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Li P, Liang X, Luo J, Li J. Omics in acute-on-chronic liver failure. Liver Int 2025; 45:e15634. [PMID: 37288724 DOI: 10.1111/liv.15634] [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: 02/07/2023] [Revised: 05/03/2023] [Accepted: 05/24/2023] [Indexed: 06/09/2023]
Abstract
Acute-on-chronic liver failure (ACLF) is a critical syndrome that develops in patients with chronic liver disease and is characterized by acute decompensation, single- or multiple-organ failure and high short-term mortality. Over the past few decades, ACLF has been progressively recognized as an independent clinical entity, and several criteria and prognostic scores have been proposed and validated by different scientific societies. However, controversies still exist in some aspects across regions, which mainly involve whether the definition of underlying liver diseases should include cirrhosis and non-cirrhosis. The pathophysiology of ACLF is complicated and remains unclear, although accumulating evidence based on different aetiologies of ACLF shows that it is closely associated with intense systemic inflammation and immune-metabolism disorder, which result in mitochondrial dysfunction and microenvironment imbalance, leading to disease development and organ failure. In-depth insight into the biological pathways involved in the mechanisms of ACLF and potential mechanistic targets that improve patient survival still needs to be investigated. Omics-based analytical techniques, including genomics, transcriptomics, proteomics, metabolomics and microbiomes, have developed rapidly and can offer novel insights into the essential pathophysiologic process of ACLF. In this paper, we briefly reviewed and summarized the current knowledge and recent advances in the definitions, criteria and prognostic assessments of ACLF; we also described the omics techniques and how omics-based analyses have been applied to investigate and characterize the biological mechanisms of ACLF and identify potential predictive biomarkers and therapeutic targets for ACLF. We also outline the challenges, future directions and limitations presented by omics-based analyses in clinical ACLF research.
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Affiliation(s)
- Peng Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xi Liang
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Jinjin Luo
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Lin W, Chen Y, Lu M, Peng C, Chen X, Liu X, Wang Y. Identification and validation of neutrophil-related biomarkers in acute-on-chronic liver failure. Front Immunol 2025; 16:1477342. [PMID: 40070835 PMCID: PMC11893565 DOI: 10.3389/fimmu.2025.1477342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 02/03/2025] [Indexed: 03/14/2025] Open
Abstract
Dysfunction of peripheral blood neutrophils occurs in acute-on-chronic liver failure (ACLF). However, the molecular mechanisms of neutrophils involved in the pathophysiology of the ACLF remains poorly understood. Data downloaded from the GEO database (GSE142255) was used to identify both ACLF and neutrophil-related genes with the help of the limma package and Weighted Gene Co-Expression Network Analysis (WGCNA) algorithms. The analysis identified 288 ACLF-related differentially expressed genes (DEGs) in the circulating blood cells. Among these, three genes were found to be related to neutrophils and were identified as diagnostic genes, exhibiting high diagnostic efficacy as evidenced by an area under the curve (AUC) value of 1. Among these, matrix metallopeptidase-9 (MMP9) and S100 calcium binding protein A12 (S100A12) were upregulated, whereas C-C chemokine ligand 5 (CCL5) was downregulated in circulating immune cells from patients with ACLF compared to those from healthy controls. These findings were corroborated using an additional GEO dataset, GSE156382. The expression levels of the three key genes demonstrated a correlation with both ferroptosis and cuprotosis. Among the three diagnostic genes, only MMP9 was validated as differentially expressed through both quantitative real-time PCR (qRT-PCR) and western blot. Moreover, a significant elevation in plasma MMP9 levels was observed in patients with ACLF compared to those with chronic hepatitis B (CHB) and acute decompensated cirrhosis (AD). Notably, ACLF patients exhibiting elevated MMP9 levels (>175.8 ng/mL) experienced higher short-term mortality rates within both 30 and 90 days (p<0.001). In addition, a total of 21 drugs targeting the three diagnostic genes were identified from the Drug Bank database. Finally, the Kinase-TF-mRNA-miRNA network was constructed utilizing Cytoscape software. This study represents the initial application of WGCNA algorithms to identify novel biomarkers related to neutrophils in ACLF. Our findings offer new perspectives on the role of neutrophil in the pathogenesis of ACLF. However, additional research is required to substantiate the effects of these key genes and therapeutic agents on ACLF.
