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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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2
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Guo R, Wang R, Zhang W, Li Y, Wang Y, Wang H, Li X, Song J. Macrophage Polarisation in the Tumour Microenvironment: Recent Research Advances and Therapeutic Potential of Different Macrophage Reprogramming. Cancer Control 2025; 32:10732748251316604. [PMID: 39849988 PMCID: PMC11758544 DOI: 10.1177/10732748251316604] [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: 10/30/2024] [Revised: 12/18/2024] [Accepted: 01/06/2025] [Indexed: 01/25/2025] Open
Abstract
BACKGROUND Macrophages are a critical component of the innate immune system, derived from monocytes, with significant roles in anti-inflammatory and anti-tumour activities. In the tumour microenvironment, however, macrophages are often reprogrammed into tumour-associated macrophages (TAMs), which promote tumour growth, metastasis, and therapeutic resistance. PURPOSE To review recent advancements in the understanding of macrophage polarisation and reprogramming, highlighting their role in tumour progression and potential as therapeutic targets. RESEARCH DESIGN This is a review article synthesising findings from recent studies on macrophage polarisation and reprogramming in tumour biology. STUDY SAMPLE Not applicable (review of existing literature). DATA COLLECTION AND/OR ANALYSIS Key studies were identified and summarised to explore mechanisms of macrophage polarisation and reprogramming, focusing on M1/M2 polarisation, metabolic and epigenetic changes, and pathway regulation. RESULTS Macrophage reprogramming in the tumour microenvironment involves complex mechanisms, including phenotypic and functional alterations. These processes are influenced by M1/M2 polarisation, metabolic and epigenetic reprogramming, and various signalling pathways. TAMs play a pivotal role in tumour progression, metastasis, and therapy resistance, making them prime targets for combination therapies. CONCLUSIONS Understanding the mechanisms underlying macrophage polarisation and reprogramming offers promising avenues for developing therapies to counteract tumour progression. Future research should focus on translating these insights into clinical applications for effective cancer treatment.
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Affiliation(s)
- Rongqi Guo
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Medical School of Nantong University, Nantong, PR China
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People's Hospital, Yancheng, PR China
| | - Rui Wang
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Medical School of Nantong University, Nantong, PR China
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People's Hospital, Yancheng, PR China
| | - Weisong Zhang
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Medical School of Nantong University, Nantong, PR China
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People's Hospital, Yancheng, PR China
| | - Yangyang Li
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Medical School of Nantong University, Nantong, PR China
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People's Hospital, Yancheng, PR China
| | - Yihao Wang
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Medical School of Nantong University, Nantong, PR China
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People's Hospital, Yancheng, PR China
| | - Hao Wang
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Medical School of Nantong University, Nantong, PR China
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People's Hospital, Yancheng, PR China
| | - Xia Li
- Department of General Medicine, Affiliated Hospital 6 of Nantong University, Yancheng Third People's Hospital, Yancheng, PR China
| | - Jianxiang Song
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Medical School of Nantong University, Nantong, PR China
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People's Hospital, Yancheng, PR China
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Zhang T, Liu Q, Chen Q, Wu H. Iron regulatory protein two facilitates ferritinophagy and DNA damage/repair through guiding ATG9A trafficking. J Biol Chem 2024; 300:107767. [PMID: 39276939 PMCID: PMC11490887 DOI: 10.1016/j.jbc.2024.107767] [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: 03/23/2024] [Revised: 07/17/2024] [Accepted: 08/25/2024] [Indexed: 09/17/2024] Open
Abstract
Trace elemental iron is an essential nutrient that participates in diverse metabolic processes. Dysregulation of cellular iron homeostasis, both iron deficiency and iron overload, is detrimental and tightly associated with disease pathogenesis. IRPs-IREs system is located at the center for iron homeostasis regulation. Additionally, ferritinophagy, the autophagy-dependent ferritin catabolism for iron recycling, is emerging as a novel mechanism for iron homeostasis regulation. It is still unclear whether IRPs-IREs system and ferritinophagy are synergistic or redundant in determining iron homeostasis. Here we report that IRP2, but not IRP1, is indispensable for ferritinophagy in response to iron depletion. Mechanistically, IRP2 ablation results in compromised AMPK activation and defective ATG9A endosomal trafficking, leading to the decreased engulfment of NCOA4-ferritin complex by endosomes and the subsequent dysregulated endosomal microferritinophagy. Moreover, this defective endosomal microferritinophagy exacerbates DNA damage and reduces colony formation in IRP2-depleted cells. Collectively, this study expands the physiological function of IRP2 in endosomal microferritinophagy and highlights potential crosstalk between IRPs-IREs and ferritinophagy in manipulating iron homeostasis.
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Affiliation(s)
- Ting Zhang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China; Hubei Hongshan Laboratory, Wuhan, Hubei, China
| | - Qian Liu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China; Hubei Hongshan Laboratory, Wuhan, Hubei, China
| | - Quan Chen
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Hao Wu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China; Hubei Hongshan Laboratory, Wuhan, Hubei, China.
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Correnti M, Gammella E, Cairo G, Recalcati S. Iron Absorption: Molecular and Pathophysiological Aspects. Metabolites 2024; 14:228. [PMID: 38668356 PMCID: PMC11052485 DOI: 10.3390/metabo14040228] [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: 03/22/2024] [Revised: 04/12/2024] [Accepted: 04/13/2024] [Indexed: 04/28/2024] Open
Abstract
Iron is an essential nutrient for growth among all branches of life, but while iron is among the most common elements, bioavailable iron is a relatively scarce nutrient. Since iron is fundamental for several biological processes, iron deficiency can be deleterious. On the other hand, excess iron may lead to cell and tissue damage. Consequently, iron balance is strictly regulated. As iron excretion is not physiologically controlled, systemic iron homeostasis is maintained at the level of absorption, which is mainly influenced by the amount of iron stores and the level of erythropoietic activity, the major iron consumer. Here, we outline recent advances that increased our understanding of the molecular aspects of iron absorption. Moreover, we examine the impact of these recent insights on dietary strategies for maintaining iron balance.
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Affiliation(s)
| | | | - Gaetano Cairo
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milan, Italy; (M.C.); (E.G.); (S.R.)
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Li J, Li L, Zhang Z, Chen P, Shu H, Yang C, Chu Y, Liu J. Ferroptosis: an important player in the inflammatory response in diabetic nephropathy. Front Immunol 2023; 14:1294317. [PMID: 38111578 PMCID: PMC10725962 DOI: 10.3389/fimmu.2023.1294317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 11/15/2023] [Indexed: 12/20/2023] Open
Abstract
Diabetic nephropathy (DN) is a chronic inflammatory disease that affects millions of diabetic patients worldwide. The key to treating of DN is early diagnosis and prevention. Once the patient enters the clinical proteinuria stage, renal damage is difficult to reverse. Therefore, developing early treatment methods is critical. DN pathogenesis results from various factors, among which the immune response and inflammation play major roles. Ferroptosis is a newly discovered type of programmed cell death characterized by iron-dependent lipid peroxidation and excessive ROS production. Recent studies have demonstrated that inflammation activation is closely related to the occurrence and development of ferroptosis. Moreover, hyperglycemia induces iron overload, lipid peroxidation, oxidative stress, inflammation, and renal fibrosis, all of which are related to DN pathogenesis, indicating that ferroptosis plays a key role in the development of DN. Therefore, this review focuses on the regulatory mechanisms of ferroptosis, and the mutual regulatory processes involved in the occurrence and development of DN and inflammation. By discussing and analyzing the relationship between ferroptosis and inflammation in the occurrence and development of DN, we can deepen our understanding of DN pathogenesis and develop new therapeutics targeting ferroptosis or inflammation-related regulatory mechanisms for patients with DN.
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Affiliation(s)
- Jialing Li
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
| | - Luxin Li
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Zhen Zhang
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
- School of First Clinical Medical College, Mudanjiang Medical University, Mudanjiang, China
| | - Peijian Chen
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Haiying Shu
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
| | - Can Yang
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
| | - Yanhui Chu
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Jieting Liu
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
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Chen W, Zheng D, Yang C. The Emerging Roles of Ferroptosis in Neonatal Diseases. J Inflamm Res 2023; 16:2661-2674. [PMID: 37396013 PMCID: PMC10312340 DOI: 10.2147/jir.s414316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Accepted: 06/13/2023] [Indexed: 07/04/2023] Open
Abstract
Ferroptosis is a novel type of programmed cell death involved in many diseases' pathological processes. Ferroptosis is characterized by lipid peroxidation, reactive oxygen species accumulation, and iron metabolism disorder. Newborns are susceptible to ferroptosis due to their special physiological state, which is prone to abnormal iron metabolism and the accumulation of reactive oxygen species. Recent studies have linked ferroptosis to a variety of diseases in the neonatal period (including hypoxic-ischemic encephalopathy, bronchopulmonary dysplasia, and necrotizing enterocolitis). Ferroptosis may become an effective target for the treatment of neonatal-related diseases. In this review, the ferroptosis molecular mechanism, metabolism characteristics of iron and reactive oxygen species in infants, the relationship between ferroptosis and common infant disorders, and the treatment of infant diseases targeted for ferroptosis are systematically summarized.
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Affiliation(s)
- Wenqian Chen
- Department of Neonatology, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China
| | - Dali Zheng
- Key Laboratory of Stomatology of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, People’s Republic of China
| | - Changyi Yang
- Department of Neonatology, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China
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Wang Y, Wang D, Yang L, Zhang Y. Metabolic reprogramming in the immunosuppression of tumor-associated macrophages. Chin Med J (Engl) 2022; 135:2405-2416. [PMID: 36385099 PMCID: PMC9945195 DOI: 10.1097/cm9.0000000000002426] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Indexed: 11/18/2022] Open
Abstract
ABSTRACT Tumor-associated macrophages (TAMs) are an essential proportion of tumor-infiltrating immune cells in the tumor microenvironment (TME) and have immunosuppressive functions. The high plasticity and corresponding phenotypic transformation of TAMs facilitate oncogenesis and progression, and suppress antineoplastic responses. Due to the uncontrolled proliferation of tumor cells, metabolism homeostasis is regulated, leading to a series of alterations in the metabolite profiles in the TME, which have a commensurate influence on immune cells. Metabolic reprogramming of the TME has a profound impact on the polarization and function of TAMs, and can alter their metabolic profiles. TAMs undergo a series of metabolic reprogramming processes, involving glucose, lipid, and amino acid metabolism, and other metabolic pathways, which terminally promote the development of the immunosuppressive phenotype. TAMs express a pro-tumor phenotype by increasing glycolysis, fatty acid oxidation, cholesterol efflux, and arginine, tryptophan, glutamate, and glutamine metabolism. Previous studies on the metabolism of TAMs demonstrated that metabolic reprogramming has intimate crosstalk with anti-tumor or pro-tumor phenotypes and is crucial for the function of TAMs themselves. Targeting metabolism-related pathways is emerging as a promising therapeutic modality because of the massive metabolic remodeling that occurs in malignant cells and TAMs. Evidence reveals that the efficacy of immune checkpoint inhibitors is improved when combined with therapeutic strategies targeting metabolism-related pathways. In-depth research on metabolic reprogramming and potential therapeutic targets provides more options for anti-tumor treatment and creates new directions for the development of new immunotherapy methods. In this review, we elucidate the metabolic reprogramming of TAMs and explore how they sustain immunosuppressive phenotypes to provide a perspective for potential metabolic therapies.
