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1
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Mataix RP, Morillo JSG, Martín JMS. Hepatic phenomena associated with SARS-CoV-2: Acute liver injury, autoimmune hepatitis and post-vaccination. Med Clin (Barc) 2025; 164:491-498. [PMID: 39909769 DOI: 10.1016/j.medcli.2024.12.006] [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: 10/09/2024] [Revised: 12/11/2024] [Accepted: 12/16/2024] [Indexed: 02/07/2025]
Abstract
The infection with SARS-CoV-2, primarily recognized for its respiratory effects, reveals itself as a multifaceted clinical phenomenon, extending beyond the pulmonary realm. Accompanied by gastrointestinal, neurological, thromboembolic, cardiovascular, and immune-related manifestations, the complexity of the systemic repercussions of the disease becomes apparent. Genetic predisposition is a significant factor in the development of autoimmune hepatitis, as both viruses, such as SARS-CoV-2, and drugs, including vaccines, can act as triggers in genetically susceptible individuals. A profound understanding of these mechanisms is essential to effectively address the clinical complexity of SARS-CoV-2 infection.
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Affiliation(s)
- Roberto Pertusa Mataix
- Unit of Systemic and Rare Autoimmune Diseases in Adults, Internal Medicine Service, Virgen del Rocío University Hospital, Manuel Siurot Avenue, S/n, 41013 Sevilla, Spain.
| | - José Salvador García Morillo
- Unit of Systemic and Rare Autoimmune Diseases in Adults, Internal Medicine Service, Virgen del Rocío University Hospital, Manuel Siurot Avenue, S/n, 41013 Sevilla, Spain
| | - José Manuel Sousa Martín
- Digestive Department, Virgen del Rocío University Hospital, Manuel Siurot Avenue, S/n, 41013 Sevilla, Spain
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2
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Zhang M, Guo M, Gao Y, Wu C, Pan X, Huang Z. Mechanisms and therapeutic targets of ferroptosis: Implications for nanomedicine design. J Pharm Anal 2024; 14:100960. [PMID: 39135963 PMCID: PMC11318476 DOI: 10.1016/j.jpha.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 02/27/2024] [Accepted: 03/04/2024] [Indexed: 08/15/2024] Open
Abstract
Ferroptosis is a nonapoptotic form of cell death and differs considerably from the well-known forms of cell death in terms of cell morphology, genetics, and biochemistry. The three primary pathways for cell ferroptosis are system Xc-/glutathione peroxidase 4 (GPX4), lipid metabolism, and ferric metabolism. Since the discovery of ferroptosis, mounting evidence has revealed its critical regulatory role in several diseases, especially as a novel potential target for cancer therapy, thereby attracting increasing attention in the fields of tumor biology and anti-tumor therapy. Accordingly, broad prospects exist for identifying ferroptosis as a potential therapeutic target. In this review, we aimed to systematically summarize the activation and defense mechanisms of ferroptosis, highlight the therapeutic targets, and discuss the design of nanomedicines for ferroptosis regulation. In addition, we opted to present the advantages and disadvantages of current ferroptosis research and provide an optimistic vision of future directions in related fields. Overall, we aim to provide new ideas for further ferroptosis research and inspire new strategies for disease diagnosis and treatment.