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Affiliation(s)
- Wei Lin
- Department of Orthopedics, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yongping Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Mingqin Lu
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Cheng Peng
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiang Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaoqin Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yunyun Wang
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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Nishijima S, Stankevic E, Aasmets O, Schmidt TSB, Nagata N, Keller MI, Ferretti P, Juel HB, Fullam A, Robbani SM, Schudoma C, Hansen JK, Holm LA, Israelsen M, Schierwagen R, Torp N, Telzerow A, Hercog R, Kandels S, Hazenbrink DHM, Arumugam M, Bendtsen F, Brøns C, Fonvig CE, Holm JC, Nielsen T, Pedersen JS, Thiele MS, Trebicka J, Org E, Krag A, Hansen T, Kuhn M, Bork P. Fecal microbial load is a major determinant of gut microbiome variation and a confounder for disease associations. Cell 2025; 188:222-236.e15. [PMID: 39541968 DOI: 10.1016/j.cell.2024.10.022] [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: 03/08/2024] [Revised: 07/12/2024] [Accepted: 10/14/2024] [Indexed: 11/17/2024]
Abstract
The microbiota in individual habitats differ in both relative composition and absolute abundance. While sequencing approaches determine the relative abundances of taxa and genes, they do not provide information on their absolute abundances. Here, we developed a machine-learning approach to predict fecal microbial loads (microbial cells per gram) solely from relative abundance data. Applying our prediction model to a large-scale metagenomic dataset (n = 34,539), we demonstrated that microbial load is the major determinant of gut microbiome variation and is associated with numerous host factors, including age, diet, and medication. We further found that for several diseases, changes in microbial load, rather than the disease condition itself, more strongly explained alterations in patients' gut microbiome. Adjusting for this effect substantially reduced the statistical significance of the majority of disease-associated species. Our analysis reveals that the fecal microbial load is a major confounder in microbiome studies, highlighting its importance for understanding microbiome variation in health and disease.
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Affiliation(s)
- Suguru Nishijima
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Evelina Stankevic
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Oliver Aasmets
- Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Thomas S B Schmidt
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Naoyoshi Nagata
- Department of Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan
| | - Marisa Isabell Keller
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Pamela Ferretti
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Helene Bæk Juel
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Anthony Fullam
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | | | - Christian Schudoma
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Johanne Kragh Hansen
- Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Louise Aas Holm
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark
| | - Mads Israelsen
- Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Robert Schierwagen
- Department of Internal Medicine B, University of Münster, Münster, Germany
| | - Nikolaj Torp
- Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Anja Telzerow
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Rajna Hercog
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Stefanie Kandels
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Diënty H M Hazenbrink
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Manimozhiyan Arumugam
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Flemming Bendtsen
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Charlotte Brøns
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Cilius Esmann Fonvig
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens-Christian Holm
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Trine Nielsen
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Medical department, University Hospital Zeeland, Køge, Denmark
| | - Julie Steen Pedersen
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Maja Sofie Thiele
- Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Jonel Trebicka
- Department of Internal Medicine B, University of Münster, Münster, Germany; European Foundation for the Study of Chronic Liver Failure, EFCLIF, Barcelona, Spain
| | - Elin Org
- Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Aleksander Krag
- Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Michael Kuhn
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
| | - Peer Bork
- Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany; Max Delbrück Centre for Molecular Medicine, Berlin, Germany; Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany.
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Schütz F, Longo L, Keingeski MB, Filippi-Chiela E, Uribe-Cruz C, Álvares-da-Silva MR. Lipophagy and epigenetic alterations are related to metabolic dysfunction-associated steatotic liver disease progression in an experimental model. World J Hepatol 2024; 16:1468-1479. [DOI: 10.4254/wjh.v16.i12.1468] [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: 05/07/2024] [Revised: 08/31/2024] [Accepted: 09/19/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Genetic and epigenetic alterations are related to metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis.