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Affiliation(s)
- Ying Wang
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Dan Wang
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Li Yang
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
- Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan 450052, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yi Zhang
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
- Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan 450052, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan 450052, China
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Sharawy N, Imam AAA, Aboulhoda BE, Khalifa MM, Morcos GNB, Abd Algaleel WA, Moustafa PE, Abdelbaset MA, Shoukry T. Iron dyshomeostasis and time-course changes in iron-uptake systems and ferritin level in relation to pro-inflammatory microglia polarization in sepsis-induced encephalopathy. Front Physiol 2022; 13:953206. [PMID: 36035473 PMCID: PMC9413069 DOI: 10.3389/fphys.2022.953206] [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: 05/26/2022] [Accepted: 07/11/2022] [Indexed: 11/13/2022] Open
Abstract
Encephalopathy is a frequent and lethal consequence of sepsis. Recently, a growing body of evidence has provided important insights into the role of iron dyshomeostasis in the context of inflammation. The molecular mechanisms underlying iron dyshomeostasis and its relationship with macrophage phenotypes are largely unknown. Here, we aimed to characterize the changes in iron-transporter and storage proteins and the microglia phenotype that occur during the course of sepsis, as well as their relationship with sepsis-induced encephalopathy. We used a cecal ligation and puncture (CLP) murine model that closely resembles sepsis-induced encephalopathy. Rats were subjected to CLP or sham laparotomy, then were neurologically assessed at 6 h, 24 h, and 3 days after sepsis induction. The serum and brain were collected for subsequent biochemical, histological, and immunohistochemical assessment. Here, an iron excess was observed at time points that followed the pro-inflammatory macrophage polarization in CLP-induced encephalopathy. Our results revealed that the upregulation of non-transferrin-bound iron uptake (NTBI) and ferritin reduction appeared to be partially responsible for the excess free iron detected within the brain tissues. We further demonstrated that the microglia were shifted toward the pro-inflammatory phenotype, leading to persistent neuro-inflammation and neuronal damage after CLP. Taken together, these findings led us to conclude that sepsis increased the susceptibility of the brain to the iron burden via the upregulation of NTBI and the reduction of ferritin, which was concomitantly and correlatively associated with dominance of pro-inflammatory microglia and could explain the neurological dysfunction observed during sepsis.
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Affiliation(s)
- Nivin Sharawy
- Department of Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ahmad Abdel-Aliem Imam
- Preclinical Sciences, College of Osteopathic Medicine, William Carey University, Hattiesburg, MS, United States
- Faculty of Medicine, Cairo University, Cairo, Egypt
- *Correspondence: Ahmad Abdel-Aliem Imam, ; Basma Emad Aboulhoda,
| | - Basma Emad Aboulhoda
- Department of Anatomy and Embryology, Faculty of Medicine, Cairo University, Cairo, Egypt
- *Correspondence: Ahmad Abdel-Aliem Imam, ; Basma Emad Aboulhoda,
| | - Mohamed Mansour Khalifa
- Department of Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
- Department of Human Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - George N. B. Morcos
- Department of Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt
- Department of Basic Medical Sciences, Faculty of Medicine, King Salman International University, El-Tor, Egypt
| | | | | | | | - Tarek Shoukry
- Department of Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
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Li F, Wang H, Chen H, Guo J, Dang X, Ru Y, Wang H. Mechanism of Ferroptosis and Its Role in Spinal Cord Injury. Front Neurol 2022; 13:926780. [PMID: 35756929 PMCID: PMC9218271 DOI: 10.3389/fneur.2022.926780] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 05/05/2022] [Indexed: 12/11/2022] Open
Abstract
Ferroptosis is a non-necrotic form of regulated cell death (RCD) that is primarily characterized by iron-dependent membrane lipid peroxidation and is regulated by cysteine transport, glutathione synthesis, and glutathione peroxidase 4 function as well as other proteins including ferroptosis suppressor protein 1. It has been found that ferroptosis played an important role in many diseases, such as neurodegenerative diseases and ischemia-reperfusion injury. Spinal cord injury (SCI), especially traumatic SCI, is an urgent problem worldwide due to its high morbidity and mortality, as well as the destruction of functions of the human body. Various RCDs, including ferroptosis, are found in SCI. Different from necrosis, since RCD is a form of cell death regulated by various molecular mechanisms in cells, the study of the role played by RCD in SCI will contribute to a deeper understanding of the pathophysiological process, as well as the treatment and functional recovery. The present review mainly introduces the main mechanism of ferroptosis and its role in SCI, so as to provide a new idea for further exploration.
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Affiliation(s)
- Fei Li
- Department of Orthopedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Haifan Wang
- Department of Orthopedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Hao Chen
- Basic Medical Science Academy, The Air Force Medical University, Xi'an, China
| | - Jianing Guo
- Basic Medical Science Academy, The Air Force Medical University, Xi'an, China
| | - Xiaoqian Dang
- Department of Orthopedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yi Ru
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Basic Medical Science Academy, The Air Force Medical University, Xi'an, China
| | - Haoyu Wang
- Department of Orthopedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Pan F, Lin X, Hao L, Wang T, Song H, Wang R. The Critical Role of Ferroptosis in Hepatocellular Carcinoma. Front Cell Dev Biol 2022; 10:882571. [PMID: 35800895 PMCID: PMC9255949 DOI: 10.3389/fcell.2022.882571] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 06/03/2022] [Indexed: 12/14/2022] Open
Abstract
Liver cancer is the sixth most frequently diagnosed cancer and the third dominant cause of cancer death worldwide. Ferroptosis is characterized as an iron-dependent form of regulated cell death, with accumulation of lipid peroxides to lethal amounts. Evidences have showed that ferroptosis is closely associated with HCC, but the mechanisms are still poorly understood. In this review, we mainly summarize the roles of several typical molecules as well as radiotherapy in regulating the ferroptosis process in HCC. Chances are that this review may help address specific issues in the treatment of HCC.
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Li Z, Heng H, Qin Q, Chen L, Wang Y, Zhou Z. Physicochemical properties, molecular structure, antioxidant activity, and biological function of extracellular melanin from Ascosphaera apis. J Zhejiang Univ Sci B 2022; 23:365-381. [PMID: 35557038 DOI: 10.1631/jzus.b2100718] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Ascosphaera apis spores containing a dark-colored pigment infect honeybee larvae, resulting in a large-scale collapse of the bee colony due to chalkbrood disease. However, little is known about the pigment or whether it plays a role in bee infection caused by A. apis. In this study, the pigment was isolated by alkali extraction, acid hydrolysis, and repeated precipitation. Ultraviolet (UV) analysis revealed that the pigment had a color value of 273, a maximum absorption peak at 195 nm, and a high alkaline solubility (7.67%) and acid precipitability. Further chemical structure analysis of the pigment, including elemental composition, Fourier transform infrared (FTIR) spectroscopy, Raman spectroscopy, mass spectrometry, and nuclear magnetic resonance (NMR), proved that it was a eumelanin with a typical indole structure. The molecular formula of melanin is C10H6O4N2, and its molecular weight is 409 Da. Melanin has hydroxyl, carboxyl, amino, and phenolic groups that can potentially chelate to metal ions. Antioxidant function analyses showed that A. apis melanin had a high scavenging activity against superoxide, hydroxyl, and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals, and a high reducing ability to Fe3+. Indirect immunofluorescence assay (IFA), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) analyses showed that A. apis melanin was located on the spore wall. The spore wall localization, antioxidant activity, and metal ion chelating properties of fungal melanin have been suggested to contribute to spore pathogenicity. However, further infection experiments showed that melanin-deficient spores did not reduce the mortality of bee larvae, indicating that melanin does not increase the virulence of A. apis spores. This study is the first report on melanin produced by A. apis, providing an important background reference for further study on its role in A. apis.
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Affiliation(s)
- Zhi Li
- College of Life Sciences, Chongqing Normal University, Chongqing 401331, China. .,Chongqing Key Laboratory of Vector Insects, Chongqing 401331, China. .,Chongqing Key Laboratory of Animal Biology, Chongqing 401331, China.
| | - Hui Heng
- College of Life Sciences, Chongqing Normal University, Chongqing 401331, China
| | - Qiqian Qin
- College of Life Sciences, Chongqing Normal University, Chongqing 401331, China
| | - Lanchun Chen
- College of Life Sciences, Chongqing Normal University, Chongqing 401331, China
| | - Yuedi Wang
- College of Life Sciences, Chongqing Normal University, Chongqing 401331, China
| | - Zeyang Zhou
- College of Life Sciences, Chongqing Normal University, Chongqing 401331, China.,Chongqing Key Laboratory of Microsporidia Infection and Control, Chongqing 400715, China.,The State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, China
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12
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Ferroptosis - A new target of osteoporosis. Exp Gerontol 2022; 165:111836. [DOI: 10.1016/j.exger.2022.111836] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/04/2022] [Accepted: 05/15/2022] [Indexed: 11/21/2022]
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Jayakumar D, S Narasimhan KK, Periandavan K. Triad role of hepcidin, ferroportin, and Nrf2 in cardiac iron metabolism: From health to disease. J Trace Elem Med Biol 2022; 69:126882. [PMID: 34710708 DOI: 10.1016/j.jtemb.2021.126882] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 09/29/2021] [Accepted: 10/19/2021] [Indexed: 11/28/2022]
Abstract
Iron is an essential trace element required for several vital physiological and developmental processes, including erythropoiesis, bone, and neuronal development. Iron metabolism and oxygen homeostasis are interlinked to perform a vital role in the functionality of the heart. The metabolic machinery of the heart utilizes almost 90 % of oxygen through the electron transport chain. To handle this tremendous level of oxygen, the iron metabolism in the heart is utmost crucial. Iron availability to the heart is therefore tightly regulated by (i) the hepcidin/ferroportin axis, which controls dietary iron absorption, storage, and recycling, and (ii) iron regulatory proteins 1 and 2 (IRP1/2) via hypoxia inducible factor 1 (HIF1) pathway. Despite iron being vital to the heart, recent investigations have demonstrated that iron imbalance is a common manifestation in conditions of heart failure (HF), since free iron readily transforms between Fe2+ and Fe3+via the Fenton reaction, leading to reactive oxygen species (ROS) production and oxidative damage. Therefore, to combat iron-mediated oxidative stress, targeting Nrf2/ARE antioxidant signaling is rational. The involvement of Nrf2 in regulating several genes engaged in heme synthesis, iron storage, and iron export is beginning to be uncovered. Consequently, it is possible that Nrf2/hepcidin/ferroportin might act as an epicenter connecting iron metabolism to redox alterations. However, the mechanism bridging the two remains obscure. In this review, we tried to summarize the contemporary insight of how cardiomyocytes regulate intracellular iron levels and discussed the mechanisms linking cardiac dysfunction with iron imbalance. Further, we emphasized the impact of Nrf2 on the interplay between systemic/cardiac iron control in the context of heart disease, particularly in myocardial ischemia and HF.
