogram parameters reflected the physiological adaptations to the oxygen need without being influenced by L-carnitine supplementation. Erythrocytic antioxidative enzymatic defence paralleled the relative development of polycythemia ap, while non-enzymatic total plasma antioxidative capacity continuously increased pp. In contrast to erythrocytes, the platelet counts of the L-carnitine supplemented cows varied at significantly higher levels. This can be interpreted as a result of a membrane-stabilizing effect of L-carnitine.
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21
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Affiliation(s)
- Thomas Kietzmann
- Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
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22
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Li RL, He LY, Zhang Q, Liu J, Lu F, Duan HXY, Fan LH, Peng W, Huang YL, Wu CJ. HIF-1α is a Potential Molecular Target for Herbal Medicine to Treat Diseases. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:4915-4949. [PMID: 33235435 PMCID: PMC7680173 DOI: 10.2147/dddt.s274980] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 10/22/2020] [Indexed: 12/12/2022]
Abstract
HIF-1α is an important factor regulating oxygen balance in mammals, and its expression is closely related to various physiological and pathological conditions of the body. Because HIF-1α plays an important role in the occurrence and development of cancer and other diseases, it has become an enduring research hotspot. At the same time, natural medicines and traditional Chinese medicine compounds have amazing curative effects in various diseases related to HIF-1 subtype due to their unique pharmacological effects and more effective ingredients. Therefore, in this article, we first outline the structure of HIF-1α and the regulation related to its expression, then introduce various diseases closely related to HIF-1α, and finally focus on the regulation of natural medicines and compound Chinese medicines through various pathways. This will help us understand HIF-1α systematically, and use HIF-1α as a target to discover more natural medicines and traditional Chinese medicines that can treat related diseases.
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Affiliation(s)
- Ruo-Lan Li
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, People's Republic of China
| | - Li-Ying He
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, People's Republic of China
| | - Qing Zhang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, People's Republic of China
| | - Jia Liu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, People's Republic of China
| | - Feng Lu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, People's Republic of China
| | - Hu-Xin-Yue Duan
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, People's Republic of China
| | - Lin-Hong Fan
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, People's Republic of China
| | - Wei Peng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, People's Republic of China
| | - Yong-Liang Huang
- Pharmacy Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, People's Republic of China
| | - Chun-Jie Wu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, People's Republic of China
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Dzhalilova D, Makarova O. Differences in Tolerance to Hypoxia: Physiological, Biochemical, and Molecular-Biological Characteristics. Biomedicines 2020; 8:E428. [PMID: 33080959 PMCID: PMC7603118 DOI: 10.3390/biomedicines8100428] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/14/2020] [Accepted: 10/15/2020] [Indexed: 02/07/2023] Open
Abstract
Hypoxia plays an important role in the development of many infectious, inflammatory, and tumor diseases. The predisposition to such disorders is mostly provided by differences in basic tolerance to oxygen deficiency, which we discuss in this review. Except the direct exposure of different-severity hypoxia in decompression chambers or in highland conditions, there are no alternative methods for determining organism tolerance. Due to the variability of the detection methods, differences in many parameters between tolerant and susceptible organisms are still not well-characterized, but some of them can serve as biomarkers of susceptibility to hypoxia. At the moment, several potential biomarkers in conditions after hypoxic exposure have been identified both in experimental animals and humans. The main potential biomarkers are Hypoxia-Inducible Factor (HIF)-1, Heat-Shock Protein 70 (HSP70), and NO. Due to the different mechanisms of various high-altitude diseases, biomarkers may not be highly specific and universal. Therefore, it is extremely important to conduct research on hypoxia susceptibility biomarkers. Moreover, it is important to develop a method for the evaluation of organisms' basic hypoxia tolerance without the necessity of any oxygen deficiency exposure. This can contribute to new personalized medicine approaches' development for diagnostics and the treatment of inflammatory and tumor diseases, taking into account hypoxia tolerance differences.
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Affiliation(s)
- Dzhuliia Dzhalilova
- Department of Immunomorphology of Inflammation, Federal State Budgetary Institution ‘Research Institute of Human Morphology’, Moscow 117418, Russia;
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Locatelli F, Del Vecchio L. Are prolyl-hydroxylase inhibitors potential alternative treatments for anaemia in patients with chronic kidney disease? Nephrol Dial Transplant 2020; 35:926-932. [DOI: 10.1093/ndt/gfz031] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
Abstract
Abstract
Prolyl-hydroxylase (PHD) inhibitors (PHD-I) are the most appealing drugs undergoing clinical development for the treatment of anaemia in patients with chronic kidney disease. PHD inhibition mimics the exposure of the body to hypoxia and activates the hypoxia-inducible factor system. Among many other pathways, this activation promotes the production of endogenous erythropoietin (EPO) and the absorption and mobilization of iron. PHD-I are given orally and, differing from erythropoiesis-stimulating agents (ESAs), they correct and maintain haemoglobin levels by stimulating endogenous EPO production. Their efficacy and safety are supported by several Phases I and II studies with relatively short follow-up. This class of drugs has the potential to have a better safety profile than ESAs and there may be additional advantages for cardiovascular disease (CVD), osteoporosis and metabolism. However, possible adverse outcomes are feared. These span from the worsening or occurrence of new cancer, to eye complications or pulmonary hypertension. The data from the ongoing Phase III studies are awaited to better clarify the long-term safety and possible advantages of PHD-I.
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Affiliation(s)
- Francesco Locatelli
- Department of Nephrology and Dialysis, Alessandro Manzoni Hospital ASST-Lecco, Lecco, Italy
| | - Lucia Del Vecchio
- Department of Nephrology and Dialysis, Alessandro Manzoni Hospital ASST-Lecco, Lecco, Italy
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25
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Fernandes MT, Calado SM, Mendes-Silva L, Bragança J. CITED2 and the modulation of the hypoxic response in cancer. World J Clin Oncol 2020; 11:260-274. [PMID: 32728529 PMCID: PMC7360518 DOI: 10.5306/wjco.v11.i5.260] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/13/2020] [Accepted: 05/12/2020] [Indexed: 02/06/2023] Open
Abstract
CITED2 (CBP/p300-interacting transactivator with Glu/Asp-rich C-terminal domain, 2) is a ubiquitously expressed protein exhibiting a high affinity for the CH1 domain of the transcriptional co-activators CBP/p300, for which it competes with hypoxia-inducible factors (HIFs). CITED2 is particularly efficient in the inhibition of HIF-1α-dependent transcription in different contexts, ranging from organ development and metabolic homeostasis to tissue regeneration and immunity, being also potentially involved in various other physiological processes. In addition, CITED2 plays an important role in inhibiting HIF in some diseases, including kidney and heart diseases and type 2-diabetes. In the particular case of cancer, CITED2 either functions by promoting or suppressing cancer development depending on the context and type of tumors. For instance, CITED2 overexpression promotes breast and prostate cancers, as well as acute myeloid leukemia, while its expression is downregulated to sustain colorectal cancer and hepatocellular carcinoma. In addition, the role of CITED2 in the maintenance of cancer stem cells reveals its potential as a target in non-small cell lung carcinoma and acute myeloid leukemia, for example. But besides the wide body of evidence linking both CITED2 and HIF signaling to carcinogenesis, little data is available regarding CITED2 role as a negative regulator of HIF-1α specifically in cancer. Therefore, comprehensive studies exploring further the interactions of these two important mediators in cancer-specific models are sorely needed and this can potentially lead to the development of novel targeted therapies.