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Affiliation(s)
- Meihong Zhang
- College of Pharmacy, University of Jinan, Guangzhou, 510632, China
| | - Mengqin Guo
- College of Pharmacy, University of Jinan, Guangzhou, 510632, China
| | - Yue Gao
- College of Pharmacy, University of Jinan, Guangzhou, 510632, China
| | - Chuanbin Wu
- College of Pharmacy, University of Jinan, Guangzhou, 510632, China
| | - Xin Pan
- College of Pharmacy, University of Sun Yat-sen, Guangzhou, 510275, China
| | - Zhengwei Huang
- College of Pharmacy, University of Jinan, Guangzhou, 510632, China
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3
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Shu YJ, Lao B, Qiu YY. Research progress of ferroptosis regulating lipid peroxidation and metabolism in occurrence and development of primary liver cancer. World J Gastrointest Oncol 2024; 16:2335-2349. [PMID: 38994128 PMCID: PMC11236230 DOI: 10.4251/wjgo.v16.i6.2335] [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: 12/12/2023] [Revised: 03/06/2024] [Accepted: 04/11/2024] [Indexed: 06/13/2024] Open
Abstract
As a highly aggressive tumor, the pathophysiological mechanism of primary liver cancer has attracted much attention. In recent years, factors such as ferroptosis regulation, lipid peroxidation and metabolic abnormalities have emerged in the study of liver cancer, providing a new perspective for understanding the development of liver cancer. Ferroptosis regulation, lipid peroxidation and metabolic abnormalities play important roles in the occurrence and development of liver cancer. The regulation of ferroptosis is involved in apoptosis and necrosis, affecting cell survival and death. Lipid peroxidation promotes oxidative damage and promotes the invasion of liver cancer cells. Metabolic abnormalities, especially the disorders of glucose and lipid metabolism, directly affect the proliferation and growth of liver cancer cells. Studies of ferroptosis regulation and lipid peroxidation may help to discover new therapeutic targets and improve therapeutic outcomes. The understanding of metabolic abnormalities can provide new ideas for the prevention of liver cancer, and reduce the risk of disease by adjusting the metabolic process. This review focuses on the key roles of ferroptosis regulation, lipid peroxidation and metabolic abnormalities in this process.
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Affiliation(s)
- Yu-Jie Shu
- Department of Gastroenterology, Yinzhou District Second Hospital, Ningbo 315199, Zhejiang Province, China
| | - Bo Lao
- Department of Gastroenterology, Yinzhou District Second Hospital, Ningbo 315199, Zhejiang Province, China
| | - Ying-Yang Qiu
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
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4
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Ding L. Ferroptosis in viral infection: a potential therapeutic target. Future Microbiol 2024; 19:519-524. [PMID: 38411103 PMCID: PMC11216501 DOI: 10.2217/fmb-2023-0186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 11/16/2023] [Indexed: 02/28/2024] Open
Abstract
Ferroptosis, known as a type of programmed cell death that is iron dependent, is characterized by intracellular iron accumulation, glutathione depletion, glutathione peroxidase inactivation and lipid peroxidation. More and more research in recent years has demonstrated the tight connection between viral infections and ferroptosis. This article reviews the potential role and mechanism of ferroptosis in viral infection, and these findings will help in the prevention and treatment of the virus.
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Affiliation(s)
- Liqiong Ding
- Department of Pharmaceutics, School of Pharmacy, Hubei University of Science & Technology, Xianning, China
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5
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Michalak A, Lach T, Szczygieł K, Cichoż-Lach H. COVID-19, Possible Hepatic Pathways and Alcohol Abuse-What Do We Know up to 2023? Int J Mol Sci 2024; 25:2212. [PMID: 38396888 PMCID: PMC10888568 DOI: 10.3390/ijms25042212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 01/23/2024] [Accepted: 01/26/2024] [Indexed: 02/25/2024] Open
Abstract
The pandemic period due to coronavirus disease 2019 (COVID-19) revolutionized all possible areas of global health. Significant consequences were also related to diverse extrapulmonary manifestations of this pathology. The liver was found to be a relatively common organ, beyond the respiratory tract, affected by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Multiple studies revealed the essential role of chronic liver disease (CLD) in the general outcome of coronavirus infection. Present concerns in this field are related to the direct hepatic consequences caused by COVID-19 and pre-existing liver disorders as risk factors for the severe course of the infection. Which mechanism has a key role in this phenomenon-previously existing hepatic disorder or acute liver failure due to SARS-CoV-2-is still not fully clarified. Alcoholic liver disease (ALD) constitutes another not fully elucidated context of coronavirus infection. Should the toxic effects of ethanol or already developed liver cirrhosis and its consequences be perceived as a causative or triggering factor of hepatic impairment in COVID-19 patients? In the face of these discrepancies, we decided to summarize the role of the liver in the whole picture of coronavirus infection, paying special attention to ALD and focusing on the pathological pathways related to COVID-19, ethanol toxicity and liver cirrhosis.