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Affiliation(s)
- Deepthy Jayakumar
- Department of Medical Biochemistry, Dr. ALM Post Graduate Institute for Basic Medical Sciences, University of Madras, Chennai, 600113, Tamil Nadu, India
| | - Kishore Kumar S Narasimhan
- Department of Pharmacology and Neurosciences, Creighton University, 2500 California Plaza, Omaha, NE, USA
| | - Kalaiselvi Periandavan
- Department of Medical Biochemistry, Dr. ALM Post Graduate Institute for Basic Medical Sciences, University of Madras, Chennai, 600113, Tamil Nadu, India.
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14
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Recalcati S, Cairo G. Macrophages and Iron: A Special Relationship. Biomedicines 2021; 9:biomedicines9111585. [PMID: 34829813 PMCID: PMC8615895 DOI: 10.3390/biomedicines9111585] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/21/2021] [Accepted: 10/28/2021] [Indexed: 02/06/2023] Open
Abstract
Macrophages perform a variety of different biological functions and are known for their essential role in the immune response. In this context, a principal function is phagocytic clearance of pathogens, apoptotic and senescent cells. However, the major targets of homeostatic phagocytosis by macrophages are old/damaged red blood cells. As such, macrophages play a crucial role in iron trafficking, as they recycle the large quantity of iron obtained by hemoglobin degradation. They also seem particularly adapted to handle and store amounts of iron that would be toxic to other cell types. Here, we examine the specific and peculiar iron metabolism of macrophages.
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15
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Thakkar D, Sicova M, Guest NS, Garcia-Bailo B, El-Sohemy A. HFE Genotype and Endurance Performance in Competitive Male Athletes. Med Sci Sports Exerc 2021; 53:1385-1390. [PMID: 33433155 DOI: 10.1249/mss.0000000000002595] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Hereditary hemochromatosis can cause individuals to absorb too much iron from their diet. Higher tissue iron content, below the threshold of toxicity, may enhance oxygen carrying capacity and offer a competitive advantage. Single nucleotide polymorphisms (SNP) in the homeostatic iron regulator (HFE) gene have been shown to modify iron metabolism and can be used to predict an individual's risk of hemochromatosis. Several studies have shown that HFE genotypes are associated with elite endurance athlete status; however, no studies have examined whether HFE genotypes are associated with endurance performance. PURPOSE The objectives of this study were to determine whether there was an association between HFE risk genotypes (rs1800562 and rs1799945) and endurance performance in a 10-km cycling time trial as well as maximal oxygen uptake (V˙O2peak), an indicator of aerobic capacity. METHODS Competitive male athletes (n = 100; age = 25 ± 4 yr) completed a 10-km cycling time trial. DNA was isolated from saliva and genotyped for the rs1800562 (C282Y) and rs1799945 (H63D) SNP in HFE. Athletes were classified as low risk (n = 88) or medium/high risk (n = 11) based on their HFE genotype for both SNP using an algorithm. ANCOVA was conducted to compare outcome variables between both groups. RESULTS Individuals with the medium- or high-risk genotype were ~8% (1.3 min) faster than those with the low-risk genotype (17.0 ± 0.8 vs 18.3 ± 0.3 min, P = 0.05). V˙O2peak was ~17% (7.9 mL·kg-1⋅min-1) higher in individuals with the medium- or high-risk genotype compared with those with the low-risk genotype (54.6 ± 3.2 vs 46.7 ± 1.0 mL·kg-1⋅min-1, P = 0.003). CONCLUSION Our findings show that HFE risk genotypes are associated with improved endurance performance and increased V˙O2peak in male athletes.
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Affiliation(s)
- Drishti Thakkar
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, CANADA
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16
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Qin Y, Guo T, Wang Z, Zhao Y. The role of iron in doxorubicin-induced cardiotoxicity: recent advances and implication for drug delivery. J Mater Chem B 2021; 9:4793-4803. [PMID: 34059858 DOI: 10.1039/d1tb00551k] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
As an anthracycline antibiotic, doxorubicin (DOX) is one of the most potent and widely used chemotherapeutic agents for treating various types of tumors. Unfortunately, the clinical application of this drug results in severe side effects, particularly dose-dependent cardiotoxicity. There are multiple mechanisms involved with the cardiotoxicity caused by DOX, among which intracellular iron homeostasis plays an essential role based on a recent discovery. In this mini-review, we summarize the clinical features and symptoms of DOX-dependent cardiotoxicity, discuss the correlation between iron and cardiotoxicity, and highlight the involvement of iron-dependent ferroptotic cell death therein. Recent advances in this topic will aid the development of novel DOX delivery systems with reduced adverse effects, and expand the clinical application of anthracycline.
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Affiliation(s)
- Yan Qin
- School of Pharmaceutical Science & Technology, Tianjin Key Laboratory for Modern Drug Delivery & High Efficiency, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, China.
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17
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Huang S, Li S, Feng H, Chen Y. Iron Metabolism Disorders for Cognitive Dysfunction After Mild Traumatic Brain Injury. Front Neurosci 2021; 15:587197. [PMID: 33796002 PMCID: PMC8007909 DOI: 10.3389/fnins.2021.587197] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 02/10/2021] [Indexed: 01/25/2023] Open
Abstract
Traumatic brain injury (TBI) is one of the most harmful forms of acute brain injury and predicted to be one of the three major neurological diseases that cause neurological disabilities by 2030. A series of secondary injury cascades often cause cognitive dysfunction of TBI patients leading to poor prognosis. However, there are still no effective intervention measures, which drive us to explore new therapeutic targets. In this process, the most part of mild traumatic brain injury (mTBI) is ignored because its initial symptoms seemed not serious. Unfortunately, the ignored mTBI accounts for 80% of the total TBI, and a large part of the patients have long-term cognitive dysfunction. Iron deposition has been observed in mTBI patients and accompanies the whole pathological process. Iron accumulation may affect long-term cognitive dysfunction from three pathways: local injury, iron deposition induces tau phosphorylation, the formation of neurofibrillary tangles; neural cells death; and neural network damage, iron deposition leads to axonal injury by utilizing the iron sensibility of oligodendrocytes. Thus, iron overload and metabolism dysfunction was thought to play a pivotal role in mTBI pathophysiology. Cerebrospinal fluid-contacting neurons (CSF-cNs) located in the ependyma have bidirectional communication function between cerebral-spinal fluid and brain parenchyma, and may participate in the pathway of iron-induced cognitive dysfunction through projected nerve fibers and transmitted factor, such as 5-hydroxytryptamine, etc. The present review provides an overview of the metabolism and function of iron in mTBI, and to seek a potential new treatment target for mTBI with a novel perspective through combined iron and CSF-cNs.
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Affiliation(s)
- Suna Huang
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University (Army Military Medical University), Chongqing, China.,State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Military Medical University), Chongqing, China.,Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Third Military Medical University (Army Military Medical University), Chongqing, China
| | - Su Li
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University (Army Military Medical University), Chongqing, China.,State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Military Medical University), Chongqing, China.,Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Third Military Medical University (Army Military Medical University), Chongqing, China
| | - Hua Feng
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University (Army Military Medical University), Chongqing, China.,State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Military Medical University), Chongqing, China.,Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Third Military Medical University (Army Military Medical University), Chongqing, China
| | - Yujie Chen
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University (Army Military Medical University), Chongqing, China.,State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Military Medical University), Chongqing, China.,Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Third Military Medical University (Army Military Medical University), Chongqing, China
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18
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Daugherty AM. Hypertension-related risk for dementia: A summary review with future directions. Semin Cell Dev Biol 2021; 116:82-89. [PMID: 33722505 DOI: 10.1016/j.semcdb.2021.03.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 03/01/2021] [Accepted: 03/06/2021] [Indexed: 02/07/2023]
Abstract
Chronic hypertension, or high blood pressure, is the most prevalent vascular risk factor that accelerates cognitive aging and increases risk for Alzheimer's disease and related dementia. Decades of observational and clinical trials have demonstrated that midlife hypertension is associated with greater gray matter atrophy, white matter damage commiserate with demyelination, and functional deficits as compared to normotension over the adult lifespan. Critically, hypertension is a modifiable dementia risk factor: successful blood pressure control with antihypertensive treatment improves outcomes as compared to uncontrolled hypertension, but does not completely negate the risk for dementia. This suggests that hypertension-related risk for neural and cognitive decline in aging cannot be due to elevations in blood pressure alone. This summary review describes three putative pathways for hypertension-related dementia risk: oxidative damage and metabolic dysfunction; systemic inflammation; and autonomic control of heart rate variability. The same processes contribute to pre-clinical hypertension, and therefore hypertension may be an early symptom of an aging nervous system that then exacerbates cumulative and progressive neurodegeneration. Current evidence is reviewed and future directions for research are outlined, including blood biomarkers and novel neuroimaging methods that may be sensitive to test the specific hypotheses.
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Affiliation(s)
- Ana M Daugherty
- Department of Psychology, Department of Psychiatry and Behavioral Neurosciences, Institute of Gerontology, Wayne State University, 5057 Woodward Ave., Detroit, MI, USA.
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19
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Behmoaras J. The versatile biochemistry of iron in macrophage effector functions. FEBS J 2020; 288:6972-6989. [PMID: 33354925 DOI: 10.1111/febs.15682] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/16/2020] [Accepted: 12/21/2020] [Indexed: 01/01/2023]
Abstract
Macrophages are mononuclear phagocytes with remarkable polarization ability that allow them to have tissue-specific functions during development, homeostasis, inflammatory and infectious disease. One particular trophic factor in the tissue environment is iron, which is intimately linked to macrophage effector functions. Macrophages have a well-described role in the control of systemic iron levels, but their activation state is also depending on iron-containing proteins/enzymes. Haemoproteins, dioxygenases and iron-sulphur (Fe-S) enzymes are iron-binding proteins that have bactericidal, metabolic and epigenetic-related functions, essential to shape the context-dependent macrophage polarization. In this review, I describe mainly pro-inflammatory macrophage polarization focussing on the role of iron biochemistry in selected haemoproteins and Fe-S enzymes. I show how iron, as part of haem or Fe-S clusters, participates in the cellular control of pro-inflammatory redox reactions in parallel with its role as enzymatic cofactor. I highlight a possible coordinated regulation of haemoproteins and Fe-S enzymes during classical macrophage activation. Finally, I describe tryptophan and α-ketoglutarate metabolism as two essential effector pathways in macrophages that use diverse iron biochemistry at different enzymatic steps. Through these pathways, I show how iron participates in the regulation of essential metabolites that shape macrophage function.
