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1
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Fan X, Cao K, Wong RSM, Yan X. A whole-body mechanistic physiologically-based pharmacokinetic modeling of intravenous iron. Drug Deliv Transl Res 2025; 15:1109-1120. [PMID: 39048784 PMCID: PMC11870943 DOI: 10.1007/s13346-024-01675-x] [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] [Accepted: 07/11/2024] [Indexed: 07/27/2024]
Abstract
Iron is essential for every cell of the mammalian organism. Iron deficiency is a major public health issue worldwide. Intravenous (IV) iron therapy has been used to treat anemia. However, IV iron therapy is known far away from ideal because the quantitative relationship between the pharmacokinetics and biodistribution of IV iron under different iron statuses remains unclear. Patients are known to suffer adverse effects from excessive iron accumulation. Our objective was to develop a physiologically based pharmacokinetic (PBPK) model of iron in mice and validate its application for predicting iron disposition in rats and humans. Previously published data on iron were collected for constructing the PBPK model of iron in mice, and then extrapolated to rats and humans based on physiologically and chemically specific parameters relevant to each species. The PBPK model characterized the distribution of iron in mice successfully. The model based on extrapolation to rats accurately simulated the ferric carboxymaltose (FCM) PK profiles in rat tissues. Similarly, the observed and simulated serum PK of FCM in humans were in reasonable agreement. This mechanistic whole-body PBPK model is useful for understanding and predicting iron effects on different species. It also establishes a foundation for future research that incorporates iron kinetics and biodistribution, along with related clinical experiments. This approach could lead to the development of effective and personalized iron deficiency anemia treatments.
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Affiliation(s)
- Xiaoqing Fan
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, 8Th Floor, Lo Kwee-Seong Integrated Biomedical Sciences Building, Area 39, Hong Kong SAR, China
| | - Kangna Cao
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, 8Th Floor, Lo Kwee-Seong Integrated Biomedical Sciences Building, Area 39, Hong Kong SAR, China
| | - Raymond S M Wong
- Division of Hematology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Xiaoyu Yan
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, 8Th Floor, Lo Kwee-Seong Integrated Biomedical Sciences Building, Area 39, Hong Kong SAR, China.
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Kouroumalis E, Tsomidis I, Voumvouraki A. HFE-Related Hemochromatosis May Be a Primary Kupffer Cell Disease. Biomedicines 2025; 13:683. [PMID: 40149659 PMCID: PMC11940282 DOI: 10.3390/biomedicines13030683] [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: 01/14/2025] [Revised: 02/28/2025] [Accepted: 03/08/2025] [Indexed: 03/29/2025] Open
Abstract
Iron overload can lead to increased deposition of iron and cause organ damage in the liver, the pancreas, the heart and the synovium. Iron overload disorders are due to either genetic or acquired abnormalities such as excess transfusions or chronic liver diseases. The most common genetic disease of iron deposition is classic hemochromatosis (HH) type 1, which is caused by mutations of HFE. Other rare forms of HH include type 2A with mutations at the gene hemojuvelin or type 2B with mutations in HAMP that encodes hepcidin. HH type 3, is caused by mutations of the gene that encodes transferrin receptor 2. Mutations of SLC40A1 which encodes ferroportin cause either HH type 4A or HH type 4B. In the present review, an overview of iron metabolism including absorption by enterocytes and regulation of iron by macrophages, liver sinusoidal endothelial cells (LSECs) and hepatocyte production of hepcidin is presented. Hereditary Hemochromatosis and the current pathogenetic model are analyzed. Finally, a new hypothesis based on published data was suggested. The Kupffer cell is the primary defect in HFE hemochromatosis (and possibly in types 2 and 3), while the hepcidin-relative deficiency, which is the common underlying abnormality in the three types of HH, is a secondary consequence.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, PAGNI University Hospital, University of Crete Medical School, 71500 Heraklion, Greece
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Greece;
| | - Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Greece;
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece;
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3
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Catapano A, Cimmino F, Petrella L, Pizzella A, D'Angelo M, Ambrosio K, Marino F, Sabbatini A, Petrelli M, Paolini B, Lucchin L, Cavaliere G, Cristino L, Crispino M, Trinchese G, Mollica MP. Iron metabolism and ferroptosis in health and diseases: The crucial role of mitochondria in metabolically active tissues. J Nutr Biochem 2025; 140:109888. [PMID: 40057002 DOI: 10.1016/j.jnutbio.2025.109888] [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: 05/17/2024] [Revised: 11/15/2024] [Accepted: 02/27/2025] [Indexed: 03/30/2025]
Abstract
Iron is essential in various physiological processes, but its accumulation leads to oxidative stress and cell damage, thus iron homeostasis has to be tightly regulated. Ferroptosis is an iron-dependent non-apoptotic regulated cell death characterized by iron overload and reactive oxygen species accumulation. Mitochondria are organelles playing a crucial role in iron metabolism and involved in ferroptosis. MitoNEET, a protein of mitochondrial outer membrane, is a key element in this process. Ferroptosis, altering iron levels in several metabolically active organs, is linked to several non-communicable diseases. For example, iron overload in the liver leads to hepatic fibrosis and cirrhosis, accelerating non-alcholic fatty liver diseases progression, in the muscle cells contributes to oxidative damage leading to sarcopenia, and in the brain is associated to neurodegeneration. The aim of this review is to investigate the intricate balance of iron regulation focusing on the role of mitochondria and oxidative stress, and analyzing the ferroptosis implications in health and disease.
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Affiliation(s)
- Angela Catapano
- Department of Biology, University of Naples Federico II, Naples, Italy
| | - Fabiano Cimmino
- Department of Biology, University of Naples Federico II, Naples, Italy; Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Lidia Petrella
- Department of Biology, University of Naples Federico II, Naples, Italy
| | - Amelia Pizzella
- Department of Biology, University of Naples Federico II, Naples, Italy
| | - Margherita D'Angelo
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Katia Ambrosio
- Department of Biology, University of Naples Federico II, Naples, Italy
| | - Francesca Marino
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Annarita Sabbatini
- Dietetic and Clinical Nutrition Unit, IEO European Institute of Oncology IRCSS, Milan, Italy
| | - Massimiliano Petrelli
- Department of Clinical and Molecular Sciences, Clinic of Endocrinology and Metabolic Diseases, Università Politecnica delle Marche, Ancona, Italy
| | - Barbara Paolini
- Department of Innovation, experimentation and clinical research, Unit of dietetics and clinical nutrition, S. Maria Alle Scotte Hospital, University of Siena, Siena, Italy
| | - Lucio Lucchin
- Dietetics and Clinical Nutrition, Bolzano Health District, Bolzano, Italy
| | - Gina Cavaliere
- Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
| | - Luigia Cristino
- Institute of Biomolecular Chemistry, National Research Council of Italy, Pozzuoli, Naples, Italy
| | - Marianna Crispino
- Department of Biology, University of Naples Federico II, Naples, Italy.
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Zhang J, Chen X, Huang D, Tan X. Impact of p. Gingivalis-induced chronic apical periodontitis on systemic iron homeostasis via the hepatic IL-6/STAT3/Hepcidin signaling pathway. Int Immunopharmacol 2025; 147:114002. [PMID: 39787762 DOI: 10.1016/j.intimp.2024.114002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/29/2024] [Accepted: 12/30/2024] [Indexed: 01/12/2025]
Abstract
BACKGROUND AND AIMS Chronic apical periodontitis (CAP), an inflammatory disease of the oral cavity caused by bacterial infections with Porphyromonas gingivalis (P. gingivalis) as a key pathogen, has been associated with systemic effects, potentially influencing distant organs including liver. The liver plays a key role in iron metabolism and immunity by hepcidin. This study aims to investigate the impact of P. gingivalis-induced CAP on liver and systemic iron metabolism, focusing on the role of the IL-6/STAT3 signaling pathway in hepatic hepcidin synthesis. METHODS A murine model of CAP was established by pulp chamber infection with P. gingivalis. Serum levels of IL-6, ferritin, and hepcidin were measured via ELISA. High-throughput sequencing was used to analyze hepatic gene expression, and immunohistochemistry with fluorescent staining was performed to validate protein expression in liver tissues. RESULTS CAP led to significant changes in serum iron, ferritin, and IL-6. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed enrichment in pathways like JAK/STAT signaling and acute-phase responses, and gene set enrichment analysis (GSEA) also indicated activation of IL-6/JAK/STAT3 signaling pathway. Iimmunofluorescence confirmed increased IL-6, p-STAT3, and hepcidin expression. These levels were alleviated by stattic treatment, mitigating CAP-induced inflammatory and iron-regulatory effects. CONCLUSION P. gingivalis-induced CAP triggered systemic inflammation and disrupts iron metabolism via the IL-6/STAT3 signaling pathway, potentially affecting liver function. Targeting this pathway may offer therapeutic strategies for managing iron dysregulation in chronic inflammatory diseases like CAP.
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Affiliation(s)
- Jinglan Zhang
- State Key Laboratory of Oral Diseases & National Center of Stomatology & National Clinical Research Center for Oral Diseases & Department of Operative Dentistry and Endodontics West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Xuan Chen
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Operative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China; Department of Endodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou 510182, Guangdong, China
| | - Dingming Huang
- State Key Laboratory of Oral Diseases & National Center of Stomatology & National Clinical Research Center for Oral Diseases & Department of Operative Dentistry and Endodontics West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
| | - Xuelian Tan
- State Key Laboratory of Oral Diseases & National Center of Stomatology & National Clinical Research Center for Oral Diseases & Department of Operative Dentistry and Endodontics West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
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Sandnes M, Reikvam H. Hepcidin as a therapeutic target in iron overload. Expert Opin Ther Targets 2024; 28:1039-1046. [PMID: 39679683 DOI: 10.1080/14728222.2024.2443081] [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: 07/13/2024] [Revised: 11/18/2024] [Accepted: 12/12/2024] [Indexed: 12/17/2024]
Abstract
INTRODUCTION Dysregulation of the hepcidin-ferroportin axis is a hallmark in the pathogenesis of iron overload, ultimately leading to end-organ injury. Hereditary hemochromatosis and iron-loading anemias are characterized by a hepcidin deficiency, making hepcidin a novel therapeutic target for preventing and managing iron overload. AREAS COVERED Modulators of hepcidin expression and molecules mimicking hepcidin are emerging as highly promising therapeutic strategies. We present a summary of results from preclinical and clinical trials of such therapies in models of iron overload. EXPERT OPINION Current treatment alternatives in iron overload fail to address the underlying hepcidin deficiency - and may even exacerbate it. Until hepcidin-targeting therapies become available, several challenges remain, including the need to optimize dosing in order to manage the narrow treatment window and improving specificity in targeting iron metabolism pathways exclusively. Long-term studies are crucial to fully assess both the benefits and risks of these therapies and to explore their potential utility in combination with existing treatment guidelines. Furthermore, these therapies are expected to have applications, particularly in addressing other iron-maldistributed disorders, as seen in anemia of chronic disease and inflammation.
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Affiliation(s)
- Miriam Sandnes
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Håkon Reikvam
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
- K.G. Jebsen Center of Myeloid Malignancies, Department of Clinical Science, University of Bergen, Bergen, Norway
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Taveepanich S, Chayajarus K, Jittimanee J, Phusri N, Thongdee P, Sawatdee K, Kamsri P, Punkvang A, Suttisintong K, Pungpo P, Suwannaloet W, Thongrung R, Pangjit K. Iron chelating, antioxidant, and anti-inflammatory properties of brazilin from Caesalpinia sappan Linn. Heliyon 2024; 10:e38213. [PMID: 39397930 PMCID: PMC11470788 DOI: 10.1016/j.heliyon.2024.e38213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 09/01/2024] [Accepted: 09/19/2024] [Indexed: 10/15/2024] Open
Abstract
Background Iron overload and inflammation are severe conditions that can lead to various chronic diseases. However, the current iron chelator drugs have their limitations. The phytochemical compounds from herbals, such as brazilin, the major active compound in Caesalpinia sappan Linn., have significant therapeutic potential in various chronic diseases. Our study was designed to examine the effect of brazilin on iron chelating properties, antioxidant activity in hepatocytes, and anti-inflammatory potential in macrophages. Methods This study focused on the isolation, purification, and evaluation of brazilin, the principal bioactive constituent found in C. sappan wood. Brazilin was extracted via methanol maceration followed by column chromatography purification. The purified compound was characterized using high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry (MS). The antioxidant potential of brazilin was assessed by in vitro assays, including 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azinobis-(3-ethylbenzthiazolin-6-sulfonic acid (ABTS), and ferric-reducing antioxidant power (FRAP). Furthermore, its cellular antioxidant activity was evaluated using hydrogen peroxide-induced oxidative stress in the hepatocellular carcinoma cell line (Huh-7). The iron-chelating capacity of brazilin was determined spectrophotometrically, and Job's plot method was used to elucidated the stoichiometry of the iron-brazilin complex formation. The anti-inflammatory properties of brazilin were investigated in lipopolysaccharide (LPS)-stimulated macrophages (RAW 264.7). Nitric oxide (NO) inhibition was quantified using the Griess reagent, while the expression levels of pro-inflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), were evaluated by RT-qPCR. Results The results demonstrated that brazilin exhibited potent antioxidant activity in vitro and hepatocytes in a concentration-dependent manner. It also showed anti-inflammatory activity, in which NO production was significantly reduced and IL-6 and TNF-α expression in LPS-induced macrophages were repressed. Furthermore, it can bind ferric and ferrous ions. Brazilin acts as a bidentate iron chelator that forms a complex with iron in a 2:1 ratio, and two water molecules are used as additional chelators in this complex. Conclusions Our findings have significant implications. Brazilin can potentially alleviate the harmful effects of iron-induced oxidative stress and inflammatory disorders.