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Affiliation(s)
- Agata Michalak
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland;
| | - Tomasz Lach
- Department of Orthopedics and Traumatology, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland;
| | - Karolina Szczygieł
- Clinical Dietetics Unit, Department of Bioanalytics, Medical University of Lublin, Chodźki 7, 20-093 Lublin, Poland;
| | - Halina Cichoż-Lach
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland;
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6
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Wang Y, Shen M, Li Y, Shao J, Zhang F, Guo M, Zhang Z, Zheng S. COVID-19-associated liver injury: Adding fuel to the flame. Cell Biochem Funct 2023; 41:1076-1092. [PMID: 37947373 DOI: 10.1002/cbf.3883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 10/19/2023] [Accepted: 10/21/2023] [Indexed: 11/12/2023]
Abstract
COVID-19 is mainly characterized by respiratory disorders and progresses to multiple organ involvement in severe cases. With expansion of COVID-19 and SARS-CoV-2 research, correlative liver injury has been revealed. It is speculated that COVID-19 patients exhibited abnormal liver function, as previously observed in the SARS and MERS pandemics. Furthermore, patients with underlying diseases such as chronic liver disease are more susceptible to SARS-CoV-2 and indicate a poor prognosis accompanied by respiratory symptoms, systemic inflammation, or metabolic diseases. Therefore, COVID-19 has the potential to impair liver function, while individuals with preexisting liver disease suffer from much worse infected conditions. COVID-19 related liver injury may be owing to direct cytopathic effect, immune dysfunction, gut-liver axis interaction, and inappropriate medication use. However, discussions on these issues are infancy. Expanding research have revealed that angiotensin converting enzyme 2 (ACE2) expression mediated the combination of virus and target cells, iron metabolism participated in the virus life cycle and the fate of target cells, and amino acid metabolism regulated immune response in the host cells, which are all closely related to liver health. Further exploration holds great significance in elucidating the pathogenesis, facilitating drug development, and advancing clinical treatment of COVID-19-related liver injury. This article provides a review of the clinical and laboratory hepatic characteristics in COVID-19 patients, describes the etiology and impact of liver injury, and discusses potential pathophysiological mechanisms.
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Affiliation(s)
- Yingqian Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Min Shen
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China
| | - Yujia Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jiangjuan Shao
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Mei Guo
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zili Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shizhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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7
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Riegler AN, Benson P, Long K, Leal SM. Differential activation of programmed cell death in patients with severe SARS-CoV-2 infection. Cell Death Discov 2023; 9:420. [PMID: 37985756 PMCID: PMC10662024 DOI: 10.1038/s41420-023-01715-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/26/2023] [Accepted: 11/07/2023] [Indexed: 11/22/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes severe lower airway disease and death in a subset of patients. Knowledge on the relative contribution of programmed cell death (PCD) to lung pathology is limited to few human autopsy studies with small sample size/scope, in vitro cell culture, and experimental model systems. In this study, we sought to identify, localize, and quantify activation of apoptosis, ferroptosis, pyroptosis, and necroptosis in FFPE lung tissues from patients that died from severe SARS-CoV-2 infection (n = 28) relative to uninfected controls (n = 13). Immunofluorescence (IF) staining, whole-slide imaging, and Image J software was used to localize and quantify expression of SARS-CoV-2 nucleoprotein and the following PCD protein markers: cleaved Caspase-3, pMLKL, cleaved Gasdermin D, and CD71, respectively. IF showed differential activation of each PCD pathway in infected lungs and dichotomous staining for SARS-CoV-2 nucleoprotein enabling distinction between high (n = 9) vs low viral burden (n = 19). No differences were observed in apoptosis and ferroptosis in SARS-CoV-2 infected lungs relative to uninfected controls. However, both pyroptosis and necroptosis were significantly increased in SARS-CoV-2-infected lungs. Increased pyroptosis was observed in SARS-CoV-2 infected lungs, irrespective of viral burden, suggesting an inflammation-driven mechanism. In contrast, necroptosis exhibited a very strong positive correlation with viral burden (R2 = 0.9925), suggesting a direct SARS-CoV-2 mediated effect. These data indicate a possible novel mechanism for viral-mediated necroptosis and a potential role for both lytic programmed cell death pathways, necroptosis and pyroptosis, in mediating infection outcome.
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Affiliation(s)
- Ashleigh N Riegler
- Division of Laboratory Medicine, Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Paul Benson
- Division of Anatomic Pathology, Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Kenneth Long
- Division of Infectious Diseases, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sixto M Leal
- Division of Laboratory Medicine, Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA.