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20
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Gammella E, Lomoriello IS, Conte A, Freddi S, Alberghini A, Poli M, Sigismund S, Cairo G, Recalcati S. Unconventional endocytosis and trafficking of transferrin receptor induced by iron. Mol Biol Cell 2020; 32:98-108. [PMID: 33236955 PMCID: PMC8120689 DOI: 10.1091/mbc.e20-02-0129] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The posttranslational regulation of transferrin receptor (TfR1) is largely unknown. We investigated whether iron availability affects TfR1 endocytic cycle and protein stability in HepG2 hepatoma cells exposed to ferric ammonium citrate (FAC). NH4Cl and bafilomycin A1, but not the proteasomal inhibitor MG132, prevented the FAC-mediated decrease in TfR1 protein levels, thus indicating lysosomal involvement. Knockdown experiments showed that TfR1 lysosomal degradation is independent of 1) endocytosis mediated by the clathrin adaptor AP2; 2) Tf, which was suggested to facilitate TfR1 internalization; 3) H-ferritin; and 4) MARCH8, previously implicated in TfR1 degradation. Notably, FAC decreased the number of TfR1 molecules at the cell surface and increased the Tf endocytic rate. Colocalization experiments confirmed that, upon FAC treatment, TfR1 was endocytosed in an AP2- and Tf-independent pathway and trafficked to the lysosome for degradation. This unconventional endocytic regulatory mechanism aimed at reducing surface TfR1 may represent an additional posttranslational control to prevent iron overload. Our results show that iron is a key regulator of the trafficking of TfR1, which has been widely used to study endocytosis, often not considering its function in iron homeostasis.
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Affiliation(s)
- Elena Gammella
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milan, Italy
| | | | - Alexia Conte
- IEO, Istituto Europeo di Oncologia IRCCS, 20141 Milan, Italy
| | - Stefano Freddi
- IEO, Istituto Europeo di Oncologia IRCCS, 20141 Milan, Italy
| | - Alessandra Alberghini
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milan, Italy
| | - Maura Poli
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Sara Sigismund
- IEO, Istituto Europeo di Oncologia IRCCS, 20141 Milan, Italy.,Department of Oncology and Hematology-Oncology, Università degli Studi di Milano, 20122, Milan, Italy
| | - Gaetano Cairo
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milan, Italy
| | - Stefania Recalcati
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milan, Italy
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21
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The Molecular Mechanisms of Iron Metabolism and Its Role in Cardiac Dysfunction and Cardioprotection. Int J Mol Sci 2020; 21:ijms21217889. [PMID: 33114290 PMCID: PMC7660609 DOI: 10.3390/ijms21217889] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 10/22/2020] [Accepted: 10/22/2020] [Indexed: 02/06/2023] Open
Abstract
Iron is an essential mineral participating in different functions of the organism under physiological conditions. Numerous biological processes, such as oxygen and lipid metabolism, protein production, cellular respiration, and DNA synthesis, require the presence of iron, and mitochondria play an important role in the processes of iron metabolism. In addition to its physiological role, iron may be also involved in the adaptive processes of myocardial "conditioning". On the other hand, disorders of iron metabolism are involved in the pathological mechanisms of the most common human diseases and include a wide range of them, such as type 2 diabetes, obesity, and non-alcoholic fatty liver disease, and accelerate the development of atherosclerosis. Furthermore, iron also exerts potentially deleterious effects that may be manifested under conditions of ischemia/reperfusion (I/R) injury, myocardial infarction, heart failure, coronary artery angioplasty, or heart transplantation, due to its involvement in reactive oxygen species (ROS) production. Moreover, iron has been recently described to participate in the mechanisms of iron-dependent cell death defined as "ferroptosis". Ferroptosis is a form of regulated cell death that is distinct from apoptosis, necroptosis, and other types of cell death. Ferroptosis has been shown to be associated with I/R injury and several other cardiac diseases as a significant form of cell death in cardiomyocytes. In this review, we will discuss the role of iron in cardiovascular diseases, especially in myocardial I/R injury, and protective mechanisms stimulated by different forms of "conditioning" with a special emphasis on the novel targets for cardioprotection.
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22
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KARAHAN İ, ÇİFCİ A, DİNDAR BADEM N. Reproduktif çağdaki anemik kadınlarda TREM-1 düzeylerinin sağlıklı kontrollerle karşılaştırılması. ACTA MEDICA ALANYA 2020. [DOI: 10.30565/medalanya.706592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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23
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Naleskina LA, Lukianova NY, Lozovska YV, Todor IM, Andrusishyna IM, Kunska LM, Chekhun VF. Changes of Morphological Characteristics and Metabolic Profile of Walker-256 Carcinosarcoma under the Impact of Exogenous Lactoferrin. CYTOL GENET+ 2020. [DOI: 10.3103/s0095452720030093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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24
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Che J, Yang J, Zhao B, Zhang G, Wang L, Peng S, Shang P. The Effect of Abnormal Iron Metabolism on Osteoporosis. Biol Trace Elem Res 2020; 195:353-365. [PMID: 31473898 DOI: 10.1007/s12011-019-01867-4] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 08/08/2019] [Indexed: 12/16/2022]
Abstract
Iron is one of the important trace elements in life activities. Abnormal iron metabolism increases the incidence of many skeletal diseases, especially for osteoporosis. Iron metabolism plays a key role in the bone homeostasis. Disturbance of iron metabolism not only promotes osteoclast differentiation and apoptosis of osteoblasts but also inhibits proliferation and differentiation of osteoblasts, which eventually destroys the balance of bone remodeling. The strength and density of bone can be weakened by the disordered iron metabolism, which increases the incidence of osteoporosis. Clinically, compounds or drugs that regulate iron metabolism are used for the treatment of osteoporosis. The goal of this review summarizes the new progress on the effect of iron overload or deficiency on osteoporosis and the mechanism of disordered iron metabolism on osteoporosis. Explaining the relationship of iron metabolism with osteoporosis may provide ideas for clinical treatment and development of new drugs.
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Affiliation(s)
- Jingmin Che
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, 518057, Guangdong, China
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, China
- Key Laboratory for Space Bioscience and Biotechnology, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, China
| | - Jiancheng Yang
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, China
- Key Laboratory for Space Bioscience and Biotechnology, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, China
| | - Bin Zhao
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, China
- Key Laboratory for Space Bioscience and Biotechnology, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, China
| | - Ge Zhang
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China
| | - Luyao Wang
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China
| | - Songlin Peng
- Department of Spine Surgery, Shenzhen People's Hospital, Shenzhen, 518000, Guangdong, China
| | - Peng Shang
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen, 518057, Guangdong, China.
- Key Laboratory for Space Bioscience and Biotechnology, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, China.
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25
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Assessment of Subcellular ROS and NO Metabolism in Higher Plants: Multifunctional Signaling Molecules. Antioxidants (Basel) 2019; 8:antiox8120641. [PMID: 31842380 PMCID: PMC6943533 DOI: 10.3390/antiox8120641] [Citation(s) in RCA: 218] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 12/01/2019] [Accepted: 12/06/2019] [Indexed: 12/22/2022] Open
Abstract
Reactive oxygen species (ROS) and nitric oxide (NO) are produced in all aerobic life forms under both physiological and adverse conditions. Unregulated ROS/NO generation causes nitro-oxidative damage, which has a detrimental impact on the function of essential macromolecules. ROS/NO production is also involved in signaling processes as secondary messengers in plant cells under physiological conditions. ROS/NO generation takes place in different subcellular compartments including chloroplasts, mitochondria, peroxisomes, vacuoles, and a diverse range of plant membranes. This compartmentalization has been identified as an additional cellular strategy for regulating these molecules. This assessment of subcellular ROS/NO metabolisms includes the following processes: ROS/NO generation in different plant cell sites; ROS interactions with other signaling molecules, such as mitogen-activated protein kinases (MAPKs), phosphatase, calcium (Ca2+), and activator proteins; redox-sensitive genes regulated by the iron-responsive element/iron regulatory protein (IRE-IRP) system and iron regulatory transporter 1(IRT1); and ROS/NO crosstalk during signal transduction. All these processes highlight the complex relationship between ROS and NO metabolism which needs to be evaluated from a broad perspective.
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26
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Cronin SJF, Woolf CJ, Weiss G, Penninger JM. The Role of Iron Regulation in Immunometabolism and Immune-Related Disease. Front Mol Biosci 2019; 6:116. [PMID: 31824960 PMCID: PMC6883604 DOI: 10.3389/fmolb.2019.00116] [Citation(s) in RCA: 183] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 10/14/2019] [Indexed: 12/28/2022] Open
Abstract
Immunometabolism explores how the intracellular metabolic pathways in immune cells can regulate their function under different micro-environmental and (patho-)-physiological conditions (Pearce, 2010; Buck et al., 2015; O'Neill and Pearce, 2016). In the last decade great advances have been made in studying and manipulating metabolic programs in immune cells. Immunometabolism has primarily focused on glycolysis, the TCA cycle and oxidative phosphorylation (OXPHOS) as well as free fatty acid synthesis and oxidation. These pathways are important for providing the energy needs of cell growth, membrane rigidity, cytokine production and proliferation. In this review, we will however, highlight the specific role of iron metabolism at the cellular and organismal level, as well as how the bioavailability of this metal orchestrates complex metabolic programs in immune cell homeostasis and inflammation. We will also discuss how dysregulation of iron metabolism contributes to alterations in the immune system and how these novel insights into iron regulation can be targeted to metabolically manipulate immune cell function under pathophysiological conditions, providing new therapeutic opportunities for autoimmunity and cancer.