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Affiliation(s)
- Mónica T Fernandes
- School of Health, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Algarve Biomedical Centre, Faro 8005-139, Portugal
| | - Sofia M Calado
- Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Algarve Biomedical Centre, Faro 8005-139, Portugal
| | - Leonardo Mendes-Silva
- Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Algarve Biomedical Centre, Faro 8005-139, Portugal
- Department of Biomedical Sciences and Medicine, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
| | - José Bragança
- Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Algarve Biomedical Centre, Faro 8005-139, Portugal
- Department of Biomedical Sciences and Medicine, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
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Toriuchi K, Kakita H, Tamura T, Takeshita S, Yamada Y, Aoyama M. Prolonged astrocyte-derived erythropoietin expression attenuates neuronal damage under hypothermic conditions. J Neuroinflammation 2020; 17:141. [PMID: 32359362 PMCID: PMC7195727 DOI: 10.1186/s12974-020-01831-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 04/27/2020] [Indexed: 02/07/2023] Open
Abstract
Background Hypoxic-ischemic encephalopathy (HIE) has a high morbidity rate and involves severe neurologic deficits, including cerebral palsy. Therapeutic hypothermia (TH) has been shown to decrease the mortality rate and provide neuroprotection in infants with HIE. However, death and disability rates in HIE infants treated with TH remain high. Although the cellular mechanism of the neuroprotective effect of TH remains unclear, astrocytic erythropoietin (EPO) is known to be a key mediator of neuroprotection under hypoxic conditions. In the present study, we investigated the hypothermia effect on EPO expression in astrocytes and determined whether hypothermia attenuates neuronal damage via EPO signaling. Methods Astrocytes derived from rat cerebral cortex were cultured under oxygen/glucose deprivation (OGD). The expression of EPO and hypoxia-inducible factor (HIF), a transcription factor of EPO, was assessed. After OGD, astrocytes were cultured under normothermic (37 °C) or hypothermic (33.5 °C) conditions, and then EPO and HIF expression was assessed. After OGD, rat cortical neurons were cultured in astrocyte-conditioned medium (ACM) derived from the hypothermic group, and neuronal apoptosis was evaluated. Results OGD induced EPO mRNA and protein expression, although at lower levels than hypoxia alone. HIF-1α and HIF-2α protein expression increased under hypoxia alone and OGD, although OGD increased HIF-2α protein expression less than hypoxia alone. EPO gene and protein expression after OGD was significantly higher under hypothermia. Moreover, expression of HIF-1α and HIF-2α protein was enhanced under hypothermia. In the presence of ACM derived from hypothermic astrocytes following OGD, the number of cleaved caspase 3 and TdT-mediated dUTP nick-end labeling-positive apoptotic neurons was lower than in the presence of ACM from normothermic astrocytes following OGD. Blockade of EPO signaling using anti-EPO neutralization antibody attenuated the anti-apoptotic effect of ACM derived from hypothermic astrocytes following OGD. Conclusions Hypothermia after OGD stabilized HIF-EPO signaling in astrocytes, and upregulated EPO expression could suppress neuronal apoptosis. Investigating the neuroprotective effect of EPO from astrocytes under hypothermic conditions may contribute to the development of novel neuroprotection-based therapies for HIE.
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Affiliation(s)
- Kohki Toriuchi
- Department of Pathobiology, Nagoya City University Graduate School of Pharmaceutical Sciences, 3-1 Tanabedori, Mizoho-ku, Nagoya, Aichi, 467-8603, Japan
| | - Hiroki Kakita
- Department of Pathobiology, Nagoya City University Graduate School of Pharmaceutical Sciences, 3-1 Tanabedori, Mizoho-ku, Nagoya, Aichi, 467-8603, Japan.,Department of Perinatal and Neonatal Medicine, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Tetsuya Tamura
- Department of Anesthesiology and Intensive Care Medicine, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan
| | - Satoru Takeshita
- Department of Pathobiology, Nagoya City University Graduate School of Pharmaceutical Sciences, 3-1 Tanabedori, Mizoho-ku, Nagoya, Aichi, 467-8603, Japan.,Department of Perinatal and Neonatal Medicine, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Yasumasa Yamada
- Department of Perinatal and Neonatal Medicine, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Mineyoshi Aoyama
- Department of Pathobiology, Nagoya City University Graduate School of Pharmaceutical Sciences, 3-1 Tanabedori, Mizoho-ku, Nagoya, Aichi, 467-8603, Japan.
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Shibuya S, Toda T, Ozawa Y, Yata MJV, Shimizu T. Acai Extract Transiently Upregulates Erythropoietin by Inducing a Renal Hypoxic Condition in Mice. Nutrients 2020; 12:nu12020533. [PMID: 32092924 PMCID: PMC7071527 DOI: 10.3390/nu12020533] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 02/12/2020] [Accepted: 02/17/2020] [Indexed: 02/06/2023] Open
Abstract
Acai (Euterpe oleracea Mart. Palmae, Arecaceae) is a palm plant native to the Brazilian Amazon. It contains many nutrients, such as polyphenols, iron, vitamin E, and unsaturated fatty acids, so in recent years, many of the antioxidant and anti-inflammatory effects of acai have been reported. However, the effects of acai on hematopoiesis have not been investigated yet. In the present study, we administered acai extract to mice and evaluated its hematopoietic effects. Acai treatment significantly increased the erythrocytes, hemoglobin, and hematocrit contents compared to controls for four days. Then, we examined the hematopoietic-related markers following a single injection. Acai administration significantly increased the levels of the hematopoietic-related hormone erythropoietin in blood compared to controls and also transiently upregulated the gene expression of Epo in the kidney. Furthermore, in the mice treated with acai extract, the kidneys were positively stained with the hypoxic probe pimonidazole in comparison to the controls. These results demonstrated that acai increases the erythropoietin expression via hypoxic action in the kidney. Acai can be expected to improve motility through hematopoiesis.
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Affiliation(s)
- Shuichi Shibuya
- Aging Stress Response Research Project Team, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu, Aichi 474-8511, Japan;
- Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan; (T.T.); (Y.O.)
| | - Toshihiko Toda
- Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan; (T.T.); (Y.O.)
| | - Yusuke Ozawa
- Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan; (T.T.); (Y.O.)
| | | | - Takahiko Shimizu
- Aging Stress Response Research Project Team, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu, Aichi 474-8511, Japan;
- Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan; (T.T.); (Y.O.)
- Correspondence: ; Tel.: +81-562-44-5651; Fax: +81-562-48-2373
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Feng HL, Chen YH, Jeng SS. Effect of Zinc Supplementation on Renal Anemia in 5/6-Nephrectomized Rats and a Comparison with Treatment with Recombinant Human Erythropoietin. Int J Mol Sci 2019; 20:E4985. [PMID: 31600973 PMCID: PMC6829362 DOI: 10.3390/ijms20204985] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 09/28/2019] [Accepted: 09/29/2019] [Indexed: 11/17/2022] Open
Abstract
Anemia is a severe complication in patients with chronic kidney disease (CKD). Treatment with exogenous erythropoietin (EPO) can correct anemia in many with CKD. We produced 5/6-nephrectomized rats that became uremic and anemic at 25 days post surgery. Injection of the anemic 5/6-nephrectomized rats with 2.8 mg zinc/kg body weight raised their red blood cell (RBC) levels from approximately 85% of the control to 95% in one day and continued for 4 days. We compared the effect of ZnSO4 and recombinant human erythropoietin (rHuEPO) injections on relieving anemia in 5/6-nephrectomized rats. After three consecutive injections, both the ZnSO4 and rHuEPO groups had significantly higher RBC levels (98 ± 6% and 102 ± 6% of the control) than the saline group (90 ± 3% of the control). In vivo, zinc relieved anemia in 5/6-nephrectomized rats similar to rHuEPO. In vitro, we cultured rat bone marrow cells supplemented with ZnCl2, rHuEPO, or saline. In a 4-day suspension culture, we found that zinc induced erythropoiesis similar to rHuEPO. When rat bone marrow cells were supplement-cultured with zinc, we found that zinc stimulated the production of EPO in the culture medium and that the level of EPO produced was dependent on the concentration of zinc supplemented. The production of EPO via zinc supplementation was involved in the process of erythropoiesis.