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Affiliation(s)
- Somjintana Taveepanich
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani, 34190, Thailand
| | - Kampanart Chayajarus
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani, 34190, Thailand
| | - Jutharat Jittimanee
- College of Medicine and Public Health, Ubon Ratchathani University, Ubon Ratchathani, 34190, Thailand
| | - Naruedon Phusri
- Department of Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani, 34190, Thailand
| | - Paptawan Thongdee
- Department of Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani, 34190, Thailand
| | - Khemmisara Sawatdee
- Department of Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani, 34190, Thailand
| | - Pharit Kamsri
- Division of Chemistry, Faculty of Science, Nakhon Phanom University, Nakhon Phanom, 48000, Thailand
| | - Auradee Punkvang
- Division of Chemistry, Faculty of Science, Nakhon Phanom University, Nakhon Phanom, 48000, Thailand
| | - Khomson Suttisintong
- National Nanotechnology Center, NSTDA, 111 Thailand Science Park, Klong Luang, Pathum Thani, 12120, Thailand
| | - Pornpan Pungpo
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani, 34190, Thailand
| | - Wanwisa Suwannaloet
- College of Medicine and Public Health, Ubon Ratchathani University, Ubon Ratchathani, 34190, Thailand
| | - Ruttiya Thongrung
- College of Medicine and Public Health, Ubon Ratchathani University, Ubon Ratchathani, 34190, Thailand
| | - Kanjana Pangjit
- College of Medicine and Public Health, Ubon Ratchathani University, Ubon Ratchathani, 34190, Thailand
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Wu K, Chen J, Lin J, Zhu E, Xu X, Yan X, Ju L, Huang M, Zhang Y. The role of ferroptosis in DM-induced liver injury. Biometals 2024; 37:1191-1200. [PMID: 38874821 DOI: 10.1007/s10534-024-00600-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 03/25/2024] [Indexed: 06/15/2024]
Abstract
The liver damage caused by Diabetes Mellitus (DM) has attracted increasing attention in recent years. Liver injury in DM can be caused by ferroptosis, a form of cell death caused by iron overload. However, the role of iron transporters in this context is still not clear. Herein, we attempted to shed light on the pathophysiological mechanism of ferroptosis. DM was induced in 8-week-old male rats by streptozotocin (STZ) before assessment of the degree of liver injury. Together with histopathological changes, variations in glutathione peroxidase 4 (GPX4), glutathione (GSH), superoxide dismutase (SOD), transferrin receptor 1 (TFR1), ferritin heavy chain (FTH), ferritin light chain (FTL), ferroportin and Prussian blue staining, were monitored in rat livers before and after treatment with Fer-1. In the liver of STZ-treated rats, GSH and SOD levels decreased, whereas those of malondialdehyde (MDA) increased. Expression of TFR1, FTH and FTL increased whereas that of glutathione peroxidase 4 (GPX4) and ferroportin did not change significantly. Prussian blue staining showed that iron levels increased. Histopathology showed liver fibrosis and decreased glycogen content. Fer-1 treatment reduced iron and MDA levels but GSH and SOD levels were unchanged. Expression of FTH and FTL was reduced whereas that of ferroportin showed a mild decrease. Fer-1 treatment alleviated liver fibrosis, increased glycogen content and mildly improved liver function. Our study demonstrates that ferroptosis is involved in DM-induced liver injury. Regulating the levels of iron transporters may become a new therapeutic strategy in ferroptosis-induced liver injury.
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Affiliation(s)
- Keping Wu
- Department of Nephrology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-Sen University), Ministry of Education, Guangzhou, China
| | - Jiasi Chen
- Department of Nephrology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jiawen Lin
- Department of Nephrology, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Enyi Zhu
- Department of Nephrology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-Sen University), Ministry of Education, Guangzhou, China
| | - Xiaochang Xu
- Department of Nephrology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-Sen University), Ministry of Education, Guangzhou, China
| | - Xiuhong Yan
- Department of Nephrology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-Sen University), Ministry of Education, Guangzhou, China
| | - Lang Ju
- Department of Nephrology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-Sen University), Ministry of Education, Guangzhou, China
| | - Mingcheng Huang
- Department of Nephrology, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China.
| | - Yimin Zhang
- Department of Nephrology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
- Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-Sen University), Ministry of Education, Guangzhou, China.
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Lee Y, Yoon S, Paek M, Han D, Choi MH, Park SH. Advanced MRI techniques in abdominal imaging. Abdom Radiol (NY) 2024; 49:3615-3636. [PMID: 38802629 DOI: 10.1007/s00261-024-04369-7] [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: 03/19/2024] [Revised: 04/30/2024] [Accepted: 05/03/2024] [Indexed: 05/29/2024]
Abstract
Magnetic resonance imaging (MRI) is a crucial modality for abdominal imaging evaluation of focal lesions and tissue properties. However, several obstacles, such as prolonged scan times, limitations in patients' breath-hold capacity, and contrast agent-associated artifacts, remain in abdominal MR images. Recent techniques, including parallel imaging, three-dimensional acquisition, compressed sensing, and deep learning, have been developed to reduce the scan time while ensuring acceptable image quality or to achieve higher resolution without extending the scan duration. Quantitative measurements using MRI techniques enable the noninvasive evaluation of specific materials. A comprehensive understanding of these advanced techniques is essential for accurate interpretation of MRI sequences. Herein, we therefore review advanced abdominal MRI techniques.
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Affiliation(s)
- Yoonhee Lee
- Department of Radiology, Gil Medical Center, Gachon University College of Medicine, 21, Namdong-daero 774beon-gil, Namdong-gu, Incheon, 21565, Republic of Korea
| | - Sungjin Yoon
- Department of Radiology, Gil Medical Center, Gachon University College of Medicine, 21, Namdong-daero 774beon-gil, Namdong-gu, Incheon, 21565, Republic of Korea
| | | | - Dongyeob Han
- Siemens Healthineers Ltd, Seoul, Republic of Korea
| | - Moon Hyung Choi
- Department of Radiology, Catholic University of Korea Eunpyeong St Mary's Hospital, Seoul, Republic of Korea
| | - So Hyun Park
- Department of Radiology, Gil Medical Center, Gachon University College of Medicine, 21, Namdong-daero 774beon-gil, Namdong-gu, Incheon, 21565, Republic of Korea.
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Xing Z, Gao S, Zheng A, Tong C, Fang Y, Xiang Z, Chen S, Wang W, Hua C. Promising roles of combined therapy based on immune response and iron metabolism in systemic lupus erythematosus. Int Immunopharmacol 2024; 138:112481. [PMID: 38917527 DOI: 10.1016/j.intimp.2024.112481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 05/14/2024] [Accepted: 06/11/2024] [Indexed: 06/27/2024]
Abstract
Systemic lupus erythematosus (SLE) is an intricate autoimmune disease with diverse manifestations. Immunometabolism reprogramming contributes to the progression of SLE by regulating the phenotype and function of immune cells. Dysregulated iron metabolism is implicated in SLE pathogenesis, affecting both systemic and immune cell-specific iron homeostasis. This review explores the systemic and cellular iron handling and regulation. Additionally, the advancements regarding iron metabolism in SLE with a focus on the distinct subsets of immune cells are highlighted. By gaining insight into the interplay between iron dysregulation and immune dysfunction, the potential therapeutic avenues may be unveiled. However, challenges remain in elucidating cell-specific iron metabolic reprogramming and its contribution to SLE pathogenesis needs further research for personalized therapeutic interventions and biomarker discovery. This review provides an in-depth understanding of immune cell-specific regulatory mechanisms of iron metabolism and new insights in current challenges as well as possible clinical applications.
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Affiliation(s)
- Zhouhang Xing
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
| | - Sheng Gao
- Laboratory Animal Center, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
| | - Anzhe Zheng
- School of the 2nd Clinical Medical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
| | - Chuyan Tong
- School of the 2nd Clinical Medical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
| | - Yuan Fang
- School of the 2nd Clinical Medical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
| | - Zheng Xiang
- School of the 2nd Clinical Medical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
| | - Siyan Chen
- School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
| | - Wenqian Wang
- Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China.
| | - Chunyan Hua
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China.
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Jia CL, Li BL, Zhao ZH, Zhang Z, Qi-Chen, Song JX, Gou Y, Gao SY, Sun CS, He Y, Ji ES, Zhao Y. Rosmarinic Acid Liposomes Downregulate Hepcidin Expression via BMP6-SMAD1/5/8 Pathway in Mice with Iron Overload. Appl Biochem Biotechnol 2024; 196:6028-6044. [PMID: 38175414 DOI: 10.1007/s12010-023-04828-9] [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] [Accepted: 12/19/2023] [Indexed: 01/05/2024]
Abstract
The objective of this study is to examine the potential protective effect of rosmarinic acid (RosA) encapsulated within nanoliposomes (RosA-LIP) on hepatic damage induced by iron overload. The characteristics, stability, and release of RosA-LIP in vitro were identified. The mice were randomly assigned to five groups: Control, Model, Model+DFO (DFO), Model+RosA (RosA), and Model+RosA-LIP (RosA-LIP). The iron overload model was induced by administering iron dextran (i.p.). The DFO, RosA, and RosA-LIP groups received iron dextran and were subsequently treated with DFO, RosA, and RosA-LIP for 14 days. We developed a novel formulation of RosA-LIP that exhibited stability and controlled release properties. Firstly, RosA-LIP improved liver function and ameliorated pathological changes in a mouse model of iron overload. Secondly, RosA-LIP demonstrated the ability to enhance the activities of T-SOD, GSH-Px, and CAT, while reducing the levels of MDA and 4-HNE, thereby effectively mitigating oxidative stress damage induced by iron overload. Thirdly, RosA-LIP reduced hepatic iron levels by downregulating FTL, FTH, and TfR1 levels. Additionally, RosA-LIP exerted a suppressive effect on hepcidin expression through the BMP6-SMAD1/5/8 signaling pathway. Furthermore, RosA-LIP upregulated FPN1 expression in both the liver and duodenum, thereby alleviating iron accumulation in these organs in mice with iron overload. Notably, RosA exhibited a comparable iron chelation effect, and RosA-LIP demonstrated superior efficacy in mitigating liver damage induced by excessive iron overload. RosA-LIP exhibited favorable sustained release properties, targeted delivery, and efficient protection against iron overload-induced liver damage.
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Affiliation(s)
- Cui-Ling Jia
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, 050200, China
| | - Bo-Liang Li
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, 050200, China
| | - Zi-Hao Zhao
- Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Pharmaceutical College, Hebei University of Chinese Medicine, Shijiazhuang City, 050200, Hebei Province, China
| | - Zhi Zhang
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, 050200, China
| | - Qi-Chen
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, 050200, China
| | - Ji-Xian Song
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, 050200, China
| | - Yujing Gou
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, 050200, China
| | - Si-Yu Gao
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, 050200, China
| | - Chen-Sha Sun
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, 050200, China
| | - Yingna He
- Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Pharmaceutical College, Hebei University of Chinese Medicine, Shijiazhuang City, 050200, Hebei Province, China.
- Hebei Higher Education Institute Applied Technology Research Center on TCM Formula Preparation, Shijiazhuang, 050200, Hebei, China.
| | - En-Sheng Ji
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, 050200, China.
| | - Yashuo Zhao
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Luquan Xingyuan Road 3, Shijiazhuang, 050200, China.
- The First Affiliated Hospital, Hebei University of Chinese Medicine, Shijiazhuang, 050013, China.
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11
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Kasahara E, Nakamura A, Morimoto K, Ito S, Hori M, Sekiyama A. Social defeat stress impairs systemic iron metabolism by activating the hepcidin-ferroportin axis. FASEB Bioadv 2024; 6:263-275. [PMID: 39114446 PMCID: PMC11301257 DOI: 10.1096/fba.2024-00071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 06/07/2024] [Accepted: 06/17/2024] [Indexed: 08/10/2024] Open
Abstract
Chronic psychological stress has been reported to decrease circulating iron concentrations and impair hematopoiesis. However, the underlying mechanisms remain unclear. This study aimed to investigate the effects of psychological stress on biological iron metabolism by using the social defeat stress (SDS) model, a widely used model of depression. Compared with control mice, mice subjected to SDS (SDS mice) had lower social interaction (SI) behavior. The SDS mice also showed impaired hematopoiesis, as evidenced by reduced circulating red blood cell counts, elevated reticulocyte counts, and decreased plasma iron levels. In the SDS mice, the iron contents in the bone marrow decreased, whereas those in the spleen increased, suggesting dysregulation in systemic iron metabolism. The concentrations of plasma hepcidin, an important regulator of systemic iron homeostasis, increased in the SDS mice. Meanwhile, the concentrations of ferroportin, an iron transport protein negatively regulated by hepcidin, were lower in the spleen and duodenum of the SDS mice than in those of the control mice. Treatment with dalteparin, a hepcidin inhibitor, prevented the decrease in plasma iron levels in the SDS mice. The gene expression and enzyme activity of furin, which converts the precursor hepcidin to active hepcidin, were high and positively correlated with plasma hepcidin concentration. Thus, furin activation might be responsible for the increased plasma hepcidin concentration. This study is the first to show that psychological stress disrupts systemic iron homeostasis by activating the hepcidin-ferroportin axis. Consideration of psychological stressors might be beneficial in the treatment of diseases with iron-refractory anemia.