AIM To evaluate micro (mi)RNAs and lipophagy markers in an experimental model of metabolic dysfunction-associated steatohepatitis (MASH).
METHODS Adult male Sprague Dawley rats were randomized into two groups: Control group (n = 10) fed a standard diet; and intervention group (n = 10) fed a high-fat-choline-deficient diet for 16 weeks. Molecular evaluation of lipophagy markers in liver tissue [sirtuin-1, p62/sequestosome-1, transcription factor-EB, perilipin-2 (Plin2), Plin3, Plin5, lysosome-associated membrane proteins-2, rubicon, and Cd36], and serum miRNAs were performed.
RESULTS Animals in the intervention group developed MASH and showed a significant decrease in sirtuin-1 (P = 0.020) and p62/sequestosome-1 (P < 0.001); the opposite was reported for transcription factor-EB (P = 0.020), Plin2 (P = 0.003), Plin3 (P = 0.031), and Plin5 (P = 0.005) compared to the control group. There was no significant difference between groups for lysosome-associated membrane proteins-2 (P = 0.715), rubicon (P = 0.166), and Cd36 (P = 0.312). The intervention group showed a significant increase in miR-34a (P = 0.005) and miR-21 (P = 0.043) compared to the control. There was no significant difference between groups for miR-375 (P = 0.905), miR-26b (P = 0.698), and miR-155 (P = 0.688).
CONCLUSION Animals with MASH presented expression changes in markers related to lysosomal stress and autophagy as well as in miRNAs related to inflammation and fibrogenesis, processes that promote MASLD progression.
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Affiliation(s)
- Felipe Schütz
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
| | - Larisse Longo
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
| | - Melina Belén Keingeski
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
| | - Eduardo Filippi-Chiela
- Center of Biotechnology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Rio Grande do Sul, Brazil
- Department of Morphological Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Rio Grande do Sul, Brazil
| | - Carolina Uribe-Cruz
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Facultad de Ciencias de la Salud, Universidad Católica de las Misiones, Posadas 3300, Misiones, Argentina
| | - Mário Reis Álvares-da-Silva
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Division of Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-007, Rio Grande do Sul, Brazil
- Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brasilia 71.605-001, Distrito Federal, Brazil
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Wang L, Liu P, Han Y. Serum microRNA-181a Expression Level in Patients with Acute Liver Failure and Its Correlation with Prognosis. Int J Gen Med 2024; 17:4815-4822. [PMID: 39440101 PMCID: PMC11495206 DOI: 10.2147/ijgm.s478709] [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: 05/17/2024] [Accepted: 09/13/2024] [Indexed: 10/25/2024] Open
Abstract
Objective This paper examined miR-181a expression in the serum of patients with acute liver failure (ALF) and investigated the impact of its expression in the prognosis of ALF patients. Methods A total of 112 ALF patients (ALF group) and 100 healthy controls during the same period (control group) were recruited as study subjects, and ALF patients were separated into the survival group and the death group. Serum ALT, AST, SCr, TBil, PTA, and International Normalized Ratio (INR) indices as well as serum miR-181a expression were assessed by using a fully automated biochemistry analyzer and RT-qPCR. Patients in the ALF group were evaluated using the Model for End-Stage Liver Disease (MELD) score. Correlation between serum miR-181a expression and MELD scores of ALF patients was processed by Pearson correlation analysis, and the diagnostic value of miR-181a level for the occurrence of ALF was estimated by ROC curve analysis. Multivariate logistic regression analysis was executed to assess the factors influencing the occurrence of death in ALF patients. Results ALF patients had higher levels of ALT, AST, TBiL, SCr, INR and miR-181a and lower PTA levels in comparison to healthy controls. Serum miR-181a expression level in ALF patients revealed a significant positive correlation with MELD score. Multivariate logistic regression analysis unveiled that TBil, INR, SCr, and miR-181a were the independent risk factors for the occurrence of death in ALF patients, and that PTA was an independent protective factor for the prognosis of ALF patients. miR-181a exhibited a favorable diagnostic value in ALF and its prognosis. Conclusion miR-181a expression is upregulated in the serum of ALF patients, and it can be utilized as an indicator for ALF diagnostic and prognostic assessment.