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Affiliation(s)
- Hui-Lin Feng
- Department of Food Science, College of Life Sciences, National Taiwan Ocean University, Keelung 20224, Taiwan.
| | - Yen-Hua Chen
- Department of Basic Medicine, The Center of Translational Medicine, Xiamen Medical College, Xiamen 361023, China.
| | - Sen-Shyong Jeng
- Department of Food Science, College of Life Sciences, National Taiwan Ocean University, Keelung 20224, Taiwan.
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Roxadustat Treatment of Chronic Kidney Disease-Associated Anemia in Japanese Patients Not on Dialysis: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial. Adv Ther 2019; 36:1438-1454. [PMID: 30953333 PMCID: PMC6824366 DOI: 10.1007/s12325-019-00943-4] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Indexed: 12/17/2022]
Abstract
Introduction This study evaluated efficacy and safety/tolerability of roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, in Japanese anemic non-dialysis-dependent chronic kidney disease (NDD-CKD) patients. Methods In this phase 2, double-blind, 24-week study, NDD-CKD patients were randomized to oral placebo or roxadustat (50, 70, or 100 mg) three times weekly (TIW) for 6 weeks followed by dose adjustments to maintain hemoglobin (Hb) at 10–12 g/dL for 18 weeks; patients meeting pre-defined criteria were re-randomized to TIW or once-weekly dosing. The primary end point was rate of rise of Hb (g/dL/week) during the first 6 weeks; secondary end points included response rate (Hb ≥ 10.0 g/dL and increase in Hb from baseline ≥ 1 g/dL) and mean Hb and change from baseline in Hb at weeks 18–24. The main safety outcomes were vital signs, laboratory test results, electrocardiograms, and frequency of treatment-emergent adverse events. Results Of 107 patients randomized, 83 completed the study. The mean (SD) rate of rise of Hb during the first 6 weeks was − 0.052 (0.142) for placebo and + 0.200 (0.160), + 0.453 (0.256), and + 0.570 (0.240) for roxadustat 50-, 70-, and 100-mg TIW groups, respectively (p < 0.001). Response rate was 14.8% for placebo and 81.5%, 100%, and 100% for roxadustat TIW groups (p < 0.001). Change in Hb from baseline at weeks 18–24 was − 0.17 (0.61) for placebo and + 1.10 (0.71), + 1.33 (0.82), and + 1.55 (0.88) g/dL for roxadustat TIW groups (p < 0.001). No deaths or major adverse cardiac events occurred with roxadustat. Conclusion Roxadustat was well tolerated and effective in correcting Hb levels within 6 weeks in Japanese anemic NDD-CKD patients. Trial registration ClinicalTrials.gov: NCT01964196. Registered 15 October 2013 (retrospectively registered). Funding Astellas Pharma Inc. Electronic supplementary material The online version of this article (10.1007/s12325-019-00943-4) contains supplementary material, which is available to authorized users.
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Berlian G, Tandrasasmita OM, Tjandrawinata RR. Upregulation of endogenous erythropoietin expression by DLBS6747, a bioactive fraction of Ipomoea batatas L. leaves, via increasing HIF1α transcription factor in HEK293 kidney cells. JOURNAL OF ETHNOPHARMACOLOGY 2019; 235:190-198. [PMID: 30685435 DOI: 10.1016/j.jep.2019.01.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 01/22/2019] [Accepted: 01/23/2019] [Indexed: 06/09/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ipomoea batatas L., locally known as ubi jalar, is widely used in Indonesia and other countries as a folk remedy for various chronic diseases, including anemia-associated chronic kidney disease by increasing hematological parameters such as packed cell volume, white blood cells and platelet counts. AIM OF THE STUDY The aim of this study is to evaluate the effect of DLBS6747, a bioactive fraction of I. batatas L. leaves, on increasing EPO expression through the upregulation of HIF1α. MATERIALS AND METHODS Effect of DLBS6747 on EPO expression and its transcription factor, HIFs, was evaluated in normoxia and hypoxia conditions. Effect of DLBS6747 on several genes involved in EPO expression were evaluated in a time-course manner using conventional and real-time PCR, while the protein level were revealed using western blot and ELISA. The involvement of HIF1α was also confirmed by HIF1α siRNA. RESULTS Administration of DLBS6747 increased transcriptional activity of EPO through the regulation of its transcriptional factors, which include HIF1α, HIF2α and NFᴋB. The effect was found to be dependent on oxygen availability, wherein DLBS6747-increased EPO expression was found to be more significant in hypoxic condition. In normoxia and hypoxia, 40 μg/mL DLBS6747 increased HIF1α and HIF2α expressions at mRNA level, wherein the peak appeared in 12 h treatment (up to 7.9- and 8.6-folds, respectively). On the other hand, increased protein level was only found in hypoxia, where the highest HIF1α expression was observed at 6 h (7.5-folds increase) and started to decrease after the hours, while HIF2α was found to be increased time-dependently (up to 13.8-folds in 24 h). The mechanism of action of DLBS6747 as erythropoietin stimulating agent is more likely to affect the regulation of HIF1α, as confirmed by HIF1α siRNA which showed that DLBS6747 failed to increase EPO expression during co-incubation with HIF1α siRNA. DLBS6747 treatment also decreased NFᴋB time-dependently in normoxia, while no NFᴋB was detected in hypoxia, which revealed mimicking hypoxia activity of DLBS6747 to increase EPO expression. CONCLUSION These findings showed convincing evidences that DLBS6747 increases endogenous EPO production primarily via upregulation of its transcription factors, especially HIF1α, in human embryonic kidney HEK293 cells. This is the first molecular report that reveals the mechanism of action of natural-based erythropenia drug in different oxygen availability.
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Affiliation(s)
- Guntur Berlian
- Dexa Laboratories of Biomolecular Sciences (DLBS), Industri Selatan V Block PP No. 7, Jababeka Industrial Estate II, Cikarang 17550, West Java, Indonesia.
| | - Olivia Mayasari Tandrasasmita
- Dexa Laboratories of Biomolecular Sciences (DLBS), Industri Selatan V Block PP No. 7, Jababeka Industrial Estate II, Cikarang 17550, West Java, Indonesia.
| | - Raymond Rubianto Tjandrawinata
- Dexa Laboratories of Biomolecular Sciences (DLBS), Industri Selatan V Block PP No. 7, Jababeka Industrial Estate II, Cikarang 17550, West Java, Indonesia.
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Hypoxia and Hypoxia-Inducible Factors in Kidney Injury and Repair. Cells 2019; 8:cells8030207. [PMID: 30823476 PMCID: PMC6468851 DOI: 10.3390/cells8030207] [Citation(s) in RCA: 183] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Revised: 02/21/2019] [Accepted: 02/25/2019] [Indexed: 02/07/2023] Open
Abstract
Acute kidney injury (AKI) is a major kidney disease characterized by an abrupt loss of renal function. Accumulating evidence indicates that incomplete or maladaptive repair after AKI can result in kidney fibrosis and the development and progression of chronic kidney disease (CKD). Hypoxia, a condition of insufficient supply of oxygen to cells and tissues, occurs in both acute and chronic kidney diseases under a variety of clinical and experimental conditions. Hypoxia-inducible factors (HIFs) are the "master" transcription factors responsible for gene expression in hypoxia. Recent researches demonstrate that HIFs play an important role in kidney injury and repair by regulating HIF target genes, including microRNAs. However, there are controversies regarding the pathological roles of HIFs in kidney injury and repair. In this review, we describe the regulation, expression, and functions of HIFs, and their target genes and related functions. We also discuss the involvement of HIFs in AKI and kidney repair, presenting HIFs as effective therapeutic targets.