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Affiliation(s)
- Emiko Kasahara
- Department of Preemptive Medical Pharmacology for Mind and Body, Graduate School and School of Pharmaceutical SciencesOsaka UniversitySuitaOsakaJapan
| | - Ayumi Nakamura
- Department of Preemptive Medical Pharmacology for Mind and Body, Graduate School and School of Pharmaceutical SciencesOsaka UniversitySuitaOsakaJapan
| | - Kenki Morimoto
- Department of Preemptive Medical Pharmacology for Mind and Body, Graduate School and School of Pharmaceutical SciencesOsaka UniversitySuitaOsakaJapan
| | - Shiho Ito
- Department of Preemptive Medical Pharmacology for Mind and Body, Graduate School and School of Pharmaceutical SciencesOsaka UniversitySuitaOsakaJapan
| | - Mika Hori
- Department of Preemptive Medical Pharmacology for Mind and Body, Graduate School and School of Pharmaceutical SciencesOsaka UniversitySuitaOsakaJapan
| | - Atsuo Sekiyama
- Department of Preemptive Medical Pharmacology for Mind and Body, Graduate School and School of Pharmaceutical SciencesOsaka UniversitySuitaOsakaJapan
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12
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Bozadjieva-Kramer N, Shin JH, Blok NB, Jain C, Das NK, Polex-Wolf J, Knudsen LB, Shah YM, Seeley RJ. Liraglutide Impacts Iron Homeostasis in a Murine Model of Hereditary Hemochromatosis. Endocrinology 2024; 165:bqae090. [PMID: 39045670 PMCID: PMC11311705 DOI: 10.1210/endocr/bqae090] [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: 04/25/2024] [Revised: 06/18/2024] [Accepted: 07/17/2024] [Indexed: 07/25/2024]
Abstract
Classic hereditary hemochromatosis (HH) is an autosomal recessive iron-overload disorder resulting from loss-of-function mutations of the HFE gene. Patients with HH exhibit excessive hepatic iron accumulation that predisposes these patients to liver disease, including the risk for developing liver cancer. Chronic iron overload also poses a risk for the development of metabolic disorders such as obesity, type 2 diabetes, and insulin resistance. We hypothesized that liraglutide, GLP1 receptor agonist, alters iron metabolism while also reducing body weight and glucose tolerance in a mouse model of HH (global HFE knockout, HFE KO) and diet-induced obesity and glucose intolerance. The total body HFE KO and wild-type control mice were fed high-fat diet for 8 weeks. Mice were subdivided into liraglutide and vehicle-treated groups and received daily subcutaneous administration of the respective treatment once daily for 18 weeks. Liraglutide improved glucose tolerance and hepatic lipid markers and reduced body weight in a mouse model of HH, the HFE KO mouse, similar to wild-type controls. Importantly, our data show that liraglutide alters iron metabolism in HFE KO mice, leading to decreased circulating and stored iron levels in HFE KO mice. These observations highlight the potential that GLP1 receptor agonist could be used to reduce iron overload in addition to reducing body weight and improving glucose regulation in HH patients.
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Affiliation(s)
- Nadejda Bozadjieva-Kramer
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
- Veterans Affairs Ann Arbor Healthcare System, Research Service, Ann Arbor, MI 48105, USA
| | - Jae Hoon Shin
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Neil B Blok
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Chesta Jain
- Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Nupur K Das
- Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA
| | | | | | - Yatrik M Shah
- Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Randy J Seeley
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
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13
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Fontes A, Jauch AT, Sailer J, Engler J, Azul AM, Zischka H. Metabolic Derangement of Essential Transition Metals and Potential Antioxidant Therapies. Int J Mol Sci 2024; 25:7880. [PMID: 39063122 PMCID: PMC11277342 DOI: 10.3390/ijms25147880] [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: 05/19/2024] [Revised: 07/08/2024] [Accepted: 07/13/2024] [Indexed: 07/28/2024] Open
Abstract
Essential transition metals have key roles in oxygen transport, neurotransmitter synthesis, nucleic acid repair, cellular structure maintenance and stability, oxidative phosphorylation, and metabolism. The balance between metal deficiency and excess is typically ensured by several extracellular and intracellular mechanisms involved in uptake, distribution, and excretion. However, provoked by either intrinsic or extrinsic factors, excess iron, zinc, copper, or manganese can lead to cellular damage upon chronic or acute exposure, frequently attributed to oxidative stress. Intracellularly, mitochondria are the organelles that require the tightest control concerning reactive oxygen species production, which inevitably leaves them to be one of the most vulnerable targets of metal toxicity. Current therapies to counteract metal overload are focused on chelators, which often cause secondary effects decreasing patients' quality of life. New therapeutic options based on synthetic or natural antioxidants have proven positive effects against metal intoxication. In this review, we briefly address the cellular metabolism of transition metals, consequences of their overload, and current therapies, followed by their potential role in inducing oxidative stress and remedies thereof.
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Affiliation(s)
- Adriana Fontes
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, D-85764 Neuherberg, Germany;
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
- CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
| | - Adrian T. Jauch
- School of Medicine and Health, Institute of Toxicology and Environmental Hygiene, Technical University Munich, D-80802 Munich, Germany
| | - Judith Sailer
- School of Medicine and Health, Institute of Toxicology and Environmental Hygiene, Technical University Munich, D-80802 Munich, Germany
| | - Jonas Engler
- School of Medicine and Health, Institute of Toxicology and Environmental Hygiene, Technical University Munich, D-80802 Munich, Germany
| | - Anabela Marisa Azul
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
- CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- IIIUC-Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
| | - Hans Zischka
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, D-85764 Neuherberg, Germany;
- School of Medicine and Health, Institute of Toxicology and Environmental Hygiene, Technical University Munich, D-80802 Munich, Germany
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14
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Tian H, Kong X, Han F, Xing F, Zhu S, Xu T, Wang W, Song N, Wu Y. Liver Iron Overload Drives COVID-19 Mortality: a Two-Sample Mendelian Randomization Study. Biol Trace Elem Res 2024; 202:2509-2517. [PMID: 37814169 DOI: 10.1007/s12011-023-03878-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 09/19/2023] [Indexed: 10/11/2023]
Abstract
Iron overload has been associated with an increased risk of COVID-19 severity and mortality in observational studies, but it remains unclear whether these associations represent causal effects. We performed a two-sample Mendelian randomization (MR) to determine associations between genetic liability to iron overload and the risk of COVID-19 severity and mortality. From genome-wide association studies of European ancestry, single-nucleotide polymorphisms associated with liver iron (n = 32,858) and ferritin (n = 23,986) were selected as exposure instruments, and summary statistics of the hospitalization (n = 16,551) and mortality (n = 15,815) of COVID-19 were utilized as the outcome. We used the inverse-variance weighted (IVW) method as the primary analysis to estimate causal effects, and other alternative approaches as well as comprehensive sensitivity analysis were conducted for estimating the robustness of identified associations. Genetically predicted high liver iron levels were associated with an increased risk of COVID-19 mortality based on the results of IVW analysis (OR = 1.38, 95% CI: 1.05-1.82, P = 0.02). Likewise, sensitivity analyses showed consistent and robust results in general (all P > 0.05). A higher risk of COVID-19 hospitalization trend was also observed in patients with high liver iron levels without statistical significance. This study suggests that COVID-19 mortality might be partially driven by the iron accumulation in the liver, supporting the classification of iron overload as one of the independent death risk factors. Therefore, avoiding iron overload and maintaining normal iron levels may be a powerful measure to reduce COVID-19 mortality.
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Affiliation(s)
- Huimin Tian
- Zhonglou District Center for Disease Control and Prevention, Changzhou, Jiangsu, China.
| | - Xiangjie Kong
- Department of Epidemiology and Health Statistics, Public Health College, Qingdao University, Qingdao, Shandong, China
| | - Fulei Han
- Department of Epidemiology and Health Statistics, Public Health College, Qingdao University, Qingdao, Shandong, China
| | - Fangjie Xing
- Department of Epidemiology and Health Statistics, Public Health College, Qingdao University, Qingdao, Shandong, China
| | - Shuai Zhu
- Department of Epidemiology and Health Statistics, Public Health College, Qingdao University, Qingdao, Shandong, China
| | - Tao Xu
- Department of Pulmonary and Critical Care Medicine, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Weijing Wang
- Department of Epidemiology and Health Statistics, Public Health College, Qingdao University, Qingdao, Shandong, China
| | - Ning Song
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorder, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Yili Wu
- Department of Epidemiology and Health Statistics, Public Health College, Qingdao University, Qingdao, Shandong, China
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15
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Alanazi ST, Salama SA, El-Ebiary AM, Altowairqi AK, Alharthi AT, Alzahrani SM, Althagafi SH, Alotaibi RA, Tammam AAE. Targeting SIRT1, NLRP3 inflammasome, and Nrf2 signaling with chrysin alleviates the iron-triggered hepatotoxicity in rats. Toxicology 2024; 504:153766. [PMID: 38432408 DOI: 10.1016/j.tox.2024.153766] [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: 12/15/2023] [Revised: 02/24/2024] [Accepted: 02/29/2024] [Indexed: 03/05/2024]
Abstract
Blood transfusion-requiring diseases such as sickle cell anemia and thalassemia are characterized by an imbalance between iron intake and excretion, resulting in an iron overload (IOL) disorder. Hepatotoxicity is prevalent under the IOL disorder because of the associated hepatocellular redox and inflammatory perturbation. The current work was devoted to investigate the potential protection against the IOL-associated hepatotoxicity using chrysin, a naturally-occurring flavone. IOL model was created in male Wistar rats by intraperitoneal injection of 100 mg/kg elemental iron subdivided on five equal injections; one injection was applied every other day over ten days. Chrysin was administered in a daily dose of 50 mg/kg over the ten-day iron treatment period. On day eleven, blood and liver samples were collected and subjected to histopathological, biochemical, and molecular investigations. Chrysin suppressed the IOL-induced hepatocellular damage as revealed by decreased serum activity of the intracellular liver enzymes and improved liver histological picture. Oxidative damage biomarkers, and pro-inflammatory cytokines were significantly suppressed. Mechanistically, the levels of the redox and inflammation-controlling proteins SIRT1 and PPARγ were efficiently up-regulated. The liver iron load, NLRP3 inflammasome activation, and NF-κB acetylation and nuclear shift were significantly suppressed in the iron-intoxicated rats. Equally important, the level of the antioxidant protein Nrf2 and its target HO-1 were up-regulated. In addition, chrysin significantly ameliorated the IOL-induced apoptosis as indicated by reduction in caspase-3 activity and modulation of BAX and Bcl2 protein abundance. Together, these findings highlight the alleviating activity of chrysin against the IOL-associated hepatotoxicity and shed light on the role of SIRT1, NLRP3 inflammasome, and Nrf2 signaling as potential contributing molecular mechanisms.
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Affiliation(s)
- Samyah T Alanazi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 11433, Saudi Arabia
| | - Samir A Salama
- Division of Biochemistry, Department of Pharmacology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
| | - Ahmed Magdy El-Ebiary
- Medical Physiology Department, Faculty of Medicine, Fayoum University, Fayoum 63511, Egypt
| | | | - Atheer T Alharthi
- College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Shahad M Alzahrani
- College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Shomokh H Althagafi
- College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Reema A Alotaibi
- College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Ahmed Abd-Eltawab Tammam
- Medical Physiology Department, Faculty of Medicine, Beni-Suef University, Beni-Suef 62514, Egypt
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16
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Chen Y, Zhao W, Hu A, Lin S, Chen P, Yang B, Fan Z, Qi J, Zhang W, Gao H, Yu X, Chen H, Chen L, Wang H. Type 2 diabetic mellitus related osteoporosis: focusing on ferroptosis. J Transl Med 2024; 22:409. [PMID: 38693581 PMCID: PMC11064363 DOI: 10.1186/s12967-024-05191-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 04/12/2024] [Indexed: 05/03/2024] Open
Abstract
With the aging global population, type 2 diabetes mellitus (T2DM) and osteoporosis(OP) are becoming increasingly prevalent. Diabetic osteoporosis (DOP) is a metabolic bone disorder characterized by abnormal bone tissue structure and reduced bone strength in patients with diabetes. Studies have revealed a close association among diabetes, increased fracture risk, and disturbances in iron metabolism. This review explores the concept of ferroptosis, a non-apoptotic cell death process dependent on intracellular iron, focusing on its role in DOP. Iron-dependent lipid peroxidation, particularly impacting pancreatic β-cells, osteoblasts (OBs) and osteoclasts (OCs), contributes to DOP. The intricate interplay between iron dysregulation, which comprises deficiency and overload, and DOP has been discussed, emphasizing how excessive iron accumulation triggers ferroptosis in DOP. This concise overview highlights the need to understand the complex relationship between T2DM and OP, particularly ferroptosis. This review aimed to elucidate the pathogenesis of ferroptosis in DOP and provide a prospective for future research targeting interventions in the field of ferroptosis.
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Affiliation(s)
- Yili Chen
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Wen Zhao
- Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006, China
| | - An Hu
- Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006, China
| | - Shi Lin
- Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006, China
| | - Ping Chen
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Bing Yang
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Zhirong Fan
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Ji Qi
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Wenhui Zhang
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Huanhuan Gao
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Xiubing Yu
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Haiyun Chen
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Luyuan Chen
- Stomatology Center, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, 510086, China.
| | - Haizhou Wang
- Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
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17
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Zhang T, Luo L, He Q, Xiao S, Li Y, Chen J, Qin T, Xiao Z, Ge Q. Research advances on molecular mechanism and natural product therapy of iron metabolism in heart failure. Eur J Med Res 2024; 29:253. [PMID: 38659000 PMCID: PMC11044586 DOI: 10.1186/s40001-024-01809-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 03/22/2024] [Indexed: 04/26/2024] Open
Abstract
The progression of heart failure (HF) is complex and involves multiple regulatory pathways. Iron ions play a crucial supportive role as a cofactor for important proteins such as hemoglobin, myoglobin, oxidative respiratory chain, and DNA synthetase, in the myocardial energy metabolism process. In recent years, numerous studies have shown that HF is associated with iron dysmetabolism, and deficiencies in iron and overload of iron can both lead to the development of various myocarditis diseases, which ultimately progress to HF. Iron toxicity and iron metabolism may be key targets for the diagnosis, treatment, and prevention of HF. Some iron chelators (such as desferrioxamine), antioxidants (such as ascorbate), Fer-1, and molecules that regulate iron levels (such as lactoferrin) have been shown to be effective in treating HF and protecting the myocardium in multiple studies. Additionally, certain natural compounds can play a significant role by mediating the imbalance of iron-related signaling pathways and expression levels. Therefore, this review not only summarizes the basic processes of iron metabolism in the body and the mechanisms by which they play a role in HF, with the aim of providing new clues and considerations for the treatment of HF, but also summarizes recent studies on natural chemical components that involve ferroptosis and its role in HF pathology, as well as the mechanisms by which naturally occurring products regulate ferroptosis in HF, with the aim of providing reference information for the development of new ferroptosis inhibitors and lead compounds for the treatment of HF in the future.
