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Anastasopoulos NA, Barbouti A, Goussia AC, Christodoulou DK, Glantzounis GK. Exploring the Role of Metabolic Hyperferritinaemia (MHF) in Steatotic Liver Disease (SLD) and Hepatocellular Carcinoma (HCC). Cancers (Basel) 2025; 17:842. [PMID: 40075688 PMCID: PMC11899477 DOI: 10.3390/cancers17050842] [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: 01/31/2025] [Revised: 02/24/2025] [Accepted: 02/26/2025] [Indexed: 03/14/2025] Open
Abstract
The increasing prevalence of the spectrum of Steatotic Liver Disease (SLD), including Metabolic-Associated Steatotic Liver Disease (MASLD), Metabolic-Associated Steatohepatitis (MASH), and progression to Cirrhosis and Hepatocellular Carcinoma (HCC) has led to intense research in disease pathophysiology, with many studies focusing on the role of iron. Iron overload, which is often observed in patients with SLD as a part of metabolic hyperferritinaemia (MHF), particularly in the reticuloendothelial system (RES), can exacerbate steatosis. This imbalance in iron distribution, coupled with a high-fat diet, can further promote the progression of SLD by means of oxidative stress triggering inflammation and activating hepatic stellate cells (HSCs), therefore leading to fibrosis and progression of simple steatosis to the more severe MASH. The influence of iron overload in disease progression has also been shown by the complex role of ferroptosis, a type of cell death driven by iron-dependent lipid peroxidation. Ferroptosis depletes the liver's antioxidant capacity, further contributing to the development of MASH, while its role in MASH-related HCC is potentially linked to alternations in the tumour microenvironment, as well as ferroptosis resistance. The iron-rich steatotic hepatic environment becomes prone to hepatocarcinogenesis by activation of several pro-carcinogenic mechanisms including epithelial-to-mesenchymal transition and deactivation of DNA damage repair. Biochemical markers of iron overload and deranged metabolism have been linked to all stages of SLD and its associated HCC in multiple patient cohorts of diverse genetic backgrounds, enhancing our daily clinical understanding of this interaction. Further understanding could lead to enhanced therapies for SLD management and prevention.
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Affiliation(s)
- Nikolaos-Andreas Anastasopoulos
- HPB Unit, Department of Surgery, University Hospital of Ioannina, 45110 Ioannina, Greece
- Imperial College Renal and Transplant Centre, Imperial College Healthcare NHS Trust, London W12 0HS, UK
| | - Alexandra Barbouti
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
| | - Anna C. Goussia
- Department of Pathology, University Hospital of Ioannina, 45110 Ioannina, Greece
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Amangurbanova M, Huang DQ, Noureddin N, Tesfai K, Bettencourt R, Siddiqi H, Lopez SJ, Cervantes V, Madamba E, Loomba R. A Prospective Study on the Prevalence of MASLD in Patients With Type 2 Diabetes and Hyperferritinaemia. Aliment Pharmacol Ther 2025; 61:456-464. [PMID: 39499168 DOI: 10.1111/apt.18377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 09/08/2024] [Accepted: 10/22/2024] [Indexed: 11/07/2024]
Abstract
BACKGROUND Elevated levels of serum ferritin, a marker of hepatic iron overload and inflammation, may be associated with metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatic fibrosis. AIM To determine the prevalence of MASLD and significant hepatic fibrosis among patients with type 2 diabetes mellitus (T2DM) and hyperferritinaemia. METHODS This is a cross-sectional analysis of a prospective cohort of 523 adults (64% female) aged 50-80 with T2DM and without a diagnosis of haemochromatosis. MASLD and significant fibrosis were defined as magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥ 5% and magnetic resonance elastography (MRE) ≥ 3.0 kPa, respectively. Hyperferritinaemia was defined as serum ferritin ≥ 200 ng/mL in females or ≥ 300 ng/mL in males. The primary objective was to determine the prevalence of MASLD and significant fibrosis in hyperferritinaemia. RESULTS The mean age and body mass index were 64.1 (±8.1) years and 31.5 (±5.9) kg/m2, respectively. The overall prevalence of hyperferritinaemia was 20.5% (n = 107). The prevalence of MASLD (78.5% vs. 62.1%, p = 0.001) and significant fibrosis (35.5% vs. 22.1%, p = 0.002) were higher in participants with hyperferritinaemia than those without. Hyperferritinaemia remained an independent predictor of MASLD (OR 2.01; 95% CI 1.19-3.39; p = 0.009) and significant fibrosis (OR 2.33; CI 1.43-3.77; p = 0.001), even after adjustment for age, sex, obesity and insulin use. CONCLUSION Approximately 80% of people with hyperferritinaemia and T2DM have MASLD, and more than a third have significant hepatic fibrosis. Hyperferritinaemia may be a useful biomarker for MASLD and significant fibrosis in people with T2DM.
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Affiliation(s)
- Maral Amangurbanova
- Division of Gastroenterology, MASLD Research Center, University of California at San Diego, La Jolla, California, USA
| | - Daniel Q Huang
- Division of Gastroenterology, MASLD Research Center, University of California at San Diego, La Jolla, California, USA
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
| | - Nabil Noureddin
- Division of Gastroenterology, MASLD Research Center, University of California at San Diego, La Jolla, California, USA
| | - Kaleb Tesfai
- Division of Gastroenterology, MASLD Research Center, University of California at San Diego, La Jolla, California, USA
| | - Richelle Bettencourt
- Division of Gastroenterology, MASLD Research Center, University of California at San Diego, La Jolla, California, USA
| | - Harris Siddiqi
- Division of Gastroenterology, MASLD Research Center, University of California at San Diego, La Jolla, California, USA
| | - Scarlett J Lopez
- Division of Gastroenterology, MASLD Research Center, University of California at San Diego, La Jolla, California, USA
| | - Vanessa Cervantes
- Division of Gastroenterology, MASLD Research Center, University of California at San Diego, La Jolla, California, USA
| | - Egbert Madamba
- Division of Gastroenterology, MASLD Research Center, University of California at San Diego, La Jolla, California, USA
| | - Rohit Loomba
- Division of Gastroenterology, MASLD Research Center, University of California at San Diego, La Jolla, California, USA
- Division of Epidemiology, Department of Family Medicine and Public Health, University of California at San Diego, San Diego, California, USA
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Jang JH, Sung JH, Huh JY. Diverse Functions of Macrophages in Obesity and Metabolic Dysfunction-Associated Steatotic Liver Disease: Bridging Inflammation and Metabolism. Immune Netw 2025; 25:e12. [PMID: 40078789 PMCID: PMC11896663 DOI: 10.4110/in.2025.25.e12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 02/12/2025] [Accepted: 02/17/2025] [Indexed: 03/14/2025] Open
Abstract
Macrophages play crucial roles in immune response and tissue homeostasis, with their functions becoming increasingly complex in obesity-mediated metabolic disorders. This review explores the extensive range of macrophage activities within adipose and liver tissues, emphasizing their contribution to the pathogenesis and progression of obesity and its related metabolic dysfunction-associated steatotic liver disease (MASLD). In the context of obesity, macrophages respond adaptively to lipid overloads and inflammatory cues in adipose tissue, profoundly influencing insulin resistance and metabolic homeostasis. Concurrently, their role in the liver extends to moderating inflammation and orchestrating fibrotic responses, integral to the development of MASLD. Highlighting the spectrum of macrophage phenotypes across these metabolic landscapes, we summarize their diverse roles in linking inflammatory processes with metabolic functions. This review advocates for a deeper understanding of macrophage subsets in metabolic tissues, proposing targeted research to harness their therapeutic potential in mitigating MASLD and other metabolic disorders.
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Affiliation(s)
- Jun Hee Jang
- Department of Life Science, Sogang University, Seoul 04107, Korea
- Center for Nano Materials, Sogang University, Seoul 04107, Korea
| | - Jin Hyun Sung
- Department of Life Science, Sogang University, Seoul 04107, Korea
- Center for Nano Materials, Sogang University, Seoul 04107, Korea
| | - Jin Young Huh
- Department of Life Science, Sogang University, Seoul 04107, Korea
- Center for Nano Materials, Sogang University, Seoul 04107, Korea
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Ma MJ, Lin J, Yang HJ, You J. Relationship between iron and lipid peroxidation in ferroptosis and effect of ferroptosis in metabolic dysfunction-associated steatotic liver disease. Shijie Huaren Xiaohua Zazhi 2025; 33:28-36. [DOI: 10.11569/wcjd.v33.i1.28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 12/26/2024] [Accepted: 01/15/2025] [Indexed: 01/25/2025] Open
Abstract
The liver plays an irreplaceable role in human body functions, and liver damage of various causes is a major problem that plagues human health. China is a country with a heavy burden of hepatitis B, but in recent years, the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has shown an increasing trend. Although the mechanism of liver injury caused by MASLD is not completely clear, it is inextricably related to the body's metabolism. MASLD is one of the most common chronic liver diseases and is considered to be a manifestation of metabolic syndrome in the liver. Ferroptosis is a cell death mechanism discovered in recent years, which is characterized by iron metabolism disorders and lipid peroxide accumulation. In recent years, several studies have found that there is an inextricable relationship between ferroptosis and liver disease. This article describes the relationship between iron or iron homeostasis and lipid peroxidation from the perspective of iron metabolism disorders, and the effect of ferroptosis in MASLD.
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Affiliation(s)
- Meng-Juan Ma
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jie Lin
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Hong-Ju Yang
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jing You
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
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Ma MJ, Lin J, Yang HJ, You J. Relationship between iron and lipid peroxidation in ferroptosis and effect of ferroptosis in metabolic dysfunction-associated steatotic liver disease. Shijie Huaren Xiaohua Zazhi 2025; 33:34-42. [DOI: 10.11569/wcjd.v33.i1.34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 12/26/2024] [Accepted: 01/15/2025] [Indexed: 01/22/2025] Open
Abstract
The liver plays an irreplaceable role in human body functions, and liver damage of various causes is a major problem that plagues human health. China is a country with a heavy burden of hepatitis B, but in recent years, the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has shown an increasing trend. Although the mechanism of liver injury caused by MASLD is not completely clear, it is inextricably related to the body's metabolism. MASLD is one of the most common chronic liver diseases and is considered to be a manifestation of metabolic syndrome in the liver. Ferroptosis is a cell death mechanism discovered in recent years, which is characterized by iron metabolism disorders and lipid peroxide accumulation. In recent years, several studies have found that there is an inextricable relationship between ferroptosis and liver disease. This article describes the relationship between iron or iron homeostasis and lipid peroxidation from the perspective of iron metabolism disorders, and the effect of ferroptosis in MASLD.
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Affiliation(s)
- Meng-Juan Ma
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jie Lin
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Hong-Ju Yang
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jing You
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
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Wang Y, Feng W, Wang F, Min J. [Research progress of iron metabolism and ferroptosis in myeloid neoplasms]. Zhejiang Da Xue Xue Bao Yi Xue Ban 2024; 53:735-746. [PMID: 39608794 PMCID: PMC11736352 DOI: 10.3724/zdxbyxb-2024-0211] [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: 05/19/2024] [Accepted: 08/05/2024] [Indexed: 11/30/2024]
Abstract
It is reported that iron metabolism and ferroptosis can influence the occurrence and development of myeloid tumors, which can serve as therapeutic targets. Dysregulation of iron metabolism is present in a variety of myeloid neoplasms. The prognosis of acute myeloid leukemia is related to differential expression of molecules related to iron metabolism. The prognosis of myelodysplastic syndrome patients with iron overload is poor. Myeloproliferative neoplasms are often characterized by the coexistence of iron deficiency and erythrocytosis, which can be treated by targeting hepcidin. Myeloid tumor cells are susceptible to oxidative damage caused by the accumulation of reactive oxygen species and are sensitive to ferroptosis. Ferroptosis has anti-tumor effect in acute myeloid leukemia and myelodysplastic syndrome. Targeting ferroptosis can reverse imatinib resistance in chronic myeloid leukemia. This article reviews the characteristics of iron metabolism in the development and progression of myeloid neoplasms, as well as the mechanism of ferroptosis, to provide a basis for the development of new therapeutic strategies.
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Affiliation(s)
- Yudi Wang
- Department of Hematology, Shaoxing People's Hospital, Shaoxing 312000, Zhejiang Province, China.
- Institute of Translational Medicine, Zhejiang University, Hangzhou 310058, China.
| | - Weiying Feng
- Department of Hematology, Shaoxing People's Hospital, Shaoxing 312000, Zhejiang Province, China
| | - Fudi Wang
- School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Junxia Min
- Institute of Translational Medicine, Zhejiang University, Hangzhou 310058, China.
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Fortier V, Mohamed A, McNabb E, Dana J, Zakarian R, Levesque IR, Reinhold C. R 2* Impact on Hepatic Fat Quantification With a Commercial Single Voxel Technique at 1.5 and 3.0 T. Can Assoc Radiol J 2024; 75:838-846. [PMID: 38832642 DOI: 10.1177/08465371241255896] [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] [Indexed: 06/05/2024] Open
Abstract
Rationale and Objectives: Fat quantification accuracy using a commercial single-voxel high speed T2-corrected multi-echo (HISTO) technique and its robustness to R2* variations at 3.0 T, such as those introduced by iron in liver, has not been fully established. This study evaluated HISTO at 3.0 T and sought to reproduce results at 1.5 T. Methods: Phantoms were prepared with a range of fat content and R2*. Data were acquired at 1.5 T and 3.0 T, using HISTO and a Dixon technique. Fat quantification accuracy was evaluated as a function of R2*. The patient study included 239 consecutive patients. Data were acquired at 1.5 T or 3.0 T, using HISTO and Dixon techniques. The techniques were compared using Bland-Altman plots. Bias significance was evaluated using a one-sample t-test. Results: In phantoms, HISTO was accurate within 10% up to a R2* of 100 s-1 at both field strengths, while Dixon was accurate within 10% where R2* was accurately quantified (up to 350 s-1 at 1.5 T, and 550 s-1 at 3.0 T). In patients, where R2* was <100 s-1, fat quantification from both techniques agreed at 1.5 T (P = .71), but not at 3.0 T (P = .007), with a bias <1%. Conclusion: Results suggest that HISTO is reliable when R2* is <100 s-1, corresponding to patients with at most mild liver iron overload, and that it should be used with caution when R2* is >100 s-1. Dixon should be preferred for hepatic fat quantification due to its robustness to R2* variations.