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Affiliation(s)
- Lili Wang
- Department of Liver Disease, Qingdao Sixth People’s Hospital, Qingdao, Shandong, 266033, People’s Republic of China
| | - Pingping Liu
- Clinical Laboratory, Qingdao Sixth People’s Hospital, Qingdao, Shandong, 266033, People’s Republic of China
| | - Yidi Han
- Department of Liver Disease, Qingdao Sixth People’s Hospital, Qingdao, Shandong, 266033, People’s Republic of China
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Zhai Y, Hai D, Zeng L, Lin C, Tan X, Mo Z, Tao Q, Li W, Xu X, Zhao Q, Shuai J, Pan J. Artificial intelligence-based evaluation of prognosis in cirrhosis. J Transl Med 2024; 22:933. [PMID: 39402630 PMCID: PMC11475999 DOI: 10.1186/s12967-024-05726-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 10/02/2024] [Indexed: 10/19/2024] Open
Abstract
Cirrhosis represents a significant global health challenge, characterized by high morbidity and mortality rates that severely impact human health. Timely and precise prognostic assessments of liver cirrhosis are crucial for improving patient outcomes and reducing mortality rates as they enable physicians to identify high-risk patients and implement early interventions. This paper features a thorough literature review on the prognostic assessment of liver cirrhosis, aiming to summarize and delineate the present status and constraints associated with the application of traditional prognostic tools in clinical settings. Among these tools, the Child-Pugh and Model for End-Stage Liver Disease (MELD) scoring systems are predominantly utilized. However, their accuracy varies significantly. These systems are generally suitable for broad assessments but lack condition-specific applicability and fail to capture the risks associated with dynamic changes in patient conditions. Future research in this field is poised for deep exploration into the integration of artificial intelligence (AI) with routine clinical and multi-omics data in patients with cirrhosis. The goal is to transition from static, unimodal assessment models to dynamic, multimodal frameworks. Such advancements will not only improve the precision of prognostic tools but also facilitate personalized medicine approaches, potentially revolutionizing clinical outcomes.
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Affiliation(s)
- Yinping Zhai
- Department of Gastroenterology Nursing Unit, Ward 192, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Darong Hai
- The School of Nursing, Wenzhou Medical University, Wenzhou, 325000, China
| | - Li Zeng
- The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, 325000, China
| | - Chenyan Lin
- The School of Nursing, Wenzhou Medical University, Wenzhou, 325000, China
| | - Xinru Tan
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, 325000, China
| | - Zefei Mo
- School of Biomedical Engineering, School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325000, China
| | - Qijia Tao
- The School of Nursing, Wenzhou Medical University, Wenzhou, 325000, China
| | - Wenhui Li
- The School of Nursing, Wenzhou Medical University, Wenzhou, 325000, China
| | - Xiaowei Xu
- Department of Gastroenterology Nursing Unit, Ward 192, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Qi Zhao
- School of Computer Science and Software Engineering, University of Science and Technology Liaoning, Anshan, 114051, China.
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China.
| | - Jianwei Shuai
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China.
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), Wenzhou, 325000, China.
| | - Jingye Pan
- Department of Big Data in Health Science, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
- Key Laboratory of Intelligent Treatment and Life Support for Critical Diseases of Zhejiang Province, Wenzhou, 325000, China.
- Zhejiang Engineering Research Center for Hospital Emergency and Process Digitization, Wenzhou, 325000, China.