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Törpel A, Peter B, Hamacher D, Schega L. Dose-response relationship of intermittent normobaric hypoxia to stimulate erythropoietin in the context of health promotion in young and old people. Eur J Appl Physiol 2019; 119:1065-1074. [PMID: 30756167 DOI: 10.1007/s00421-019-04096-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 02/06/2019] [Indexed: 10/27/2022]
Abstract
PURPOSE Erythropoietin (EPO) has multifactorial positive effects on health and can be increased by intermittent normobaric hypoxia (IH). Recommendations about the intensity and duration of IH to increase EPO exist, but only for young people. Therefore, the aim of the study was to investigate the dose-response relationship regarding the duration of hypoxia until an EPO expression and the amount of EPO expression in old vs. young cohorts. METHODS 56 young and 67 old people were assigned to two separate investigations with identical study designs (3-h hypoxic exposure) but with different approaches to adjust the intensity of hypoxia: (i) the fraction of inspired oxygen (FiO2) was 13.5%; (ii) the FiO2 was individually adjusted to an oxygen saturation of the blood of 80%. Age groups were randomly assigned to a hypoxia or control group (normoxic exposure). EPO was assessed before, during (90 and 180 min), and 30 min after the hypoxia. RESULTS EPO increased significantly after 180 min in both cohorts and in both investigations [old: (i) + 16%, p = 0.007 and (ii) + 14%, p < 0.001; young: (i) + 27%, p < 0.001 and (ii) + 45%, p = 0.007]. In investigation (i), EPO expression was significantly higher in young than in old people after 180 min of hypoxic exposure (p = 0.024) and 30 min afterwards (p = 0.001). CONCLUSION The results indicate that after a normobaric hypoxia of 180 min, EPO increases significantly in both age cohorts. The amount of EPO expression is significantly higher in young people during the same internal intensity of hypoxia than in old people.
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Affiliation(s)
- Alexander Törpel
- Institute III: Sport Science, Otto von Guericke University Magdeburg, Zschokkestr. 32, 39104, Magdeburg, Germany.
| | - Beate Peter
- Institute III: Sport Science, Otto von Guericke University Magdeburg, Zschokkestr. 32, 39104, Magdeburg, Germany
| | - Dennis Hamacher
- Institute III: Sport Science, Otto von Guericke University Magdeburg, Zschokkestr. 32, 39104, Magdeburg, Germany
| | - Lutz Schega
- Institute III: Sport Science, Otto von Guericke University Magdeburg, Zschokkestr. 32, 39104, Magdeburg, Germany
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Dzhalilova DS, Diatroptov ME, Tsvetkov IS, Makarova OV, Kuznetsov SL. Expression of Hif-1α, Nf-κb, and Vegf Genes in the Liver and Blood Serum Levels of HIF-1α, Erythropoietin, VEGF, TGF-β, 8-Isoprostane, and Corticosterone in Wistar Rats with High and Low Resistance to Hypoxia. Bull Exp Biol Med 2018; 165:781-785. [PMID: 30353332 DOI: 10.1007/s10517-018-4264-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Indexed: 10/28/2022]
Abstract
We studied the expression of Hif-1α, Nf-κb, and Vegf genes in the liver and serum levels of HIF-1α, erythropoietin, VEGF, TGF-β, 8-isoprostane, and corticosterone in Wistar rats with different resistance to hypoxia in 5 and 90 min after acute exposure to hypobaric hypoxia. In 5 min after hypoxic exposure, Hif-1α expression in the liver and serum levels of erythropoietin, VEGF, and TGF-β in high-resistant rats were higher than in low-resistant animals. In highresistant rats, the increment in expression of Nf-κb gene responsible for the control over the inflammatory processes was more pronounced than in low-resistant animals. In 90 min after hypoxic exposure, the serum levels of HIF-1α, erythropoietin, VEGF, and TGF-β returned to normal in high-resistant rats, while in low-resistant animals, an increase in 8-isoprostane and TGF-β concentrations was observed. The rats with different resistance to hypoxia were characterized by different changes in biomolecular parameters determining predilection to inflammatory diseases.
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Affiliation(s)
| | | | - I S Tsvetkov
- Research Institute of Human Morphology, Moscow, Russia
| | - O V Makarova
- Research Institute of Human Morphology, Moscow, Russia
| | - S L Kuznetsov
- I. M. Sechenov First Moscow State Medical University, Moscow, Russia
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Xu M, Tan X, Li N, Wu H, Wang Y, Xie J, Wang J. Differential regulation of estrogen in iron metabolism in astrocytes and neurons. J Cell Physiol 2018; 234:4232-4242. [PMID: 30132882 DOI: 10.1002/jcp.27188] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Accepted: 07/17/2018] [Indexed: 12/19/2022]
Abstract
Previous studies have demonstrated an effect of estrogen on iron metabolism in peripheral tissues. The role of estrogen on brain iron metabolism is currently unknown. In this study, we investigated the effect and mechanism of estrogen on iron transport proteins. We demonstrated that the iron exporter ferroportin 1 (FPN1) and iron importer divalent metal transporter 1 (DMT1) were upregulated and iron content was decreased after estrogen treatment for 12 hr in primary cultured astrocytes. Hypoxia-inducible factor-1 alpha (HIF-1α) was upregulated, but HIF-2α remained unchanged after estrogen treatment for 12 hr in primary cultured astrocytes. In primary cultured neurons, DMT1 was downregulated, FPN1 was upregulated, iron content decreased, iron regulatory protein (IRP1) was downregulated, but HIF-1α and HIF-2α remained unchanged after estrogen treatment for 12 hr. These results suggest that the regulation of iron metabolism by estrogen in astrocytes and neurons is different. Estrogen increases FPN1 and DMT1 expression by inducing HIF-1α in astrocytes, whereas decreased expression of IRP1 may account for the decreased DMT1 and increased FPN1 expression in neurons.
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Affiliation(s)
- Manman Xu
- Department of Physiology and Pathophysiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China
| | - Xu Tan
- Department of Physiology and Pathophysiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China
| | - Na Li
- Department of Physiology and Pathophysiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China
| | - Hao Wu
- Clinical Medicine of Class Excellence, Grade 2013, Medical College of Qingdao University, Qingdao, China
| | - Yue Wang
- Clinical Medicine of Class 3, Grade 2014, Medical College of Qingdao University, Qingdao, China
| | - Junxia Xie
- Department of Physiology and Pathophysiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China
| | - Jun Wang
- Department of Physiology and Pathophysiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China
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Dulgar O, Cil I, Zirtiloglu A, Tural D. Long-lasting response with polycythemia to third-line axitinib treatment in metastatic renal cell carcinoma: Very rare case presentation. J Oncol Pharm Pract 2018; 25:1512-1515. [PMID: 30058939 DOI: 10.1177/1078155218790342] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
INTRODUCTION Clear cell renal cell carcinoma is characterized by mutation or inactivation of Von Hippel-Lindau suppressor gene. The mutation of Von Hippel-Lindau mechanism is associated with the upregulation of the hypoxia-inducible factor protein, inducing the overexpression of proteins including erythropoietin and vascular endothelial growth factor. Vascular endothelial growth factor receptor-targeted tyrosine kinase inhibitors are widely used in treatment of metastatic renal cell carcinoma. In paradoxical hematological effect with tyrosine kinase inhibitor therapies, hemoglobin level may be increased, but polycythemia requiring phlebotomy is very rare. CASE DESCRIPTION We present here a case of renal cell carcinoma who received successive treatment with sunitinib, everolimus, and axitinib. While he had a normal hemoglobin level with prior sunitinib treatment, on the sixth week of axitinib treatment, he developed polycythemia and treatment response was seen after axitinib-associated polycythemia. CONCLUSION Progression-free survival (PFS) was 30 months in our case with third-line treatment axitinib. Higher hemoglobin levels may be associated with longer survival. Polycythemia was the first response to treatment of axitinib in our patient. It may be an indicator of persistent treatment response.