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Affiliation(s)
- Véronique Fortier
- Department of Medical Imaging, McGill University Health Centre, Montreal, QC, Canada
- Diagnostic Radiology, McGill University, Montreal, QC, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada
- Medical Physics Unit, McGill University, Montreal, QC, Canada
| | - Ahmed Mohamed
- Radiology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Evan McNabb
- Department of Medical Imaging, McGill University Health Centre, Montreal, QC, Canada
| | - Jérémy Dana
- Department of Medical Imaging, McGill University Health Centre, Montreal, QC, Canada
| | - Rita Zakarian
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Ives R Levesque
- Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada
- Medical Physics Unit, McGill University, Montreal, QC, Canada
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Caroline Reinhold
- Department of Medical Imaging, McGill University Health Centre, Montreal, QC, Canada
- Diagnostic Radiology, McGill University, Montreal, QC, Canada
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Montreal Imaging Experts Inc., Montreal, QC, Canada
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Yang Y, Wu J, Wang L, Ji G, Dang Y. Copper homeostasis and cuproptosis in health and disease. MedComm (Beijing) 2024; 5:e724. [PMID: 39290254 PMCID: PMC11406047 DOI: 10.1002/mco2.724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 08/21/2024] [Accepted: 08/21/2024] [Indexed: 09/19/2024] Open
Abstract
Copper is a vital trace element in human physiology, essential for the synthesis of numerous crucial metabolic enzymes and facilitation of various biological processes. Regulation of copper levels within a narrow range is imperative for maintaining metabolic homeostasis. Numerous studies have demonstrated the significant roles of copper homeostasis and cuproptosis in health and disease pathogenesis. However, a comprehensive and up-to-date systematic review in this domain remains absent. This review aims to consolidate recent advancements in understanding the roles of cuproptosis and copper homeostasis in health and disease, focusing on the underlying mechanisms and potential therapeutic interventions. Dysregulation of copper homeostasis, manifesting as either copper excess or deficiency, is implicated in the etiology of various diseases. Cuproptosis, a recently identified form of cell death, is characterized by intracellular copper overload. This phenomenon mediates a diverse array of evolutionary processes in organisms, spanning from health to disease, and is implicated in genetic disorders, liver diseases, neurodegenerative disorders, and various cancers. This review provides a comprehensive summary of the pathogenic mechanisms underlying cuproptosis and copper homeostasis, along with associated targeted therapeutic agents. Furthermore, it explores future research directions with the potential to yield significant advancements in disease treatment, health management, and disease prevention.
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Affiliation(s)
- Yunuo Yang
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Jiaxuan Wu
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Lisheng Wang
- Department of Biochemistry, Microbiology and Immunology, Faculty of MedicineUniversity of OttawaOttawaOntarioCanada
- China‐Canada Centre of Research for Digestive DiseasesUniversity of OttawaOttawaOntarioCanada
| | - Guang Ji
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Yanqi Dang
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
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Lonardo A, Weiskirchen R. Copper and liver fibrosis in MASLD: the two-edged sword of copper deficiency and toxicity. METABOLISM AND TARGET ORGAN DAMAGE 2024. [DOI: 10.20517/mtod.2024.47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Copper is a trace metal whose absence or deficiency can cause structural and functional alterations that can be corrected by copper administration. Copper excess is associated with significant liver toxicity, such as that seen in Wilson’s disease, which often exhibits liver steatosis and can be managed by copper sequestrants. Copper, due to its ability to either accept or donate electrons, is a cofactor in many physiological redox reactions, playing an essential role in cell energy homeostasis, detoxification of reactive oxygen species, and hepatic immunometabolism. Given these facts, it is reasonable to speculate that copper might be involved in the pathogenesis of liver fibrosis in the setting of metabolic dysfunction-associated fatty liver disease (MASLD). To address this research question, a narrative review of published studies was conducted, spanning from the needs, sources, and toxicity of copper to Menkes and Wilson’s disease. Most epidemiological studies have demonstrated that MASLD is associated with copper deficiency. However, several studies show that MASLD is associated with copper excess and very few conclude that copper is not associated with MASLD. Therefore, the putative pathomechanisms associating both copper excess and deficiency with MASLD development and progression are reviewed. In conclusion, epidemiological and pathogenic data support the notion that well-balanced copper homeostasis is a prerequisite for liver health. Accordingly, both copper excess and deficiency may potentially predispose to liver fibrosis via the development of MASLD. Therefore, studies aimed at restoring normal bodily stores of copper should be tailored according to precision medicine approaches based on the specific features of copper metabolism in individual MASLD patients.
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Cheng Z, Chu H, Seki E, Lin R, Yang L. Hepatocyte programmed cell death: the trigger for inflammation and fibrosis in metabolic dysfunction-associated steatohepatitis. Front Cell Dev Biol 2024; 12:1431921. [PMID: 39071804 PMCID: PMC11272544 DOI: 10.3389/fcell.2024.1431921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 06/28/2024] [Indexed: 07/30/2024] Open
Abstract
By replacing and removing defective or infected cells, programmed cell death (PCD) contributes to homeostasis maintenance and body development, which is ubiquitously present in mammals and can occur at any time. Besides apoptosis, more novel modalities of PCD have been described recently, such as necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death. PCD not only regulates multiple physiological processes, but also participates in the pathogenesis of diverse disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is mainly classified into metabolic dysfunction-associated steatotic liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH), and the latter putatively progresses to cirrhosis and hepatocellular carcinoma. Owing to increased incidence and obscure etiology of MASH, its management still remains a tremendous challenge. Recently, hepatocyte PCD has been attracted much attention as a potent driver of the pathological progression from MASL to MASH, and some pharmacological agents have been proved to exert their salutary effects on MASH partly via the regulation of the activity of hepatocyte PCD. The current review recapitulates the pathogenesis of different modalities of PCD, clarifies the mechanisms underlying how metabolic disorders in MASLD induce hepatocyte PCD and how hepatocyte PCD contributes to inflammatory and fibrotic progression of MASH, discusses several signaling pathways in hepatocytes governing the execution of PCD, and summarizes some potential pharmacological agents for MASH treatment which exert their therapeutic effects partly via the regulation of hepatocyte PCD. These findings indicate that hepatocyte PCD putatively represents a new therapeutic point of intervention for MASH.
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Affiliation(s)
- Zilu Cheng
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Huikuan Chu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ekihiro Seki
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Rong Lin
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ling Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Torrez CZ, Easley A, Bouamar H, Zheng G, Gu X, Yang J, Chiu YC, Chen Y, Halff GA, Cigarroa FG, Sun LZ. STEAP2 promotes hepatocellular carcinoma progression via increased copper levels and stress-activated MAP kinase activity. Sci Rep 2024; 14:12753. [PMID: 38830975 PMCID: PMC11148201 DOI: 10.1038/s41598-024-63368-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 05/28/2024] [Indexed: 06/05/2024] Open
Abstract
Six Transmembrane Epithelial Antigen of Prostate 2 (STEAP2) belongs to a family of metalloreductases, which indirectly aid in uptake of iron and copper ions. Its role in hepatocellular carcinoma (HCC) remains to be characterized. Here, we report that STEAP2 expression was upregulated in HCC tumors compared with paired adjacent non-tumor tissues by RNA sequencing, RT-qPCR, Western blotting, and immunostaining. Public HCC datasets demonstrated upregulated STEAP2 expression in HCC and positive association with tumor grade. Transient and stable knockdown (KD) of STEAP2 in HCC cell lines abrogated their malignant phenotypes in vitro and in vivo, while STEAP2 overexpression showed opposite effects. STEAP2 KD in HCC cells led to significant alteration of genes associated with extracellular matrix organization, cell adhesion/chemotaxis, negative enrichment of an invasiveness signature gene set, and inhibition of cell migration/invasion. STEAP2 KD reduced intracellular copper levels and activation of stress-activated MAP kinases including p38 and JNK. Treatment with copper rescued the reduced HCC cell migration due to STEAP2 KD and activated p38 and JNK. Furthermore, treatment with p38 or JNK inhibitors significantly inhibited copper-mediated cell migration. Thus, STEAP2 plays a malignant-promoting role in HCC cells by driving migration/invasion via increased copper levels and MAP kinase activities. Our study uncovered a novel molecular mechanism contributing to HCC malignancy and a potential therapeutic target for HCC treatment.
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Affiliation(s)
- Carla Zeballos Torrez
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Acarizia Easley
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Hakim Bouamar
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Guixi Zheng
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Xiang Gu
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Junhua Yang
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Yu-Chiao Chiu
- Department of Population Health Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Yidong Chen
- Department of Population Health Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Glenn A Halff
- Transplant Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Francisco G Cigarroa
- Transplant Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
| | - Lu-Zhe Sun
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
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12
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Shen X, Yu Z, Wei C, Hu C, Chen J. Iron metabolism and ferroptosis in nonalcoholic fatty liver disease: what is our next step? Am J Physiol Endocrinol Metab 2024; 326:E767-E775. [PMID: 38506752 PMCID: PMC11376490 DOI: 10.1152/ajpendo.00260.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 03/06/2024] [Accepted: 03/09/2024] [Indexed: 03/21/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with increasing prevalence worldwide. NAFLD could develop from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), NASH-related fibrosis, cirrhosis, and even hepatocellular carcinoma. However, the mechanism of NAFLD development has not yet been fully defined. Recently, emerging evidence shows that the dysregulated iron metabolism marked by elevated serum ferritin, and ferroptosis are involved in the NAFLD. Understanding iron metabolism and ferroptosis can shed light on the mechanisms of NAFLD development. Here, we summarized studies on iron metabolism and the ferroptosis process involved in NAFLD development to highlight potential medications and therapies for treating NAFLD.
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Affiliation(s)
- Xiang Shen
- Munich Medical Research School, Ludwig Maximilian University of Munich, Munich, Germany
| | - Ziqi Yu
- Munich Medical Research School, Ludwig Maximilian University of Munich, Munich, Germany
| | - Changli Wei
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang Medical College, Jiangxi Provincial People's Hospital, Nanchang, People's Republic of China
| | - Chong Hu
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang Medical College, Jiangxi Provincial People's Hospital, Nanchang, People's Republic of China
| | - Jianyong Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang Medical College, Jiangxi Provincial People's Hospital, Nanchang, People's Republic of China
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13
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Zou H, Wong RSM, Yan X. Erythropoietin hyporesponsiveness in non-alcoholic fatty liver disease. Clin Exp Pharmacol Physiol 2024; 51:e13869. [PMID: 38725222 DOI: 10.1111/1440-1681.13869] [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: 10/29/2023] [Revised: 04/06/2024] [Accepted: 04/18/2024] [Indexed: 06/15/2024]
Abstract
Treatment with erythropoietin (EPO) can correct anaemia in chronic kidney disease (CKD) patients; however, up to 10% exhibit resistance or hyporesponsiveness to EPO. Non-alcoholic fatty liver disease (NAFLD), prevalent liver disease in CKD patients, may limit EPO response because of thrombopoietin deficiency, iron homeostasis disorder and inflammation. Therefore, we hypothesized NAFLD is a risk factor for EPO responsiveness. To test our hypothesis, we evaluated the effect of EPO in healthy rats and rats with NAFLD induced by a high-fat, high-carbohydrate (HFHC) diet. After 12 weeks on the HFHC diet, NAFLD rats showed lower erythroid response to EPO treatment than healthy rats. We, then, determined that the primary cause of EPO hyporesponsiveness could be iron deficiency associated with inflammation, which reduces erythroid cell production. Specifically, the concentrations of hepcidin, ferritin, transferrin and white blood cells in NAFLD rats were 12.8-, 16.4-, 2.51- and 1.40-fold higher than those in healthy rats, respectively. However, erythroid cell types in the bone marrow of NAFLD rats were significantly reduced. In conclusion, our data suggest that NAFLD could be a risk factor for EPO responsiveness, which is attributed to functional iron deficiency associated with inflammation.
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Affiliation(s)
- Huixi Zou
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Raymond S M Wong
- Division of Hematology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Xiaoyu Yan
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
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14
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Tinkov AA, Korobeinikova TV, Morozova GD, Aschner M, Mak DV, Santamaria A, Rocha JBT, Sotnikova TI, Tazina SI, Skalny AV. Association between serum trace element, mineral, and amino acid levels with non-alcoholic fatty liver disease (NAFLD) in adult women. J Trace Elem Med Biol 2024; 83:127397. [PMID: 38290269 DOI: 10.1016/j.jtemb.2024.127397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 12/29/2023] [Accepted: 01/13/2024] [Indexed: 02/01/2024]
Abstract
The objective of the present study is assessment of serum trace element and amino acid levels in non-alcoholic fatty liver disease (NAFLD) patients with subsequent evaluation of its independent associations with markers of liver injury and metabolic risk. MATERIALS AND METHODS 140 women aged 20-90 years old with diagnosed NAFLD and 140 healthy women with a respective age range were enrolled in the current study. Analysis of serum and hair levels of trace elements and minerals was performed with inductively-coupled plasma mass-spectrometry (ICP-MS). Serum amino acid concentrations were evaluated by high-pressure liquid chromatography (HPLC) with UV-detection. In addition, routine biochemical parameters including liver damage markers, alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT), were assessed spectrophotometrically. RESULTS The findings demonstrated that patients with NAFLD were characterized by higher ALT, GGT, lactate dehydrogenase (LDH) and cholinesterase (CE) activity, as well as increased levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and uric acid. NAFLD patients were characterized by reduced serum and hair Co, Se, and Zn levels, as well as hair Cu content and serum Mn concentrations in comparison to controls. Circulating Ala, Cit, Glu, Gly, Ile, Leu, Phe, and Tyr levels in NAFLD patients exceeded those in the control group. Multiple linear regression demonstrated that serum and hair trace element levels were significantly associated with circulating amino acid levels after adjustment for age, BMI, and metabolic parameters including liver damage markers. CONCLUSION It is proposed that altered trace element handling may contribute to NAFLD pathogenesis through modulation of amino acid metabolism.