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7
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Tavabie OD, Patel VC, Salehi S, Stamouli M, Trovato FM, Maxan ME, Jeyanesan D, Rivera S, Mujib S, Zamalloa A, Corcoran E, Menon K, Prachalias A, Heneghan MA, Agarwal K, McPhail MJW, Aluvihare VR. microRNA associated with hepatocyte injury and systemic inflammation may predict adverse outcomes in cirrhotic patients. Sci Rep 2024; 14:23831. [PMID: 39394217 PMCID: PMC11470138 DOI: 10.1038/s41598-024-72416-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 09/06/2024] [Indexed: 10/13/2024] Open
Abstract
As the global prevalence of chronic liver disease continues to rise, the need to determine which patients will develop end-stage liver disease and require liver transplantation is increasingly important. However, current prognostic models perform sub-optimally. We aim to determine microRNA profiles associated with clinical decompensation and mortality/transplantation within 1 year. We examined microRNA expression profiles in plasma samples from patients across the spectrum of cirrhosis (n = 154), acute liver failure (ALF) (n = 22), sepsis (n = 20) and healthy controls (HC) (n = 20). We demonstrated that a microRNA-based model (miR-24 and -27a) associated with systemic inflammation differentiated decompensated cirrhosis states from compensated cirrhosis and HC (AUC 0.77 (95% CI 0.69-0.85)). 6 patients within the compensated cirrhosis group decompensated the subsequent year and their exclusion improved model performance (AUC 0.81 (95% CI 0.71-0.89)). miR-191 (associated with liver injury) predicted risk of mortality across the cohort when acutely decompensated and acute-on-chronic-liver failure patients were included. When they were excluded miR-24 (associated with systemic inflammation) predicted risk of mortality. Our findings demonstrate that microRNA associated with systemic inflammation and liver injury predict adverse outcomes in cirrhosis. miR-24 and -191 require further investigation as prognostic biomarkers and therapeutic targets for patients with liver disease.
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Affiliation(s)
- Oliver D Tavabie
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
- Department of Inflammation Biology, School of Immunity and Microbial Sciences, King's College London, London, UK
| | - Vishal C Patel
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
- Department of Inflammation Biology, School of Immunity and Microbial Sciences, King's College London, London, UK
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK
| | - Siamak Salehi
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
| | - Marilena Stamouli
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK
| | - Francesca M Trovato
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
- Department of Inflammation Biology, School of Immunity and Microbial Sciences, King's College London, London, UK
| | - Maria-Emanuela Maxan
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK
| | - Dhaarica Jeyanesan
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
| | - Savannah Rivera
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK
| | - Salma Mujib
- Department of Inflammation Biology, School of Immunity and Microbial Sciences, King's College London, London, UK
| | - Ane Zamalloa
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
| | - Eleanor Corcoran
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
| | - Krishna Menon
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
| | - Andreas Prachalias
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
| | - Michael A Heneghan
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
- Department of Inflammation Biology, School of Immunity and Microbial Sciences, King's College London, London, UK
| | - Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
| | - Mark J W McPhail
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
- Department of Inflammation Biology, School of Immunity and Microbial Sciences, King's College London, London, UK
| | - Varuna R Aluvihare
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK.
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Tavabie OD, Salehi S, Aluvihare VR. The challenges and potential of microRNA-based therapy for patients with liver failure syndromes and hepatocellular carcinoma. Expert Opin Ther Targets 2024; 28:179-191. [PMID: 38487923 DOI: 10.1080/14728222.2024.2331598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 03/13/2024] [Indexed: 03/20/2024]
Abstract
INTRODUCTION Morbidity and mortality from liver disease continues to rise worldwide. There are currently limited curative treatments for patients with liver failure syndromes, encompassing acute liver failure and decompensated cirrhosis states, outside of transplantation. Whilst there have been improvements in therapeutic options for patients with hepatocellular carcinoma (HCC), there remain challenges necessitating novel therapeutic agents. microRNA have long been seen as potential therapeutic targets but there has been limited clinical translation. AREAS COVERED We will discuss the limitations of conventional non-transplant management of patients with liver failure syndromes and HCC. We will provide an overview of microRNA and the challenges in developing and delivering microRNA-based therapeutic agents. We will finally provide an overview of microRNA-based therapeutic agents which have progressed to clinical trials. EXPERT OPINION microRNA have great potential to be developed into therapeutic agents due to their association with critical biological processes which govern health and disease. Utilizing microRNA sponges to target multiple microRNA associated with specific biological processes may improve their therapeutic efficacy. However, there needs to be significant improvements in delivery systems to ensure the safe delivery of microRNA to target sites and minimize systemic distribution. This currently significantly impacts the clinical translation of microRNA-based therapeutic agents.