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Affiliation(s)
- Shane J F Cronin
- IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria
| | - Clifford J Woolf
- Department of Neurobiology, Harvard Medical School, Boston, MA, United States.,FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, United States
| | - Guenter Weiss
- Department of Internal Medicine II (Infectious Diseases, Immunology, Rheumatology and Pneumology), Medical University of Innsbruck, Innsbruck, Austria.,Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
| | - Josef M Penninger
- IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.,Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
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27
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Zhou DR, Eid R, Miller KA, Boucher E, Mandato CA, Greenwood MT. Intracellular second messengers mediate stress inducible hormesis and Programmed Cell Death: A review. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2019; 1866:773-792. [PMID: 30716408 DOI: 10.1016/j.bbamcr.2019.01.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 01/25/2019] [Accepted: 01/29/2019] [Indexed: 12/11/2022]
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28
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Guest NS, Horne J, Vanderhout SM, El-Sohemy A. Sport Nutrigenomics: Personalized Nutrition for Athletic Performance. Front Nutr 2019; 6:8. [PMID: 30838211 PMCID: PMC6389634 DOI: 10.3389/fnut.2019.00008] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 01/18/2019] [Indexed: 12/14/2022] Open
Abstract
An individual's dietary and supplement strategies can influence markedly their physical performance. Personalized nutrition in athletic populations aims to optimize health, body composition, and exercise performance by targeting dietary recommendations to an individual's genetic profile. Sport dietitians and nutritionists have long been adept at placing additional scrutiny on the one-size-fits-all general population dietary guidelines to accommodate various sporting populations. However, generic "one-size-fits-all" recommendations still remain. Genetic differences are known to impact absorption, metabolism, uptake, utilization and excretion of nutrients and food bioactives, which ultimately affects a number of metabolic pathways. Nutrigenomics and nutrigenetics are experimental approaches that use genomic information and genetic testing technologies to examine the role of individual genetic differences in modifying an athlete's response to nutrients and other food components. Although there have been few randomized, controlled trials examining the effects of genetic variation on performance in response to an ergogenic aid, there is a growing foundation of research linking gene-diet interactions on biomarkers of nutritional status, which impact exercise and sport performance. This foundation forms the basis from which the field of sport nutrigenomics continues to develop. We review the science of genetic modifiers of various dietary factors that impact an athlete's nutritional status, body composition and, ultimately athletic performance.
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Affiliation(s)
- Nanci S Guest
- Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada.,Nutrigenomix Inc., Toronto, ON, Canada
| | - Justine Horne
- Department of Health and Rehabilitation Sciences, University of Western Ontario, London, ON, Canada
| | - Shelley M Vanderhout
- Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada.,Nutrigenomix Inc., Toronto, ON, Canada
| | - Ahmed El-Sohemy
- Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada.,Nutrigenomix Inc., Toronto, ON, Canada
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29
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Abstract
SIGNIFICANCE Iron-sulfur cluster proteins carry out multiple functions, including as regulators of gene transcription/translation in response to environmental stimuli. In all known cases, the cluster acts as the sensory module, where the inherent reactivity/fragility of iron-sulfur clusters with small/redox-active molecules is exploited to effect conformational changes that modulate binding to DNA regulatory sequences. This promotes an often substantial reprogramming of the cellular proteome that enables the organism or cell to adapt to, or counteract, its changing circumstances. Recent Advances: Significant progress has been made recently in the structural and mechanistic characterization of iron-sulfur cluster regulators and, in particular, the O2 and NO sensor FNR, the NO sensor NsrR, and WhiB-like proteins of Actinobacteria. These are the main focus of this review. CRITICAL ISSUES Striking examples of how the local environment controls the cluster sensitivity and reactivity are now emerging, but the basis for this is not yet fully understood for any regulatory family. FUTURE DIRECTIONS Characterization of iron-sulfur cluster regulators has long been hampered by a lack of high-resolution structural data. Although this still presents a major future challenge, recent advances now provide a firm foundation for detailed understanding of how a signal is transduced to effect gene regulation. This requires the identification of often unstable intermediate species, which are difficult to detect and may be hard to distinguish using traditional techniques. Novel approaches will be required to solve these problems.
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Affiliation(s)
- Jason C Crack
- Centre for Molecular and Structural Biochemistry, School of Chemistry, University of East Anglia , Norwich Research Park, Norwich, United Kingdom
| | - Nick E Le Brun
- Centre for Molecular and Structural Biochemistry, School of Chemistry, University of East Anglia , Norwich Research Park, Norwich, United Kingdom
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30
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Dong D, Zhang G, Yang J, Zhao B, Wang S, Wang L, Zhang G, Shang P. The role of iron metabolism in cancer therapy focusing on tumor-associated macrophages. J Cell Physiol 2018; 234:8028-8039. [PMID: 30362549 DOI: 10.1002/jcp.27569] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 09/17/2018] [Indexed: 12/11/2022]
Abstract
Iron is an essential micronutrient in mammalian cells for basic processes such as DNA synthesis, cell cycle progression, and mitochondrial activity. Macrophages play a vital role in iron metabolism, which is tightly linked to their phagocytosis of senescent and death erythrocytes. It is now recognized that the polarization process of macrophages determines the expression profile of genes associated with iron metabolism. Although iron metabolism is strictly controlled by physiology, cancer has recently been connected with disordered iron metabolism. Moreover, in the environment of cancer, tumor-associated macrophages (TAMs) exhibit an iron release phenotype, which stimulates tumor cell survival and growth. Usually, the abundance of TAMs in the tumor is implicated in poor disease prognosis. Therefore, important attention has been drawn toward the development of tumor immunotherapies targeting these TAMs focussing on iron metabolism and reprogramming polarized phenotypes. Although further systematic research is still required, these efforts are almost certainly valuable in the search for new and effective cancer treatments.
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Affiliation(s)
- Dandan Dong
- School of Life Sciences, Northwestern Polytechnical University, Xi'an Shanxi, China.,Key Laboratory for Space Biosciences and Biotechnology, Xi'an Shanxi, China
| | - Gejing Zhang
- School of Life Sciences, Northwestern Polytechnical University, Xi'an Shanxi, China.,Key Laboratory for Space Biosciences and Biotechnology, Xi'an Shanxi, China
| | - Jiancheng Yang
- School of Life Sciences, Northwestern Polytechnical University, Xi'an Shanxi, China.,Key Laboratory for Space Biosciences and Biotechnology, Xi'an Shanxi, China
| | - Bin Zhao
- School of Life Sciences, Northwestern Polytechnical University, Xi'an Shanxi, China.,Key Laboratory for Space Biosciences and Biotechnology, Xi'an Shanxi, China
| | - Shenghang Wang
- School of Life Sciences, Northwestern Polytechnical University, Xi'an Shanxi, China.,Key Laboratory for Space Biosciences and Biotechnology, Xi'an Shanxi, China
| | - Luyao Wang
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong, China
| | - Ge Zhang
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong, China
| | - Peng Shang
- Research & Development Institute in Shenzhen, Northwestern Polytechnical University, Shenzhen, China.,Key Laboratory for Space Biosciences and Biotechnology, Xi'an Shanxi, China
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31
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Zhang J, Chen X. p53 tumor suppressor and iron homeostasis. FEBS J 2018; 286:620-629. [PMID: 30133149 DOI: 10.1111/febs.14638] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 07/16/2018] [Accepted: 08/20/2018] [Indexed: 12/20/2022]
Abstract
Iron is an essential nutrient for all living organisms and plays a vital role in many fundamental biochemical processes, such as oxygen transport, energy metabolism, and DNA synthesis. Due to its capability to produce free radicals, iron has deleterious effects and thus, its level needs to be tightly controlled in the body. Deregulation of iron metabolism is known to cause diseases, including anemia by iron deficiency and hereditary hemochromatosis by iron overload. Interestingly, dysregulated iron metabolism occurs frequently in tumor cells and contributes to tumorigenesis. In this review, we will discuss the role of p53 tumor suppressor in iron homeostasis.
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Affiliation(s)
- Jin Zhang
- Comparative Oncology Laboratory, School of Veterinary Medicine and Medicine, University of California at Davis, CA, USA
| | - Xinbin Chen
- Comparative Oncology Laboratory, School of Veterinary Medicine and Medicine, University of California at Davis, CA, USA
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32
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Xu H, Liu X, Xia J, Yu T, Qu Y, Jiang H, Xie J. Activation of NMDA receptors mediated iron accumulation via modulating iron transporters in Parkinson's disease. FASEB J 2018; 32:fj201800060RR. [PMID: 29897813 DOI: 10.1096/fj.201800060rr] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Increasing evidence has confirmed that nigral iron accumulation and activation of NMDA receptors (NRs) contribute to the neurodegeneration of dopamine (DA) neurons in Parkinson's disease (PD). Earlier work indicated that activation of NRs participated in iron metabolism in the hippocampus. However, the relationship between activation of NRs and iron accumulation in DA neurons of the substantia nigra in PD was unknown. In this study, our results showed that NRs inhibitors MK-801 and AP5 protected nigrostriatal projection system and reduced nigral iron levels of 6-hydroxydopamine (6-OHDA)-induced PD rats. In vitro studies demonstrated that NMDA treatment increased the expression of iron importer divalent metal transporter 1 (DMT1) and decreased the expression of iron exporter ferropotin 1 (Fpn1), which were dependent on iron regulatory protein 1 (IRP1). This led to increased intracellular iron levels and intensified the decrease in mitochondrial transmembrane potential in MES23.5 dopaminergic neurons. In addition, we reported that MK801 and neuronal nitric oxide synthase inhibitor could antagonize 6-OHDA-induced up-regulation of IRP1 and DMT1 and down-regulation of Fpn1, thus attenuating 6-OHDA-induced iron accumulation in MES23.5 cells. This suggested that 6-OHDA-induced activation of NRs might modulate the expression of DMT1 and Fpn1 via the neuronal nitric oxide synthase-IRP1 pathway.-Xu, H., Liu, X., Xia, J., Yu, T., Qu, Y., Jiang, H., Xie, J., Activation of NMDA receptors mediated iron accumulation via modulating iron transporters in Parkinson's disease.
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Affiliation(s)
- Huamin Xu
- Department of Physiology, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, and Institute of Brain Science and Disease, Qingdao University, Qingdao, China
| | - Xiaodong Liu
- Department of Physiology, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, and Institute of Brain Science and Disease, Qingdao University, Qingdao, China
| | - Jianjian Xia
- Department of Physiology, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, and Institute of Brain Science and Disease, Qingdao University, Qingdao, China
| | - Tianshu Yu
- Department of Physiology, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, and Institute of Brain Science and Disease, Qingdao University, Qingdao, China
| | - Yanan Qu
- Department of Physiology, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, and Institute of Brain Science and Disease, Qingdao University, Qingdao, China
| | - Hong Jiang
- Department of Physiology, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, and Institute of Brain Science and Disease, Qingdao University, Qingdao, China
| | - Junxia Xie
- Department of Physiology, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, and Institute of Brain Science and Disease, Qingdao University, Qingdao, China
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33
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Zhou L, Zhao B, Zhang L, Wang S, Dong D, Lv H, Shang P. Alterations in Cellular Iron Metabolism Provide More Therapeutic Opportunities for Cancer. Int J Mol Sci 2018; 19:E1545. [PMID: 29789480 PMCID: PMC5983609 DOI: 10.3390/ijms19051545] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Revised: 05/16/2018] [Accepted: 05/17/2018] [Indexed: 01/19/2023] Open
Abstract
Iron is an essential element for the growth and proliferation of cells. Cellular iron uptake, storage, utilization and export are tightly regulated to maintain iron homeostasis. However, cellular iron metabolism pathways are disturbed in most cancer cells. To maintain rapid growth and proliferation, cancer cells acquire large amounts of iron by altering expression of iron metabolism- related proteins. In this paper, normal cellular iron metabolism and the alterations of iron metabolic pathways in cancer cells were summarized. Therapeutic strategies based on targeting the altered iron metabolism were also discussed and disrupting redox homeostasis by intracellular high levels of iron provides new insight for cancer therapy. Altered iron metabolism constitutes a promising therapeutic target for cancer therapy.