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Affiliation(s)
- Alexey A Tinkov
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University, 150003 Yaroslavl, Russia; Department of Medical Elementology, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia.
| | - Tatiana V Korobeinikova
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; Department of Medical Elementology, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia
| | - Galina D Morozova
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, 10461 Bronx, NY, USA
| | - Daria V Mak
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia
| | - Abel Santamaria
- Faculty of Sciencies, National Autonomous University of Mexico, 04510 Mexico City, Mexico
| | - Joao B T Rocha
- Departamento de Bioquímica e Biologia Molecular, CCNE, Universidade Federal de Santa Maria, Santa Maria 97105-900 RS, Brazil
| | - Tatiana I Sotnikova
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; City Clinical Hospital n. a. S.P. Botkin of the Moscow City Health Department, 125284 Moscow, Russia
| | - Serafima Ia Tazina
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; City Clinical Hospital n. a. S.P. Botkin of the Moscow City Health Department, 125284 Moscow, Russia
| | - Anatoly V Skalny
- Center of Bioelementology and Human Ecology, and World-Class Research Center "Digital Biodesign and Personalized Healthcare", and Department of Therapy of the Institute of Postgraduate Education, IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University, 150003 Yaroslavl, Russia; Department of Medical Elementology, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia
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15
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Tyczyńska M, Hunek G, Szczasny M, Brachet A, Januszewski J, Forma A, Portincasa P, Flieger J, Baj J. Supplementation of Micro- and Macronutrients-A Role of Nutritional Status in Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2024; 25:4916. [PMID: 38732128 PMCID: PMC11085010 DOI: 10.3390/ijms25094916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 04/28/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a condition in which the pathological cumulation of fat with coexisting inflammation and damage of hepatic cells leads to progressive dysfunctions of the liver. Except for the commonly well-known major causes of NAFLD such as obesity, dyslipidemia, insulin resistance, or diabetes, an unbalanced diet and imbalanced nutritional status should also be taken into consideration. In this narrative review, we summarized the current knowledge regarding the micro- and macronutrient status of patients suffering from NAFLD considering various diets and supplementation of chosen supplements. We aimed to summarize the knowledge indicating which nutritional impairments may be associated with the onset and progression of NAFLD at the same time evaluating the potential therapy targets that could facilitate the healing process. Except for the above-mentioned objectives, one of the most important aspects of this review was to highlight the possible strategies for taking care of NAFLD patients taking into account the challenges and opportunities associated with the micronutrient status of the patients. The current research indicates that a supplementation of chosen vitamins (e.g., vitamin A, B complex, C, or D) as well as chosen elements such as zinc may alleviate the symptoms of NAFLD. However, there is still a lack of sufficient data regarding healthy ranges of dosages; thus, further research is of high importance in this matter.
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Affiliation(s)
- Magdalena Tyczyńska
- Department of Correct, Clinical and Imaging Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland;
| | - Gabriela Hunek
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (G.H.); (A.B.)
| | - Martyna Szczasny
- Chair and Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (M.S.); (J.J.)
| | - Adam Brachet
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (G.H.); (A.B.)
| | - Jacek Januszewski
- Chair and Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (M.S.); (J.J.)
| | - Alicja Forma
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (G.H.); (A.B.)
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy;
| | - Jolanta Flieger
- Department of Analytical Chemistry, Medical University of Lublin, Chodźki 4A, 20-093 Lublin, Poland;
| | - Jacek Baj
- Chair and Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (M.S.); (J.J.)
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16
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Pan Z, Deng C, Shui L, Yin H, Liu B. Copper Deficiency Induces Oxidative Stress in Liver of Mice by Blocking the Nrf 2 Pathway. Biol Trace Elem Res 2024; 202:1603-1611. [PMID: 37436649 DOI: 10.1007/s12011-023-03769-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 07/07/2023] [Indexed: 07/13/2023]
Abstract
Copper (Cu) is an essential metal required for many physiological processes and biological reactions. Liver is the main organ of metabolism of Cu and is also the site where synthesis of some metalloproteins. The purpose of this study is to explore the effects of Cu deficiency on the liver and to evaluate the changes in liver oxidative stress levels to reveal its possible impact mechanisms. Mice were feed to a nutritional Cu-deficiency diet from weaning and injected with copper sulfate (CuSO4) intraperitoneally to correct Cu deficiency. Cu deficiency resulted in reduced liver index, liver histological alteration, and oxidative stress; decreased the contents of Cu and ALB; elevated ALT and AST concentrations in serum together with decreased mRNA and protein expressions of Nrf2 pathway related molecules (Nrf2, HO-1, NQO1); and increased mRNA and protein expressions of Keap1. However, the supplement of copper sulfate (CuSO4) significantly ameliorated the changes mentioned above. Our results indicate that Cu deficiency can cause hepatic damage in mice is associated with the activation of oxidative stress and inhibition of Nrf2 pathway.
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Affiliation(s)
- Zhiying Pan
- Sichuan Mianyang 404 Hospital, Mianyang, 621010, Sichuan, People's Republic of China
| | - Chengfeng Deng
- Sichuan Mianyang 404 Hospital, Mianyang, 621010, Sichuan, People's Republic of China
| | - Lian Shui
- Sichuan Mianyang 404 Hospital, Mianyang, 621010, Sichuan, People's Republic of China
| | - Heng Yin
- School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang, 621010, Sichuan, People's Republic of China
| | - Bing Liu
- Sichuan Mianyang 404 Hospital, Mianyang, 621010, Sichuan, People's Republic of China.
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17
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Gensluckner S, Wernly B, Datz C, Aigner E. Iron, Oxidative Stress, and Metabolic Dysfunction-Associated Steatotic Liver Disease. Antioxidants (Basel) 2024; 13:208. [PMID: 38397806 PMCID: PMC10886327 DOI: 10.3390/antiox13020208] [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: 12/22/2023] [Revised: 01/25/2024] [Accepted: 02/01/2024] [Indexed: 02/25/2024] Open
Abstract
Excess free iron is a substrate for the formation of reactive oxygen species (ROS), thereby augmenting oxidative stress. Oxidative stress is a well-established cause of organ damage in the liver, the main site of iron storage. Ferroptosis, an iron-dependent mechanism of regulated cell death, has recently been gaining attention in the development of organ damage and the progression of liver disease. We therefore summarize the main mechanisms of iron metabolism, its close connection to oxidative stress and ferroptosis, and its particular relevance to disease mechanisms in metabolic-dysfunction-associated fatty liver disease and potential targets for therapy from a clinical perspective.
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Affiliation(s)
- Sophie Gensluckner
- Department of Internal Medicine I, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
- Obesity Research Unit, Paracelsus Medical University, 5020 Salzburg, Austria
| | - Bernhard Wernly
- Department of Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University, 5110 Oberndorf, Austria; (B.W.); (C.D.)
| | - Christian Datz
- Department of Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University, 5110 Oberndorf, Austria; (B.W.); (C.D.)
| | - Elmar Aigner
- Department of Internal Medicine I, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
- Obesity Research Unit, Paracelsus Medical University, 5020 Salzburg, Austria
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18
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Sun K, Zhao JV, Nelson EAS, Wong VWS, Lam HSHS, Hui LL. Iron status and non-alcoholic fatty liver disease: A Mendelian randomization study. Nutrition 2024; 118:112295. [PMID: 38103266 DOI: 10.1016/j.nut.2023.112295] [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: 05/15/2023] [Revised: 10/10/2023] [Accepted: 10/30/2023] [Indexed: 12/18/2023]
Abstract
OBJECTIVES The aim of this study was to assess the association of genetically determined iron status with the risk for non-alcoholic fatty liver disease (NAFLD) using two-sample Mendelian randomization (MR) analysis. METHODS We applied single nucleotide polymorphisms (SNPs) associated at genome-wide significance with iron status proxied by serum iron, ferritin, transferrin, and transferrin saturation from the Genetics of Iron status Consortium (N = 48 793), in a genome-wide association study of 1664 NAFLD cases and 400 055 controls from the United Kingdom Biobank. A SNP associated with multiple markers of iron status was only applied to one marker with the strongest association in the main analysis. Their effects on NAFLD were calculated using inverse variance weighting after excluding SNPs associated with alkaline phosphatase and lipid metabolism. RESULTS The risk for NAFLD is negatively associated with genetically predicted serum transferrin level with a 20% reduction in NAFLD risk per SD (0.65g/L) increase in transferrin (95% confidence interval [CI], 0.66-0.97), and trending positive association with transferrin saturation (odds ratio [OR], 1.50; 95% CI, 0.96-2.35) but it was not associated with serum iron (OR, 0.90; 95% CI, 0.63-1.29) and ferritin (OR, 1.33; 95% CI, 0.54-3.30). CONCLUSIONS MR analysis provided evidence that genetically predicted higher serum transferrin, indicating lower iron status, may be protective against NAFLD, whereas higher transferrin saturation, indicating higher iron status, might increase the risk for NAFLD and its pathogenesis.
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Affiliation(s)
- Kexin Sun
- Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Jie V Zhao
- School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China
| | - Edmund Anthony Severn Nelson
- Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China; School of Medicine, The Chinese University of Hong Kong, Shenzhen, PR China
| | - Vincent Wai Sun Wong
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Hugh Simon Hung San Lam
- Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Lai Ling Hui
- Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China; Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong SAR, PR China.
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19
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Hassan A, Rijo P, Abuamara TMM, Ali Lashin LS, Kamar SA, Bangay G, Al-Sawahli MM, Fouad MK, Zoair MA, Abdalrhman TI, Elebeedy D, Ibrahim IA, Mohamed AF, Abd El Maksoud AI. Synergistic Differential DNA Demethylation Activity of Danshensu ( Salvia miltiorrhiza) Associated with Different Probiotics in Nonalcoholic Fatty Liver Disease. Biomedicines 2024; 12:279. [PMID: 38397881 PMCID: PMC10886676 DOI: 10.3390/biomedicines12020279] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 01/13/2024] [Accepted: 01/16/2024] [Indexed: 02/25/2024] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a major hepatic disorder occurring in non-alcohol-drinking individuals. Salvianic acid A or Danshensu (DSS, 3-(3, 4-dihydroxyphenyl)-(2R)-lactic acid), derived from the root of Danshen (Salvia miltiorrhiza), has demonstrated heart and liver protective properties. In this work, we investigated the antioxidant activity and hepatoprotective activity of Danshensu alone and in combination with different agents, such as probiotic bacteria (Lactobacillus casei and Lactobacillus acidophilus), against several assays. The inhibition mechanism of the methylation gene biomarkers, such as DNMT-1, MS, STAT-3, and TET-1, against DSS was evaluated by molecular docking and RT-PCR techniques. The physicochemical and pharmacokinetic ADMET properties of DSS were determined by SwissADME and pkCSM. The results indicated that all lipid blood test profiles, including cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), were reduced after the oral administration of Danshensu combined with probiotics (L. casei and L. acidophilus) that demonstrated good, efficient free radical scavenging activity, measured using anti-oxidant assays. ADMET and drug-likeness properties certify that the DSS could be utilized as a feasible drug since DSS showed satisfactory physicochemical and pharmacokinetic ADMET properties.
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Affiliation(s)
- Amr Hassan
- Department of Bioinformatics, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Sadat 32897, Egypt
| | - Patrícia Rijo
- CBIOS—Lusófona University’s Research Center for Biosciences and Health Technologies, 1749-024 Lisbon, Portugal;
- Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal
| | - Tamer M. M. Abuamara
- Department of Basic Medical Science, Faculty of Dentistry, Al-Ahliyya Amman University, Amman 19111, Jordan; (T.M.M.A.); (L.S.A.L.); (S.A.K.)
- Department of Histology, Faculty of Medicine, Al-Azhar University, Cairo 11884, Egypt
| | - Lashin Saad Ali Lashin
- Department of Basic Medical Science, Faculty of Dentistry, Al-Ahliyya Amman University, Amman 19111, Jordan; (T.M.M.A.); (L.S.A.L.); (S.A.K.)
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Sherif A. Kamar
- Department of Basic Medical Science, Faculty of Dentistry, Al-Ahliyya Amman University, Amman 19111, Jordan; (T.M.M.A.); (L.S.A.L.); (S.A.K.)
- Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Gabrielle Bangay
- CBIOS—Lusófona University’s Research Center for Biosciences and Health Technologies, 1749-024 Lisbon, Portugal;
- Universidad de Alcalá de Henares. Facultad de Farmacia, Departamento de Ciencias Biomédicas (Área de Farmacología; Nuevos agentes antitumorales, Acción tóxica sobre células leucémicas), Ctra. Madrid-Barcelona km. 33,600, 28805 Alcalá de Henares, Madrid, España
| | - Majid Mohammed Al-Sawahli
- Department of Pharmaceutics, College of Pharmacy, The Islamic University, Najaf 54001, Iraq;
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Kafr Elsheikh University, Kafr Elsheikh 33516, Egypt
| | - Marina K. Fouad
- College of Biotechnology, Misr University of Science and Technology, Giza 12573, Egypt; (M.K.F.); (D.E.); (A.I.A.E.M.)
| | - Mohammad A. Zoair
- Department of Physiology, Faculty of Medicine, Al-Azhar University, Cairo 11884, Egypt;
| | - Tamer I. Abdalrhman
- Department of Histology, Faculty of Medicine, Al-Azhar University, Assiut 71524, Egypt;
| | - Dalia Elebeedy
- College of Biotechnology, Misr University of Science and Technology, Giza 12573, Egypt; (M.K.F.); (D.E.); (A.I.A.E.M.)
| | - Ibrahim A. Ibrahim
- Department of Plant Biotechnology, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Sadat 32897, Egypt;
| | - Aly F. Mohamed
- Holding Company for Vaccine and Sera Production (VACSERA), Giza 22311, Egypt;
| | - Ahmed I. Abd El Maksoud
- College of Biotechnology, Misr University of Science and Technology, Giza 12573, Egypt; (M.K.F.); (D.E.); (A.I.A.E.M.)
- Department of Industrial Biotechnology, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Sadat 32897, Egypt
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20
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Gensluckner S, Wernly B, Koutny F, Strebinger G, Zandanell S, Stechemesser L, Paulweber B, Iglseder B, Trinka E, Frey V, Langthaler P, Semmler G, Valenti L, Corradini E, Datz C, Aigner E. Prevalence and Characteristics of Metabolic Hyperferritinemia in a Population-Based Central-European Cohort. Biomedicines 2024; 12:207. [PMID: 38255312 PMCID: PMC10813305 DOI: 10.3390/biomedicines12010207] [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: 12/12/2023] [Revised: 01/07/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
BACKGROUND Hyperferritinemia (HF) is a common finding and can be considered as metabolic HF (MHF) in combination with metabolic diseases. The definition of MHF was heterogenous until a consensus statement was published recently. Our aim was to apply the definition of MHF to provide data on the prevalence and characteristics of MHF in a Central-European cohort. METHODS This study was a retrospective analysis of the Paracelsus 10,000 study, a population-based cohort study from the region of Salzburg, Austria. We included 8408 participants, aged 40-77. Participants with HF were divided into three categories according to their level of HF and evaluated for metabolic co-morbidities defined by the proposed criteria for MHF. RESULTS HF was present in 13% (n = 1111) with a clear male preponderance (n = 771, 69% of HF). Within the HF group, 81% (n = 901) of subjects fulfilled the metabolic criteria and were defined as MHF, of which 75% (n = 674) were characterized by a major criterion. In the remaining HF cohort, 52% (n = 227 of 437) of subjects were classified as MHF after application of the minor criteria. CONCLUSION HF is a common finding in the general middle-aged population and the majority of cases are classified as MHF. The new classification provides useful criteria for defining MHF.