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8
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Wufuer D, Li Y, Aierken H, Zheng J. Bioinformatics-led discovery of ferroptosis-associated diagnostic biomarkers and molecule subtypes for tuberculosis patients. Eur J Med Res 2023; 28:445. [PMID: 37853432 PMCID: PMC10585777 DOI: 10.1186/s40001-023-01371-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 09/13/2023] [Indexed: 10/20/2023] Open
Abstract
BACKGROUND Ferroptosis is closely associated with the pathophysiological processes of many diseases, such as infection, and is characterized by the accumulation of excess lipid peroxides on the cell membranes. However, studies on the ferroptosis-related diagnostic markers in tuberculosis (TB) is still lacking. Our study aimed to explore the role of ferroptosis-related biomarkers and molecular subtypes in TB. METHODS GSE83456 dataset was applied to identify ferroptosis-related genes (FRGs) associated with TB, and GSE42826, GSE28623, and GSE34608 datasets for external validation of core biomarkers. Core FRGs were identified using weighted gene co-expression network analysis (WGCNA). Subsequently, two ferroptosis-related subtypes were constructed based on ferroptosis score, and differently expressed analysis, GSEA, GSEA, immune cell infiltration analysis between the two subtypes were performed.Affiliations: Please check and confirm that the authors and their respective affiliations have been correctly identified and amend if necessary.correctly RESULTS: A total of 22 FRGs were identified, of which three genes (CHMP5, SAT1, ZFP36) were identified as diagnostic biomarkers that were enriched in pathways related to immune-inflammatory response. In addition, TB patients were divided into high- and low-ferroptosis subtypes (HF and LF) based on ferroptosis score. HF patients had activated immune- and inflammation-related pathways and higher immune cell infiltration levels than LF patients. CONCLUSION Three potential diagnostic biomarkers and two ferroptosis-related subtypes were identified in TB patients, which would help to understand the pathogenesis of TB.Author names: Kindly check and confirm the process of the author names [2,4]correctly.
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Affiliation(s)
- Dilinuer Wufuer
- The First Affiliated Hospital of Guangzhou Medical University/National Clinical Research Center for Respiratory Disease/National Respiratory Medical Center/State Key Laboratory of Respiratory Disease/Guangzhou Institute of Respiratory Health, NO. 151 Yanjang Road, Guangzhou, 510120, China
| | - YuanYuan Li
- Department of Respiratory Medicine, Eighth Affiliated Hospital of Xinjiang Medical University, Urumqi, 830049, Xinjiang, China
| | - Haidiya Aierken
- Department of Respiratory Medicine, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, Xinjiang, China
| | - JinPing Zheng
- The First Affiliated Hospital of Guangzhou Medical University/National Clinical Research Center for Respiratory Disease/National Respiratory Medical Center/State Key Laboratory of Respiratory Disease/Guangzhou Institute of Respiratory Health, NO. 151 Yanjang Road, Guangzhou, 510120, China.
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9
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Riegler A, Benson P, Long K, Leal S. Differential Activation of Programmed Cell Death in Patients with Severe SARS-CoV-2 Infection. RESEARCH SQUARE 2023:rs.3.rs-3059466. [PMID: 37461686 PMCID: PMC10350212 DOI: 10.21203/rs.3.rs-3059466/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/24/2023]
Abstract
SARS-CoV-2 (SARS-2) causes severe lower airway disease and death in a subset of patients. Knowledge on the relative contribution of programmed cell death (PCD) to lung pathology is limited to few human autopsy studies with small sample size/scope, in vitro cell culture, and experimental model systems. In this study, we sought to identify, localize, and quantify activation of apoptosis, ferroptosis, pyroptosis, and necroptosis in FFPE lung tissues from patients that died from severe SARS-2 infection (n=28) relative to uninfected controls (n=13). Immunofluorescence (IF) staining, whole-slide imaging, and Image J software was used to localize and quantify expression of SARS-2 nucleoprotein and the following PCD protein markers: cleaved Caspase-3, pMLKL, cleaved Gasdermin D, and CD71, respectively. IF showed differential activation of each PCD pathway in SARS-2 infected lungs and dichotomous staining for SARS-2 nucleoprotein enabling distinction between high (n=9) vs low viral burden (n= 19). No differences were observed in apoptosis and ferroptosis in SARS-2 infected lungs relative to uninfected controls. However, both pyroptosis and necroptosis were significantly increased in SARS-2 infected lungs. Increased pyroptosis was observed in SARS-2 infected lungs, irrespective of viral burden, suggesting an inflammation-driven mechanism. In contrast, necroptosis exhibited a very strong positive correlation with viral burden (R2=0.9925), suggesting a direct SARS-2 mediated effect. These data indicate a possible novel mechanism for viral-mediated necroptosis and a potential role for both lytic programmed cell death pathways, necroptosis and pyroptosis, in mediating infection outcome.