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Affiliation(s)
- Ozgecan Dulgar
- Department of Medical Oncology, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, İstanbul, Turkey
| | - Ibrahim Cil
- Department of Medical Oncology, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, İstanbul, Turkey
| | - Alisan Zirtiloglu
- Department of Medical Oncology, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, İstanbul, Turkey
| | - Deniz Tural
- Department of Medical Oncology, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, İstanbul, Turkey
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Geiseler SJ, Morland C. The Janus Face of VEGF in Stroke. Int J Mol Sci 2018; 19:ijms19051362. [PMID: 29734653 PMCID: PMC5983623 DOI: 10.3390/ijms19051362] [Citation(s) in RCA: 122] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 04/27/2018] [Accepted: 05/01/2018] [Indexed: 12/12/2022] Open
Abstract
The family of vascular endothelial growth factors (VEGFs) are known for their regulation of vascularization. In the brain, VEGFs are important regulators of angiogenesis, neuroprotection and neurogenesis. Dysregulation of VEGFs is involved in a large number of neurodegenerative diseases and acute neurological insults, including stroke. Stroke is the main cause of acquired disabilities, and normally results from an occlusion of a cerebral artery or a hemorrhage, both leading to focal ischemia. Neurons in the ischemic core rapidly undergo necrosis. Cells in the penumbra are exposed to ischemia, but may be rescued if adequate perfusion is restored in time. The neuroprotective and angiogenic effects of VEGFs would theoretically make VEGFs ideal candidates for drug therapy in stroke. However, contradictory to what one might expect, endogenously upregulated levels of VEGF as well as the administration of exogenous VEGF is detrimental in acute stroke. This is probably due to VEGF-mediated blood–brain-barrier breakdown and vascular leakage, leading to edema and increased intracranial pressure as well as neuroinflammation. The key to understanding this Janus face of VEGF function in stroke may lie in the timing; the harmful effect of VEGFs on vessel integrity is transient, as both VEGF preconditioning and increased VEGF after the acute phase has a neuroprotective effect. The present review discusses the multifaceted action of VEGFs in stroke prevention and therapy.
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Affiliation(s)
- Samuel J Geiseler
- Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, 0371 Oslo, Norway.
| | - Cecilie Morland
- Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, 0371 Oslo, Norway.
- Institute for Behavioral Sciences, Faculty of Health Sciences, OsloMet-Oslo Metropolitan University, 0166 Oslo, Norway.
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DiPasquale DM. Moving the Debate Forward: Are Normobaric and Hypobaric Hypoxia Interchangeable in the Study of Altitude? Curr Sports Med Rep 2018; 16:68-70. [PMID: 28282350 DOI: 10.1249/jsr.0000000000000337] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Affiliation(s)
- Dana M DiPasquale
- Biomedical Department, Navy Experimental Diving Unit, Panama City, FL
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Ostrowski D, Heinrich R. Alternative Erythropoietin Receptors in the Nervous System. J Clin Med 2018; 7:E24. [PMID: 29393890 PMCID: PMC5852440 DOI: 10.3390/jcm7020024] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 01/24/2018] [Accepted: 01/26/2018] [Indexed: 12/18/2022] Open
Abstract
In addition to its regulatory function in the formation of red blood cells (erythropoiesis) in vertebrates, Erythropoietin (Epo) contributes to beneficial functions in a variety of non-hematopoietic tissues including the nervous system. Epo protects cells from apoptosis, reduces inflammatory responses and supports re-establishment of compromised functions by stimulating proliferation, migration and differentiation to compensate for lost or injured cells. Similar neuroprotective and regenerative functions of Epo have been described in the nervous systems of both vertebrates and invertebrates, indicating that tissue-protective Epo-like signaling has evolved prior to its erythropoietic function in the vertebrate lineage. Epo mediates its erythropoietic function through a homodimeric Epo receptor (EpoR) that is also widely expressed in the nervous system. However, identification of neuroprotective but non-erythropoietic Epo splice variants and Epo derivatives indicated the existence of other types of Epo receptors. In this review, we summarize evidence for potential Epo receptors that might mediate Epo's tissue-protective function in non-hematopoietic tissue, with focus on the nervous system. In particular, besides EpoR, we discuss three other potential neuroprotective Epo receptors: (1) a heteroreceptor consisting of EpoR and common beta receptor (βcR), (2) the Ephrin (Eph) B4 receptor and (3) the human orphan cytokine receptor-like factor 3 (CRLF3).
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Affiliation(s)
- Daniela Ostrowski
- Department of Biology, Truman State University, Kirksville, MO 63501, USA.
| | - Ralf Heinrich
- Department of Cellular Neurobiology, Institute for Zoology, Georg-August-University Göttingen, 37073 Göttingen, Germany.
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Wang J, Hayashi Y, Yokota A, Xu Z, Zhang Y, Huang R, Yan X, Liu H, Ma L, Azam M, Bridges JP, Cancelas JA, Kalfa TA, An X, Xiao Z, Huang G. Expansion of EPOR-negative macrophages besides erythroblasts by elevated EPOR signaling in erythrocytosis mouse models. Haematologica 2017; 103:40-50. [PMID: 29051279 PMCID: PMC5777189 DOI: 10.3324/haematol.2017.172775] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 10/10/2017] [Indexed: 02/04/2023] Open
Abstract
Activated erythropoietin (EPO) receptor (EPOR) signaling causes erythrocytosis. The important role of macrophages for the erythroid expansion and differentiation process has been reported, both in baseline and stress erythropoiesis. However, the significance of EPOR signaling for regulation of macrophages contributing to erythropoiesis has not been fully understood. Here we show that EPOR signaling activation quickly expands both erythrocytes and macrophages in vivo in mouse models of primary and secondary erythrocytosis. To mimic the chimeric condition and expansion of the disease clone in the polycythemia vera patients, we combined Cre-inducible Jak2V617F/+ allele with LysM-Cre allele which expresses in mature myeloid cells and some of the HSC/Ps (LysM-Cre;Jak2V617F/+ mice). We also generated inducible EPO-mediated secondary erythrocytosis models using Alb-Cre, Rosa26-loxP-stop-loxP-rtTA, and doxycycline inducible EPAS1-double point mutant (DPM) alleles (Alb-Cre;DPM mice). Both models developed a similar degree of erythrocytosis. Macrophages were also increased in both models without increase of major inflammatory cytokines and chemokines. EPO administration also quickly induced these macrophages in wild-type mice before observable erythrocytosis. These findings suggest that EPOR signaling activation could induce not only erythroid cell expansion, but also macrophages. Surprisingly, an in vivo genetic approach indicated that most of those macrophages do not express EPOR, but erythroid cells and macrophages contacted tightly with each other. Given the importance of the central macrophages as a niche for erythropoiesis, further elucidation of the EPOR signaling mediated-regulatory mechanisms underlying macrophage induction might reveal a potential therapeutic target for erythrocytosis.