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Affiliation(s)
- Tianqing Zhang
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Li Luo
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Qi He
- People's Hospital of Ningxiang City, Ningxiang City, China
| | - Sijie Xiao
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Yuwei Li
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Junpeng Chen
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Tao Qin
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Zhenni Xiao
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Qingliang Ge
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China.
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18
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Bian Y, Qu X, Zhang F, Zhang Z, Kang J. The Monitoring and Cell Imaging of Fe 3+ Using a Chromone-Based Fluorescence Probe. Molecules 2024; 29:1504. [PMID: 38611784 PMCID: PMC11013790 DOI: 10.3390/molecules29071504] [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: 01/25/2024] [Revised: 03/23/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
A new structurally simple fluorescent CP probe based on chromone was designed and synthesized, and its structure was fully characterized using various analytical techniques. The CP probe displays a high selectivity and sensitivity for sensing Fe3+ with a "turn-off" fluorescence response over other metal ions in a DMSO/H2O (4:1, v/v) solution. The experiment results show that the CP probe is stable over a wide pH range of 2.0-12.0. The detection limit for Fe3+ was calculated to be 0.044 μmol•L-1. The molar ratio method indicated that the binding mode between the CP probe and Fe3+ is a 1:1 complex formation. HR-MS and density functional theory (DFT) calculations were also performed to further confirm the recognition mechanism. Both fluorescence imaging experiments and the MTT assay demonstrated that the CP probe was suitable for detecting intracellular Fe3+ and no significant cytotoxicity in living cells.
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Affiliation(s)
- Yongjun Bian
- College of Chemistry and Chemical Engineering, Jinzhong University, Jinzhong 030619, China; (X.Q.); (Z.Z.); (J.K.)
| | - Xingyu Qu
- College of Chemistry and Chemical Engineering, Jinzhong University, Jinzhong 030619, China; (X.Q.); (Z.Z.); (J.K.)
| | - Fengying Zhang
- Department of Materials Science and Engineering, Jinzhong University, Jinzhong 030619, China
| | - Zhengwei Zhang
- College of Chemistry and Chemical Engineering, Jinzhong University, Jinzhong 030619, China; (X.Q.); (Z.Z.); (J.K.)
| | - Jin Kang
- College of Chemistry and Chemical Engineering, Jinzhong University, Jinzhong 030619, China; (X.Q.); (Z.Z.); (J.K.)
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Chen Y, Tan X, Zhang W, Li Y, Deng X, Zeng J, Huang L, Ma X. Natural products targeting macroautophagy signaling in hepatocellular carcinoma therapy: Recent evidence and perspectives. Phytother Res 2024; 38:1623-1650. [PMID: 38302697 DOI: 10.1002/ptr.8103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 12/07/2023] [Accepted: 12/16/2023] [Indexed: 02/03/2024]
Abstract
Hepatocellular carcinoma (HCC), presently the second leading cause of global cancer-related mortality, continues to pose significant challenges in the realm of medical oncology, impacting both clinical drug selection and mechanistic research. Recent investigations have unveiled autophagy-related signaling as a promising avenue for HCC treatment. A growing body of research has highlighted the pivotal role of autophagy-modulating natural products in inhibiting HCC progression. In this context, we provide a concise overview of the fundamental autophagy mechanism and delineate the involvement of autophagic signaling pathways in HCC development. Additionally, we review pertinent studies demonstrating how natural products regulate autophagy to mitigate HCC. Our findings indicate that natural products exhibit cytotoxic effects through the induction of excessive autophagy, simultaneously impeding HCC cell proliferation by autophagy inhibition, thereby depriving HCC cells of essential energy. These effects have been associated with various signaling pathways, including PI3K/AKT, MAPK, AMPK, Wnt/β-catenin, Beclin-1, and ferroautophagy. These results underscore the considerable therapeutic potential of natural products in HCC treatment. However, it is important to note that the present study did not establish definitive thresholds for autophagy induction or inhibition by natural products. Further research in this domain is imperative to gain comprehensive insights into the dual role of autophagy, equipping us with a better understanding of this double-edged sword in HCC management.
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Affiliation(s)
- Yuan Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiyue Tan
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wenwen Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yubing Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xinyu Deng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jinhao Zeng
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lihua Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Wang J, Lv S, Zuo J, Liang S, Yang J, Liu L, Wei D. Preparation and performance study of rhodamine B naphthylamide, a fluorescent probe, for the detection of Fe 3. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2023. [PMID: 38050678 DOI: 10.1039/d3ay01809a] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/06/2023]
Abstract
Fe3+ is essential for humans, and its deficiency or excess can be harmful to human health; thus, it is crucial to detect Fe3+. Herein, a novel 1,8-naphthylimide rhodamine-based fluorescent probe (NA-RhBEA) was prepared from rhodamine B, anhydrous ethylenediamine, and 1,8-naphthoic anhydride. This fluorescent probe complexes Fe3+ with N and O on the carboxyl groups of its spironolactam structure and part of the 1,8-naphthalenedicarboxylic anhydride structure, which results in spironolactam ring-opening and fluorescence. NA-RhBEA has high selectivity for Fe3+ in ethanol/buffer solution (4 : 1, v/v), and fluorescence is detected at an excitation wavelength λEX = 500 nm, an absorption peak appears at 585 nm, and a significant color change appears. The effect of the fluorescence intensity of Fe3+ under a series of different concentration conditions was investigated, and it was concluded that the fluorescence intensity increased with increasing Fe3+ concentration in the range of 0-500 μmol, and its detection limit was 0.84 μmol L-1. In addition, we explored the detection ability of NA-RhBEA in solutions with different pH values, mixed metal ions, and different solvents, and the results showed that the fluorescent sensor also has good anti-interference properties and some practical applicability.
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Affiliation(s)
- Jialin Wang
- College of Bioresources Chemical and Materials Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China.
| | - Shenghua Lv
- College of Bioresources Chemical and Materials Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China.
| | - Jingjing Zuo
- College of Bioresources Chemical and Materials Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China.
| | - Shan Liang
- College of Bioresources Chemical and Materials Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China.
| | - Juhui Yang
- College of Bioresources Chemical and Materials Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China.
| | - Leipeng Liu
- College of Bioresources Chemical and Materials Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China.
| | - Dequan Wei
- College of Bioresources Chemical and Materials Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China.
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Yang W, Li J, Hu J, Yuan X, Ding J, Jiang H, Wang G, Luo Q. Hypobaric hypoxia induces iron mobilization from liver and spleen and increases serum iron via activation of ghrelin/GHSR1a/MAPK signalling pathway in mice. Sci Rep 2023; 13:20254. [PMID: 37985861 PMCID: PMC10662372 DOI: 10.1038/s41598-023-47596-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 11/15/2023] [Indexed: 11/22/2023] Open
Abstract
Hypobaric hypoxia (HH) exposure affects appetite and serum iron levels in both humans and animals. Thus, whether appetite-regulating ghrelin is involved in iron regulation under HH needs to be elucidated. In vivo, C57BL/6J mice were placed in a hypobaric chamber to establish a 6000-m-high altitude exposure animal model. In vitro, mouse primary hepatocytes and peritoneal macrophages were exposed to hypoxia (1% O2) to examine the effects of ghrelin on iron-regulating proteins. HH obviously reduced the body weight of mice and significantly increased the levels of erythrocytes, and also significantly enhanced the levels of serum iron and plasma ghrelin. However, iron content in the liver and spleen was decreased, while ferroportin (Fpn) expression was increased. Moreover, ghrelin significantly induced Fpn and pERK expression in both hepatocytes and macrophages under hypoxia, which were reversed by pretreatment with growth hormone secretagogue receptor 1a (GHSR1a) antagonist or pERK inhibitor. Our findings indicated that HH leads to decreased appetite and insufficient dietary intake, which may negatively regulate the levels of ghrelin. Furthermore, GHSR1a/ERK signalling pathway is further activated to upregulate the expression of Fpn, and then promoting iron mobilization both in the liver/hepatocytes and spleen/macrophages in mice. Thus, these results revealed that ghrelin may be a potential iron regulatory hormone, and raised the possibility of ghrelin as a promising therapeutic target against iron disorders under HH.
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Affiliation(s)
- Wanping Yang
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine, Nantong University, 9 Seyuan Road, Chongchuan District, Nantong, 226019, Jiangsu, China
| | - Jiayan Li
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine, Nantong University, 9 Seyuan Road, Chongchuan District, Nantong, 226019, Jiangsu, China
| | - Jianan Hu
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine, Nantong University, 9 Seyuan Road, Chongchuan District, Nantong, 226019, Jiangsu, China
| | - Xiaoyu Yuan
- Department of Emergency, Affiliated Hospital of Nantong University, 20 XiSi Road, Nantong, 226001, China
| | - Jie Ding
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine, Nantong University, 9 Seyuan Road, Chongchuan District, Nantong, 226019, Jiangsu, China
| | - Hui Jiang
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine, Nantong University, 9 Seyuan Road, Chongchuan District, Nantong, 226019, Jiangsu, China
| | - Guohua Wang
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine, Nantong University, 9 Seyuan Road, Chongchuan District, Nantong, 226019, Jiangsu, China.
| | - Qianqian Luo
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine, Nantong University, 9 Seyuan Road, Chongchuan District, Nantong, 226019, Jiangsu, China.
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22
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Salau VF, Erukainure OL, Olofinsan KA, Schoeman RLS, Matsabisa MG. Lippia javanica (Burm. F.) Herbal Tea: Modulation of Hepatoprotective Effects in Chang Liver Cells via Mitigation of Redox Imbalance and Modulation of Perturbed Metabolic Activities. Front Pharmacol 2023; 14:1221769. [PMID: 37608895 PMCID: PMC10441784 DOI: 10.3389/fphar.2023.1221769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 07/27/2023] [Indexed: 08/24/2023] Open
Abstract
Introduction: Hepatic oxidative injury is one of the pathological mechanisms that significantly contributes to the development of several liver diseases. In the present study, the hepatoprotective effect of Lippia javanica herbal tea was investigated in Fe2+- mediated hepatic oxidative injury. Methods: Using an in vitro experimental approach, hepatic oxidative injury was induced by co-incubating 7 mM FeSO4 with Chang liver cells that have been pre-incubated with or without different concentrations (15-240 μg/mL) of L. javanica infusion. Gallic acid and ascorbic acid served as the standard antioxidants. Results: The infusion displayed a reducing antioxidant activity in ferric-reducing antioxidant power (FRAP) assay and a potent scavenging activity on 2,2-diphenyl-2- picrylhydrazyl (DPPH) radical. Pretreatment with L. javanica infusion significantly elevated the levels of reduced glutathione and non-protein thiol, and the activities of superoxide dismutase (SOD) and catalase, with concomitant decrease in hepatic malondialdehyde levels, acetylcholinesterase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glycogen phosphorylase and lipase activities. The infusion showed the presence of phytoconstituents such as phenolic compounds, tannins, phenolic glycosides and terpenoids when subjected to liquid chromatography-mass spectrometry analysis. Molecular docking revealed a strong binding affinity of dihydroroseoside and obacunone with both SOD and catalase compared to other phytoconstituents. Conclusion: These results portray a potent antioxidant and hepatoprotective effect of L. javanica, which may support the local usage of the herbal tea as a prospective therapeutic agent for oxidative stress-related liver diseases.
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Affiliation(s)
- Veronica F. Salau
- Department of Pharmacology, University of the Free State, Bloemfontein, South Africa
| | | | - Kolawole A. Olofinsan
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, Doornfontein, South Africa
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23
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Pasquadibisceglie A, Bonaccorsi di Patti MC, Musci G, Polticelli F. Membrane Transporters Involved in Iron Trafficking: Physiological and Pathological Aspects. Biomolecules 2023; 13:1172. [PMID: 37627237 PMCID: PMC10452680 DOI: 10.3390/biom13081172] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/25/2023] [Accepted: 07/26/2023] [Indexed: 08/27/2023] Open
Abstract
Iron is an essential transition metal for its involvement in several crucial biological functions, the most notable being oxygen storage and transport. Due to its high reactivity and potential toxicity, intracellular and extracellular iron levels must be tightly regulated. This is achieved through transport systems that mediate cellular uptake and efflux both at the level of the plasma membrane and on the membranes of lysosomes, endosomes and mitochondria. Among these transport systems, the key players are ferroportin, the only known transporter mediating iron efflux from cells; DMT1, ZIP8 and ZIP14, which on the contrary, mediate iron influx into the cytoplasm, acting on the plasma membrane and on the membranes of lysosomes and endosomes; and mitoferrin, involved in iron transport into the mitochondria for heme synthesis and Fe-S cluster assembly. The focus of this review is to provide an updated view of the physiological role of these membrane proteins and of the pathologies that arise from defects of these transport systems.