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Affiliation(s)
- Sophie Gensluckner
- Department of Internal Medicine I, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; (S.G.)
- Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
| | - Bernhard Wernly
- Department of Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University, Paracelsusstraße 37, 5110 Oberndorf, Austria
| | - Florian Koutny
- Department of Internal Medicine 2, Gastroenterology and Hepatology and Rheumatology, University Hospital of St. Pölten, Karl Landsteiner University of Health Sciences, Dunant-Platz 1, Kremser Landstraße 40, 3100 St. Pölten, Austria
| | - Georg Strebinger
- Department of Internal Medicine I, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; (S.G.)
- Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
| | - Stephan Zandanell
- Department of Internal Medicine I, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; (S.G.)
- Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
| | - Lars Stechemesser
- Department of Internal Medicine I, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; (S.G.)
- Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
| | - Bernhard Paulweber
- Department of Internal Medicine I, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; (S.G.)
| | - Bernhard Iglseder
- Department of Geriatric Medicine, Christian Doppler University Hospital, Paracelsus Medical University, Ignaz-Harrer-Straße 79, 5020 Salzburg, Austria
| | - Eugen Trinka
- Department of Neurology, Christian Doppler University Hospital, Paracelsus Medical University and Centre for Cognitive Neuroscience, Affiliated Member of the European Reference Network EpiCARE, Ignaz-Harrer-Straße 79, 5020 Salzburg, Austria
| | - Vanessa Frey
- Department of Neurology, Christian Doppler University Hospital, Paracelsus Medical University and Centre for Cognitive Neuroscience, Affiliated Member of the European Reference Network EpiCARE, Ignaz-Harrer-Straße 79, 5020 Salzburg, Austria
| | - Patrick Langthaler
- Department of Neurology, Christian Doppler University Hospital, Paracelsus Medical University and Centre for Cognitive Neuroscience, Affiliated Member of the European Reference Network EpiCARE, Ignaz-Harrer-Straße 79, 5020 Salzburg, Austria
| | - Georg Semmler
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Via Francesco Forza 35, 20122 Milan, Italy;
- Precision Medicine, Biological Resource Center Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Francesco Sforza, 35, 20122 Milan, Italy
| | - Elena Corradini
- Department of Medical and Surgical Sciences, Università degli Studi di Modena e Reggio Emilia, Via del Pozzo 71, 41124 Modena, Italy;
- Internal Medicine and Centre for Hemochromatosis and Hereditary Liver Diseases, Azienda Ospedaliero-Universitaria di Modena Policlinico, 41124 Modena, Italy
| | - Christian Datz
- Department of Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University, Paracelsusstraße 37, 5110 Oberndorf, Austria
| | - Elmar Aigner
- Department of Internal Medicine I, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; (S.G.)
- Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
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21
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Kerkadi A, Raïq H, Prince MS, Bader L, Soltani A, Agouni A. A cross-sectional analysis of zinc and copper levels and their relationship to cardiovascular disease risk markers in Qatar biobank participants. Front Cardiovasc Med 2024; 10:1305588. [PMID: 38250034 PMCID: PMC10796498 DOI: 10.3389/fcvm.2023.1305588] [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: 10/03/2023] [Accepted: 12/06/2023] [Indexed: 01/23/2024] Open
Abstract
Cardiovascular diseases (CVD) are the leading cause of mortality and morbidity worldwide. Dietary intake, particularly zinc (Zn) and copper (Cu) has been strongly associated with CVD. These trace elements play a crucial role in human enzyme activity, suppressing inflammation, catalyzing lipid metabolism enzymes, reducing oxidative stress, and regulating glucose metabolism. However, imbalances in these elements are linked to cardiovascular disturbances. Thus, this study aimed to investigate the association between circulating levels of Zn, Cu, and Zn/Cu ratio with CVD risk factors in the Qatari population. Bivariate logistic regression, adjusted for age, nationality, gender, and education was performed to examine the impact of Zn, Cu, and Zn/Cu ratio (as independent variables) on major CVD risk markers (as dependent variables). Participants in the highest Zn tertiles (T2 and T3) were at greater odds ratio (OR) of unfavorable metabolic functions such as elevated HbA1C [OR = 2.5, p = 0.015 (T2) and OR = 3.2, p = 0.002 (T3)], triglycerides [OR = 2.17, p = 0.015 (T2), and TyG index [OR = 2.21, p = 0.004 (T2), and OR = 2.67, p < 0.001 (T3)] compared to T1. Conversely, they had significantly lower ORs for prolonged prothrombin time [OR = 0.37, p = 0.001 (T3)]. Higher levels of Cu (T2 and T3) had higher OR for elevated HDL-C levels [OR = 1.69, p = 0.046 (T2), and OR = 2.27, p = 0.002 (T3)] and lower OR for elevated levels of triglycerides (OR = 0.4, p = 0.009, T3), diastolic blood pressure [OR = 0.41, p = 0.024 (T2), and OR = 0.47, p = 0.049 (T3)], and creatinine kinase (OR = 0.27, p = 0.014, T3) compared to T1. Higher levels of Cu (T2 and T3) were associated with a higher risk for elevated fibrinogen levels [OR = 3.1, p = 0.035 (T2), and OR = 5.04, p = 0.002 (T3)]. Additionally, higher Zn/Cu ratio (T2 and T3) were associated with lower ORs for elevated fibrinogen levels [OR = 0.3, p = 0.005 (T2), and OR = 0.27, p = 0.005 (T3)] compared to T1, indicating a lower risk of developing CVD. The study reveals a link between Zn, Cu, and the Zn/Cu ratio and cardiovascular disease risk. A higher Zn/Cu ratio may protect against CVD, while elevated Cu levels are linked to obesity, fibrinogen levels, and HbA1C. Maintaining optimal levels of these trace elements, either through diet or supplementation, may help reduce CVD risk.
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Affiliation(s)
- Abdelhamid Kerkadi
- Department of Patient Care & Health Technology, College of Health Sciences, University of Doha for Science and Technology, Doha, Qatar
| | - Hicham Raïq
- Department of Social Sciences, College of Arts and Sciences, Qatar University, Doha, Qatar
| | - Mohammad Shoaib Prince
- Sport and Wellness Department, University of Doha for Science and Technology (UDST), Doha, Qatar
| | - Loulia Bader
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Abderrezzaq Soltani
- College of Pharmacy, QU Health, Qatar University, Doha, Qatar
- Office of Vice President for Health & Medical Sciences, Qatar University, Doha, Qatar
| | - Abdelali Agouni
- College of Pharmacy, QU Health, Qatar University, Doha, Qatar
- Office of Vice President for Research & Graduate Studies, Qatar University, Doha, Qatar
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22
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Petri BJ, Piell KM, Wahlang B, Head KZ, Rouchka EC, Park JW, Hwang JY, Banerjee M, Cave MC, Klinge CM. Altered splicing factor and alternative splicing events in a mouse model of diet- and polychlorinated biphenyl-induced liver disease. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2023; 103:104260. [PMID: 37683712 PMCID: PMC10591945 DOI: 10.1016/j.etap.2023.104260] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/30/2023] [Accepted: 09/04/2023] [Indexed: 09/10/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is associated with human environmental exposure to polychlorinated biphenyls (PCBs). Alternative splicing (AS) is dysregulated in steatotic liver disease and is regulated by splicing factors (SFs) and N-6 methyladenosine (m6A) modification. Here integrated analysis of hepatic mRNA-sequencing data was used to identify differentially expressed SFs and differential AS events (ASEs) in the livers of high fat diet-fed C57BL/6 J male mice exposed to Aroclor1260, PCB126, Aroclor1260 + PCB126, or vehicle control. Aroclor1260 + PCB126 co-exposure altered 100 SFs and replicate multivariate analysis of transcript splicing (rMATS) identified 449 ASEs in 366 genes associated with NAFLD pathways. These ASEs were similar to those resulting from experimental perturbations in m6A writers, readers, and erasers. These results demonstrate specific hepatic SF and AS regulatory mechanisms are disrupted by HFD and PCB exposures, contributing to the expression of altered isoforms that may play a role in NAFLD progression to NASH.
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Affiliation(s)
- Belinda J Petri
- Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Kellianne M Piell
- Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Banrida Wahlang
- University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA; University of Louisville Hepatobiology and Toxicology Center, USA; The University of Louisville Superfund Research Center, USA; Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Louisville School of Medicine, USA
| | - Kimberly Z Head
- University of Louisville Hepatobiology and Toxicology Center, USA; The University of Louisville Superfund Research Center, USA; Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Louisville School of Medicine, USA
| | - Eric C Rouchka
- Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40292, USA; KY INBRE Bioinformatics Core, University of Louisville, USA
| | - Juw Won Park
- University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA; KY INBRE Bioinformatics Core, University of Louisville, USA; Department of Computer Science and Engineering, University of Louisville, Louisville, KY 40292, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292 USA
| | - Jae Yeon Hwang
- Department of Computer Science and Engineering, University of Louisville, Louisville, KY 40292, USA
| | - Mayukh Banerjee
- University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292 USA
| | - Matthew C Cave
- Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40292, USA; University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA; University of Louisville Hepatobiology and Toxicology Center, USA; The University of Louisville Superfund Research Center, USA; Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Louisville School of Medicine, USA
| | - Carolyn M Klinge
- Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40292, USA; University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA.
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23
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Baj J, Kowalska B, Barbachowska A, Forma A, Flieger M, Majerek D, Teresiński G, Flieger W, Portincasa P, Buszewicz G, Radzikowska-Büchner E, Flieger J. Linking Metallic Micronutrients and Toxic Xenobiotics to Atherosclerosis and Fatty Liver Disease-Postmortem ICP-MS Analysis of Selected Human Tissues. Nutrients 2023; 15:3458. [PMID: 37571395 PMCID: PMC10420647 DOI: 10.3390/nu15153458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 07/30/2023] [Accepted: 08/02/2023] [Indexed: 08/13/2023] Open
Abstract
Dyslipidaemia is a disorder of the lipid metabolism, caused mainly by poor eating habits. The most severe consequence of an inappropriate diet is the development of atherosclerosis and hepatic steatosis. It is generally believed that a change in nutrition, and increased physical activity can eliminate these health problems. The contemporary research and therapies used to treat dyslipidemia mainly focus on lowering the triglyceride and cholesterol levels. However, disturbances in trace element homeostasis or the accumulation of toxic elements can also affect physiological processes, and be involved in the development of metabolically mediated diseases. The present study aimed to determine the mineral profiles of liver and brain tissues collected at autopsy (n = 39) in groups of people with hepatic steatosis (n = 5), atherosclerosis (n = 9), hepatic steatosis, and atherosclerosis (n = 16), and others without the selected disorders (n = 9). Concentrations of 51 elements were analysed via inductively coupled plasma mass spectrometry (ICP-MS) after the initial wet mineralisation of the samples with nitric acid. The results obtained allow us to conclude that the hepatic steatosis group suffers from a deficiency of important trace elements, such as copper, zinc, and molybdenum (p < 0.05), whereas the group with atherosclerosis is characterised by elevated levels of cadmium in the liver tissue (p = 0.01). Analysing the mean values of the element concentrations measured in 11 brain areas, statistically significant higher levels of calcium and copper (p < 0.001) were found in the atherosclerosis group, compared to the hepatic steatosis group, confirming the involvement of these elements in the pathogenesis of atherosclerosis. In addition, an accumulation of cadmium, lead, titanium, and strontium in the brain tissue was observed in the atherosclerosis group. While the accumulation of individual elements differs in different parts of the brain, the differences in the cadmium content (p < 0.05) between the study groups apply to the whole brain, except for the nucleus accumbens septi area, where a statistically significant titanium accumulation occurs in the atherosclerosis and steatosis groups, compared to the others (p < 0.05). In addition, the disruption of elemental homeostasis in the brain of a single case with bipolar disorder, and a case with hip replacement was observed. Our results confirm the involvement of chemical elements in the pathogenesis of selected metabolic diseases, and the need for further studies in larger populations.
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Affiliation(s)
- Jacek Baj
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (A.F.); (W.F.)
| | - Beata Kowalska
- Department of Water Supply and Wastewater Disposal, Lublin University of Technology, 20-618 Lublin, Poland;
| | - Aleksandra Barbachowska
- Department of Plastic, Reconstructive and Burn Surgery, ul. Krasnystawska, 21-010 Łęczna, Poland;
| | - Alicja Forma
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (A.F.); (W.F.)
| | - Michał Flieger
- Chair and Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (M.F.); (G.T.); (G.B.)
| | - Dariusz Majerek
- Department of Applied Mathematics, University of Technology, 20-618 Lublin, Poland;
| | - Grzegorz Teresiński
- Chair and Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (M.F.); (G.T.); (G.B.)
| | - Wojciech Flieger
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (A.F.); (W.F.)
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Meical School, 70124 Bari, Italy;
| | - Grzegorz Buszewicz
- Chair and Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (M.F.); (G.T.); (G.B.)
| | | | - Jolanta Flieger
- Department of Analytical Chemistry, Medical University of Lublin, 20-093 Lublin, Poland
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24
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Hu S, Lin S, Feng Q, He X, Xu H, Chen L, Sun N. Iron Complexes with Antarctic Krill-Derived Peptides Show Superior Effectiveness to Their Original Protein-Iron Complexes in Mice with Iron Deficiency Anemia. Nutrients 2023; 15:nu15112510. [PMID: 37299473 DOI: 10.3390/nu15112510] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/21/2023] [Accepted: 05/27/2023] [Indexed: 06/12/2023] Open
Abstract
Antarctic krill protein-iron complex and peptide-iron complex were acquired to investigate their iron bioavailability, expression of iron-regulated genes, and in vivo antioxidant capacity. Results indicated that the Antarctic krill peptide-iron complex significantly increased the hemoglobin (Hb), serum iron (SI), and iron contents in the liver and spleen in iron-deficiency anemia (IDA) mice (p < 0.05) compared with those of the Antarctic krill protein-iron complex. Despite the gene expressions of the divalent metal transporter 1(DMT1), the transferrin (Tf), and the transferrin receptor (TfR) being better regulated by both Antarctic krill peptide-iron complex and protein-iron complex, the relative iron bioavailability of the Antarctic krill peptide-iron complex group (152.53 ± 21.05%) was significantly higher than that of the protein-iron complex group (112.75 ± 9.60%) (p < 0.05). Moreover, Antarctic krill peptide-iron complex could enhance the antioxidant enzyme activities of superoxidase dismutase (SOD) and glutathione peroxidase (GSH-Px), reduce the malondialdehyde (MDA) level in IDA mice compared with the protein-iron complex, and reduce the cell damage caused by IDA. Therefore, these results indicated that Antarctic krill peptide-iron complex could be used as a highly efficient and multifunctional iron supplement.