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Affiliation(s)
| | - Siamak Salehi
- Institute of Liver Studies, King's College Hospital, London, UK
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9
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Wang Y, Li Y, Lv L, Zhu L, Hong L, Wang X, Zhang Y, Wang X, Diao H. Faecal hsa-miR-7704 inhibits the growth and adhesion of Bifidobacterium longum by suppressing ProB and aggravates hepatic encephalopathy. NPJ Biofilms Microbiomes 2024; 10:13. [PMID: 38396001 PMCID: PMC10891095 DOI: 10.1038/s41522-024-00487-8] [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: 07/29/2023] [Accepted: 02/12/2024] [Indexed: 02/25/2024] Open
Abstract
Both gut microbiome and microRNAs (miRNAs) play a role in the development of hepatic encephalopathy (HE). However, the functional link between the microbiome and host-derived miRNAs in faeces remains poorly understood. In the present study, patients with HE had an altered gut microbiome and faecal miRNAs compared with patients with chronic hepatitis B. Transferring faeces and faecal miRNAs from patients with HE to the recipient mice aggravated thioacetamide-induced HE. Oral gavage of hsa-miR-7704, a host-derived miRNA highly enriched in faeces from patients with HE, aggravated HE in mice in a microbiome-dependent manner. Mechanistically, hsa-miR-7704 inhibited the growth and adhesion of Bifidobacterium longum by suppressing proB. B. longum and its metabolite acetate alleviated HE by inhibiting microglial activation and ammonia production. Our findings reveal the role of miRNA-microbiome axis in HE and suggest that faecal hsa-miR-7704 are potential regulators of HE progression.
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Affiliation(s)
- Yuchong Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yuyu Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Longxian Lv
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Liying Zhu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China
| | - Liang Hong
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Xueyao Wang
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province, China
| | - Yu Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Xin Wang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China
| | - Hongyan Diao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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10
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Guan W, Chen Y, Fan Y. miR-26a is a Key Therapeutic Target with Enormous Potential in the Diagnosis and Prognosis of Human Disease. Curr Med Chem 2024; 31:2550-2570. [PMID: 38204224 DOI: 10.2174/0109298673271808231116075056] [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: 07/12/2023] [Revised: 09/29/2023] [Accepted: 10/16/2023] [Indexed: 01/12/2024]
Abstract
MicroRNA-26a (miR-26a) belongs to small non-coding regulatory RNA molecules emerging as fundamental post-transcriptional regulators inhibiting gene expression that plays vital roles in various processes of human diseases such as depression, renal ischemia and reperfusion injury, liver injury and some refractory cancer. In this review, we expound on the results of studies about miR-26a with emphasis on its function in animal models or in vitro cell culture to simulate the most common human disease in the clinic. Furthermore, we also illustrate the underlying mechanisms of miR-26a in strengthening the antitumor activity of antineoplastic drugs. Importantly, dysregulation of miR-26a has been related to many chronic and malignant diseases, especially in neurological disorders in the brain such as depression and neurodegenerative diseases as well as cancers such as papillary thyroid carcinoma, hepatocellular carcinoma and so on. It follows that miR-26a has a strong possibility to be a potential therapeutic target for the treatment of neurological disorders and cancers. Although the research of miRNAs has made great progress in the last few decades, much is yet to be discovered, especially regarding their underlying mechanisms and roles in the complex diseases of humans. Consequently, miR-26a has been analyzed in chronic and malignant diseases, and we discuss the dysregulation of miR-26a and functional roles in the development and pathogenesis of these diseases, which is very helpful for understanding their mechanisms as new biomarkers for diagnosing and curing diseases in the near future.