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Affiliation(s)
| | | | - Giovanni Musci
- Department of Biosciences and Territory, University of Molise, 86090 Pesche, Italy;
| | - Fabio Polticelli
- Department of Sciences, University Roma Tre, 00146 Rome, Italy;
- National Institute of Nuclear Physics, Roma Tre Section, 00146 Rome, Italy
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24
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Yehia A, Sousa RAL, Abulseoud OA. Sex difference in the association between blood alcohol concentration and serum ferritin. Front Psychiatry 2023; 14:1230406. [PMID: 37547205 PMCID: PMC10401063 DOI: 10.3389/fpsyt.2023.1230406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 07/07/2023] [Indexed: 08/08/2023] Open
Abstract
Introduction The sex difference in alcohol use disorder (AUD) is ingrained in distinctive neurobiological responses between men and women, which necessitates further investigation for a more tailored management. Methods Minding the findings of iron dysregulation in AUD and the sex difference in iron homeostasis in multiple physiological and pathological settings, we examined the sex difference in the association between serum ferritin and blood alcohol concentration (BAC) in intoxicated males (n = 125) and females (n = 59). We included patients with both serum ferritin tested of any value and a BAC above the level of detection during the same hospital admission period. We investigated sex difference in the relationship between BAC, serum ferritin and liver enzymes in intoxicated critically ill and noncritically ill patients. Results We found a negative association between serum ferritin and BAC in critically ill, intoxicated females [R2 = 0.44, F(1,14) = 11.02, p = 0.005], with much attenuated serum ferritin in females compared to their male counterparts (194.5 ± 280.4 vs. 806.3 ± 3405.7 ng/L, p = 0.002). We found a positive association between serum ferritin and liver enzymes [alanine transaminase (ALT) and aspartate transferase (AST)] in critically ill intoxicated females [ALT: R2 = 0.48, F(1,10) = 9.1, p = 0.013; AST: R2 = 0.68, F(1,10) = 21.2, p = 0.001] and in noncritically ill intoxicated males [ALT: R2 = 0.1, F(1,83) = 9.4, p = 0.003; AST: R2 = 0.1, F(1,78) = 10.5, p = 0.002]. The effect of BAC on serum ferritin was not mediated by ALT [indirect effect: (B = 0.13, p = 0.1)]. We also found a significant effect of sex, anemia, intensive care unit (ICU) admission and mortality on serum ferritin. Discussion Our results suggest that high BAC in intoxicated female patients is associated with attenuated serum ferritin levels, questioning the role of low serum ferritin in female vulnerability to alcohol.
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Affiliation(s)
- Asmaa Yehia
- Department of Neuroscience, Graduate School of Biomedical Sciences, Mayo Clinic College of Medicine, Phoenix, AZ, United States
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ricardo A L Sousa
- Department of Psychiatry and Psychology, Mayo Clinic Arizona, Phoenix, AZ, United States
| | - Osama A Abulseoud
- Department of Neuroscience, Graduate School of Biomedical Sciences, Mayo Clinic College of Medicine, Phoenix, AZ, United States
- Department of Psychiatry and Psychology, Mayo Clinic Arizona, Phoenix, AZ, United States
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25
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Kirchner R, Kirchnerová S, Tirpák F, Halo M, Slanina T, Tokárová K, Kováčik A, Miškeje M, Komárňanská V, Greń A, Formicki G, Massányi P. Biogenic Elements and Heavy Metals in Hermann's Tortoises- Testudo hermanni: Effect on Serum Biochemistry and Oxidative Status Parameters. Animals (Basel) 2023; 13:2218. [PMID: 37444016 DOI: 10.3390/ani13132218] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/30/2023] [Accepted: 07/04/2023] [Indexed: 07/15/2023] Open
Abstract
BACKGROUND Conservation of species diversity is the need of the hour for preserving life forms on Earth. Extinction of any part of the ecosystem has negative impacts on many processes and systems. The objective of this work was to analyze some biochemical and molecular indicators and their correlations to biogenic elements and heavy metals in Testudo hermanni (n = 16). METHODS Biochemical parameters were analyzed using the commercial kit DiaSys and biochemical analyzer Randox RX Monza. Sodium, potassium, and chlorides were measured using the EasyLite analyzer. Oxidative stress was evaluated using colorimetric and luminometric methods. Quantification of chemical elements in the blood was carried out using inductively coupled plasma mass spectrometry (ICPS). RESULTS Biochemical values of analyzed samples from Hermann's tortoises were almost the same as referential values described by multiple authors, with minor aberrations in the total protein parameter. Values of arsenic (As) and nickel (Ni) showed correlation with biochemical parameters and the parameters of oxidative stress. Cadmium (Cd) exhibited correlation with aspartate aminotransferase (AST). CONCLUSIONS This study reports correlations among four heavy metals, and their levels were again correlated with biochemical and molecular parameters in Hermann's tortoises.
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Affiliation(s)
- Róbert Kirchner
- Institute of Applied Biology, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovakia
- Institute of Animal Husbandry, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovakia
| | - Soňa Kirchnerová
- Institute of Applied Biology, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovakia
- Institute of Animal Husbandry, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovakia
| | - Filip Tirpák
- AgroBioTech Research Centre, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovakia
| | - Marko Halo
- Institute of Applied Biology, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovakia
| | - Tomáš Slanina
- Institute of Applied Biology, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovakia
| | - Katarína Tokárová
- Institute of Applied Biology, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovakia
| | - Anton Kováčik
- Institute of Applied Biology, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovakia
| | - Michal Miškeje
- AgroBioTech Research Centre, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovakia
| | - Veronika Komárňanská
- Institute of Animal Husbandry, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovakia
| | - Agnieszka Greń
- Institute of Biology, Pedagogical University of Krakow, Podchorazych 2, 30-084 Krakow, Poland
| | - Grzegorz Formicki
- Institute of Biology, Pedagogical University of Krakow, Podchorazych 2, 30-084 Krakow, Poland
| | - Peter Massányi
- Institute of Applied Biology, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovakia
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26
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Moura Cunha G, Kolokythas O, Chen W, Akcicek H, Hitt D, Briller NE, Amin K. Intra-examination agreement between multi-echo gradient echo and confounder-corrected chemical shift-encoded MR sequences for R2* estimation as a biomarker of liver iron content in patients with a wide range of T2*/R2* and proton density fat fraction values. Abdom Radiol (NY) 2023; 48:2302-2310. [PMID: 37055586 DOI: 10.1007/s00261-023-03902-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 03/26/2023] [Accepted: 03/28/2023] [Indexed: 04/15/2023]
Abstract
PURPOSE To investigate the intra-examination agreement between multi-echo gradient echo (MEGE) and confounder-corrected chemical shift-encoded (CSE) sequences for liver T2*/R2* estimations in a wide range of T2*/R2* and proton density fat fraction (PDFF) values. Exploratorily, to search for the T2*/R2* value where the agreement line breaks and examine differences between regions of low and high agreement. METHODS Consecutive patients at risk for liver iron overload who underwent MEGE and CSE sequences within the same exam at 1.5 T were retrospectively selected. Regions of interest were drawn in the right and one in the left liver lobes on post-processed images for R2*(sec-1) and PDFF (%) estimation. Agreement between MEGE-R2* and CSE-R2* was evaluated using intra-class correlation coefficient (ICC) and Bland-Altman analysis. 95% confidence intervals (CI) were computed. Segment-and-regression analysis was performed to find the point where the agreement between sequences is interrupted. Regions of low and high agreement were examined using tree-based partitioning analyses. RESULTS 49 patients were included. Mean MEGE-R2* was 94.2 s-1 (range: 31.0-737.1) and mean CSE-R2* 87.7 (29.7-748.1). Mean CSE-PDFF was 9.12% (0.1-43.3). Agreement was strong for R2* estimations (ICC: 0.992,95%CI 0.987,0.996), but the relation was nonlinear and possibly heteroskedastic. Lower agreement occurred when MEGE-R2* > 235 s-1, with MEGE-R2* values consistently lower than CSE-R2*. Higher agreement was observed when PDFF < 14%. CONCLUSION MEGE-R2* and CSE-R2* strongly agree, though at higher iron content, MEGE-R2* is consistently lower than CSE-R2*. In this preliminary dataset, a breaking point for agreement was found at R2* > 235. Lower agreement was observed in patients with moderate to severe liver steatosis.
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Affiliation(s)
- Guilherme Moura Cunha
- Department of Radiology, University of Washington, 1705 NE Pacific St., Box 357233, Seattle, WA, 98195, USA.
| | - Orpheus Kolokythas
- Department of Radiology, University of Washington, 1705 NE Pacific St., Box 357233, Seattle, WA, 98195, USA
| | - Wenyu Chen
- Department of Statistics, University of Washington, Seattle, WA, USA
| | - Halit Akcicek
- Department of Radiology, University of Washington, 1705 NE Pacific St., Box 357233, Seattle, WA, 98195, USA
| | - Dave Hitt
- Philips Healthcare North America, Cleveland, OH, USA
| | - Noah E Briller
- Department of Radiology, University of Washington, 1705 NE Pacific St., Box 357233, Seattle, WA, 98195, USA
| | - Kathan Amin
- Department of Radiology, University of Washington, 1705 NE Pacific St., Box 357233, Seattle, WA, 98195, USA
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Cardona CJ, Montgomery MR. Iron regulatory proteins: players or pawns in ferroptosis and cancer? Front Mol Biosci 2023; 10:1229710. [PMID: 37457833 PMCID: PMC10340119 DOI: 10.3389/fmolb.2023.1229710] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 06/21/2023] [Indexed: 07/18/2023] Open
Abstract
Cells require iron for essential functions like energy production and signaling. However, iron can also engage in free radical formation and promote cell proliferation thereby contributing to both tumor initiation and growth. Thus, the amount of iron within the body and in individual cells is tightly regulated. At the cellular level, iron homeostasis is maintained post-transcriptionally by iron regulatory proteins (IRPs). Ferroptosis is an iron-dependent form of programmed cell death with vast chemotherapeutic potential, yet while IRP-dependent targets have established roles in ferroptosis, our understanding of the contributions of IRPs themselves is still in its infancy. In this review, we present the growing circumstantial evidence suggesting that IRPs play critical roles in the adaptive response to ferroptosis and ferroptotic cell death and describe how this knowledge can be leveraged to target neoplastic iron dysregulation more effectively.
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28
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Dimov AV, Li J, Nguyen TD, Roberts AG, Spincemaille P, Straub S, Zun Z, Prince MR, Wang Y. QSM Throughout the Body. J Magn Reson Imaging 2023; 57:1621-1640. [PMID: 36748806 PMCID: PMC10192074 DOI: 10.1002/jmri.28624] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/19/2023] [Accepted: 01/20/2023] [Indexed: 02/08/2023] Open
Abstract
Magnetic materials in tissue, such as iron, calcium, or collagen, can be studied using quantitative susceptibility mapping (QSM). To date, QSM has been overwhelmingly applied in the brain, but is increasingly utilized outside the brain. QSM relies on the effect of tissue magnetic susceptibility sources on the MR signal phase obtained with gradient echo sequence. However, in the body, the chemical shift of fat present within the region of interest contributes to the MR signal phase as well. Therefore, correcting for the chemical shift effect by means of water-fat separation is essential for body QSM. By employing techniques to compensate for cardiac and respiratory motion artifacts, body QSM has been applied to study liver iron and fibrosis, heart chamber blood and placenta oxygenation, myocardial hemorrhage, atherosclerotic plaque, cartilage, bone, prostate, breast calcification, and kidney stone.
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Affiliation(s)
- Alexey V. Dimov
- Department of Radiology, Weill Cornell Medicine, New York, NY, United States
| | - Jiahao Li
- Department of Radiology, Weill Cornell Medicine, New York, NY, United States
| | - Thanh D. Nguyen
- Department of Radiology, Weill Cornell Medicine, New York, NY, United States
| | | | - Pascal Spincemaille
- Department of Radiology, Weill Cornell Medicine, New York, NY, United States
| | - Sina Straub
- Department of Radiology, Mayo Clinic, Jacksonville, FL, United States
| | - Zungho Zun
- Department of Radiology, Weill Cornell Medicine, New York, NY, United States
| | - Martin R. Prince
- Department of Radiology, Weill Cornell Medicine, New York, NY, United States
| | - Yi Wang
- Department of Radiology, Weill Cornell Medicine, New York, NY, United States
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29
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Jin X, Jiang C, Zou Z, Huang H, Li X, Xu S, Tan R. Ferritinophagy in the etiopathogenic mechanism of related diseases. J Nutr Biochem 2023; 117:109339. [PMID: 37061010 DOI: 10.1016/j.jnutbio.2023.109339] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 03/18/2023] [Accepted: 03/23/2023] [Indexed: 04/17/2023]
Abstract
Iron is an essential trace element that is involved in a variety of physiological processes. Ferritinophagy is selective autophagy mediated by nuclear receptor coactivator 4 (NCOA4), which regulates iron homeostasis in the body. Upon iron depletion or starvation, ferritinophagy is activated, releasing large amounts of Fe2+ and increasing reactive oxygen species (ROS), leading to ferroptosis. This plays a significant role in the etiopathogenesis of many diseases, such as metabolic diseases, neurodegenerative diseases, infectious diseases, tumors, cardiomyopathy, and ischemia-reperfusion ischemia-reperfusion injury. Here, we first review the regulation and functions of ferritinophagy and then describe its involvement in different diseases, with hopes of providing new understanding and insights into iron metabolism and iron disorder-related diseases and the therapeutic opportunity for targeting ferritinophagy.
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Affiliation(s)
- Xuemei Jin
- Department of Preventive Medicine, School of Medicine, Yanbian University, Yanji, China; Department of Clinical Nutrition, Guangzhou Institute of Disease-Oriented Nutritional Research, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Chunjie Jiang
- Department of Clinical Nutrition, Guangzhou Institute of Disease-Oriented Nutritional Research, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Zhizhou Zou
- Department of Preventive Medicine, School of Medicine, Yanbian University, Yanji, China; Department of Clinical Nutrition, Guangzhou Institute of Disease-Oriented Nutritional Research, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - He Huang
- Department of Preventive Medicine, School of Medicine, Yanbian University, Yanji, China; Department of Clinical Nutrition, Guangzhou Institute of Disease-Oriented Nutritional Research, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Xiaojian Li
- Department of Burn, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Songji Xu
- Department of Preventive Medicine, School of Medicine, Yanbian University, Yanji, China
| | - Rongshao Tan
- Department of Clinical Nutrition, Guangzhou Institute of Disease-Oriented Nutritional Research, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China.