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Affiliation(s)
- Shengjie Hu
- School of Food Science and Technology, National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian 116034, China
| | - Songyi Lin
- School of Food Science and Technology, National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian 116034, China
- State Key Laboratory of Marine Food Processing and Safety Control, Dalian Polytechnic University, Dalian 116034, China
| | - Qi Feng
- School of Food Science and Technology, National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian 116034, China
| | - Xueqing He
- School of Food Science and Technology, National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian 116034, China
| | - Haowei Xu
- School of Food Science and Technology, National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian 116034, China
| | - Lei Chen
- School of Food Science and Technology, National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian 116034, China
| | - Na Sun
- School of Food Science and Technology, National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian 116034, China
- State Key Laboratory of Marine Food Processing and Safety Control, Dalian Polytechnic University, Dalian 116034, China
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25
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Zhong CC, Zhao T, Hogstrand C, Song CC, Zito E, Tan XY, Xu YC, Song YF, Wei XL, Luo Z. Copper induces liver lipotoxicity disease by up-regulating Nrf2 expression via the activation of MTF-1 and inhibition of SP1/Fyn pathway. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166752. [PMID: 37182554 DOI: 10.1016/j.bbadis.2023.166752] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 04/19/2023] [Accepted: 05/09/2023] [Indexed: 05/16/2023]
Abstract
Excessive copper (Cu) intake leads to hepatic lipotoxicity disease, which has adverse effects on health, but the underlying mechanism is unclear. We found that Cu increased lipotoxicity by promoting Nrf2 recruitment to the ARE site in the promoters of five lipogenic genes (g6pd, 6pgd, me, icdh and pparγ). We also found that Cu affected the Nrf2 expression via different pathways: metal regulatory transcription factor 1 (MTF-1) mediated the Cu-induced Nrf2 transcriptional activation; Cu also enhanced the expression of Nrf2 by inhibiting the SP1 expression, which was achieved by inhibiting the negative regulator Fyn of Nrf2. These promoted the enrichment of Nrf2 in the nucleus and ultimately affected lipotoxicity. Thus, for the first time, we elucidated that Cu induced liver lipotoxicity disease by up-regulating Nrf2 expression via the MTF-1 activation and the inhibition of SP1/Fyn pathway. Our study elucidates the Cu-associated obesity and NAFLD for fish and possibly humans.
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Affiliation(s)
- Chong-Chao Zhong
- Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China
| | - Tao Zhao
- Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China
| | - Christer Hogstrand
- Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, London, UK
| | - Chang-Chun Song
- Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China
| | - Ester Zito
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy; Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy
| | - Xiao-Ying Tan
- Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China
| | - Yi-Chuang Xu
- Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China
| | - Yu-Feng Song
- Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China
| | - Xiao-Lei Wei
- Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China
| | - Zhi Luo
- Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan 430070, Hubei Province, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, Shandong Province, China.
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26
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Low G, Ferguson C, Locas S, Tu W, Manolea F, Sam M, Wilson MP. Multiparametric MR assessment of liver fat, iron, and fibrosis: a concise overview of the liver "Triple Screen". Abdom Radiol (NY) 2023; 48:2060-2073. [PMID: 37041393 DOI: 10.1007/s00261-023-03887-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/12/2023] [Accepted: 03/13/2023] [Indexed: 04/13/2023]
Abstract
Chronic liver disease (CLD) is a common source of morbidity and mortality worldwide. Non-alcoholic fatty liver disease (NAFLD) serves as a major cause of CLD with a rising annual prevalence. Additionally, iron overload can be both a cause and effect of CLD with a negative synergistic effect when combined with NAFLD. The development of state-of-the-art multiparametric MR solutions has led to a change in the diagnostic paradigm in CLD, shifting from traditional liver biopsy to innovative non-invasive methods for providing accurate and reliable detection and quantification of the disease burden. Novel imaging biomarkers such as MRI-PDFF for fat, R2 and R2* for iron, and liver stiffness for fibrosis provide important information for diagnosis, surveillance, risk stratification, and treatment. In this article, we provide a concise overview of the MR concepts and techniques involved in the detection and quantification of liver fat, iron, and fibrosis including their relative strengths and limitations and discuss a practical abbreviated MR protocol for clinical use that integrates these three MR biomarkers into a single simplified MR assessment. Multiparametric MR techniques provide accurate and reliable non-invasive detection and quantification of liver fat, iron, and fibrosis. These techniques can be combined in a single abbreviated MR "Triple Screen" assessment to offer a more complete metabolic imaging profile of CLD.
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Affiliation(s)
- Gavin Low
- Department of Radiology and Diagnostic Imaging, University of Alberta Hospital, WMC 2B2.41 8440-112 ST, Edmonton, AB, T6G2B7, Canada
| | - Craig Ferguson
- Department of Radiology and Diagnostic Imaging, University of Alberta Hospital, WMC 2B2.41 8440-112 ST, Edmonton, AB, T6G2B7, Canada
| | - Stephanie Locas
- Department of Radiology and Diagnostic Imaging, University of Alberta Hospital, WMC 2B2.41 8440-112 ST, Edmonton, AB, T6G2B7, Canada
| | - Wendy Tu
- Department of Radiology and Diagnostic Imaging, University of Alberta Hospital, WMC 2B2.41 8440-112 ST, Edmonton, AB, T6G2B7, Canada
| | - Florin Manolea
- Department of Radiology and Diagnostic Imaging, University of Alberta Hospital, WMC 2B2.41 8440-112 ST, Edmonton, AB, T6G2B7, Canada
| | - Medica Sam
- Department of Radiology and Diagnostic Imaging, University of Alberta Hospital, WMC 2B2.41 8440-112 ST, Edmonton, AB, T6G2B7, Canada
| | - Mitchell P Wilson
- Department of Radiology and Diagnostic Imaging, University of Alberta Hospital, WMC 2B2.41 8440-112 ST, Edmonton, AB, T6G2B7, Canada.
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27
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Shih SF, Kafali SG, Calkins KL, Wu HH. Uncertainty-aware physics-driven deep learning network for free-breathing liver fat and R 2 * quantification using self-gated stack-of-radial MRI. Magn Reson Med 2023; 89:1567-1585. [PMID: 36426730 PMCID: PMC9892263 DOI: 10.1002/mrm.29525] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 10/02/2022] [Accepted: 10/25/2022] [Indexed: 11/26/2022]
Abstract
PURPOSE To develop a deep learning-based method for rapid liver proton-density fat fraction (PDFF) and R2 * quantification with built-in uncertainty estimation using self-gated free-breathing stack-of-radial MRI. METHODS This work developed an uncertainty-aware physics-driven deep learning network (UP-Net) to (1) suppress radial streaking artifacts because of undersampling after self-gating, (2) calculate accurate quantitative maps, and (3) provide pixel-wise uncertainty maps. UP-Net incorporated a phase augmentation strategy, generative adversarial network architecture, and an MRI physics loss term based on a fat-water and R2 * signal model. UP-Net was trained and tested using free-breathing multi-echo stack-of-radial MRI data from 105 subjects. UP-Net uncertainty scores were calibrated in a validation dataset and used to predict quantification errors for liver PDFF and R2 * in a testing dataset. RESULTS Compared with images reconstructed using compressed sensing (CS), UP-Net achieved structural similarity index >0.87 and normalized root mean squared error <0.18. Compared with reference quantitative maps generated using CS and graph-cut (GC) algorithms, UP-Net achieved low mean differences (MD) for liver PDFF (-0.36%) and R2 * (-0.37 s-1 ). Compared with breath-holding Cartesian MRI results, UP-Net achieved low MD for liver PDFF (0.53%) and R2 * (6.75 s-1 ). UP-Net uncertainty scores predicted absolute liver PDFF and R2 * errors with low MD of 0.27% and 0.12 s-1 compared to CS + GC results. The computational time for UP-Net was 79 ms/slice, whereas CS + GC required 3.2 min/slice. CONCLUSION UP-Net rapidly calculates accurate liver PDFF and R2 * maps from self-gated free-breathing stack-of-radial MRI. The pixel-wise uncertainty maps from UP-Net predict quantification errors in the liver.
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Affiliation(s)
- Shu-Fu Shih
- Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Department of Bioengineering, University of California Los Angeles, Los Angeles, CA, USA
| | - Sevgi Gokce Kafali
- Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Department of Bioengineering, University of California Los Angeles, Los Angeles, CA, USA
| | - Kara L. Calkins
- Department of Pediatrics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Holden H. Wu
- Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Department of Bioengineering, University of California Los Angeles, Los Angeles, CA, USA
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28
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Kouroumalis E, Tsomidis I, Voumvouraki A. Iron as a therapeutic target in chronic liver disease. World J Gastroenterol 2023; 29:616-655. [PMID: 36742167 PMCID: PMC9896614 DOI: 10.3748/wjg.v29.i4.616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/03/2022] [Accepted: 12/31/2022] [Indexed: 01/20/2023] Open
Abstract
It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71003, Greece
| | - Ioannis Tsomidis
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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Zhang Y, Huang B, Jin J, Xiao Y, Ying H. Recent advances in the application of ionomics in metabolic diseases. Front Nutr 2023; 9:1111933. [PMID: 36726817 PMCID: PMC9884710 DOI: 10.3389/fnut.2022.1111933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 12/30/2022] [Indexed: 01/19/2023] Open
Abstract
Trace elements and minerals play a significant role in human health and diseases. In recent years, ionomics has been rapidly and widely applied to explore the distribution, regulation, and crosstalk of different elements in various physiological and pathological processes. On the basis of multi-elemental analytical techniques and bioinformatics methods, it is possible to elucidate the relationship between the metabolism and homeostasis of diverse elements and common diseases. The current review aims to provide an overview of recent advances in the application of ionomics in metabolic disease research. We mainly focuses on the studies about ionomic or multi-elemental profiling of different biological samples for several major types of metabolic diseases, such as diabetes mellitus, obesity, and metabolic syndrome, which reveal distinct and dynamic patterns of ion contents and their potential benefits in the detection and prognosis of these illnesses. Accumulation of copper, selenium, and environmental toxic metals as well as deficiency of zinc and magnesium appear to be the most significant risk factors for the majority of metabolic diseases, suggesting that imbalance of these elements may be involved in the pathogenesis of these diseases. Moreover, each type of metabolic diseases has shown a relatively unique distribution of ions in biofluids and hair/nails from patients, which might serve as potential indicators for the respective disease. Overall, ionomics not only improves our understanding of the association between elemental dyshomeostasis and the development of metabolic disease but also assists in the identification of new potential diagnostic and prognostic markers in translational medicine.
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Affiliation(s)
- Yan Zhang
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, Brain Disease and Big Data Research Institute, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China,Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China,*Correspondence: Yan Zhang ✉
| | - Biyan Huang
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, Brain Disease and Big Data Research Institute, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China
| | - Jiao Jin
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, Brain Disease and Big Data Research Institute, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China
| | - Yao Xiao
- Shenzhen Key Laboratory of Marine Bioresources and Ecology, Brain Disease and Big Data Research Institute, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China
| | - Huimin Ying
- Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, China,Huimin Ying ✉
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Yang J, Tang Q, Zeng Y. Melatonin: Potential avenue for treating iron overload disorders. Ageing Res Rev 2022; 81:101717. [PMID: 35961513 DOI: 10.1016/j.arr.2022.101717] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 07/10/2022] [Accepted: 08/08/2022] [Indexed: 02/08/2023]
Abstract
Iron overload as a highly risk factor, can be found in almost all human chronic and common diseases. Iron chelators are often used to treat iron overload; however, patient adherence to these chelators is poor due to obvious side effects and other disadvantages. Numerous studies have shown that melatonin has a high iron chelation ability and direct free radical scavenging activity, and can inhibit the lipid peroxidation process caused by iron overload. Therefore, melatonin may become potential complementary therapy for iron overload-related disorders due to its iron chelating and antioxidant activities. Here, the research progress of iron overload is reviewed and the therapeutic potential of melatonin in the treatment of iron overload is analyzed. In addition, studies related to the protective effects of melatonin on oxidative damage induced by iron overload are discussed. This review provides a foundation for preventing and treating iron homeostasis disorders with melatonin.
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Affiliation(s)
- Jiancheng Yang
- Department of Osteoporosis, Honghui Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Qinghua Tang
- Department of Osteoporosis, Honghui Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Yuhong Zeng
- Department of Osteoporosis, Honghui Hospital, Xi'an Jiaotong University, Xi'an, China.
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31
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Bathish B, Robertson H, Dillon JF, Dinkova-Kostova AT, Hayes JD. Nonalcoholic steatohepatitis and mechanisms by which it is ameliorated by activation of the CNC-bZIP transcription factor Nrf2. Free Radic Biol Med 2022; 188:221-261. [PMID: 35728768 DOI: 10.1016/j.freeradbiomed.2022.06.226] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 06/13/2022] [Indexed: 12/11/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) represents a global health concern. It is characterised by fatty liver, hepatocyte cell death and inflammation, which are associated with lipotoxicity, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, iron overload and oxidative stress. NF-E2 p45-related factor 2 (Nrf2) is a transcription factor that combats oxidative stress. Remarkably, Nrf2 is downregulated during the development of NASH, which probably accelerates disease, whereas in pre-clinical studies the upregulation of Nrf2 inhibits NASH. We now review the scientific literature that proposes Nrf2 downregulation during NASH involves its increased ubiquitylation and proteasomal degradation, mediated by Kelch-like ECH-associated protein 1 (Keap1) and/or β-transducin repeat-containing protein (β-TrCP) and/or HMG-CoA reductase degradation protein 1 (Hrd1, also called synoviolin (SYVN1)). Additionally, downregulation of Nrf2-mediated transcription during NASH may involve diminished recruitment of coactivators by Nrf2, due to increased levels of activating transcription factor 3 (ATF3) and nuclear factor-kappaB (NF-κB) p65, or competition for promoter binding due to upregulation of BTB and CNC homology 1 (Bach1). Many processes that downregulate Nrf2 are triggered by transforming growth factor-beta (TGF-β), with oxidative stress amplifying its signalling. Oxidative stress may also increase suppression of Nrf2 by β-TrCP through facilitating formation of the DSGIS-containing phosphodegron in Nrf2 by glycogen synthase kinase-3. In animal models, knockout of Nrf2 increases susceptibility to NASH, while pharmacological activation of Nrf2 by inducing agents that target Keap1 inhibits development of NASH. These inducing agents probably counter Nrf2 downregulation affected by β-TrCP, Hrd1/SYVN1, ATF3, NF-κB p65 and Bach1, by suppressing oxidative stress. Activation of Nrf2 is also likely to inhibit NASH by ameliorating lipotoxicity, inflammation, ER stress and iron overload. Crucially, pharmacological activation of Nrf2 in mice in which NASH has already been established supresses liver steatosis and inflammation. There is therefore compelling evidence that pharmacological activation of Nrf2 provides a comprehensive multipronged strategy to treat NASH.