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Affiliation(s)
- Liangfu Zhou
- School of Life Science, Northwestern Polytechnical University, Xi'an 710072, China.
| | - Bin Zhao
- School of Life Science, Northwestern Polytechnical University, Xi'an 710072, China.
| | - Lixiu Zhang
- School of Life Science, Northwestern Polytechnical University, Xi'an 710072, China.
| | - Shenghang Wang
- School of Life Science, Northwestern Polytechnical University, Xi'an 710072, China.
| | - Dandan Dong
- School of Life Science, Northwestern Polytechnical University, Xi'an 710072, China.
| | - Huanhuan Lv
- School of Life Science, Northwestern Polytechnical University, Xi'an 710072, China.
- Research & Development Institute in Shenzhen, Northwestern Polytechnical University, Shenzhen 518057, China.
- Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, Northwestern Polytechnical University, Xi'an 710072, China.
| | - Peng Shang
- Research & Development Institute in Shenzhen, Northwestern Polytechnical University, Shenzhen 518057, China.
- Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, Northwestern Polytechnical University, Xi'an 710072, China.
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34
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Pourcelot E, Lénon M, Charbonnier P, Louis F, Mossuz P, Moulis JM. The iron regulatory proteins are defective in repressing translation via exogenous 5' iron responsive elements despite their relative abundance in leukemic cellular models. Metallomics 2018; 10:639-649. [PMID: 29652073 DOI: 10.1039/c8mt00006a] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
In animal cells the specific translational control of proteins contributing to iron homeostasis is mediated by the interaction between the Iron Regulatory Proteins (IRP1 and IRP2) and the Iron Responsive Elements (IRE) located in the untranslated regions (UTR) of regulated messengers, such as those encoding ferritin or the transferrin receptor. The absolute concentrations of the components of this regulatory system in hematopoietic cells and the ability of the endogenous IRP to regulate exogenous IRE have been measured. The IRP concentration is in the low μM (10-6 M) range, whereas the most abundant IRE-containing messenger RNA (mRNA), i.e. those of the ferritin subunits, do not exceed 100 nM (10-7 M). Most other IRP mRNA targets are around or below 1 nM. The distribution of the mRNA belonging to the cellular iron network is similar in human leukemic cell lines and in normal cord blood progenitors, with differences among the cellular models only associated with their different propensities to synthesize hemoglobin. Thus, the IRP regulator is in large excess over its presently identified regulated mRNA targets. Yet, despite this excess, endogenous IRP poorly represses translation of transfected luciferase cDNA engineered with a series of IRE sequences in the 5' UTR. The cellular concentrations of the central hubs of the mammalian translational iron network will have to be included in the description of the proliferative phenotype of leukemic cells and in assessing any therapeutic action targeting iron provision.
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Affiliation(s)
- Emmanuel Pourcelot
- Univ. Grenoble Alpes, Inserm U1055, Laboratory of Fundamental and Applied Bioenergetics (LBFA) and SFR BEeSy, 38000 Grenoble, France
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35
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Gammella E, Buratti P, Cairo G, Recalcati S. The transferrin receptor: the cellular iron gate. Metallomics 2018; 9:1367-1375. [PMID: 28671201 DOI: 10.1039/c7mt00143f] [Citation(s) in RCA: 179] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The transferrin receptor (TfR1), which mediates cellular iron uptake through clathrin-dependent endocytosis of iron-loaded transferrin, plays a key role in iron homeostasis. Since the number of TfR1 molecules at the cell surface is the rate-limiting step for iron entry into cells and is essential to prevent iron overload, TfR1 expression is precisely controlled at multiple levels. In this review, we have discussed the latest advances in the molecular regulation of TfR1 expression and we have considered current understanding of TfR1 function beyond its canonical role in providing iron for erythroid precursors and rapidly proliferating cells.
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Affiliation(s)
- Elena Gammella
- Department of Biomedical Sciences for Health, University of Milan, Via Mangiagalli 31, 20133 Milano, Italy.
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36
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Raggi C, Gammella E, Correnti M, Buratti P, Forti E, Andersen JB, Alpini G, Glaser S, Alvaro D, Invernizzi P, Cairo G, Recalcati S. Dysregulation of Iron Metabolism in Cholangiocarcinoma Stem-like Cells. Sci Rep 2017; 7:17667. [PMID: 29247214 PMCID: PMC5732280 DOI: 10.1038/s41598-017-17804-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 11/26/2017] [Indexed: 12/13/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a devastating liver tumour arising from malignant transformation of bile duct epithelial cells. Cancer stem cells (CSC) are a subset of tumour cells endowed with stem-like properties, which play a role in tumour initiation, recurrence and metastasis. In appropriate conditions, CSC form 3D spheres (SPH), which retain stem-like tumour-initiating features. Here, we found different expression of iron proteins indicating increased iron content, oxidative stress and higher expression of CSC markers in CCA-SPH compared to tumour cells growing as monolayers. Exposure to the iron chelator desferrioxamine decreased SPH forming efficiency and the expression of CSC markers and stem-like genes, whereas iron had an opposite effect. Microarray profiles in CCA samples (n = 104) showed decreased H ferritin, hepcidin and ferroportin expression in tumours respect to surrounding liver, whereas transferrin receptor was up-regulated. Moreover, we found a trend toward poorer outcome in CCA patients with elevated expression of ferritin and hepcidin, two major proteins of iron metabolism. These findings, which represent the first evidence of a role for iron in the stem cell compartment as a novel metabolic factor involved in CCA growth, may have implications for a better therapeutic approach.
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Affiliation(s)
- Chiara Raggi
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy
- Dipartimento Medicina Sperimentale e Clinica, University of Firence, Firenze, Italy
| | - Elena Gammella
- Department of Biomedical Sciences for Health, University of Milan, Milano, Italy
| | - Margherita Correnti
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Paolo Buratti
- Department of Biomedical Sciences for Health, University of Milan, Milano, Italy
| | - Elisa Forti
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Jesper B Andersen
- Biotech Research and Innovation Centre, Department of Health and Medical Sciences University of Copenhagen, Copenhagen, Denmark
| | - Gianfranco Alpini
- Research, Central Texas Veterans Health Care System, Baylor Scott & White Digestive Disease Research Center, Scott & White Health, Department of Medicine, Texas A&M Health Science Center, Temple, TX, USA
| | - Shannon Glaser
- Research, Central Texas Veterans Health Care System, Baylor Scott & White Digestive Disease Research Center, Scott & White Health, Department of Medicine, Texas A&M Health Science Center, Temple, TX, USA
| | - Domenico Alvaro
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy.
| | - Gaetano Cairo
- Department of Biomedical Sciences for Health, University of Milan, Milano, Italy.
| | - Stefania Recalcati
- Department of Biomedical Sciences for Health, University of Milan, Milano, Italy
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37
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Abstract
SIGNIFICANCE Iron-sulfur cluster proteins carry out a wide range of functions, including as regulators of gene transcription/translation in response to environmental stimuli. In all known cases, the cluster acts as the sensory module, where the inherent reactivity/fragility of iron-sulfur clusters towards small/redox active molecules is exploited to effect conformational changes that modulate binding to DNA regulatory sequences. This promotes an often substantial re-programming of the cellular proteome that enables the organism or cell to adapt to, or counteract, its changing circumstances. Recent Advances. Significant progress has been made recently in the structural and mechanistic characterization of iron-sulfur cluster regulators and, in particular, the O2 and NO sensor FNR, the NO sensor NsrR, and WhiB-like proteins of Actinobacteria. These are the main focus of this review. CRITICAL ISSUES Striking examples of how the local environment controls the cluster sensitivity and reactivity are now emerging, but the basis for this is not yet fully understood for any regulatory family. FUTURE DIRECTIONS Characterization of iron-sulfur cluster regulators has long been hampered by a lack of high resolution structural data. Though this still presents a major future challenge, recent advances now provide a firm foundation for detailed understanding of how a signal is transduced to effect gene regulation. This requires the identification of often unstable intermediate species, which are difficult to detect and may be hard to distinguish using traditional techniques. Novel approaches will be required to solve these problems.
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Affiliation(s)
- Jason C Crack
- School of Chemistry , University of East Anglia , Norwich, United Kingdom of Great Britain and Northern Ireland , NR4 7TJ ;
| | - Nick E Le Brun
- University of East Anglia, School of Chemistry , University plain , Norwich, United Kingdom of Great Britain and Northern Ireland , NR4 7TJ ;
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38
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Recalcati S, Gammella E, Buratti P, Cairo G. Molecular regulation of cellular iron balance. IUBMB Life 2017; 69:389-398. [PMID: 28480557 DOI: 10.1002/iub.1628] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 03/19/2017] [Indexed: 12/12/2022]
Abstract
Handling a life-supporting yet redox-active metal like iron represents a significant challenge to cells and organisms that must not only tightly balance intra- and extracellular iron concentrations but also chaperone it during its journey from its point of entry to final destinations, to prevent inappropriate generation of damaging reactive oxygen species. Accordingly, regulatory mechanisms have been developed to maintain appropriate cellular and body iron levels. In intracellular compartments, about 95% of iron is protein-bound and the expression of the major proteins of iron metabolism is controlled by an integrated and dynamic system involving multilayered levels of regulation. However, dysregulation of iron homeostasis, which could result from both iron-related and unrelated effectors, may occur and have important pathological consequences in a number of human disorders. In this review, we describe the current understanding of the mechanisms that keep cellular iron balance and outline recent advances that increased our knowledge of the molecular physiology of iron metabolism. © 2017 IUBMB Life, 69(6):389-398, 2017.