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Iron metabolism and ferroptosis in type 2 diabetes mellitus and complications: mechanisms and therapeutic opportunities. Cell Death Dis 2023; 14:186. [PMID: 36882414 PMCID: PMC9992652 DOI: 10.1038/s41419-023-05708-0] [Citation(s) in RCA: 70] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 02/18/2023] [Accepted: 02/22/2023] [Indexed: 03/09/2023]
Abstract
The maintenance of iron homeostasis is essential for proper endocrine function. A growing body of evidence suggests that iron imbalance is a key factor in the development of several endocrine diseases. Nowadays, ferroptosis, an iron-dependent form of regulated cell death, has become increasingly recognized as an important process to mediate the pathogenesis and progression of type 2 diabetes mellitus (T2DM). It has been shown that ferroptosis in pancreas β cells leads to decreased insulin secretion; and ferroptosis in the liver, fat, and muscle induces insulin resistance. Understanding the mechanisms concerning the regulation of iron metabolism and ferroptosis in T2DM may lead to improved disease management. In this review, we summarized the connection between the metabolic pathways and molecular mechanisms of iron metabolism and ferroptosis in T2DM. Additionally, we discuss the potential targets and pathways concerning ferroptosis in treating T2DM and analysis the current limitations and future directions concerning these novel T2DM treatment targets.
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The anti-toxic effect of the date palm fruit extract loaded on chitosan nanoparticles against CCl 4-induced liver fibrosis in a mouse model. Int J Biol Macromol 2023; 235:123804. [PMID: 36842736 DOI: 10.1016/j.ijbiomac.2023.123804] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 02/12/2023] [Accepted: 02/18/2023] [Indexed: 02/28/2023]
Abstract
The liver is the most important organ in the body. Hepatocyte oxidative damage occurs to excess ROS. Liver fibrosis is a mechanism that the immune system uses to treat extreme inflammation by repairing damaged tissue with the creation of a scar. The outcome of fibrosis may be reversed by consuming natural plant extracts with high ROS-scavenging ability. The date palm fruits contain caffeic acid, gallic acid, syringic acid, and ferulic acid, which have anti-inflammatory, antioxidant, and hepatoprotective properties. This study aimed to prepare a date fruit extract, load it onto chitosan nanoparticles, and compare its anti-fibrotic activity with the unloaded crude extract in the CCl4-mouse model. Our findings show that nanocomposite (Cs@FA/DEx) has anti-fibrotic properties and can improve liver function enzymes and endogenous antioxidant enzymes by inhibiting cell apoptosis caused by CCl4-induction in mice. Furthermore, significantly reduced CD95 and ICAM1 levels and down-regulation of TGFβ-1 and collagen-α-1 expression demonstrated the anti-fibrotic effects of the Cs@FA/DEx. Therefore, the Cs@FA/DEx might be an innovative supplement for inhibiting liver fibrosis and hepatocyte inflammation induced by chemical toxins. Besides, this nano-supplement could be a promising anti-hepatocellular carcinoma agent as it has potent in vitro anticancer activity against the HePG2 cell line.
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Duan G, Li J, Duan Y, Zheng C, Guo Q, Li F, Zheng J, Yu J, Zhang P, Wan M, Long C. Mitochondrial Iron Metabolism: The Crucial Actors in Diseases. Molecules 2022; 28:29. [PMID: 36615225 PMCID: PMC9822237 DOI: 10.3390/molecules28010029] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/12/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022] Open
Abstract
Iron is a trace element necessary for cell growth, development, and cellular homeostasis, but insufficient or excessive level of iron is toxic. Intracellularly, sufficient amounts of iron are required for mitochondria (the center of iron utilization) to maintain their normal physiologic function. Iron deficiency impairs mitochondrial metabolism and respiratory activity, while mitochondrial iron overload promotes ROS production during mitochondrial electron transport, thus promoting potential disease development. This review provides an overview of iron homeostasis, mitochondrial iron metabolism, and how mitochondrial iron imbalances-induced mitochondrial dysfunction contribute to diseases.
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Affiliation(s)
- Geyan Duan
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jianjun Li
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yehui Duan
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Changbing Zheng
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Qiuping Guo
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Fengna Li
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jie Zheng
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jiayi Yu
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Peiwen Zhang
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Mengliao Wan
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Cimin Long
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
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Chen L, Zhao Q, Du X, Chen X, Jiao Q, Jiang H. Effects of oxidative stress caused by iron overload on arachidonic acid metabolites in MES23.5 cells. J Biosci 2022. [DOI: 10.1007/s12038-022-00321-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Zhang S, Sun Z, Jiang X, Lu Z, Ding L, Li C, Tian X, Wang Q. Ferroptosis increases obesity: Crosstalk between adipocytes and the neuroimmune system. Front Immunol 2022; 13:1049936. [PMID: 36479119 PMCID: PMC9720262 DOI: 10.3389/fimmu.2022.1049936] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 11/07/2022] [Indexed: 11/22/2022] Open
Abstract
Ferroptosis requires not only the accumulation of iron ions, but also changes in many ferroptosis-related regulators, including a decrease in GPX4 and inhibition of SLC7A11 for classical ferroptosis, a deletion of FSP1 or GCH1. Surprisingly, adipose tissue (AT) in the obesity conditions is also accompanied by iron buildup, decreased GSH, and increased ROS. On the neurological side, the pro-inflammatory factor released by AT may have first caused ferroptosis in the vagus nerve by inhibiting of the NRF2-GPX4 pathway, resulting in disorders of the autonomic nervous system. On the immune side, obesity may cause M2 macrophages ferroptosis due to damage to iron-rich ATMs (MFehi) and antioxidant ATMs (Mox), and lead to Treg cells ferroptosis through reductions in NRF2, GPX4, and GCH1 levels. At the same time, the reduction in GPX4 may also trigger the ferroptosis of B1 cells. In addition, some studies have also found the role of GPX4 in neutrophil autophagy, which is also worth pondering whether there is a connection with ferroptosis. In conclusion, this review summarizes the associations between neuroimmune regulation associated with obesity and ferroptosis, and on the basis of this, highlights their potential molecular mechanisms, proposing that ferroptosis in one or more cells in a multicellular tissue changes the fate of that tissue.
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Affiliation(s)
| | | | | | | | | | | | - Xuewen Tian
- *Correspondence: Xuewen Tian, ; Qinglu Wang,
| | - Qinglu Wang
- *Correspondence: Xuewen Tian, ; Qinglu Wang,
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Oliveira PMCD, Espósito BP, Carvente C, Silva GA, Dellavance A, Baldo DC, Ferraz MLG. Transferrin saturation as a surrogate marker for assessment of labile nontransferrin bound iron in chronic liver disease. Eur J Gastroenterol Hepatol 2022; 34:1047-1052. [PMID: 36052686 DOI: 10.1097/meg.0000000000002416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND Increased transferrin saturation (TS) and ferritin are common in hereditary hemochromatosis (HH) but also in chronic liver diseases (CLD). Nontransferrin bound iron (NTBI) is believed to be associated with iron-induced cell damage. We aimed to evaluate NTBI in CLD and their relationship with liver damage. METHODS Two groups of patients were studied. Group 1 (G1): 94 CLD patients from an Outpatient Hepatology Unit. Group 2 (G2): 36 healthy individuals form a Medical Checkup Clinic. Transferrin iron-binding capacity, TS, ferritin, AST, ALT, and red cell count were performed using standard tests. NTBI was assessed as enhanced labile plasma iron (eLPi). Levels of eLPi less than 0.4 µmol/l were considered within the normal range. RESULTS Prevalence of increased iron tests (elevated TS and ferritin) was 14% in G1 and 5.5% in G2 ( P = 0.19). Positive NTBI was found in 12 patients (11 in G1 and 1 in G2). Positivity to NTBI was associated with increased iron tests ( P = 0.03), cirrhosis ( P = 0.03) and AST index (ASTI) ( P = 0.03). NTBI was associated with TS of more than 70% ( P = 0.002) but not to elevated ferritin ( P = 0.74). Variables strongly associated with a positive NTBI in univariate analysis (TS > 70%, cirrhosis and ASTI) were submitted to binary regression analysis. TS of more than 70% was the only independent predictive factor ( P = 0.049; odds ratio, 6.8). CONCLUSION NTBI was associated with TS in CLD, but not with ferritin. NTBI testing could be useful for CLD patients with increased iron tests. Alternatively, a TS of more than 70% can be used as a surrogate marker.
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Affiliation(s)
| | | | - Claudia Carvente
- Gastroenterology Division, Federal University of São Paulo (UNIFESP)
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On the Core Prescriptions and Their Mechanisms of Traditional Chinese Medicine in Hepatitis B, Liver Cirrhosis, and Liver Cancer Treatment. JOURNAL OF ONCOLOGY 2022; 2022:5300523. [PMID: 36193202 PMCID: PMC9525786 DOI: 10.1155/2022/5300523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 07/23/2022] [Indexed: 12/02/2022]
Abstract
Background As a frequent cause of death in cancer patients, liver cancer usually occurs in hepatitis B and cirrhosis. In China, Chinese people have been using traditional Chinese medicine (TCM) in treating various chronic liver diseases, which could effectively improve the symptoms and slow down the progression of liver diseases. However, due to the complexity rules of TCM prescription, their action mechanisms are still not clearly understood, which may affect the popularization of effective prescriptions. This study aims to identify the core TCM herbs in the treatment of hepatitis B, liver cirrhosis, and liver cancer so as to clarify the mechanism of action of the core herb networks. Methods There were 1,673 prescriptions for chronic liver diseases collected in this study, of which 854 were hepatic B prescriptions, 530 were for liver cirrhosis, and 289 were for liver cancer. The basic characteristics of herbal medicine were firstly explained via descriptive analysis, then the core prescriptions of herbal medicine were analyzed through association rule, and finally, the mechanism of core prescriptions was explored with the help of systematic network pharmacology and by applying such databases as TCMIP, HERB, OMIM, GeneCards, KEGG, and software like RStudio and Cytoscape. Results The rule of the core prescriptions in these cases was characterized by the application of herbs with both cold and warm properties, in which bitter herbs with cold property took priority. Tonifying deficiency, clearing heat, and activating blood circulations to remove stasis were common treatment principles for the three liver diseases. Turmeric Root Tuber (YuJin), White Peony Root (BaiShao), Bupleurum (ChaiHu), Salvia miltiorrhiza (DanShen), and Astragali Radix (HuangQi) were prescribed the most in hepatitis B treatment to invigorate the spleen and soothe the liver. Astragali Radix (HuangQi), Tuckahoe (FuLing), Atractylodis Macrocephalae Rhizoma (BaiZhu), Fructus Polygoni Orientalis (ShuiHongHuaZi), and Curcumae Rhizome (EZhu) were most frequently applied in liver cirrhosis treatment to replenish qi and activate blood. Oldenlandia (BaiHuaSheSheCao), Bearded Scutellaria (BanZhiLian), Curcumae Rhizome (EZhu), and Cardamom (DouKou) were most frequently prescribed to eliminate cancer toxin, invigorate the spleen, and activate blood. These core herbs mainly act through signal transduction and immune system pathways, in which the PI3K-Akt pathway plays a key role. The core prescription for liver cirrhosis regulated more endocrine system pathways than the hepatitis B prescription, and liver cancer prescription regulated more nervous system-related pathways. Conclusion Three core prescriptions for hepatitis B, liver cirrhosis, and liver cancer treatment were identified, which acted mainly through signal transduction and immune system pathways to regulate immunity and cell growth and participate in inflammation inhibition, in which liver cancer prescription regulated more pathways, especially more nervous system-related pathways than the other two.
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Rieg CEH, Cattani D, Naspolini NF, Cenci VH, de Liz Oliveira Cavalli VL, Jacques AV, Nascimento MVPDS, Dalmarco EM, De Moraes ACR, Santos-Silva MC, Silva FRMB, Parisotto EB, Zamoner A. Perinatal exposure to a glyphosate pesticide formulation induces offspring liver damage. Toxicol Appl Pharmacol 2022; 454:116245. [PMID: 36116562 DOI: 10.1016/j.taap.2022.116245] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 09/07/2022] [Accepted: 09/12/2022] [Indexed: 11/28/2022]
Abstract
The present study investigated the effects of perinatal exposure to glyphosate-based herbicide (GBH) in offspring's liver. Pregnant Wistar rats were exposed to GBH (70 mg glyphosate/Kg body weight/day) in drinking water from gestation day 5 to postnatal day 15. The perinatal exposure to GBH increased 45Ca2+ influx in offspring's liver. Pharmacological tools indicated a role played by oxidative stress, phospholipase C (PLC) and Akt pathways, as well as voltage-dependent Ca2+ channel modulation on GBH-induced Ca2+ influx in offspring's liver. In addition, changes in the enzymatic antioxidant defense system, decreased GSH content, lipid peroxidation and protein carbonylation suggest a connection between GBH-induced hepatotoxic mechanism and redox imbalance. The perinatal exposure to GBH also increased the enzymatic activities of transaminases and gamma-glutamyl transferase in offspring's liver and blood, suggesting a pesticide-induced liver injury. Moreover, we detected increased iron levels in liver, blood and bone marrow of GBH-exposed rats, which were accompanied by increased transferrin saturation and decreased transferrin levels in blood. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were increased in the liver of rats perinatally exposed to GBH, which were associated with. Increased phospho-p65NFκB immunocontent. Therefore, we propose that excessive amounts of iron in offspring's liver, blood and bone marrow induced by perinatal exposure to GBH may account for iron-driven hepatotoxicity, which was associated with Ca2+ influx, oxidative damage and inflammation. Further studies will clarify whether these events can ultimately impact on liver function.