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Affiliation(s)
- Boushra Bathish
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK
| | - Holly Robertson
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge, CB10 1SA, UK
| | - John F Dillon
- Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK
| | - Albena T Dinkova-Kostova
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK
| | - John D Hayes
- Jacqui Wood Cancer Centre, Division of Cellular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK.
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Abbas AS, Akhtar T, Shaheen N, Aslam S, Sheikh N. Mechanistic study of regulation of iron homeostasis by N. sativa seeds and P. ovata husks on high fat/high sucrose diet induced non-alcoholic fatty liver disease. Mol Biol Rep 2022; 49:7417-7424. [PMID: 35705770 DOI: 10.1007/s11033-022-07538-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND In recent years, nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions. Characteristic findings in NAFLD patients are elevated iron stores, as iron plays an important role in the pathophysiology of chronic liver disease. The current study was aimed at investigating the possible protective effects of N. sativa seeds and P. ovata husks on the regulation of iron homeostasis in NAFLD. METHODS Two age groups of Wistar rats (four weeks and twelve weeks old), further subdivided into four groups were fed on high fat/high sucrose (HF/SF) diet for sixteen weeks to induce NAFLD and randomized into three groups (HF/SF diet control (Group I), HF/SF diet with N. sativa seeds (Group II) and HF/SF diet with P. ovata husks (Group III) and normal diet, serving as negative control (Group 0). At the end of the experiment, histochemical analysis of hepatic sections, biochemical evaluates of the blood, and gene expression analysis were conducted. RESULTS The results revealed that both N. sativa seeds and P. ovata husks possess the capacity to maintain iron homeostasis by regulating the level of blood hemoglobin, serum iron contents, expression of key genes involved in iron metabolism, and iron deposition in hepatic sections. While N. sativa seeds proved more effective. CONCLUSIONS N. sativa seeds are a more potent iron regulator compared to P. ovata husks at reducing the iron overburden associated with NAFLD.
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Affiliation(s)
- Afshan Syed Abbas
- Cell and Molecular Biology Lab, Department of Zoology, University of the Punjab, Q-A Campus, Lahore, Pakistan
- Department of Zoology, University of Education, Lower Mall Campus, Lahore, Pakistan
| | - Tasleem Akhtar
- Department of pharmacology, University of Health Sciences Lahore, Lahore, Pakistan
| | - Najma Shaheen
- Department of Zoology, IMBB/CRIMM, University of Lahore, Lahore, Pakistan
| | - Sumaira Aslam
- Department of Zoology, Government College Women University, Faisalabad, Pakistan
| | - Nadeem Sheikh
- Cell and Molecular Biology Lab, Department of Zoology, University of the Punjab, Q-A Campus, Lahore, Pakistan.
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Liu G, Li J, Pang B, Li Y, Xu F, Liao N, Shao D, Jiang C, Shi J. Potential role of selenium in alleviating obesity-related iron dyshomeostasis. Crit Rev Food Sci Nutr 2022; 63:10032-10046. [PMID: 35574661 DOI: 10.1080/10408398.2022.2074961] [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] [Indexed: 11/03/2022]
Abstract
Obesity is a serious health problem in modern life and increases the risk of many comorbidities including iron dyshomeostasis. In contrast to malnourished anemia, obesity-related iron dyshomeostasis is mainly caused by excessive fat accumulation, inflammation, and disordered gut microbiota. In obesity, iron dyshomeostasis also induces disorders associated with gut microbiota, neurodegenerative injury, oxidative damage, and fat accumulation in the liver. Selenium deficiency is often accompanied by obesity or iron deficiency, and selenium supplementation has been shown to alleviate obesity and overcome iron deficiency. Selenium inhibits fat accumulation and exhibits anti-inflammatory activity. It regulates gut microbiota, prevents neurodegenerative injury, alleviates oxidative damage to the body, and ameliorates hepatic fat accumulation. These effects theoretically meet the requirements for the inhibition of factors underlying obesity-related iron dyshomeostasis. Selenium supplementation may have a potential role in the alleviation of obesity-related iron dyshomeostasis. This review verifies this hypothesis in theory. All the currently reported causes and results of obesity-related iron dyshomeostasis are reviewed comprehensively, together with the effects of selenium. The challenges and strategies of selenium supplementation are also discussed. The findings demonstrate the possibility of selenium-containing drugs or functional foods in alleviating obesity-related iron dyshomeostasis.
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Affiliation(s)
- Guanwen Liu
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
| | - Junjun Li
- College of Enology, Northwest A&F University, Yangling, Shaanxi, People's Republic of China
| | - Bing Pang
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
| | - Yinghui Li
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
| | - Fengqin Xu
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
| | - Ning Liao
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
| | - Dongyan Shao
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
| | - Chunmei Jiang
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
| | - Junling Shi
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China
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34
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Serum levels of copper and zinc in diabetic retinopathy: Potential new therapeutic targets (Review). Exp Ther Med 2022; 23:324. [DOI: 10.3892/etm.2022.11253] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 12/08/2021] [Indexed: 11/05/2022] Open
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35
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Wang K, Yang F, Zhang P, Yang Y, Jiang L. Genetic effects of iron levels on liver injury and risk of liver diseases: A two-sample Mendelian randomization analysis. Front Nutr 2022; 9:964163. [PMID: 36185655 PMCID: PMC9523310 DOI: 10.3389/fnut.2022.964163] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 08/18/2022] [Indexed: 11/13/2022] Open
Abstract
Background and aims Although iron homeostasis has been associated with liver function in many observational studies, the causality in this relationship remains unclear. By using Mendelian Randomization analyses, we aimed to evaluate the genetic effects of increased systemic iron levels on the risk of liver injury and various liver diseases. Moreover, in light of the sex-dependent iron regulation in human beings, we further estimated the sex-specific effect of iron levels in liver diseases. Methods Independent single nucleotide polymorphisms associated with systemic iron status (including four indicators) at the genome-wide significance level from the Genetics of Iron Status (GIS) Consortium were selected as instrumental variables. Summary data for six liver function biomarkers and five liver diseases were obtained from the UK Biobank, the Estonian Biobank, the eMERGE network, and FinnGen consortium. Mendelian Randomization assessment of the effect of iron on liver function and liver diseases was conducted. Results Genetically predicted iron levels were positively and significantly associated with an increased risk of different dimensions of liver injury. Furthermore, increased iron status posed hazardous effects on non-alcoholic fatty liver disease, alcoholic liver disease, and liver fibrosis/cirrhosis. Sex-stratified analyses indicated that the hepatoxic role of iron might exist in NAFLD and liver fibrosis/cirrhosis development among men. No significantly causal relationship was found between iron status and viral hepatitis. Conclusion Our study adds to current knowledge on the genetic role of iron in the risk of liver injury and related liver diseases, which provides clinical and public health implications for liver disease prevention as iron status can be modified.
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Affiliation(s)
- Kai Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China.,Eye Center of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Zhejiang Provincial Key Lab of Ophthalmology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Fangkun Yang
- Department of Cardiology, Ningbo First Hospital, School of Medicine, Zhejiang University, Ningbo, China
| | - Pengcheng Zhang
- Department of Gastroenterology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yang Yang
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Li Jiang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
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Liu L, Li X, Wu M, Yu M, Wang L, Hu L, Li Y, Song L, Wang Y, Mei S. Individual and joint effects of metal exposure on metabolic syndrome among Chinese adults. CHEMOSPHERE 2022; 287:132295. [PMID: 34563779 DOI: 10.1016/j.chemosphere.2021.132295] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 09/10/2021] [Accepted: 09/17/2021] [Indexed: 06/13/2023]
Abstract
Growing evidence suggests that metal exposure contributes to metabolic syndrome (MetS), but little is known about the effects of combined exposure to metal mixtures. This cross-sectional study included 3748 adults who were recruited from the Medical Physical Examination Center of Tongji Hospital, Wuhan, China. The levels of 21 metal(loid)s in urine were measured by inductively coupled plasma mass spectrometry. MetS was diagnosed according to National Cholesterol Education Program's Adult Treatment Panel III recommendations. Multivariate logistic regression model was uesd to explore the effects of single-metal and multi-metal exposures. The elastic net (ENET) regularization with an environmental risk score (ERS) was performed to estimate the joint effects of exposure to metal mixtures. A total of 636 participants (17%) were diagnosed with MetS. In single metal models, MetS was positively associated with zinc (Zn) and negatively associated with nickel (Ni). In multiple metal models, the associations remained significant after adjusting for the other metals. In the joint association analysis, the ENET models selected Zn as the strongest predictor of MetS. Compared to the lowest quartile, the highest quartile of ERS was associated with an elevated risk of MetS (OR = 3.72; 95% CI: 2.77, 5.91; P-trend < 0.001). Overall, we identified that the combined effect of multiple metals was related to an increased MetS risk, with Zn being the major contributor. These findings need further validation in prospective studies.
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Affiliation(s)
- Ling Liu
- State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment and Health, Ministry of Education, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, #13 Hongkong Road, Wuhan, Hubei, 430030, China
| | - Xiang Li
- State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment and Health, Ministry of Education, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, #13 Hongkong Road, Wuhan, Hubei, 430030, China
| | - Mingyang Wu
- Department of Maternal and Child Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Meng Yu
- State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment and Health, Ministry of Education, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, #13 Hongkong Road, Wuhan, Hubei, 430030, China
| | - Limei Wang
- State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment and Health, Ministry of Education, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, #13 Hongkong Road, Wuhan, Hubei, 430030, China
| | - Liqin Hu
- State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment and Health, Ministry of Education, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, #13 Hongkong Road, Wuhan, Hubei, 430030, China
| | - Yaping Li
- State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment and Health, Ministry of Education, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, #13 Hongkong Road, Wuhan, Hubei, 430030, China
| | - Lulu Song
- Department of Maternal and Child Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Youjie Wang
- State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment and Health, Ministry of Education, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, #13 Hongkong Road, Wuhan, Hubei, 430030, China; Department of Maternal and Child Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Surong Mei
- State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment and Health, Ministry of Education, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, #13 Hongkong Road, Wuhan, Hubei, 430030, China.
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Marku A, Galli A, Marciani P, Dule N, Perego C, Castagna M. Iron Metabolism in Pancreatic Beta-Cell Function and Dysfunction. Cells 2021; 10:2841. [PMID: 34831062 PMCID: PMC8616520 DOI: 10.3390/cells10112841] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/15/2021] [Accepted: 10/19/2021] [Indexed: 12/26/2022] Open
Abstract
Iron is an essential element involved in a variety of physiological functions. In the pancreatic beta-cells, being part of Fe-S cluster proteins, it is necessary for the correct insulin synthesis and processing. In the mitochondria, as a component of the respiratory chain, it allows the production of ATP and reactive oxygen species (ROS) that trigger beta-cell depolarization and potentiate the calcium-dependent insulin release. Iron cellular content must be finely tuned to ensure the normal supply but also to prevent overloading. Indeed, due to the high reactivity with oxygen and the formation of free radicals, iron excess may cause oxidative damage of cells that are extremely vulnerable to this condition because the normal elevated ROS production and the paucity in antioxidant enzyme activities. The aim of the present review is to provide insights into the mechanisms responsible for iron homeostasis in beta-cells, describing how alteration of these processes has been related to beta-cell damage and failure. Defects in iron-storing or -chaperoning proteins have been detected in diabetic conditions; therefore, the control of iron metabolism in these cells deserves further investigation as a promising target for the development of new disease treatments.
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Affiliation(s)
| | | | | | | | - Carla Perego
- Department of Excellence Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Trentacoste, 22134 Milano, Italy; (A.M.); (A.G.); (P.M.); (N.D.)
| | - Michela Castagna
- Department of Excellence Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Trentacoste, 22134 Milano, Italy; (A.M.); (A.G.); (P.M.); (N.D.)
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Armstrong T, Zhong X, Shih SF, Felker E, Lu DS, Dale BM, Wu HH. Free-breathing 3D stack-of-radial MRI quantification of liver fat and R 2* in adults with fatty liver disease. Magn Reson Imaging 2021; 85:141-152. [PMID: 34662702 DOI: 10.1016/j.mri.2021.10.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 10/07/2021] [Accepted: 10/12/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE To investigate the agreement, intra-session repeatability, and inter-reader agreement of liver proton-density fat fraction (PDFF) and R2* quantification using free-breathing 3D stack-of-radial MRI, with and without self-gated motion compensation, compared to reference breath-hold techniques in subjects with fatty liver disease (FLD). METHODS In this institutional review board-approved prospective study, thirty-eight adults with FLD and/or iron overload (24 male, 58 ± 12 years) were imaged at 3T using free-breathing stack-of-radial MRI, breath-hold 3D Cartesian MRI, and breath-hold single-voxel MR spectroscopy (SVS). Each sequence was acquired twice in random order. To assess agreement compared to reference breath-hold techniques, the dependency of liver PDFF and/or R2* quantification on the sequence, radial sampling factor, and radial self-gating temporal resolution was assessed by calculating the Bayesian mean difference (MDB) of the posteriors. Intra-session repeatability and inter-reader agreement (two independent readers) were assessed by the coefficient of repeatability (CR) and intraclass correlation coefficient (ICC), respectively. RESULTS Thirty-five participants (21 male, 57 ± 12 years) were included for analysis. Both free-breathing radial MRI techniques (with and without self-gating) achieved ICC ≥ 0.92 for quantifying PDFF and R2*, and quantified PDFF with MDB < 1.2% compared to breath-hold techniques. Free-breathing radial MRI required self-gating to accurately quantify R2* (MDB < 10s-1 with self-gating; MDB < 50s-1 without self-gating). The radial sampling factor affected PDFF and R2* quantification while the radial self-gating temporal resolution only affected R2* quantification. Repeated self-gated free-breathing radial MRI scans achieved CR < 3% and CR < 27 s-1 for PDFF and R2*, respectively. CONCLUSION A free-breathing stack-of-radial MRI technique with self-gating demonstrated agreement, repeatability, and inter-reader agreement compared to reference breath-hold techniques for quantification of liver PDFF and R2* in adults with FLD.