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10
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Roshanshad R, Roshanshad A, Fereidooni R, Hosseini-Bensenjan M. COVID-19 and liver injury: Pathophysiology, risk factors, outcome and management in special populations. World J Hepatol 2023; 15:441-459. [PMID: 37206656 PMCID: PMC10190688 DOI: 10.4254/wjh.v15.i4.441] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 02/05/2023] [Accepted: 03/20/2023] [Indexed: 04/20/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 is an ongoing health concern. In addition to affecting the respiratory system, COVID-19 can potentially damage other systems in the body, leading to extra-pulmonary manifestations. Hepatic manifestations are among the common consequences of COVID-19. Although the precise mechanism of liver injury is still questionable, several mechanisms have been hypothesized, including direct viral effect, cytokine storm, hypoxic-ischemic injury, hypoxia-reperfusion injury, ferroptosis, and hepatotoxic medications. Risk factors of COVID-19-induced liver injury include severe COVID-19 infection, male gender, advanced age, obesity, and underlying diseases. The presentations of liver involvement comprise abnormalities in liver enzymes and radiologic findings, which can be utilized to predict the prognosis. Increased gamma-glutamyltransferase, aspartate aminotransferase, and alanine aminotransferase levels with hypoalbuminemia can indicate severe liver injury and anticipate the need for intensive care units’ hospitalization. In imaging, a lower liver-to-spleen ratio and liver computed tomography attenuation may indicate a more severe illness. Furthermore, chronic liver disease patients are at a higher risk for severe disease and death from COVID-19. Nonalcoholic fatty liver disease had the highest risk of advanced COVID-19 disease and death, followed by metabolic-associated fatty liver disease and cirrhosis. In addition to COVID-19-induced liver injury, the pandemic has also altered the epidemiology and pattern of some hepatic diseases, such as alcoholic liver disease and hepatitis B. Therefore, it warrants special vigilance and awareness by healthcare professionals to screen and treat COVID-19-associated liver injury accordingly.
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Affiliation(s)
- Romina Roshanshad
- Student Research Committee, School of Medicine, Shiraz University of Medical Sciences, Shiraz 7184731443, Iran
| | | | - Reza Fereidooni
- Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz 7134814336, Iran
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11
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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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12
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Jia FJ, Han J. Liver injury in COVID-19: Holds ferritinophagy-mediated ferroptosis accountable. World J Clin Cases 2022; 10:13148-13156. [PMID: 36683648 PMCID: PMC9850986 DOI: 10.12998/wjcc.v10.i36.13148] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 11/20/2022] [Accepted: 12/08/2022] [Indexed: 12/26/2022] Open
Abstract
Even in patients without a history of liver disease, liver injury caused by coronavirus disease 2019 (COVID-19) is gradually becoming more common. However, the precise pathophysiological mechanisms behind COVID-19's liver pathogenicity are still not fully understood. We hypothesize that inflammation may become worse by cytokine storms caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Elevated ferritin levels can initiate ferritinophagy mediated by nuclear receptor coactivator 4 (NCOA4), which leads to iron elevation, and ferroptosis. In COVID-19 patients, ferroptosis can be restricted to reduce disease severity and liver damage by targeting NCOA4-mediated ferritinophagy. To confirm the role of ferritinophagy-mediated ferroptosis in SARS-CoV-2 infection, further research is required.