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Affiliation(s)
- Carla Elise Heinz Rieg
- Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Daiane Cattani
- Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Nathalia Ferrazzo Naspolini
- Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Vitoria Hayduck Cenci
- Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | | | - Amanda Virtuoso Jacques
- Department of Clinical Analysis, Center of Health Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | | | - Eduardo Monguilhott Dalmarco
- Department of Clinical Analysis, Center of Health Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Ana Carolina Rabello De Moraes
- Department of Clinical Analysis, Center of Health Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Maria Cláudia Santos-Silva
- Department of Clinical Analysis, Center of Health Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Fátima Regina Mena Barreto Silva
- Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Eduardo Benedetti Parisotto
- Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Ariane Zamoner
- Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil.
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Malesza IJ, Bartkowiak-Wieczorek J, Winkler-Galicki J, Nowicka A, Dzięciołowska D, Błaszczyk M, Gajniak P, Słowińska K, Niepolski L, Walkowiak J, Mądry E. The Dark Side of Iron: The Relationship between Iron, Inflammation and Gut Microbiota in Selected Diseases Associated with Iron Deficiency Anaemia—A Narrative Review. Nutrients 2022; 14:nu14173478. [PMID: 36079734 PMCID: PMC9458173 DOI: 10.3390/nu14173478] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 08/18/2022] [Accepted: 08/19/2022] [Indexed: 12/21/2022] Open
Abstract
Iron is an indispensable nutrient for life. A lack of it leads to iron deficiency anaemia (IDA), which currently affects about 1.2 billion people worldwide. The primary means of IDA treatment is oral or parenteral iron supplementation. This can be burdened with numerous side effects such as oxidative stress, systemic and local-intestinal inflammation, dysbiosis, carcinogenic processes and gastrointestinal adverse events. Therefore, this review aimed to provide insight into the physiological mechanisms of iron management and investigate the state of knowledge of the relationship between iron supplementation, inflammatory status and changes in gut microbiota milieu in diseases typically complicated with IDA and considered as having an inflammatory background such as in inflammatory bowel disease, colorectal cancer or obesity. Understanding the precise mechanisms critical to iron metabolism and the awareness of serious adverse effects associated with iron supplementation may lead to the provision of better IDA treatment. Well-planned research, specific to each patient category and disease, is needed to find measures and methods to optimise iron treatment and reduce adverse effects.
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Affiliation(s)
- Ida J. Malesza
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | | | - Jakub Winkler-Galicki
- Department of Physiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Aleksandra Nowicka
- Department of Physiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | | | - Marta Błaszczyk
- Department of Physiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Paulina Gajniak
- Department of Physiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Karolina Słowińska
- Department of Physiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Leszek Niepolski
- Department of Physiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Jarosław Walkowiak
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Edyta Mądry
- Department of Physiology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
- Correspondence:
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Iron deficiency promotes aortic media degeneration by activating endoplasmic reticulum stress-mediated IRE1 signaling pathway. Pharmacol Res 2022; 183:106366. [PMID: 35882294 DOI: 10.1016/j.phrs.2022.106366] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 07/02/2022] [Accepted: 07/22/2022] [Indexed: 11/23/2022]
Abstract
BACKGROUND Aortic dissection (AD) is a macrovascular disease which is pathologically characterized by aortic media degeneration (AMD). Our team's previous research found that iron deficiency (ID) promoted the formation of AMD through presentative research. In this study, we aimed to investigate the underlying mechanism of ID promoting AMD formation. METHODS The human aortic tissues were harvested from AD patients and organ donors. ApoE-/- mice were simultaneously given AngII infusion and low-iron feed to investigate the relationship between ID and AD. The IRE1-XBP1-CHOP signal axis of endoplasmic reticulum (ER) stress was selectively inhibited with 4μ8C. Iron contents were detected by Perls staining. The expression of iron metabolism and ER stress-relative proteins were analyzed by IF and western blotting. Apoptosis rates of aortic tissue and ASMCs were detected by TUNEL staining and flow cytometry, and ROS content was also measured by the flow cytometry. RESULTS ID was accompanied by ER stress in patients with AD. Among the three signaling pathways of ER stress in ID-induced AMD, proteins of IRE1, PERK and ATF6 signaling pathways were up-regulated by 2.65 times, 1.14 times and 1.24 times, respectively. ID was positively related to ER stress, mitochondrial oxidative stress and aortic media apoptosis in vivo and in vitro assays, while 4μ8C reversed the severity of ER stress and AMD. CONCLUSIONS ID could activate ER stress by eliciting mitochondrial oxidative stress to activate the IRE1-XBP1-CHOP signaling pathway in the ER, which accelerated the apoptosis of ASMCs in aortic media, thus promoting the formation of AMD.
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Li ZD, Geng MY, Dou SR, Wang X, Zhang ZH, Chang YZ. Caffeine Decreases Hepcidin Expression to Alleviate Aberrant Iron Metabolism under Inflammation by Regulating the IL-6/STAT3 Pathway. Life (Basel) 2022; 12:1025. [PMID: 35888113 PMCID: PMC9317204 DOI: 10.3390/life12071025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 06/29/2022] [Accepted: 07/08/2022] [Indexed: 12/02/2022] Open
Abstract
Caffeine is well-known as a psychostimulant, and it can also be beneficial in numerous diseases such as diabetes and different types of cancer. Previous studies have shown that caffeine can have a protective role in bacterial infection-induced inflammation and hyperoxia-mediated pulmonary inflammation. Hepcidin, which is regulated by the IL-6/STAT3 inflammation pathway, is a peptide hormone that maintains systemic iron homeostasis. We hypothesized that caffeine's effects on inflammation may also influence hepcidin production and therefore systemic iron metabolism. To this end, we treated 2-month-old mice with caffeine by daily intragastric administration for 7 days, administering intraperitoneal LPS after the final caffeine treatment. Twelve hours after LPS treatment the mice were euthanized, and tissues were collected. We found that caffeine decreased hepatic hepcidin expression and attenuated LPS-induced hepatic hepcidin overexpression. IL-6 expression and STAT3 phosphorylation were also reduced upon caffeine administration. Additionally, hepatic and splenic FPN1 levels increased after caffeine treatment, leading to lower iron levels in liver and spleen tissues and higher iron levels in serum. Caffeine also prevented the increase in spleen weight and decrease in body weight after LPS treatment. Together, our findings suggest that caffeine decreases hepcidin expression via inhibiting inflammation and the activation of the IL-6/STAT3 pathway, thus presenting an attractive, potential therapeutic for the treatment of anemia of inflammation.
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Affiliation(s)
| | | | | | | | | | - Yan-Zhong Chang
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, The Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, No. 20 Nan’erhuan Eastern Road, Shijiazhuang 050024, China; (Z.-D.L.); (M.-Y.G.); (S.-R.D.); (X.W.); (Z.-H.Z.)
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Tsuchiya H. Iron-Induced Hepatocarcinogenesis—Preventive Effects of Nutrients. Front Oncol 2022; 12:940552. [PMID: 35832553 PMCID: PMC9271801 DOI: 10.3389/fonc.2022.940552] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 06/03/2022] [Indexed: 01/10/2023] Open
Abstract
The liver is a primary organ that stores body iron, and plays a central role in the regulation of iron homeostasis. Hepatic iron overload (HIO) is a prevalent feature among patients with chronic liver diseases (CLDs), including alcoholic/nonalcoholic liver diseases and hepatitis C. HIO is suggested to promote the progression toward hepatocellular carcinoma because of the pro-oxidant nature of iron. Iron metabolism is tightly regulated by various factors, such as hepcidin and ferroportin, in healthy individuals to protect the liver from such deteriorative effects. However, their intrinsic expressions or functions are frequently compromised in patients with HIO. Thus, various nutrients have been reported to regulate hepatic iron metabolism and protect the liver from iron-induced damage. These nutrients are beneficial in HIO-associated CLD treatment and eventually prevent iron-mediated hepatocarcinogenesis. This mini-review aimed to discuss the mechanisms and hepatocarcinogenic risk of HIO in patients with CLDs. Moreover, nutrients that hold the potential to prevent iron-induced hepatocarcinogenesis are summarized.
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Yang Y, Lu Y, Zhang C, Guo Q, Zhang W, Wang T, Xia Z, Liu J, Cheng X, Xi T, Jiang F, Zheng L. Phenazine derivatives attenuate the stemness of breast cancer cells through triggering ferroptosis. Cell Mol Life Sci 2022; 79:360. [PMID: 35690642 PMCID: PMC11072418 DOI: 10.1007/s00018-022-04384-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 05/17/2022] [Accepted: 05/17/2022] [Indexed: 11/03/2022]
Abstract
Breast cancer stem cells (BCSCs) are positively correlated with the metastasis, chemoresistance, and recurrence of breast cancer. However, there are still no drugs targeting BCSCs in clinical using for breast cancer treatment. Here, we tried to screen out small-molecule compounds targeting BCSCs from the phenazine library established by us before. We focused on the compounds without affecting cell viability and screened out three potential compounds (CPUL119, CPUL129, CPUL149) that can significantly attenuate the stemness of breast cancer cells, as evident by the decrease of stemness marker expression, CD44+/CD24- subpopulation, mammary spheroid-formation ability, and tumor-initiating capacity. Additionally, these compounds suppressed the metastatic ability of breast cancer cells in vitro and in vivo. Combined with the transcriptome sequencing analysis, ferroptosis was shown on the top of the most upregulated pathways by CPUL119, CPUL129, and CPUL149, respectively. Mechanistically, we found that these three compounds could trigger ferroptosis by accumulating and sequestering iron in lysosomes through interacting with iron, and by regulating the expression of proteins (IRP2, TfR1, ferritin) engaged in iron transport and storage. Furthermore, inhibition of ferroptosis rescued the suppression of these three compounds on breast cancer cell stemness. This study suggests that CPUL119, CPUL129, and CPUL149 can specifically inhibit the stemness of breast cancer cells through triggering ferroptosis and may be the potential compounds for breast cancer treatment.
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Affiliation(s)
- Yue Yang
- School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Yuanyuan Lu
- School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Chunhua Zhang
- School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Qianqian Guo
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, 127 Dongming Road, Zhengzhou, 450003, People's Republic of China
| | - Wenzhou Zhang
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, 127 Dongming Road, Zhengzhou, 450003, People's Republic of China
| | - Ting Wang
- School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Zhuolu Xia
- School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Jing Liu
- School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Xiangyu Cheng
- School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Tao Xi
- School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China.
| | - Feng Jiang
- School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China.
| | - Lufeng Zheng
- School of Life Science and Technology, School of Engineering, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China.
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Jia R, Hou Y, Feng W, Li B, Zhu J. Alterations at biochemical, proteomic and transcriptomic levels in liver of tilapia (Oreochromis niloticus) under chronic exposure to environmentally relevant level of glyphosate. CHEMOSPHERE 2022; 294:133818. [PMID: 35114268 DOI: 10.1016/j.chemosphere.2022.133818] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 01/03/2022] [Accepted: 01/28/2022] [Indexed: 06/14/2023]
Abstract
The toxicity of glyphosate (Gly) on aquatic animals has received attention from many researchers. However, the chronic toxicity mechanism of Gly on fish has not yet been clarified entirely. Thus, this study aimed to explore the potential toxicity mechanism of Gly at 2 mg/L, a possibly existing concentration in the aquatic environment, via biochemical, transcriptomic and proteomic analyses in the liver of tilapia. Long-term Gly exposure increased lipid content, and altered redox status in liver. Transcriptomic analysis revealed that Gly exposure changed dramatically the expression of 225 genes in liver, including 94 up-regulated genes and 131 down-regulated genes. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analyses showed that these genes were predominantly enriched in ion transport, lipid metabolism and PPAR (peroxisome proliferator-activated receptor) signaling pathway. Meanwhile, at proteomic level, long-term Gly exposure resulted in alteration of 21 proteins, which were principally related to hepatic metabolism function. In conclusion, our data displayed a potential toxicity, mainly manifested as redox imbalance and dysregulation of metabolism function, in the liver of tilapia after long-term Gly exposure at 2 mg/L. This study provided novel insight into underlying toxicity mechanism of long-term Gly exposure at an environmentally relevant concentration in fish.
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Affiliation(s)
- Rui Jia
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China; International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Yiran Hou
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Wenrong Feng
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Bing Li
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China.
| | - Jian Zhu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China.
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Pecorelli A, Franceschi P, Braccischi L, Izzo F, Renzulli M, Golfieri R. MRI Appearance of Focal Lesions in Liver Iron Overload. Diagnostics (Basel) 2022; 12:diagnostics12040891. [PMID: 35453939 PMCID: PMC9029711 DOI: 10.3390/diagnostics12040891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/30/2022] [Accepted: 04/01/2022] [Indexed: 11/16/2022] Open
Abstract
Liver iron overload is defined as an accumulation of the chemical element Fe in the hepatic parenchyma that exceeds the normal storage. When iron accumulates, it can be toxic for the liver by producing inflammation and cell damage. This can potentially lead to cirrhosis and hepatocellular carcinoma, as well as to other liver lesions depending on the underlying condition associated to liver iron overload. The correct assessment of liver iron storage is pivotal to drive the best treatment and prevent complication. Nowadays, magnetic resonance imaging (MRI) is the best non-invasive modality to detect and quantify liver iron overload. However, due to its superparamagnetic properties, iron provides a natural source of contrast enhancement that can make challenging the differential diagnosis between different focal liver lesions (FLLs). To date, a fully comprehensive description of MRI features of liver lesions commonly found in iron-overloaded liver is lacking in the literature. Through an extensive review of the published literature, we aim to summarize the MRI signal intensity and enhancement pattern of the most common FLLs that can occur in liver iron overload.