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Affiliation(s)
- Wei Guan
- Department of Pharmacology, Pharmacy College, Nantong University, Nantong 226001, Jiangsu, China
| | - Yan Chen
- Department of Neurology, Nantong Third People's Hospital, Affiliated Nantong Hospital 3 of Nantong University, Nantong, 226006, Jiangsu, China
| | - Yan Fan
- Department of Pharmacy, Zhangjiagang Second People's Hospital, Zhangjiagang, 215600, Jiangsu, China
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Tavabie OD, Salehi S, Aluvihare VR. The challenges and potential in developing microRNA associated with regeneration as biomarkers to improve prognostication for liver failure syndromes and hepatocellular carcinoma. Expert Rev Mol Diagn 2024; 24:5-22. [PMID: 38059597 DOI: 10.1080/14737159.2023.2292642] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 12/05/2023] [Indexed: 12/08/2023]
Abstract
INTRODUCTION Determining the need for liver transplantation remains critical in the management of hepatocellular carcinoma (HCC) and liver failure syndromes (including acute liver failure and decompensated cirrhosis states). Conventional prognostic models utilize biomarkers of liver and non-liver failure and have limitations in their application. Novel biomarkers which predict regeneration may fulfil this niche. microRNA are implicated in health and disease and are present in abundance in the circulation. Despite this, they have not translated into mainstream clinical biomarkers. AREAS COVERED We will discuss current challenges in the prognostication of patients with liver failure syndromes as well as for patients with HCC. We will discuss biomarkers implicated with liver regeneration. We then provide an overview of the challenges in developing microRNA into clinically tractable biomarkers. Finally, we will provide a scoping review of microRNA which may have potential as prognostic biomarkers in liver failure syndromes and HCC. EXPERT OPINION Novel biomarkers are needed to improve prognostic models in liver failure syndromes and HCC. Biomarkers associated with liver regeneration are currently lacking and may fulfil this niche. microRNA have the potential to be developed into clinically tractable biomarkers but a consensus on standardizing methodology and reporting is required prior to large-scale studies.
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Affiliation(s)
| | - Siamak Salehi
- Institute of Liver Studies, King's College Hospital, London, UK
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12
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Tsoneva DK, Ivanov MN, Vinciguerra M. Liquid Liver Biopsy for Disease Diagnosis and Prognosis. J Clin Transl Hepatol 2023; 11:1520-1541. [PMID: 38161500 PMCID: PMC10752811 DOI: 10.14218/jcth.2023.00040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 05/24/2023] [Accepted: 06/07/2023] [Indexed: 01/03/2024] Open
Abstract
Liver diseases are a major burden worldwide, the scope of which is expected to further grow in the upcoming years. Clinically relevant liver dysfunction-related blood markers such as alanine aminotransferase and aspartate aminotransferase have limited accuracy. Nowadays, liver biopsy remains the gold standard for several liver-related pathologies, posing a risk of complication due to its invasive nature. Liquid biopsy is a minimally invasive approach, which has shown substantial potential in the diagnosis, prognosis, and monitoring of liver diseases by detecting disease-associated particles such as proteins and RNA molecules in biological fluids. Histones are the core components of the nucleosomes, regulating essential cellular processes, including gene expression and DNA repair. Following cell death or activation of immune cells, histones are released in the extracellular space and can be detected in circulation. Histones are stable in circulation, have a long half-life, and retain their post-translational modifications. Here, we provide an overview of the current research on histone-mediated liquid biopsy methods for liver diseases, with a focus on the most common detection methods.