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Affiliation(s)
- Stefania Recalcati
- Department of Biomedical Sciences for Health, University of Milan, Milano, Italy
| | - Elena Gammella
- Department of Biomedical Sciences for Health, University of Milan, Milano, Italy
| | - Paolo Buratti
- Department of Biomedical Sciences for Health, University of Milan, Milano, Italy
| | - Gaetano Cairo
- Department of Biomedical Sciences for Health, University of Milan, Milano, Italy
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39
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Martins AC, Almeida JI, Lima IS, Kapitão AS, Gozzelino R. Iron Metabolism and the Inflammatory Response. IUBMB Life 2017; 69:442-450. [PMID: 28474474 DOI: 10.1002/iub.1635] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 04/06/2017] [Indexed: 12/19/2022]
Abstract
Iron (Fe) is essential to almost all organisms, as required by cells to satisfy metabolic needs and accomplish specialized functions. Its ability to exchange electrons between different substrates, however, renders it potentially toxic. Fine tune-mechanisms are necessary to maintain Fe homeostasis and, as such, to prevent its participation into the Fenton reaction and generation of oxidative stress. These are particularly important in the context of inflammation/infection, where restricting Fe availability to invading pathogens is one, if not, the main host defense strategy against microbial growth. The ability of Fe to modulate several aspects of the immune response is associated with a number of "costs" and "benefits", some of which have been described in this review. © 2017 IUBMB Life, 69(6):442-450, 2017.
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Affiliation(s)
- Ana C Martins
- Chronic Diseases Research Center (CEDOC)/NOVA Medical School, NOVA University of Lisbon, Portugal
| | - Joana I Almeida
- Chronic Diseases Research Center (CEDOC)/NOVA Medical School, NOVA University of Lisbon, Portugal
| | - Illyane S Lima
- Chronic Diseases Research Center (CEDOC)/NOVA Medical School, NOVA University of Lisbon, Portugal
| | - Antonino S Kapitão
- Chronic Diseases Research Center (CEDOC)/NOVA Medical School, NOVA University of Lisbon, Portugal
| | - Raffaella Gozzelino
- Chronic Diseases Research Center (CEDOC)/NOVA Medical School, NOVA University of Lisbon, Portugal
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40
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Asano M, Yamasaki K, Yamauchi T, Terui T, Aiba S. Epidermal iron metabolism for iron salvage. J Dermatol Sci 2017; 87:101-109. [PMID: 28450059 DOI: 10.1016/j.jdermsci.2017.04.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 03/30/2017] [Accepted: 04/11/2017] [Indexed: 01/01/2023]
Abstract
BACKGROUND The epidermis shows a reverse iron gradient from the basal layer to the stratum corneum and consequently, little epidermal intracellular iron is lost by desquamation. OBJECTIVE To clarify the underlying mechanism of iron salvage. METHODS We first used immunohistochemistry and mRNA quantification to demonstrate the distinctive expression pattern of iron metabolism molecules. The obtained results were confirmed using normal human epidermal keratinocytes (NHEKs) during in vitro differentiation. We next examined the effects of reducing ferroportin expression in vitro by ferroportin-specific siRNAs or hepcidin on the intracellular iron content of cultured NHEKs. Finally, we compared epidermal and systemic iron metabolism between FpnEpi-KO mice and control mice. RESULTS The results of both mRNA and protein expression analysis showed that most molecules participating in iron import and storage were expressed in the lower epidermis, while those involved in iron release from heme or iron transport were expressed in the upper epidermis. Consistent with their expression, keratinocyte differentiation reduced intracellular iron content. We next demonstrated that reducing ferroportin expression in vitro by ferroportin-specific siRNAs or hepcidin significantly increased the intracellular iron content. Finally, we showed that the iron content of the epidermis and squames was significantly greater in FpnEpi-KO mice than in control mice, and that FpnEpi-KO exhibited a more rapid decrease in blood hemoglobin concentration than control mice on a low iron diet. CONCLUSION These studies demonstrated that the epidermis is equipped with a machinery by which intracellular iron in differentiated keratinocytes is excreted to the extracellular space before reaching the stratum corneum.
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Affiliation(s)
- Masayuki Asano
- Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Kenshi Yamasaki
- Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Takashi Yamauchi
- Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Tadashi Terui
- Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Setsuya Aiba
- Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
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Elevated Serum Hepcidin Levels during an Intensified Training Period in Well-Trained Female Long-Distance Runners. Nutrients 2017; 9:nu9030277. [PMID: 28335426 PMCID: PMC5372940 DOI: 10.3390/nu9030277] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 02/23/2017] [Accepted: 03/03/2017] [Indexed: 12/18/2022] Open
Abstract
Iron is essential for providing oxygen to working muscles during exercise, and iron deficiency leads to decreased exercise capacity during endurance events. However, the mechanism of iron deficiency among endurance athletes remains unclear. In this study, we compared iron status between two periods involving different training regimens. Sixteen female long-distance runners participated. Over a seven-month period, fasting blood samples were collected during their regular training period (LOW; middle of February) and during an intensified training period (INT; late of August) to determine blood hematological, iron, and inflammatory parameters. Three-day food diaries were also assessed. Body weight and lean body mass did not differ significantly between LOW and INT, while body fat and body fat percentage were significantly lower in INT (p < 0.05). Blood hemoglobin, serum ferritin, total protein, and iron levels, total iron-binding capacity, and transferrin saturation did not differ significantly between the two periods. Serum hepcidin levels were significantly higher during INT than LOW (p < 0.05). Carbohydrate and iron intakes from the daily diet were significantly higher during INT than LOW (p < 0.05). In conclusion, an elevated hepcidin level was observed during an intensified training period in long-distance runners, despite an apparently adequate daily intake of iron.
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42
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Ingrassia R, Memo M, Garavaglia B. Ferrous Iron Up-regulation in Fibroblasts of Patients with Beta Propeller Protein-Associated Neurodegeneration (BPAN). Front Genet 2017; 8:18. [PMID: 28261264 PMCID: PMC5314138 DOI: 10.3389/fgene.2017.00018] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 02/06/2017] [Indexed: 11/13/2022] Open
Abstract
Mutations in WDR45 gene, coding for a beta-propeller protein, have been found in patients affected by Neurodegeneration with Brain Iron Accumulation, NBIA5 (also known as BPAN). BPAN is a movement disorder with Non Transferrin Bound Iron (NTBI) accumulation in the basal ganglia as common hallmark between NBIA classes (Hayflick et al., 2013). WDR45 has been predicted to have a role in autophagy, while the impairment of iron metabolism in the different NBIA subclasses has not currently been clarified. We found the up-regulation of the ferrous iron transporter (-)IRE/Divalent Metal Transporter1 and down-regulation of Transferrin receptor in the fibroblasts of two BPAN affected patients with splicing mutations 235+1G>A (BPAN1) and 517_519ΔVal 173 (BPAN2). The BPAN patients showed a concomitant increase of intracellular ferrous iron after starvation. An altered pattern of iron transporters with iron overload is highlighted in BPAN human fibroblasts, supporting for a role of DMT1 in NBIA. We here present a novel element, about iron accumulation, to the existing knowledge in field of NBIA. Attention is focused to a starvation-dependent iron overload, possibly accounting for iron accumulation in the basal ganglia. Further investigation could clarify iron regulation in BPAN.
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Affiliation(s)
- Rosaria Ingrassia
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia Brescia, Italy
| | - Maurizio Memo
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia Brescia, Italy
| | - Barbara Garavaglia
- Molecular Neurogenetics Unit, Foundation IRCCS Neurological Institute Carlo Besta Milan, Italy
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Huang X, Wu J, Li Q, Gu S, Chen Z, Wang K. Silkworm feces extract improves iron deficiency anemia via suppressing hepcidin expression and promoting iron-regulatory proteins expression. RSC Adv 2017. [DOI: 10.1039/c7ra09576g] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
In this study, we aimed to explore the preventive efficacy of SFE toward iron deficiency anemia in rats and clarify the underlying mechanisms. Findings suggest that SFE may be an efficient oral iron supplement to ameliorate iron deficiency anemia.
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Affiliation(s)
- Xiao Huang
- Union Hospital of Tongji Medical College
- Huazhong University of Science and Technology
- Wuhan
- China
| | - Jun Wu
- Hubei Key Laboratory of Nature Medicinal Chemistry and Resource Evaluation
- Tongji Medical College of Huazhong University of Science and Technology
- Wuhan
- China
| | - Qiang Li
- Union Hospital of Tongji Medical College
- Huazhong University of Science and Technology
- Wuhan
- China
| | - Saisai Gu
- Hubei Key Laboratory of Nature Medicinal Chemistry and Resource Evaluation
- Tongji Medical College of Huazhong University of Science and Technology
- Wuhan
- China
| | - Zehong Chen
- Union Hospital of Tongji Medical College
- Huazhong University of Science and Technology
- Wuhan
- China
| | - Kaiping Wang
- Hubei Key Laboratory of Nature Medicinal Chemistry and Resource Evaluation
- Tongji Medical College of Huazhong University of Science and Technology
- Wuhan
- China
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Boumaiza M, Carmona F, Poli M, Asperti M, Gianoncelli A, Bertuzzi M, Ruzzenenti P, Arosio P, Marzouki MN. Production and characterization of functional recombinant hybrid heteropolymers of camel hepcidin and human ferritin H and L chains. Protein Eng Des Sel 2016; 30:77-84. [PMID: 27980120 DOI: 10.1093/protein/gzw066] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 10/24/2016] [Accepted: 11/16/2016] [Indexed: 11/14/2022] Open
Abstract
Hepcidin is a liver-synthesized hormone that plays a central role in the regulation of systemic iron homeostasis. To produce a new tool for its functional properties the cDNA coding for camel hepcidin-25 was cloned at the 5'end of human FTH sequence into the pASK-IBA43plus vector for expression in Escherichia coli The recombinant fusion hepcidin-ferritin-H subunit was isolated as an insoluble iron-containing protein. When alone it did not refold in a 24-mer ferritin molecule, but it did when renatured together with H- or L-ferritin chains. We obtained stable ferritin shells exposing about 4 hepcidin peptides per 24-mer shell. The molecules were then reduced and re-oxidized in a controlled manner to allow the formation of the proper hepcidin disulfide bridges. The functionality of the exposed hepcidin was confirmed by its ability to specifically bind the mouse macrophage cell line J774 that express ferroportin and to promote ferroportin degradation. This chimeric protein may be useful for studying the hepcidin-ferroportin interaction in cells and also as drug-delivery agent.