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Affiliation(s)
- Jieyu Wang
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA.,Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yoshihiro Hayashi
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Asumi Yokota
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Zefeng Xu
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA.,State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Yue Zhang
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA.,State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Rui Huang
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Xiaomei Yan
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Hongyun Liu
- Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Liping Ma
- Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Mohammad Azam
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - James P Bridges
- Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Jose A Cancelas
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Theodosia A Kalfa
- Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, OH, USA
| | - Xiuli An
- Laboratory of Membrane Biology, New York Blood Center, New York, NY, USA
| | - Zhijian Xiao
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Gang Huang
- Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA .,State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
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Zhou J, Li J, Rosenbaum DM, Zhuang J, Poon C, Qin P, Rivera K, Lepore J, Willette RN, Hu E, Barone FC. The prolyl 4-hydroxylase inhibitor GSK360A decreases post-stroke brain injury and sensory, motor, and cognitive behavioral deficits. PLoS One 2017; 12:e0184049. [PMID: 28880966 PMCID: PMC5589177 DOI: 10.1371/journal.pone.0184049] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 08/17/2017] [Indexed: 12/20/2022] Open
Abstract
There is interest in pharmacologic preconditioning for end-organ protection by targeting the HIF system. This can be accomplished by inhibition of prolyl 4-hydroxylase (PHD). GSK360A is an orally active PHD inhibitor that has been previously shown to protect the failing heart. We hypothesized that PHD inhibition can also protect the brain from injuries and resulting behavioral deficits that can occur as a result of surgery. Thus, our goal was to investigate the effect of pre-stroke surgery brain protection using a verified GSK360A PHD inhibition paradigm on post-stroke surgery outcomes. Vehicle or an established protective dose (30 mg/kg, p.o.) of GSK360A was administered to male Sprague-Dawley rats. Initially, GSK360A pharmacokinetics and organ distribution were determined, and then PHD-HIF pharmacodynamic markers were measured (i.e., to validate the pharmacological effects of the GSK360A administration regimen). Results obtained using this validated PHD dose-regimen indicated significant improvement by GSK360A (30mg/kg); administered at 18 and 5 hours prior to transient middle cerebral artery occlusion (stroke). GSK360A exposure and plasma, kidney and brain HIF-PHD pharmacodynamics endpoints (e.g., erythropoietin; EPO and Vascular Endothelial Growth Factor; VEGF) were measured. GSK360A provided rapid exposure in plasma (7734 ng/ml), kidney (45–52% of plasma level) and brain (1–4% of plasma level), and increased kidney EPO mRNA (80-fold) and brain VEGF mRNA (2-fold). We also observed that GSK360A increased plasma EPO (300-fold) and VEGF (2-fold). Further assessments indicated that GSK360A reduced post-stroke surgery neurological deficits (47–64%), cognitive dysfunction (60–75%) and brain infarction (30%) 4 weeks later. Thus, PHD inhibition using GSK360A pretreatment produced long-term post-stroke brain protection and improved behavioral functioning. These data support PHD inhibition, specifically by GSK360A, as a potential strategy for pre-surgical use to reduce brain injury and functional decline due to surgery-related cerebral injury.
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MESH Headings
- Administration, Oral
- Animals
- Behavior, Animal/drug effects
- Brain/drug effects
- Brain/metabolism
- Brain/pathology
- Brain Injuries/blood
- Brain Injuries/drug therapy
- Brain Injuries/etiology
- Brain Injuries/physiopathology
- Cognition Disorders/drug therapy
- Cognition Disorders/etiology
- Erythropoietin/blood
- Erythropoietin/genetics
- Glycine/administration & dosage
- Glycine/analogs & derivatives
- Glycine/pharmacokinetics
- Glycine/pharmacology
- Glycine/therapeutic use
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Infarction, Middle Cerebral Artery/blood
- Infarction, Middle Cerebral Artery/complications
- Infarction, Middle Cerebral Artery/pathology
- Infarction, Middle Cerebral Artery/physiopathology
- Male
- Motor Activity/drug effects
- Organ Specificity/drug effects
- Prolyl Hydroxylases/metabolism
- Prolyl-Hydroxylase Inhibitors/administration & dosage
- Prolyl-Hydroxylase Inhibitors/pharmacology
- Prolyl-Hydroxylase Inhibitors/therapeutic use
- Quinolones/administration & dosage
- Quinolones/pharmacokinetics
- Quinolones/pharmacology
- Quinolones/therapeutic use
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Rats, Sprague-Dawley
- Sensation/drug effects
- Stroke/blood
- Stroke/complications
- Stroke/physiopathology
- Vascular Endothelial Growth Factor A/blood
- Vascular Endothelial Growth Factor A/genetics
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Affiliation(s)
- Jin Zhou
- Department of Neurology, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America
| | - Jie Li
- Department of Neurology, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America
| | - Daniel M. Rosenbaum
- Department of Neurology, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America
- Robert F. Furchgott Foundation, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America
- Department of Physiology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America
| | - Jian Zhuang
- Department of Neurology, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America
| | - Carrie Poon
- Department of Neurology, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America
| | - Pu Qin
- Cardiac Biology, Heart Failure Discovery Performance Unit, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania, United States of America
| | - Katrina Rivera
- Cardiac Biology, Heart Failure Discovery Performance Unit, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania, United States of America
| | - John Lepore
- Cardiac Biology, Heart Failure Discovery Performance Unit, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania, United States of America
| | - Robert N. Willette
- Cardiac Biology, Heart Failure Discovery Performance Unit, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania, United States of America
| | - Erding Hu
- Cardiac Biology, Heart Failure Discovery Performance Unit, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania, United States of America
| | - Frank C. Barone
- Department of Neurology, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America
- Robert F. Furchgott Foundation, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America
- Department of Physiology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America
- * E-mail:
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Ghigna MR, Mooi WJ, Grünberg K. Pulmonary hypertensive vasculopathy in parenchymal lung diseases and/or hypoxia: Number 1 in the Series "Pathology for the clinician" Edited by Peter Dorfmüller and Alberto Cavazza. Eur Respir Rev 2017; 26:26/144/170003. [PMID: 28659502 DOI: 10.1183/16000617.0003-2017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 03/01/2017] [Indexed: 01/01/2023] Open
Abstract
Pulmonary hypertension (PH) with complicating chronic lung diseases and/or hypoxia falls into group 3 of the updated classification of PH. Patients with chronic obstructive lung disease (COPD), diffuse lung disease (such as idiopathic pulmonary fibrosis (IPF)) and with sleep disordered breathing are particularly exposed to the risk of developing PH. Although PH in such a context is usually mild, a minority of patients exhibit severe haemodynamic impairment, defined by a mean pulmonary arterial pressure (mPAP) of ≥35 mmHg or mPAP values ranging between 25 mmHg and 35 mmHg with a low cardiac index (<2 L·min-1·m-2). The overlap between lung parenchymal disease and PH heavily affects life expectancy in such a patient population and complicates their therapeutic management. In this review we illustrate the pathological features and the underlying pathophysiological mechanisms of pulmonary circulation in chronic lung diseases, with an emphasis on COPD, IPF and obstructive sleep apnoea syndrome.