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Affiliation(s)
- Feng-Ju Jia
- School of Nursing, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Jing Han
- School of Nursing, Qingdao University, Qingdao 266071, Shandong Province, China
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13
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Dufrusine B, Valentinuzzi S, Bibbò S, Damiani V, Lanuti P, Pieragostino D, Del Boccio P, D’Alessandro E, Rabottini A, Berghella A, Allocati N, Falasca K, Ucciferri C, Mucedola F, Di Perna M, Martino L, Vecchiet J, De Laurenzi V, Dainese E. Iron Dyshomeostasis in COVID-19: Biomarkers Reveal a Functional Link to 5-Lipoxygenase Activation. Int J Mol Sci 2022; 24:15. [PMID: 36613462 PMCID: PMC9819889 DOI: 10.3390/ijms24010015] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/13/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19) is characterized by a broad spectrum of clinical symptoms. After acute infection, some subjects develop a post-COVID-19 syndrome known as long-COVID. This study aims to recognize the molecular and functional mechanisms that occur in COVID-19 and long-COVID patients and identify useful biomarkers for the management of patients with COVID-19 and long-COVID. Here, we profiled the response to COVID-19 by performing a proteomic analysis of lymphocytes isolated from patients. We identified significant changes in proteins involved in iron metabolism using different biochemical analyses, considering ceruloplasmin (Cp), transferrin (Tf), hemopexin (HPX), lipocalin 2 (LCN2), and superoxide dismutase 1 (SOD1). Moreover, our results show an activation of 5-lipoxygenase (5-LOX) in COVID-19 and in long-COVID possibly through an iron-dependent post-translational mechanism. Furthermore, this work defines leukotriene B4 (LTB4) and lipocalin 2 (LCN2) as possible markers of COVID-19 and long-COVID and suggests novel opportunities for prevention and treatment.
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Affiliation(s)
- Beatrice Dufrusine
- Department of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, 64100 Teramo, Italy
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Silvia Valentinuzzi
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Sandra Bibbò
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Verena Damiani
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Paola Lanuti
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Department of Medicine and Aging Science, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
| | - Damiana Pieragostino
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Piero Del Boccio
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Ersilia D’Alessandro
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Alberto Rabottini
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Alessandro Berghella
- Department of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, 64100 Teramo, Italy
| | - Nerino Allocati
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Katia Falasca
- Department of Medicine and Aging Science, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
- Clinic of Infectious Diseases, S.S. Annunziata Hospital, 66100 Chieti, Italy
| | - Claudio Ucciferri
- Clinic of Infectious Diseases, S.S. Annunziata Hospital, 66100 Chieti, Italy
| | - Francesco Mucedola
- Clinic of Infectious Diseases, S.S. Annunziata Hospital, 66100 Chieti, Italy
| | - Marco Di Perna
- Pneumology Department, “SS Annunziata” Hospital, 66100 Chieti, Italy
| | - Laura Martino
- Pneumology Department, “SS Annunziata” Hospital, 66100 Chieti, Italy
| | - Jacopo Vecchiet
- Department of Medicine and Aging Science, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
- Clinic of Infectious Diseases, S.S. Annunziata Hospital, 66100 Chieti, Italy
| | - Vincenzo De Laurenzi
- Department of Innovative Technologies in Medicine and Dentistry, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Enrico Dainese
- Department of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, 64100 Teramo, Italy
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14
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Long COVID and the Neuroendocrinology of Microbial Translocation Outside the GI Tract: Some Treatment Strategies. ENDOCRINES 2022. [DOI: 10.3390/endocrines3040058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Similar to previous pandemics, COVID-19 has been succeeded by well-documented post-infectious sequelae, including chronic fatigue, cough, shortness of breath, myalgia, and concentration difficulties, which may last 5 to 12 weeks or longer after the acute phase of illness. Both the psychological stress of SARS-CoV-2 infection and being diagnosed with COVID-19 can upregulate cortisol, a stress hormone that disrupts the efferocytosis effectors, macrophages, and natural killer cells, leading to the excessive accumulation of senescent cells and disruption of biological barriers. This has been well-established in cancer patients who often experience unrelenting fatigue as well as gut and blood–brain barrier dysfunction upon treatment with senescence-inducing radiation or chemotherapy. In our previous research from 2020 and 2021, we linked COVID-19 to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) via angiotensin II upregulation, premature endothelial senescence, intestinal barrier dysfunction, and microbial translocation from the gastrointestinal tract into the systemic circulation. In 2021 and 2022, these hypotheses were validated and SARS-CoV-2-induced cellular senescence as well as microbial translocation were documented in both acute SARS-CoV-2 infection, long COVID, and ME/CFS, connecting intestinal barrier dysfunction to disabling fatigue and specific infectious events. The purpose of this narrative review is to summarize what is currently known about host immune responses to translocated gut microbes and how these responses relate to fatiguing illnesses, including long COVID. To accomplish this goal, we examine the role of intestinal and blood–brain barriers in long COVID and other illnesses typified by chronic fatigue, with a special emphasis on commensal microbes functioning as viral reservoirs. Furthermore, we discuss the role of SARS-CoV-2/Mycoplasma coinfection in dysfunctional efferocytosis, emphasizing some potential novel treatment strategies, including the use of senotherapeutic drugs, HMGB1 inhibitors, Toll-like receptor 4 (TLR4) blockers, and membrane lipid replacement.