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Affiliation(s)
- Mohamed Boumaiza
- Laboratoire d'ingénierie des protéines et des molécules bioactives, Institut Nationale des Sciences Appliquées et de Technologie (I.N.S.A.T.) BP 676, Tunis Cedex 1080, Tunisie
| | - Fernando Carmona
- Molecular Biology Laboratory, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11 , Brescia, Italy
| | - Maura Poli
- Molecular Biology Laboratory, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11 , Brescia, Italy
| | - Michela Asperti
- Molecular Biology Laboratory, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11 , Brescia, Italy
| | - Alessandra Gianoncelli
- Proteomics Platform, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, Brescia, Italy
| | - Michela Bertuzzi
- Proteomics Platform, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, Brescia, Italy
| | - Paola Ruzzenenti
- Molecular Biology Laboratory, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11 , Brescia, Italy
| | - Paolo Arosio
- Molecular Biology Laboratory, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11 , Brescia, Italy
| | - Mohamed Nejib Marzouki
- Laboratoire d'ingénierie des protéines et des molécules bioactives, Institut Nationale des Sciences Appliquées et de Technologie (I.N.S.A.T.) BP 676, Tunis Cedex 1080, Tunisie
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45
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Eid R, Arab NTT, Greenwood MT. Iron mediated toxicity and programmed cell death: A review and a re-examination of existing paradigms. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1864:399-430. [PMID: 27939167 DOI: 10.1016/j.bbamcr.2016.12.002] [Citation(s) in RCA: 180] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 11/08/2016] [Accepted: 12/04/2016] [Indexed: 12/11/2022]
Abstract
Iron is an essential micronutrient that is problematic for biological systems since it is toxic as it generates free radicals by interconverting between ferrous (Fe2+) and ferric (Fe3+) forms. Additionally, even though iron is abundant, it is largely insoluble so cells must treat biologically available iron as a valuable commodity. Thus elaborate mechanisms have evolved to absorb, re-cycle and store iron while minimizing toxicity. Focusing on rarely encountered situations, most of the existing literature suggests that iron toxicity is common. A more nuanced examination clearly demonstrates that existing regulatory processes are more than adequate to limit the toxicity of iron even in response to iron overload. Only under pathological or artificially harsh situations of exposure to excess iron does it become problematic. Here we review iron metabolism and its toxicity as well as the literature demonstrating that intracellular iron is not toxic but a stress responsive programmed cell death-inducing second messenger.
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Affiliation(s)
- Rawan Eid
- Department of Chemistry and Chemical Engineering, Royal Military College of Canada, Kingston, Ontario, Canada
| | - Nagla T T Arab
- Department of Chemistry and Chemical Engineering, Royal Military College of Canada, Kingston, Ontario, Canada
| | - Michael T Greenwood
- Department of Chemistry and Chemical Engineering, Royal Military College of Canada, Kingston, Ontario, Canada.
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Intracellular Iron Chelation Modulates the Macrophage Iron Phenotype with Consequences on Tumor Progression. PLoS One 2016; 11:e0166164. [PMID: 27806101 PMCID: PMC5091876 DOI: 10.1371/journal.pone.0166164] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 10/23/2016] [Indexed: 12/23/2022] Open
Abstract
A growing body of evidence suggests that macrophage polarization dictates the expression of iron-regulated genes. Polarization towards iron sequestration depletes the microenvironment, whereby extracellular pathogen growth is limited and inflammation is fostered. In contrast, iron release contributes to cell proliferation, which is important for tissue regeneration. Moreover, macrophages constitute a major component of the infiltrates in most solid tumors. Considering the pivotal role of macrophages for iron homeostasis and their presence in association with poor clinical prognosis in tumors, we approached the possibility to target macrophages with intracellular iron chelators. Analyzing the expression of iron-regulated genes at mRNA and protein level in primary human macrophages, we found that the iron-release phenotype is a characteristic of polarized macrophages that, in turn, stimulate tumor cell growth and progression. The application of the intracellular iron chelator (TC3-S)2 shifted the macrophage phenotype from iron release towards sequestration, as determined by the iron-gene profile and atomic absorption spectroscopy (AAS). Moreover, whereas the addition of macrophage supernatants to tumor cells induced tumor growth and metastatic behavior, the supernatant of chelator-treated macrophages reversed this effect. Iron chelators demonstrated potent anti-neoplastic properties in a number of cancers, both in cell culture and in clinical trials. Our results suggest that iron chelation could affect not only cancer cells but also the tumor microenvironment by altering the iron-release phenotype of tumor-associated macrophages (TAMs). The study of iron chelators in conjunction with the effect of TAMs on tumor growth could lead to an improved understanding of the role of iron in cancer biology and to novel therapeutic avenues for iron chelation approaches.
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da Costa JP, Vitorino R, Silva GM, Vogel C, Duarte AC, Rocha-Santos T. A synopsis on aging-Theories, mechanisms and future prospects. Ageing Res Rev 2016; 29:90-112. [PMID: 27353257 PMCID: PMC5991498 DOI: 10.1016/j.arr.2016.06.005] [Citation(s) in RCA: 228] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Revised: 06/23/2016] [Accepted: 06/23/2016] [Indexed: 12/31/2022]
Abstract
Answering the question as to why we age is tantamount to answering the question of what is life itself. There are countless theories as to why and how we age, but, until recently, the very definition of aging - senescence - was still uncertain. Here, we summarize the main views of the different models of senescence, with a special emphasis on the biochemical processes that accompany aging. Though inherently complex, aging is characterized by numerous changes that take place at different levels of the biological hierarchy. We therefore explore some of the most relevant changes that take place during aging and, finally, we overview the current status of emergent aging therapies and what the future holds for this field of research. From this multi-dimensional approach, it becomes clear that an integrative approach that couples aging research with systems biology, capable of providing novel insights into how and why we age, is necessary.
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Affiliation(s)
- João Pinto da Costa
- CESAM and Department of Chemistry, University of Aveiro, Campus de Santiago, 3810-193 Aveiro, Portugal.
| | - Rui Vitorino
- Department of Medical Sciences, Institute for Biomedicine-iBiMED, University of Aveiro, Campus de Santiago, 3810-193 Aveiro, Portugal; Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Gustavo M Silva
- Department of Biology, Center for Genomics and Systems Biology, NY, NY 10003, USA
| | - Christine Vogel
- Department of Biology, Center for Genomics and Systems Biology, NY, NY 10003, USA
| | - Armando C Duarte
- CESAM and Department of Chemistry, University of Aveiro, Campus de Santiago, 3810-193 Aveiro, Portugal
| | - Teresa Rocha-Santos
- CESAM and Department of Chemistry, University of Aveiro, Campus de Santiago, 3810-193 Aveiro, Portugal
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48
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Buratti P, Gammella E, Rybinska I, Cairo G, Recalcati S. Recent Advances in Iron Metabolism: Relevance for Health, Exercise, and Performance. Med Sci Sports Exerc 2016; 47:1596-604. [PMID: 25494391 DOI: 10.1249/mss.0000000000000593] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Iron is necessary for physiological processes essential for athletic performance, such as oxygen transport, energy production, and cell division. However, an excess of "free" iron is toxic because it produces reactive hydroxyl radicals that damage biological molecules, thus leading to cell and tissue injury. Therefore, iron homeostasis is strictly regulated; and in recent years, there have been important advancements in our knowledge of the underlying processes. Hepcidin is the central regulator of systemic iron homeostasis and exerts its function by controlling the presence of the iron exporter ferroportin on the cell membrane. Hepcidin binding induces ferroportin degradation, thus leading to cellular iron retention and decreased levels of circulating iron. As iron is required for hemoglobin synthesis, the tight link between erythropoiesis and iron metabolism is particularly relevant to sports physiology. The iron needed for hemoglobin synthesis is ensured by inhibiting hepcidin to increase ferroportin activity and iron availability and hence to make certain that efficient blood oxygen transport occurs for aerobic exercise. However, hepcidin expression is also affected by exercise-associated conditions, such as iron deficiency, anemia or hypoxia, and, particularly, inflammation, which can play a role in the pathogenesis of sports anemia. Here, we review recent advances showing the relevance of iron for physical exercise and athletic performance. Low body iron levels can cause anemia and thus limit the delivery of oxygen to exercising muscle, but tissue iron deficiency may also affect performance by, for example, hampering muscle oxidative metabolism. Accordingly, a hemoglobin-independent effect of iron on exercise capacity has been demonstrated in animal models and humans. Here, we review recent advances showing the relevance of iron for physical exercise and athletic performance.
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Affiliation(s)
- Paolo Buratti
- Department of Biomedical Sciences for Health, University of Milan, Milan, ITALY
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Dual Role of ROS as Signal and Stress Agents: Iron Tips the Balance in favor of Toxic Effects. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:8629024. [PMID: 27006749 PMCID: PMC4783558 DOI: 10.1155/2016/8629024] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 01/28/2016] [Indexed: 01/01/2023]
Abstract
Iron is essential for life, while also being potentially harmful. Therefore, its level is strictly monitored and complex pathways have evolved to keep iron safely bound to transport or storage proteins, thereby maintaining homeostasis at the cellular and systemic levels. These sequestration mechanisms ensure that mildly reactive oxygen species like anion superoxide and hydrogen peroxide, which are continuously generated in cells living under aerobic conditions, keep their physiologic role in cell signaling while escaping iron-catalyzed transformation in the highly toxic hydroxyl radical. In this review, we describe the multifaceted systems regulating cellular and body iron homeostasis and discuss how altered iron balance may lead to oxidative damage in some pathophysiological settings.
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50
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Chekhun VF, Lozovska YV, Burlaka AP, Ganusevich LI, Shvets YV, Lukyanova NY, Todor IM, Tregubova NA, Naleskina LA. Remodulating effect of doxorubicin on the state of iron-containing proteins, and redox characteristics of tumor with allowance for its sensitivity to cytostatic agents. UKRAINIAN BIOCHEMICAL JOURNAL 2016; 88:99-108. [PMID: 29227592 DOI: 10.15407/ubj88.01.099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The study was aimed at determining the changes of metal-containing proteins in blood serum and
tumor tissue of animals with parental and doxorubicin-resistant strains of Walker-256 carcinosarcoma before
and after the cytostatic administration. It has been shown that upon doxorubicin action the levels of total iron
and transferrin in the tissues from the both groups of animals decreased while that of ferritine simultaneously
increased with more pronounced pattern in the group of animals with resistant tumor strain. It has been
shown that upon the action of doxorubicin in tumor tissue of animals with different sensitivity to the cytostatic
there could be observed oppositely directed changes in the redox state of these cells that in turn determined
the content of “ free iron” complexes, RO S generation and concentration of active forms of matrix metaloproteinase-
2 and matrix metaloproteinase-9, namely, the increase of these indexes in animals with parental strain
and their decrease in animals with the resistant one. So, our study has demonstrated the remodulating effect
of doxorubicin on the state of metal-containing proteins and redox characteristics of tumor dependent on its
sensitivity to cytostatic, at the levels of the tumor and an organism. These data may serve as a criterion for
the development of programs for the correction of malfunction of iron metabolism aimed at elevating tumor
sensitivity to cytostatic agents.
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