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Affiliation(s)
- Maria Rosa Ghigna
- Service d'Anatomie et de Cytologie Pathologiques, Hôpital Marie Lannelongue, Le Plessis Robinson, France
| | - Wolter J Mooi
- Dept of Pathology, VU University Medical Center, Amsterdam, The Netherlands
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Bonnas C, Wüstefeld L, Winkler D, Kronstein-Wiedemann R, Dere E, Specht K, Boxberg M, Tonn T, Ehrenreich H, Stadler H, Sillaber I. EV-3, an endogenous human erythropoietin isoform with distinct functional relevance. Sci Rep 2017; 7:3684. [PMID: 28623280 PMCID: PMC5473850 DOI: 10.1038/s41598-017-03167-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 04/25/2017] [Indexed: 01/14/2023] Open
Abstract
Generation of multiple mRNAs by alternative splicing is well known in the group of cytokines and has recently been reported for the human erythropoietin (EPO) gene. Here, we focus on the alternatively spliced EPO transcript characterized by deletion of exon 3 (hEPOΔ3). We show co-regulation of EPO and hEPOΔ3 in human diseased tissue. The expression of hEPOΔ3 in various human samples was low under normal conditions, and distinctly increased in pathological states. Concomitant up-regulation of hEPOΔ3 and EPO in response to hypoxic conditions was also observed in HepG2 cell cultures. Using LC-ESI-MS/MS, we provide first evidence for the existence of hEPOΔ3 derived protein EV-3 in human serum from healthy donors. Contrary to EPO, recombinant EV-3 did not promote early erythroid progenitors in cultures of human CD34+ haematopoietic stem cells. Repeated intraperitoneal administration of EV-3 in mice did not affect the haematocrit. Similar to EPO, EV-3 acted anti-apoptotic in rat hippocampal neurons exposed to oxygen-glucose deprivation. Employing the touch-screen paradigm of long-term visual discrimination learning, we obtained first in vivo evidence of beneficial effects of EV-3 on cognition. This is the first report on the presence of a naturally occurring EPO protein isoform in human serum sharing non-erythropoietic functions with EPO.
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Affiliation(s)
| | - Liane Wüstefeld
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine and DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany
| | - Daniela Winkler
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine and DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany
| | - Romy Kronstein-Wiedemann
- German Red Cross Blood Donor Service North-East, Institute of Transfusion Medicine, Dresden, Germany
| | - Ekrem Dere
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine and DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany
| | - Katja Specht
- Institute of Pathology, Technische Universität München, Munich, Germany
| | - Melanie Boxberg
- Institute of Pathology, Technische Universität München, Munich, Germany
| | - Torsten Tonn
- German Red Cross Blood Donor Service North-East, Institute of Transfusion Medicine, Dresden, Germany
- Department of Experimental Transfusion Medicine, Medical Faculty Carl Gustav Carus, Technische Universität Desden, Dresden, Germany
| | - Hannelore Ehrenreich
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine and DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany
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Yu DF, Zhu LH, Jiang L. Recombinant Human Erythropoietin Augments Neovascularization Responses in a Neonatal Rat Model of Premature Brain Damage by Phosphatidylinositol 3 Kinase/Akt Pathway. Chin Med J (Engl) 2017; 130:854-858. [PMID: 28345550 PMCID: PMC5381320 DOI: 10.4103/0366-6999.202744] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Background: Recombinant human-erythropoietin (rh-EPO) has therapeutic efficacy for premature infants with brain damage during the active rehabilitation and anti-inflammation. In the present study, we found that the rh-EPO was related to the promotion of neovascularization. Our aim was to investigate whether rh-EPO augments neovascularization in the neonatal rat model of premature brain damage through the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway. Methods: Postnatal day 5 (PD5), rats underwent permanent ligation of the right common carotid artery and were exposed to hypoxia for 2 h. All the rat pups were randomized into five groups as follows: (1) control group; (2) hypoxia-ischemic (HI) group; (3) HI + LY294002 group; (4) HI + rh-EPO group; and (5) HI + rh-EPO + LY294002 group. The phospho-Akt protein was tested 90 min after the whole operation, and CD34, vascular endothelial growth factor receptor 2 (VEGFR2), and vascular endothelial growth factor (VEGF) were also tested 2 days after the whole operation. Results: In the hypoxic and ischemic zone of the premature rat brain, the rh-EPO induced CD34+ cells to immigrate to the HI brain zone (P < 0.05) and also upregulated the VEGFR2 protein expression (P < 0.05) and VEGF mRNA level (P < 0.05) through the PI3K/Akt (P < 0.05) signaling pathway when compared with other groups. Conclusions: The rh-EPO treatment augments neovascularization responses in the neonatal rat model of premature brain damage through the PI3K/Akt signaling pathway. Besides, the endogenous EPO may exist in the HI zone of rat brain and also has neovascularization function through the PI3K/Akt signaling pathway.
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Affiliation(s)
- Da-Fan Yu
- Department of Clinical Medcine, Medical School of Southeast University, Jiangsu 210009, China
| | - Li-Hua Zhu
- Department of Pediatrics, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, China
| | - Li Jiang
- Department of Pediatrics, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, China
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Córdova Martínez A, Pascual Fernández J, Fernandez Lázaro D, Alvarez Mon M. Muscular and heart adaptations of execise in hypoxia. Is training in slow hypoxy healthy? Med Clin (Barc) 2017; 148:469-474. [PMID: 28341369 DOI: 10.1016/j.medcli.2017.02.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 02/02/2017] [Accepted: 02/09/2017] [Indexed: 12/22/2022]
Affiliation(s)
- Alfredo Córdova Martínez
- Departamento de Bioquímica, Biología Molecular y Fisiología, Facultad de Fisioterapia, Campus Universitario de Soria, Universidad de Valladolid, Soria, España.
| | | | - Diego Fernandez Lázaro
- Departamento de Bioquímica, Biología Molecular y Fisiología, Facultad de Fisioterapia, Campus Universitario de Soria, Universidad de Valladolid, Soria, España
| | - Melchor Alvarez Mon
- Departamento de Medicina y Especialidades Médicas, Hospital Universitario Príncipe de Asturias, Universidad de Alcalá, Alcalá de Henares, Madrid, España
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Abstract
The human brain requires uninterrupted delivery of blood-borne oxygen and nutrients to sustain its function. Focal ischemia, particularly, ischemic stroke, and global ischemia imposed by cardiac arrest disrupt the brain's fuel supply. The resultant ATP depletion initiates a complex injury cascade encompassing intracellular Ca2+ overload, glutamate excitotoxicity, oxido-nitrosative stress, extracellular matrix degradation, and inflammation, culminating in neuronal and astroglial necrosis and apoptosis, neurocognitive deficits, and even death. Unfortunately, brain ischemia has proven refractory to pharmacological intervention. Many promising treatments afforded brain protection in animal models of focal and global ischemia, but failed to improve survival and neurocognitive recovery of stroke and cardiac arrest patients in randomized clinical trials. The culprits are the blood-brain barrier (BBB) that limits transferral of medications to the brain parenchyma, and the sheer complexity of the injury cascade, which presents a daunting array of targets unlikely to respond to monotherapies. Erythropoietin is a powerful neuroprotectant capable of interrupting multiple aspects of the brain injury cascade. Preclinical research demonstrates erythropoietin's ability to suppress glutamate excitotoxicity and intracellular Ca2+ overload, dampen oxidative stress and inflammation, interrupt the apoptotic cascade, and preserve BBB integrity. However, the erythropoietin dosages required to traverse the BBB and achieve therapeutically effective concentrations in the brain parenchyma impose untoward side effects. Recent discoveries that hypoxia induces erythropoietin production within the brain and that neurons, astroglia, and cerebrovascular endothelium harbor membrane erythropoietin receptors, raise the exciting prospect of harnessing endogenous erythropoietin to protect the brain from the ravages of ischemia-reperfusion.