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15
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Teschke R. Aluminum, Arsenic, Beryllium, Cadmium, Chromium, Cobalt, Copper, Iron, Lead, Mercury, Molybdenum, Nickel, Platinum, Thallium, Titanium, Vanadium, and Zinc: Molecular Aspects in Experimental Liver Injury. Int J Mol Sci 2022; 23:12213. [PMID: 36293069 PMCID: PMC9602583 DOI: 10.3390/ijms232012213] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 09/30/2022] [Accepted: 10/11/2022] [Indexed: 11/25/2022] Open
Abstract
Experimental liver injury with hepatocelluar necrosis and abnormal liver tests is caused by exposure to heavy metals (HMs) like aluminum, arsenic, beryllium, cadmium, chromium, cobalt, copper, iron, lead, mercury, molybdenum, nickel, platinum, thallium, titanium, vanadium, and zinc. As pollutants, HMs disturb the ecosystem, and as these substances are toxic, they may affect the health of humans and animals. HMs are not biodegradable and may be deposited preferentially in the liver. The use of animal models can help identify molecular and mechanistic steps leading to the injury. HMs commonly initiate hepatocellular overproduction of ROS (reactive oxygen species) due to oxidative stress, resulting in covalent binding of radicals to macromolecular proteins or lipids existing in membranes of subcellular organelles. Liver injury is facilitated by iron via the Fenton reaction, providing ROS, and is triggered if protective antioxidant systems are exhausted. Ferroptosis syn pyroptosis was recently introduced as mechanistic concept in explanations of nickel (Ni) liver injury. NiCl2 causes increased iron deposition in the liver, upregulation of cyclooxygenase 2 (COX-2) protein and mRNA expression levels, downregulation of glutathione eroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), nuclear receptor coactivator 4 (NCOA4) protein, and mRNA expression levels. Nickel may cause hepatic injury through mitochondrial damage and ferroptosis, defined as mechanism of iron-dependent cell death, similar to glutamate-induced excitotoxicity but likely distinct from apoptosis, necrosis, and autophagy. Under discussion were additional mechanistic concepts of hepatocellular uptake and biliary excretion of mercury in exposed animals. For instance, the organic anion transporter 3 (Oat3) and the multidrug resistance-associated protein 2 (Mrp2) were involved in the hepatic handling of mercury. Mercury treatment modified the expression of Mrp2 and Oat3 as assessed by immunoblotting, partially explaining its impaired biliary excretion. Concomitantly, a decrease in Oat3 abundance in the hepatocyte plasma membranes was observed that limits the hepatic uptake of mercury ions. Most importantly and shown for the first time in liver injury caused by HMs, titanium changed the diversity of gut microbiota and modified their metabolic functions, leading to increased generation of lipopolysaccharides (LPS). As endotoxins, LPS may trigger and perpetuate the liver injury at the level of gut-liver. In sum, mechanistic and molecular steps of experimental liver injury due to HM administration are complex, with ROS as the key promotional compound. However, additional concepts such as iron used in the Fenton reaction, ferroptosis, modification of transporter systems, and endotoxins derived from diversity of intestinal bacteria at the gut-liver level merit further consideration.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt, 63450 Hanau, Germany
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