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Jiao L, Dai T, Lu J, Tao X, Jin M, Sun P, Zhou Q. Excess iron supplementation induced hepatopancreas lipolysis, destroyed intestinal function in Pacific white shrimp Litopenaeus vannamei. MARINE POLLUTION BULLETIN 2022; 176:113421. [PMID: 35183027 DOI: 10.1016/j.marpolbul.2022.113421] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 12/08/2021] [Accepted: 01/30/2022] [Indexed: 06/14/2023]
Abstract
So far, the adverse effects of excess Fe in shrimp have been ignored for years as it was thought that extra Fe supplementation was not needed in the practical diets. Nowadays, Fe concentration in commercial shrimp feed from feed enterprises could be around 301.34-545.5 mg/kg, which is mainly due to the fish meal containing up to 1500 mg/kg Fe. Therefore, the purpose of this experiment was to investigate the effects of Fe supplementation on the growth performance, tissue Fe deposition, hepatopancreas lipid metabolism, intestinal function in L. vannamei. The results showed that although growth performance was not influenced by the dietary Fe supplementation, excess Fe supplementation (955.00 mg/kg) significantly increased hepatopancreas Fe deposition and induced lipolysis. Moreover, excess Fe supplementation impaired intestinal immune function and disrupted microbiota homeostasis. These findings might provide partial theoretical evidence for the effect of dietary Fe supplementation on physiological metabolism in L. vannamei.
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Affiliation(s)
- Lefei Jiao
- Laboratory of Fish Nutrition, School of Marine Sciences, Ningbo University, Ningbo 315211, PR China
| | - Tianmeng Dai
- Laboratory of Fish Nutrition, School of Marine Sciences, Ningbo University, Ningbo 315211, PR China
| | - Jingjing Lu
- Laboratory of Fish Nutrition, School of Marine Sciences, Ningbo University, Ningbo 315211, PR China
| | - Xinyue Tao
- Laboratory of Fish Nutrition, School of Marine Sciences, Ningbo University, Ningbo 315211, PR China
| | - Min Jin
- Laboratory of Fish Nutrition, School of Marine Sciences, Ningbo University, Ningbo 315211, PR China
| | - Peng Sun
- Laboratory of Fish Nutrition, School of Marine Sciences, Ningbo University, Ningbo 315211, PR China
| | - Qicun Zhou
- Laboratory of Fish Nutrition, School of Marine Sciences, Ningbo University, Ningbo 315211, PR China.
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Kupffer Cells and Blood Monocytes Orchestrate the Clearance of Iron-Carbohydrate Nanoparticles from Serum. Int J Mol Sci 2022; 23:ijms23052666. [PMID: 35269805 PMCID: PMC8910242 DOI: 10.3390/ijms23052666] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 02/05/2022] [Accepted: 02/25/2022] [Indexed: 02/01/2023] Open
Abstract
Intravenous (IV) iron nanoparticle preparations are widely used to treat iron deficiency. The mechanism of mononuclear phagocyte system-mediated clearance of IV iron nanoparticles is unknown. The early uptake and homeostasis of iron after injection of ferric carboxymaltose (FCM) in mice was studied. An increase in serum iron was observed at 2.5 h followed by a return to baseline by 24 h. An increase in circulating monocytes was observed, particularly Ly6Chi and Ly6Clow. FCM was also associated with a time-dependent decrease in liver Kupffer cells (KCs) and increase in liver monocytes. The increase in liver monocytes suggests an influx of iron-rich blood monocytes, while some KCs underwent apoptosis. Adoptive transfer experiments demonstrated that following liver infiltration, blood monocytes differentiated to KCs. KCs were also critical for IV iron uptake and biodegradation. Indeed, anti-Colony Stimulating Factor 1 Receptor (CSF1R)-mediated depletion of KCs resulted in elevated serum iron levels and impaired iron uptake by the liver. Gene expression profiling indicated that C-C chemokine receptor type 5 (CCR5) might be involved in monocyte recruitment to the liver, confirmed by pharmaceutical inhibition of CCR5. Liver KCs play a pivotal role in the clearance and storage of IV iron and KCs appear to be supported by the expanded blood monocyte population.
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Iron in Porphyrias: Friend or Foe? Diagnostics (Basel) 2022; 12:diagnostics12020272. [PMID: 35204362 PMCID: PMC8870839 DOI: 10.3390/diagnostics12020272] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/10/2022] [Accepted: 01/13/2022] [Indexed: 02/04/2023] Open
Abstract
Iron is a trace element that is important for many vital processes, including oxygen transport, oxidative metabolism, cellular proliferation, and catalytic reactions. Iron supports these functions mainly as part of the heme molecule. Heme synthesis is an eight-step process which, when defective at the level of one of the eight enzymes involved, can cause the development of a group of diseases, either inherited or acquired, called porphyrias. Despite the strict link between iron and heme, the role of iron in the different types of porphyrias, particularly as a risk factor for disease development/progression or as a potential therapeutic target or molecule, is still being debated, since contrasting results have emerged from clinical observations, in vitro studies and animal models. In this review we aim to deepen such aspects by drawing attention to the current evidence on the role of iron in porphyrias and its potential implication. Testing for iron status and its metabolic pathways through blood tests, imaging techniques or genetic studies on patients affected by porphyrias can provide additional diagnostic and prognostic value to the clinical care, leading to a more tailored and effective management.
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Morão IFC, Lemos MFL, Félix R, Vieira S, Barata C, Novais SC. Stress response markers in the blood of São Tomé green sea turtles (Chelonia mydas) and their relation with accumulated metal levels. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2022; 293:118490. [PMID: 34780755 DOI: 10.1016/j.envpol.2021.118490] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 11/10/2021] [Accepted: 11/11/2021] [Indexed: 06/13/2023]
Abstract
Metals are persistent worldwide being harmful for diverse organisms and having complex and combined effects with other contaminants in the environment. Sea turtles accumulate these contaminants being considered good bioindicator species for marine pollution. However, very little is known on how this is affecting these charismatic animals. São Tomé and Príncipe archipelago harbours important green sea turtle (Chelonia mydas) nesting and feeding grounds. The main goal of this study was to determine metal and metalloid accumulation in the blood of females C. mydas nesting in São Tomé Island, and evaluate the possible impacts of this contamination by addressing molecular stress responses. Gene expression analysis was performed in blood targeting genes involved in detoxification/sequestration and metal transport (mt, mtf and fer), and in antioxidant and oxidative stress responses (cat, sod, gr, tdx, txrd, selp and gclc). Micronuclei analysis in blood was also addressed as a biomarker of genotoxicity. Present results showed significant correlations between different gene expressions with the metals evaluated. The best GLM models and significant relationships were found for mt expression, for which 78% of the variability was attributed to metal levels (Al, Cu, Fe, Hg, Pb and Zn), followed by micronuclei count (65% - Cr, Cu, Fe, Hg, Mn and Zn), tdx expression (52% - Cd, Fe, Mn, Pb and Se), and cat expression (52% - As, Fe, Se and Cd x Hg). Overall, this study demonstrates that these green sea turtles are trying to adapt to the oxidative stress and damage produced by metals through the increased expression of antioxidants and other protectors, which raises concerns about the impacts on these endangered organisms' fitness. Furthermore, promising biomarker candidates associated to metal stress were identified in this species that may be used in future biomonitoring studies using C. mydas' blood, allowing for a temporal follow-up of the organisms.
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Affiliation(s)
- Inês F C Morão
- MARE - Marine and Environmental Sciences Centre, ESTM, Politécnico de Leiria, Portugal
| | - Marco F L Lemos
- MARE - Marine and Environmental Sciences Centre, ESTM, Politécnico de Leiria, Portugal
| | - Rafael Félix
- MARE - Marine and Environmental Sciences Centre, ESTM, Politécnico de Leiria, Portugal
| | - Sara Vieira
- Associação Programa Tatô, Avenida Marginal 12 de Julho, Cidade de São Tomé, São Tomé e Príncipe, Portugal
| | - Carlos Barata
- Environmental Chemistry Department, IDAEA-CSIC, Jordi Girona 18-26, 08034, Barcelona, Spain
| | - Sara C Novais
- MARE - Marine and Environmental Sciences Centre, ESTM, Politécnico de Leiria, Portugal.
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Wang K, Yang F, Zhang P, Yang Y, Jiang L. Genetic effects of iron levels on liver injury and risk of liver diseases: A two-sample Mendelian randomization analysis. Front Nutr 2022; 9:964163. [PMID: 36185655 PMCID: PMC9523310 DOI: 10.3389/fnut.2022.964163] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 08/18/2022] [Indexed: 11/13/2022] Open
Abstract
Background and aims Although iron homeostasis has been associated with liver function in many observational studies, the causality in this relationship remains unclear. By using Mendelian Randomization analyses, we aimed to evaluate the genetic effects of increased systemic iron levels on the risk of liver injury and various liver diseases. Moreover, in light of the sex-dependent iron regulation in human beings, we further estimated the sex-specific effect of iron levels in liver diseases. Methods Independent single nucleotide polymorphisms associated with systemic iron status (including four indicators) at the genome-wide significance level from the Genetics of Iron Status (GIS) Consortium were selected as instrumental variables. Summary data for six liver function biomarkers and five liver diseases were obtained from the UK Biobank, the Estonian Biobank, the eMERGE network, and FinnGen consortium. Mendelian Randomization assessment of the effect of iron on liver function and liver diseases was conducted. Results Genetically predicted iron levels were positively and significantly associated with an increased risk of different dimensions of liver injury. Furthermore, increased iron status posed hazardous effects on non-alcoholic fatty liver disease, alcoholic liver disease, and liver fibrosis/cirrhosis. Sex-stratified analyses indicated that the hepatoxic role of iron might exist in NAFLD and liver fibrosis/cirrhosis development among men. No significantly causal relationship was found between iron status and viral hepatitis. Conclusion Our study adds to current knowledge on the genetic role of iron in the risk of liver injury and related liver diseases, which provides clinical and public health implications for liver disease prevention as iron status can be modified.
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Affiliation(s)
- Kai Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China.,Eye Center of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Zhejiang Provincial Key Lab of Ophthalmology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Fangkun Yang
- Department of Cardiology, Ningbo First Hospital, School of Medicine, Zhejiang University, Ningbo, China
| | - Pengcheng Zhang
- Department of Gastroenterology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yang Yang
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Li Jiang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
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Xu J, Ma J, Chen J, Zhang S, Zheng C, Si H, Wu Y, Liu Y, Li M, Wu L, Shen B. No genetic causal association between iron status and osteoporosis: A two-sample Mendelian randomization. Front Endocrinol (Lausanne) 2022; 13:996244. [PMID: 36568116 PMCID: PMC9780364 DOI: 10.3389/fendo.2022.996244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 11/21/2022] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE To explore the genetic causal association between osteoporosis (OP) and iron status through Mendelian randomization (MR). METHODS Publicly available genome-wide association study (GWAS) summary data were used for MR analysis with four iron status-related indicators (ferritin, iron, total iron binding capacity, and transferrin saturation) as exposures and three different types of OP (OP, OP with pathological fracture, and postmenopausal OP with pathological fracture) as outcomes. The inverse-variance weighted (IVW) method was used to analyze the genetic causal association between the four indicators of iron status and OP. The heterogeneity of MR results was determined using IVW and MR-Egger methods. The pleiotropy of MR results was determined using MR-Egger regression. A leave-one-SNP-out test was performed to determine whether the MR results were affected by a single nucleotide polymorphism (SNP). The weighted median method was conducted to further validate our results. RESULTS Based on IVW, MR-Egger and weighted median models, we found no causal association between iron status (ferritin, iron, total iron binding capacity, or transferrin saturation) and OP (Pbeta > 0.05 in all models). IVW and MR-Egger analysis of OP with pathological fracture and iron status indicators showed no potential genetic causal association (Pbeta> 0.05 in the two analyses). The results of the weighted median were consistent with those of IVW (Pbeta> 0.05 in all analyses). There was no potential genetic causal association between iron status and postmenopausal OP with pathological fracture based on serum iron (Pbeta>0.05 in all models). No heterogeneity or horizontal pleiotropy was found in any of the analyses. None of the leave-one-out tests in the analyses found any SNP that could affect the results of MR. CONCLUSION Our results demonstrate that there is no genetic causal association between OP and iron status, but the effects of other factors were not excluded.
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Affiliation(s)
- Jiawen Xu
- Orthopedic Research Institute, Department of Orthopedics, Sichuan University West China Hospital, Chengdu, Sichuan, China
| | - Jun Ma
- Orthopedic Research Institute, Department of Orthopedics, Sichuan University West China Hospital, Chengdu, Sichuan, China
| | - Jialei Chen
- Orthopedic Research Institute, Department of Orthopedics, Sichuan University West China Hospital, Chengdu, Sichuan, China
| | - Shaoyun Zhang
- Orthopedic Research Institute, Department of Orthopedics, Sichuan University West China Hospital, Chengdu, Sichuan, China
- Department of Orthopedics, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, China
| | - Che Zheng
- Orthopedic Research Institute, Department of Orthopedics, Sichuan University West China Hospital, Chengdu, Sichuan, China
| | - Haibo Si
- Orthopedic Research Institute, Department of Orthopedics, Sichuan University West China Hospital, Chengdu, Sichuan, China
| | - Yuangang Wu
- Orthopedic Research Institute, Department of Orthopedics, Sichuan University West China Hospital, Chengdu, Sichuan, China
| | - Yuan Liu
- Orthopedic Research Institute, Department of Orthopedics, Sichuan University West China Hospital, Chengdu, Sichuan, China
| | - Mingyang Li
- Orthopedic Research Institute, Department of Orthopedics, Sichuan University West China Hospital, Chengdu, Sichuan, China
| | - Limin Wu
- Orthopedic Research Institute, Department of Orthopedics, Sichuan University West China Hospital, Chengdu, Sichuan, China
| | - Bin Shen
- Orthopedic Research Institute, Department of Orthopedics, Sichuan University West China Hospital, Chengdu, Sichuan, China
- *Correspondence: Bin Shen,
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