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Affiliation(s)
- Robert T Mallet
- Institute for Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX, United States.
| | - Myoung-Gwi Ryou
- Institute for Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX, United States; Tarleton State University, Fort Worth, TX, United States
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Renal Anemia Model Mouse Established by Transgenic Rescue with an Erythropoietin Gene Lacking Kidney-Specific Regulatory Elements. Mol Cell Biol 2017; 37:MCB.00451-16. [PMID: 27920250 DOI: 10.1128/mcb.00451-16] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2016] [Accepted: 11/20/2016] [Indexed: 01/05/2023] Open
Abstract
The erythropoietin (Epo) gene is under tissue-specific inducible regulation. Because the kidney is the primary EPO-producing tissue in adults, impaired EPO production in chronic kidney disorders results in serious renal anemia. The Epo gene contains a liver-specific enhancer in the 3' region, but the kidney-specific enhancer for gene expression in renal EPO-producing (REP) cells remains elusive. Here, we examined a conserved upstream element for renal Epo regulation (CURE) region that spans 17.4 kb to 3.6 kb upstream of the Epo gene and harbors several phylogenetically conserved elements. We prepared various Epo gene-reporter constructs utilizing a bacterial artificial chromosome and generated a number of transgenic-mouse lines. We observed that deletion of the CURE region (δCURE) abrogated Epo gene expression in REP cells. Although transgenic expression of the δCURE construct rescued Epo-deficient mice from embryonic lethality, the rescued mice had severe EPO-dependent anemia. These mouse lines serve as an elaborate model for the search for erythroid stimulatory activity and are referred to as AnRED (anemic model with renal EPO deficiency) mice. We also dissected the CURE region by exploiting a minigene harboring four phylogenetically conserved elements in reporter transgenic-mouse analyses. Our analyses revealed that Epo gene regulation in REP cells is a complex process that utilizes multiple regulatory influences.
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Locatelli F, Fishbane S, Block GA, Macdougall IC. Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients. Am J Nephrol 2017; 45:187-199. [PMID: 28118622 DOI: 10.1159/000455166] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Anemia, a common complication of chronic kidney disease (CKD), has previously been attributed primarily to decreased production of erythropoietin. More recently, it has become apparent that the etiology of anemia involves several other factors, most notably dysfunctional iron metabolism, mediated via increased hepcidin activity and reduced clearance. Current management of anemia in patients with advanced CKD is based on erythropoiesis-stimulating agents and iron supplementation, along with red blood cell transfusions when necessary; however, safety considerations associated with these therapies highlight the need to pursue alternative treatment options targeting other mechanisms such as hypoxia-inducible factors (HIFs) that act as central regulators of erythropoiesis by coordinating a series of graded hypoxic responses. SUMMARY This review discusses the discovery of the HIF pathway and its regulation via HIF prolyl hydroxylase enzymes in the context of erythropoiesis and iron metabolism. The rationale for targeting this pathway and the clinical development of HIF prolyl hydroxylase inhibitors are reviewed, with a commentary on the potential implications of this class of agents in CKD anemia management. Key Messages: Pharmacologic activation of the HIF pathway results in a transient pseudo-hypoxic state that stimulates erythropoiesis in CKD patients with anemia. Results from clinical studies of a number of HIF prolyl hydroxylase inhibitors are increasingly available and provide support for the continued evaluation of the risk-benefit ratio of this novel therapeutic approach to the treatment of anemia in CKD.
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Dalko E, Tchitchek N, Pays L, Herbert F, Cazenave PA, Ravindran B, Sharma S, Nataf S, Das B, Pied S. Erythropoietin Levels Increase during Cerebral Malaria and Correlate with Heme, Interleukin-10 and Tumor Necrosis Factor-Alpha in India. PLoS One 2016; 11:e0158420. [PMID: 27441662 PMCID: PMC4956275 DOI: 10.1371/journal.pone.0158420] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 06/15/2016] [Indexed: 12/12/2022] Open
Abstract
Cerebral malaria (CM) caused by Plasmodium falciparum parasites often leads to the death of infected patients or to persisting neurological sequelae despite anti-parasitic treatments. Erythropoietin (EPO) was recently suggested as a potential adjunctive treatment for CM. However diverging results were obtained in patients from Sub-Saharan countries infected with P. falciparum. In this study, we measured EPO levels in the plasma of well-defined groups of P. falciparum-infected patients, from the state of Odisha in India, with mild malaria (MM), CM, or severe non-CM (NCM). EPO levels were then correlated with biological parameters, including parasite biomass, heme, tumor necrosis factor (TNF)-α, interleukin (IL)-10, interferon gamma-induced protein (IP)-10, and monocyte chemoattractant protein (MCP)-1 plasma concentrations by Spearman’s rank and multiple correlation analyses. We found a significant increase in EPO levels with malaria severity degree, and more specifically during fatal CM. In addition, EPO levels were also found correlated positively with heme, TNF-α, IL-10, IP-10 and MCP-1 during CM. We also found a significant multivariate correlation between EPO, TNF-α, IL-10, IP-10 MCP-1 and heme, suggesting an association of EPO with a network of immune factors in CM patients. The contradictory levels of circulating EPO reported in CM patients in India when compared to Africa highlights the need for the optimization of adjunctive treatments according to the targeted population.
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Affiliation(s)
- Esther Dalko
- Centre for Infection and Immunity of Lille, INSERM U1019, CNRS UMR 8204, Université Lille Nord de France, Institut Pasteur de Lille, Lille 59019, France
| | - Nicolas Tchitchek
- CEA, DSV/iMETI, Immunology of viral infections and autoimmune diseases research unit, UMR1184, IDMIT infrastructure, Fontenay-aux-Roses, France
| | - Laurent Pays
- Lyon 1 University, CarMeN Laboratory, INSERM U-1060, INRA USC-1235, 69921, Oullins, France; Banque de Tissus et de Cellules des Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France
| | - Fabien Herbert
- Centre for Infection and Immunity of Lille, INSERM U1019, CNRS UMR 8204, Université Lille Nord de France, Institut Pasteur de Lille, Lille 59019, France
| | - Pierre-André Cazenave
- Centre for Infection and Immunity of Lille, INSERM U1019, CNRS UMR 8204, Université Lille Nord de France, Institut Pasteur de Lille, Lille 59019, France
| | | | - Shobhona Sharma
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra 400005, India
| | - Serge Nataf
- Lyon 1 University, CarMeN Laboratory, INSERM U-1060, INRA USC-1235, 69921, Oullins, France; Banque de Tissus et de Cellules des Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France
| | - Bidyut Das
- SCB Medical College, Cuttack, Odisha 753007, India
| | - Sylviane Pied
- Centre for Infection and Immunity of Lille, INSERM U1019, CNRS UMR 8204, Université Lille Nord de France, Institut Pasteur de Lille, Lille 59019, France
- * E-mail:
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Hu J, Bernardini A, Fandrey J. Optical Analysis of Hypoxia Inducible Factor (HIF)-1 Complex Assembly: Imaging of Cellular Oxygen Sensing. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 903:247-58. [DOI: 10.1007/978-1-4899-7678-9_17] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
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Siwaponanan P, Fucharoen S, Sirankapracha P, Winichagoon P, Umemura T, Svasti S. Elevated levels of miR-210 correlate with anemia in β-thalassemia/HbE patients. Int J Hematol 2016; 104:338-43. [DOI: 10.1007/s12185-016-2032-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Revised: 05/26/2016] [Accepted: 05/26/2016] [Indexed: 02/02/2023]
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