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Affiliation(s)
- Tess Armstrong
- Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States
| | - Xiaodong Zhong
- MR R&D Collaborations, Siemens Medical Solutions USA, Inc., Los Angeles, CA, United States
| | - Shu-Fu Shih
- Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States; Department of Bioengineering, University of California Los Angeles, Los Angeles, CA, United States
| | - Ely Felker
- Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States
| | - David S Lu
- Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States
| | - Brian M Dale
- MR R&D Collaborations, Siemens Medical Solutions USA, Inc., Cary, NC, United States
| | - Holden H Wu
- Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States; Department of Bioengineering, University of California Los Angeles, Los Angeles, CA, United States.
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Dutta S, Karkada IR, Sengupta P, Chinni SV. Anthropometric Markers With Specific Cut-Offs Can Predict Anemia Occurrence Among Malaysian Young Adults. Front Physiol 2021; 12:731416. [PMID: 34603084 PMCID: PMC8481777 DOI: 10.3389/fphys.2021.731416] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 08/13/2021] [Indexed: 12/31/2022] Open
Abstract
Objective: Anemia bears a high global prevalence with about 1.6 billion people living with this affliction. Malaysia carries the burden of 13.8% anemia prevalence which urges for extensive research directed to its prediction and amelioration. This is the first study that aims to (a) propose simple non-invasive predictive anthropometric markers and their specific cut-off values for early prediction of anemia among the young adults in Malaysia, (b) provide anemia prevalence based on both gender and ethnicity among young adults of Malaysia. Method: The present cross-sectional study included 245 participants (113 men and 132 women) aged between 18 and 30 years. Anthropometric parameters were measured following the standard protocols. Blood samples were collected and hemoglobin levels were determined using the HemoCue haemoglobinometer (Hb 201+ System, Angelhom, Sweden) to detect the presence of anemia. The receiver operating characteristics (ROC) curve was employed to assess and compare the efficacy of anthropometric indices in the prediction of anemia. Data were analyzed using SPSS (v. 22.0, IBM, Chicago, IL, USA) and MedCalc (v. 19.05, Ostend, Belgium). Result: The ROC analysis indicates that body mass index (BMI) is the best anthropometric marker with the highest area under the curve (AUC) and specificity (SP) for predicting the presence of anemia in young adults in Malaysia. Thus, the study proposes the optimal cut-off value of BMI for young men of Malaysia as 20.65 kg/m2 (AUC: 0.889) and young women of Malaysia as 19.7 kg/m2 (AUC: 0.904). The study also reports that Malaysian Indians have the highest prevalence of anemia (26.22%) followed by Malays (21.54%), “Others” (indigenous ethnic group) (20%), and Chinese (14.5%), with an overall higher prevalence of anemia in young adult women (21.96%) than in men (18.6%) of Malaysia. Conclusion: The proposed anemia-predictive anthropometric markers with optimal cut-off values will aid early detection of anemia among young adults in Malaysia, and given its simple, inexpensive, and intelligible approach, it can be widely used. The ease of anemia prediction together with the reported distribution of anemia prevalence based on gender and ethnicity will facilitate in gauging the necessary extent of strategies of anemia management in the young adult population of Malaysia.
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Affiliation(s)
- Sulagna Dutta
- Department of Oral Biology and Biomedical Sciences, Faculty of Dentistry, MAHSA University, Jenjarum, Malaysia
| | - Ivan Rolland Karkada
- Physiology Unit, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Jenjarum, Malaysia
| | - Pallav Sengupta
- Physiology Unit, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Jenjarum, Malaysia
| | - Suresh V Chinni
- Department of Biotechnology, Faculty of Applied Sciences, AIMST University, Bedong, Malaysia
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Nasr P, Ignatova S, Lundberg P, Kechagias S, Ekstedt M. Low hepatic manganese concentrations in patients with hepatic steatosis - A cohort study of copper, iron and manganese in liver biopsies. J Trace Elem Med Biol 2021; 67:126772. [PMID: 34000573 DOI: 10.1016/j.jtemb.2021.126772] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 04/27/2021] [Accepted: 05/03/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Hepatic steatosis is the most common histopathological finding on liver biopsy, with the most prevalent etiology being NAFLD. The pathogenesis of hepatic steatosis and NAFLD is multifactorial, however, studies on the importance of manganese in NAFLD are limited. We aimed to study hepatic manganese content, and other trace elements, in relation to hepatic steatosis in patients with chronic liver diseases of different etiology, mainly NAFLD. METHODS Patients with chronically elevated liver function tests underwent a diagnostic work-up, including routine blood tests and two liver biopsies. One of the biopsies was sent for histopathological evaluation, and the other for ultra-trace elemental determinations. Steatosis was graded using conventional histopathological methodology, and fat content was also quantitated in biopsy samples by measuring the steatotic area of the section using stereological point counting (SPC). Ultra-trace elemental analysis was utilized for determining manganese, iron, and copper using inductively coupled plasma sector field mass spectrometry (ICP-SFMS). RESULTS 76 patients were included in the study. Hepatic manganese concentrations in patients with steatosis were lower than in patients without hepatic steatosis (3.8 ± 1.1 vs. 6.4 ± 1.8, P < 0.001). Similar results were seen for blood manganese levels and hepatic steatosis. We found a strong inverse correlation between steatosis grade and hepatic manganese content (ρ=-0.743, P < 0.001). Also, low levels of manganese independently predicted the presence of steatosis (aOR 0.07 [95%CI: 0.01-0.63]). CONCLUSION Patients with NAFLD, or other CLD and concomitant hepatic steatosis, showed lower levels of hepatic manganese content with increasing grade of steatosis.
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Affiliation(s)
- Patrik Nasr
- Department of Gastroenterology and Hepatology, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
| | - Simone Ignatova
- Department of Clinical Pathology and Clinical Genetics, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
| | - Peter Lundberg
- Center for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden; Department of Radiation Physics, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
| | - Stergios Kechagias
- Department of Gastroenterology and Hepatology, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
| | - Mattias Ekstedt
- Department of Gastroenterology and Hepatology, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden; Center for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden.
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Kerkadi A, Alkudsi DS, Hamad S, Alkeldi HM, Salih R, Agouni A. The Association between Zinc and Copper Circulating Levels and Cardiometabolic Risk Factors in Adults: A Study of Qatar Biobank Data. Nutrients 2021; 13:nu13082729. [PMID: 34444889 PMCID: PMC8398315 DOI: 10.3390/nu13082729] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 07/26/2021] [Accepted: 07/28/2021] [Indexed: 11/16/2022] Open
Abstract
Cardiometabolic risk (CMR) factors increase the likelihood of developing cardiovascular diseases (CVD). In Qatar, 24% of the total deaths are attributed to CVDs. Several nutritional disturbances have been linked to high risk of CVD. Many studies have discussed the effects of zinc (Zn) and copper (Cu) on CMR factors; however, evidence has been controversial. This investigated the association between CMR factors and the status of Zn and Cu, in addition to Zn/Cu ratio. A total of 575 Qatari men and women aged 18 years and older were obtained from Qatar Biobank. Plasma levels of Zn and Cu were determined using inductively coupled plasma mass spectrometry (ICP-MS). Anthropometric data and CMR factors were determined using standard methods. Adjusted associations between trace minerals and CMR were estimated by logistic regression. Partial correlation was performed to test the strength of the associations. Zn was not strongly correlated (p-value ˃ 0.01) or significantly associated with CMR factors and metabolic syndrome (MetS). Cu levels correlated positively with body mass index (BMI) (0.23; p ˂ 0.001), pulse rate (PR) (0.18; p ˂ 0.001), total cholesterol (0.13; p = 0.01), and high-density lipoproteins (HDL) (0.27; p ˂ 0.001); and negatively with diastolic blood pressure (DBP) (−0.13; p = 0.01). High plasma Cu significantly decreased the risk of metabolic syndrome (MetS) (0.121; p ˂ 0.001). Furthermore, Zn/Cu ratio positively correlated with waist circumference (0.13; p = 0.01), systolic blood pressure (0.13; p ˂ 0.01), and DBP (0.14; p ˂ 0.01); and negatively with BMI (−0.19; p ˂ 0.001), PR (−0.17; p ˂ 0.001), and HDL (−0.27; p ˂ 0.001). High Zn/Cu ratio increased the prevalence of low HDL (4.508; p ˂ 0.001) and MetS (5.570; p ˂ 0.01). These findings suggest that high plasma Cu levels are associated with a protective effect on DBP, HDL and MetS and that high plasma Zn/Cu ratio is associated with the risk of having low HDL and MetS.
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Affiliation(s)
- Abdelhamid Kerkadi
- Human Nutrition Department, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (D.S.A.); (S.H.); (H.M.A.); (R.S.)
- Correspondence: ; Tel.: +974-4403-4806; Fax: +974-4403-4801
| | - Dana Samir Alkudsi
- Human Nutrition Department, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (D.S.A.); (S.H.); (H.M.A.); (R.S.)
| | - Sara Hamad
- Human Nutrition Department, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (D.S.A.); (S.H.); (H.M.A.); (R.S.)
| | - Hanan Mohamed Alkeldi
- Human Nutrition Department, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (D.S.A.); (S.H.); (H.M.A.); (R.S.)
| | - Reem Salih
- Human Nutrition Department, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (D.S.A.); (S.H.); (H.M.A.); (R.S.)
| | - Abdelali Agouni
- Pharmaceutical Sciences Department, College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar;
- Biomedical and Pharmaceutical Research Unit (BPRU), QU Health, Qatar University, Doha P.O. Box 2713, Qatar
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Tsutsumi N, Nishimata S, Shimura M, Kashiwagi Y, Kawashima H. Hepcidin Levels and Pathological Characteristics in Children with Fatty Liver Disease. Pediatr Gastroenterol Hepatol Nutr 2021; 24:295-305. [PMID: 34046333 PMCID: PMC8128777 DOI: 10.5223/pghn.2021.24.3.295] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 12/18/2020] [Accepted: 02/02/2021] [Indexed: 12/20/2022] Open
Abstract
PURPOSE Hepcidin levels have previously been reported to be correlated with liver damage. However, the association between hepcidin levels and liver fibrosis in children with fatty liver disease remains unclear. This study therefore aimed to investigate the pathophysiology of fibrosis in children with fatty liver disease and its association with hepcidin levels. METHODS This retrospective case series included 12 boys aged 6-17 years who were diagnosed with nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) at the Tokyo Medical University Hospital. Sixteen liver biopsy samples from 12 subjects were analyzed. Serum hepcidin levels were assayed using enzyme-linked immunosorbent assay. Immunostaining for hepcidin was performed, and the samples were stratified by staining intensity. RESULTS Serum hepcidin levels were higher in pediatric NAFLD/NASH patients than in controls. Conversely, a significant inverse correlation was observed between hepcidin immunostaining and Brunt grade scores and between hepcidin scores and gamma-glutamyltranspeptidase, hyaluronic acid, and leukocyte levels. We observed inverse correlations with a high correlation coefficient of >0.4 between hepcidin immunostaining and aspartate aminotransferase, alanine aminotransferase, total bile acid, and platelet count. CONCLUSION There was a significant inverse correlation between hepcidin immunoreactivity and fibrosis in pediatric NAFLD patients; however, serum hepcidin levels were significantly higher, suggesting that these patients experienced a reduction in the hepcidin-producing ability of the liver in response to iron levels, leading to subsequent fibrosis. Therefore, hepcidin levels can be used as markers to identify the progression of fibrosis in patients with NAFLD.
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Affiliation(s)
- Norito Tsutsumi
- Department of Pediatrics and Adolescent Medicine, Tokyo Medical University, Tokyo, Japan
| | - Shigeo Nishimata
- Department of Pediatrics and Adolescent Medicine, Tokyo Medical University, Tokyo, Japan
| | - Masaru Shimura
- Department of Pediatrics and Adolescent Medicine, Tokyo Medical University, Tokyo, Japan.,Depatrment of Metabolism, Chiba Children's Hospital, Center for Medical Genetics, Chiba, Japan
| | - Yasuyo Kashiwagi
- Department of Pediatrics and Adolescent Medicine, Tokyo Medical University, Tokyo, Japan
| | - Hisashi Kawashima
- Department of Pediatrics and Adolescent Medicine, Tokyo Medical University, Tokyo, Japan
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Nunes VS, Andrade AR, Guedes ALV, Diniz MA, Oliveira CP, CanÇado ELR. DISTINCT PHENOTYPE OF NON-ALCOHOLIC FATTY LIVER DISEASE IN PATIENTS WITH LOW LEVELS OF FREE COPPER AND OF CERULOPLASMIN. ARQUIVOS DE GASTROENTEROLOGIA 2021; 57:249-253. [PMID: 32935743 DOI: 10.1590/s0004-2803.202000000-47] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 06/05/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Copper deficiency has been linked to alterations in lipid metabolism and hepatic steatosis. Oxidative stress plays a role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). One of the enzymes that neutralize oxidative stress is Cu/Zn superoxide dismutase, which depends on the availability of adequate amounts of copper. OBJECTIVE Correlate the levels of ceruloplasmin and of non-ceruloplasmin-bound copper (NCBC) with clinical, biochemical and histological parameters of non-alcoholic fatty liver disease (NAFLD) patients. METHODS Data from 95 consecutively admitted NAFLD patients who underwent liver biopsy composed the groups based on ceruloplasmin levels lower than 25 mg/dL and on negative NCBC. The risk factors for NAFLD in each group were compared. RESULTS Body mass index was lower in patients with ceruloplasmin <25 mg/dL (29.1±3.47 vs 32.8±6.24 kg/m2; P=0.005) as were the levels of LDL, HDL and total cholesterol, when compared with their counterparts with ceruloplasmin >25 mg/dL (101±38 vs 116±35 mg/dL, P=0.05; 43±9 vs 51±16 mg/dL, P=0.01; 174±43 vs 197±39 mg/dL, P=0.01, respectively). Mean serum ferritin levels were higher in the ceruloplasmin <25 mg/dL group (343±327 vs 197±190 ng/mL; P=0.02). Otherwise, patients with negative NCBC had higher HOMA-IR (8.2±14.7 vs 4.6±3.7; P=0.03). Age, gender, hypertension and diabetes showed no statistical difference. CONCLUSION Patients with NAFLD had different clinical and biochemical markers according to the levels of NCBC and ceruloplasmin.
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Affiliation(s)
- Vinicius S Nunes
- Faculdade de Medicina da Universidade de São Paulo, Hospital das Clínicas, Departamento de Gastroenterologia, São Paulo, SP, Brasil
| | - Adriana R Andrade
- Faculdade de Medicina da Universidade de São Paulo, Hospital das Clínicas, Departamento de Gastroenterologia, São Paulo, SP, Brasil
| | - Ana L V Guedes
- Faculdade de Medicina da Universidade de São Paulo, Hospital das Clínicas, Departamento de Gastroenterologia, São Paulo, SP, Brasil
| | - Marcio A Diniz
- Faculdade de Medicina da Universidade de São Paulo, Hospital das Clínicas, Departamento de Gastroenterologia, São Paulo, SP, Brasil
| | - Claudia P Oliveira
- Faculdade de Medicina da Universidade de São Paulo, Hospital das Clínicas, Departamento de Gastroenterologia, São Paulo, SP, Brasil
| | - Eduardo L R CanÇado
- Faculdade de Medicina da Universidade de São Paulo, Hospital das Clínicas, Departamento de Gastroenterologia, São Paulo, SP, Brasil
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Anastasopoulos NAT, Lianos GD, Tatsi V, Karampa A, Goussia A, Glantzounis GK. Clinical heterogeneity in patients with non-alcoholic fatty liver disease-associated hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2020; 14:1025-1033. [PMID: 32746645 DOI: 10.1080/17474124.2020.1802244] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION The indisputable increase in nonalcoholic Fatty Liver Disease (NAFLD) prevalence (25% of population) has consequently led to an increase in Hepatocellular Carcinoma (HCC) and liver-related mortality worldwide. The characteristics of patients with HCC, secondary to NAFLD, are older age, large tumors due to late diagnosis, often without cirrhosis and high prevalence of the metabolic syndrome components, leading to an increased mortality rate. Although the mechanisms of disease remain partially obscure, insulin resistance, oxidative stress, apoptosis, iron overload, and excessive local and systemic inflammation are identified as culprits for hepatocarcinogenesis in the presence of NAFLD. AREA COVERED In this review, the authors report that there are no uniform guidelines for surveillance and early diagnosis in this patient group. Barcelona Clinic Liver Cancer staging is generally applicable to HCC due to NAFLD and management depends on liver function, tumor characteristics, and cardiovascular comorbidity. Evidence suggests that HCC due to NAFLD can be associated with worse survival due to late diagnosis. EXPERT OPINION The need for effective early diagnosis and management of NAFLD is urgent, considering the galloping incidence of the obesity and the fact that liver cirrhosis and HCC due to NAFLD will become the first indication for liver transplantation in foreseeable future.
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Affiliation(s)
- Nikolaos-Andreas T Anastasopoulos
- First Propaedeutic Department of General Surgery, National and Kapodistrian University of Athens, "Hippokrateion" General Hospital of Athens , Athens, Greece.,Department of Surgery, University Hospital of Ioannina and School of Medicine, University of Ioannina , Ioannina, Greece
| | - Georgios D Lianos
- Department of Surgery, University Hospital of Ioannina and School of Medicine, University of Ioannina , Ioannina, Greece
| | - Vera Tatsi
- Department of Surgery, University Hospital of Ioannina and School of Medicine, University of Ioannina , Ioannina, Greece
| | - Anastasia Karampa
- Department of Surgery, University Hospital of Ioannina and School of Medicine, University of Ioannina , Ioannina, Greece
| | - Anna Goussia
- Department of Pathology, University Hospital of Ioannina and School of Medicine, University of Ioannina , Ioannina, Greece
| | - Georgios K Glantzounis
- Department of Surgery, University Hospital of Ioannina and School of Medicine, University of Ioannina , Ioannina, Greece
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Marin-Alejandre BA, Abete I, Monreal JI, Elorz M, Benito-Boillos A, Herrero JI, Navarro-Blasco I, Tur JA, Bandarra NM, Zulet MA, Martinez JA. Effects of a 6-month dietary-induced weight loss on erythrocyte membrane omega-3 fatty acids and hepatic status of subjects with nonalcoholic fatty liver disease: The Fatty Liver in Obesity study. J Clin Lipidol 2020; 14:837-849.e2. [DOI: 10.1016/j.jacl.2020.08.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 08/18/2020] [Accepted: 08/18/2020] [Indexed: 02/07/2023]
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Shao M, Ye Z, Qin Y, Wu T. Abnormal metabolic processes involved in the pathogenesis of non-alcoholic fatty liver disease (Review). Exp Ther Med 2020; 20:26. [PMID: 32934691 PMCID: PMC7471863 DOI: 10.3892/etm.2020.9154] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 05/28/2020] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases and can lead to liver cirrhosis or liver cancer in severe cases. In recent years, the incidence of NAFLD has increased substantially. The trend has continued to increase and has become a key point of concern for health systems. NAFLD is often associated with metabolic abnormalities caused by increased visceral obesity, including insulin resistance, diabetes mellitus, hypertension, dyslipidemia, atherosclerosis and systemic microinflammation. Therefore, the pathophysiological mechanisms of NAFLD must be clarified to develop new drug treatment strategies. Recently, researchers have conducted numerous studies on the pathogenesis of NAFLD and have identified various important regulatory factors and potential molecular mechanisms, providing new targets and a theoretical basis for the treatment of NAFLD. However, the pathogenesis of NAFLD is extremely complex and involves the interrelationship and influence of multiple organs and systems. Therefore, the condition must be explored further. In the present review, the abnormal metabolic process, including glucose, lipid, amino acid, bile acid and iron metabolism are reviewed. It was concluded that NAFLD is associated with an imbalanced metabolic network that involves glucose, lipids, amino acids, bile acids and iron, and lipid metabolism is the core metabolic process. The current study aimed to provide evidence and hypotheses for research and clinical treatment of NAFLD.
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Affiliation(s)
- Mingmei Shao
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Zixiang Ye
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Yanhong Qin
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Tao Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
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Gatiatulina ER, Sheina EA, Nemereshina ON, Popova EV, Polyakova VS, Agletdinov EF, Sinitskii AI, Skalny AV, Nikonorov AA, Tinkov AA. Effect of Zn Supplementation on Trace Element Status in Rats with Diet-Induced Non-alcoholic Fatty Liver Disease. Biol Trace Elem Res 2020; 197:202-212. [PMID: 31832925 DOI: 10.1007/s12011-019-01985-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 11/13/2019] [Indexed: 12/19/2022]
Abstract
The present study aimed to assess the effect of Zn supplementation on trace element levels in the liver, serum, and hair of rats with dietary-induced non-alcoholic fatty liver disease (NAFLD). A total of 26 3-month-old female Wistar rats were divided into four groups: control, NAFLD, Zn-supplemented (227 mg/L zinc as Zn sulfate Zn(SO)4 dissolved in a drinking water), and NAFLD-Zn-supplemented. NAFLD was verified by histological assessment of liver samples. The serum was examined for routine biochemical parameters. Trace elements content was assessed using inductively coupled plasma mass spectrometry (ICP-MS). Zn treatment resulted in an improvement in liver weight and morphology. Dietary supplementation with Zn prevented NAFLD-induced decrease liver Co. The tendency to increase liver Fe in the Zn-treated group was observed. Zn treatment decreased hepatic Al and serum V levels. However, Zn administration did not affect NAFLD-induced I, Mn, and Se depletion in the liver. Hair Zn levels raised in Zn-supplemented groups. Conclusively, the results of the study indicate that Zn supplementation could have a beneficial effect in modulation of the altered trace element status and liver morphology. HIGHLIGHTS: •Zn treatment improved liver weight and morphology in rats with NAFLD. •Zn supplementation decreased liver Al in NAFLD. •Treatment by Zn prevented depletion of liver Co. •Zn decreased serum V and increased hair Zn levels. •No effect of Zn on NAFLD-induced hepatic I, Mn and Se depletion was observed.
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Affiliation(s)
- Eugenia R Gatiatulina
- All-Russian Research Institute of Medicinal and Aromatic Plants (VILAR), Grina St., 7, Moscow, 117216, Russia.
| | - Evgenia A Sheina
- Peoples' Friendship University of Russia (RUDN University), Miklukho-Maklaya St., 6, Moscow, 105064, Russia
| | - Olga N Nemereshina
- Orenburg State Medical University, Sovetskaya St., 6, Orenburg, 460000, Russia
| | - Elizaveta V Popova
- St. Joseph College of Health and Allied Sciences, St Joseph University in Tanzania, 11007, Dar es Salaam, Tanzania
| | | | | | - Anton I Sinitskii
- South Ural State Medical University, Vorovskogo St., 64, Chelyabinsk, 454092, Russia
| | - Anatoly V Skalny
- Peoples' Friendship University of Russia (RUDN University), Miklukho-Maklaya St., 6, Moscow, 105064, Russia
- Yaroslavl State University, Sovetskaya St., 14, Yaroslavl, 150000, Russia
- IM Sechenov First Moscow State Medical University, Trubetskaya St., 8-2, Moscow, 119991, Russia
| | - Alexandr A Nikonorov
- State Research Center of Dermatovenerology and Cosmetology, Korolenko St., 3-6, Moscow, 107076, Russia
| | - Alexey A Tinkov
- Peoples' Friendship University of Russia (RUDN University), Miklukho-Maklaya St., 6, Moscow, 105064, Russia
- Yaroslavl State University, Sovetskaya St., 14, Yaroslavl, 150000, Russia
- IM Sechenov First Moscow State Medical University, Trubetskaya St., 8-2, Moscow, 119991, Russia
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Xu Y, Wei Y, Long T, Wang R, Li Z, Yu C, Wu T, He M. Association between urinary metals levels and metabolic phenotypes in overweight and obese individuals. CHEMOSPHERE 2020; 254:126763. [PMID: 32957263 DOI: 10.1016/j.chemosphere.2020.126763] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 04/06/2020] [Accepted: 04/07/2020] [Indexed: 06/11/2023]
Abstract
Epidemiologic studies suggest that circulating metals from the natural environment are linked with cardiometabolic health. However, few studies examined the relationship between multiple metals exposure and metabolic phenotypes, especially in obese individuals. We conducted a cross-sectional study to explore the association between 23 urinary metals and metabolic phenotypes in 1392 overweight and obese individuals (592 males, 800 females, mean age 43.1 ± 9.8 years). Participants were classified as metabolically unhealthy if they had ≥2 of the following metabolic abnormalities: elevated blood pressure, elevated fasting blood glucose, elevated triglycerides, and reduced high-density lipoprotein cholesterol. Odds ratios (ORs) of unhealthy metabolic phenotypes for metal levels categorized into tertiles were assessed using logistic regression models. Five metals (barium, copper, iron, uranium, and zinc) were associated with unhealthy metabolic phenotypes in single-metal models, while in the multiple-metal model, only zinc and zinc-copper ratio remained significant. The ORs (95% CIs) comparing extreme tertiles were 2.57 (1.69, 3.89) for zinc and 1.68 (1.24, 2.27) for zinc-copper ratio after adjustment for confounders (both p-trends were <0.001). The numbers of metabolic abnormalities significantly increased with the levels of zinc and the zinc-copper ratio increased. Similar associations were observed with metabolic syndrome risk. High levels of urinary zinc were positively associated with elevated fasting blood glucose (p-trend < 0.001) and elevated triglycerides (p-trend = 0.003). The results suggest that urinary zinc and zinc-copper ratio are positively associated with increased risk of unhealthy metabolic phenotype. Further prospective studies with a larger sample size are required to verify these findings.
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Affiliation(s)
- Yali Xu
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yue Wei
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Tengfei Long
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ruixin Wang
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhaoyang Li
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Caizheng Yu
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Public Health, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tangchun Wu
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Meian He
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Himoto T, Masaki T. Current Trends of Essential Trace Elements in Patients with Chronic Liver Diseases. Nutrients 2020; 12:nu12072084. [PMID: 32674425 PMCID: PMC7400835 DOI: 10.3390/nu12072084] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/16/2020] [Accepted: 06/29/2020] [Indexed: 02/06/2023] Open
Abstract
Essential trace elements play crucial roles in the maintenance of health, since they are involved in many metabolic pathways. A deficiency or an excess of some trace elements, including zinc, selenium, iron, and copper, frequently causes these metabolic disorders such as impaired glucose tolerance and dyslipidemia. The liver largely regulates most of the metabolism of trace elements, and accordingly, an impairment of liver functions can result in numerous metabolic disorders. The administration or depletion of these trace elements can improve such metabolic disorders and liver dysfunction. Recent advances in molecular biological techniques have helped to elucidate the putative mechanisms by which liver disorders evoke metabolic abnormalities that are due to deficiencies or excesses of these trace elements. A genome-wide association study revealed that a genetic polymorphism affected the metabolism of a specific trace element. Gut dysbiosis was also responsible for impairment of the metabolism of a trace element. This review focuses on the current trends of four trace elements in chronic liver diseases, including chronic hepatitis, liver cirrhosis, nonalcoholic fatty liver disease, and autoimmune liver diseases. The novel mechanisms by which the trace elements participated in the pathogenesis of the chronic liver diseases are also mentioned.
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Affiliation(s)
- Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, 281-1, Hara, Mure-Cho, Takamatsu, Kagawa 761-0123, Japan
- Correspondence: ; Tel.: +81-87-870-1240; Fax: +81-87-870-1202
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0123, Japan;
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50
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Zhang Y, Zhang G, Liang Y, Wang H, Wang Q, Zhang Y, Zhang X, Zhang J, Chu L. Potential Mechanisms Underlying the Hepatic–Protective Effects of Danshensu on Iron Overload Mice. Biol Pharm Bull 2020; 43:968-975. [DOI: 10.1248/bpb.b19-01084] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Yuanyuan Zhang
- School of Pharmacy, Hebei University of Chinese Medicine
| | - Gaohua Zhang
- School of Basic Medicine, Hebei University of Chinese Medicine
| | - Yingran Liang
- School of Basic Medicine, Hebei University of Chinese Medicine
| | - Hongfang Wang
- School of Pharmacy, Hebei University of Chinese Medicine
| | - Qian Wang
- School of Pharmacy, Hebei University of Chinese Medicine
| | - Ying Zhang
- School of Basic Medicine, Hebei University of Chinese Medicine
| | - Xuan Zhang
- School of Basic Medicine, Hebei University of Chinese Medicine
| | - Jianping Zhang
- School of Basic Medicine, Hebei University of Chinese Medicine
| | - Li Chu
- School of Pharmacy, Hebei University of Chinese Medicine
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns
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