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Affiliation(s)
- Desislava K. Tsoneva
- Department of Medical Genetics, Medical University of Varna, Varna, Bulgaria
- Department of Stem Cell Biology and Transplantology, Research Institute, Medical University of Varna, Varna, Bulgaria
| | - Martin N. Ivanov
- Department of Stem Cell Biology and Transplantology, Research Institute, Medical University of Varna, Varna, Bulgaria
- Department of Anatomy and Cell Biology, Research Institute, Medical University of Varna, Varna, Bulgaria
| | - Manlio Vinciguerra
- Department of Stem Cell Biology and Transplantology, Research Institute, Medical University of Varna, Varna, Bulgaria
- Faculty of Health, Liverpool John Moores University, Liverpool, United Kingdom
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Chouik Y, Lebossé F, Plissonnier ML, Lega JC, Pradat P, Antonini T, Subic M, Hartig-Lavie K, Erard D, Villeret F, Guichon C, Payancé A, Radenne S, Rautou PE, Zoulim F, Levrero M. Circulating microRNAs improve bacterial infection diagnosis and overall survival prediction in acute decompensation of liver cirrhosis. iScience 2023; 26:107427. [PMID: 37575179 PMCID: PMC10415934 DOI: 10.1016/j.isci.2023.107427] [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: 01/20/2023] [Revised: 05/23/2023] [Accepted: 07/17/2023] [Indexed: 08/15/2023] Open
Abstract
Bacterial infections are the most frequent precipitating event in patients with acute decompensation of cirrhosis (AD) and are associated with high mortality. Early diagnosis is challenging due to cirrhosis-related systemic inflammation. Here we investigated the potential of circulating microRNAs to diagnose bacterial infections and predict survival in cirrhotic patients with AD. High throughput profiling of circulating microRNAs was performed using the Nanostring technology in 57 AD patients and 24 patients with compensated cirrhosis (CC). Circulating miRs profiling showed that: (a) miRs differentially detected in AD vs. CC were mostly down-regulated; (b) a composite score including absolute neutrophil count, C reactive protein and miR-362-3p could diagnose bacterial infection with an excellent performance (AUC of 0.825 [95% CI = 0.671-0.980; p < 0.001]); (c) a composite score including miR-382-5p, miR-592 and MELD-Na improved 6-month survival prediction. Circulating miRs are strongly dysregulated in patients with AD and may help to improve bacterial infection diagnosis and survival prediction.
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Affiliation(s)
- Yasmina Chouik
- Cancer Research Center of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Lyon, France
- Department of Hepatology, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France
- University of Lyon Claude Bernard 1 (UCLB1), Lyon, France
| | - Fanny Lebossé
- Cancer Research Center of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Lyon, France
- Department of Hepatology, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France
- University of Lyon Claude Bernard 1 (UCLB1), Lyon, France
| | | | - Jean-Christophe Lega
- Department of Internal Medicine, Hôpital Lyon Sud, Hospices Civils de Lyon, Lyon, France
| | - Pierre Pradat
- Clinical Research Center, GHN, Hospices Civils de Lyon, Lyon, France
| | - Teresa Antonini
- Department of Hepatology, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | | | - Kerstin Hartig-Lavie
- Department of Hepatology, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | - Domitille Erard
- Department of Hepatology, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | - François Villeret
- Department of Hepatology, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France
- University of Lyon Claude Bernard 1 (UCLB1), Lyon, France
| | - Céline Guichon
- Department of Anesthesiology and Intensive Care, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | - Audrey Payancé
- Université Paris-Cité, Inserm, Centre de recherche sur l’inflammation, UMR 1149, Paris, France
| | - Sylvie Radenne
- Department of Hepatology, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | - Pierre-Emmanuel Rautou
- Université Paris-Cité, Inserm, Centre de recherche sur l’inflammation, UMR 1149, Paris, France
- Service d'Hépatologie, AP-HP, Hôpital Beaujon, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, France
| | - Fabien Zoulim
- Cancer Research Center of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Lyon, France
- Department of Hepatology, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France
- University of Lyon Claude Bernard 1 (UCLB1), Lyon, France
| | - Massimo Levrero
- Cancer Research Center of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Lyon, France
- Department of Hepatology, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France
- University of Lyon Claude Bernard 1 (UCLB1), Lyon, France
- Department of Medicine SCIAC and the Italian Institute of Technology (IIT) Center for Life Nanosciences (CLNS), University of Rome La Sapienza, Rome, Italy
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Mastoridis S, Patel V, Christakoudi S, Lozano JJ, Salehi S, Kurt A, Grossart C, Kodela E, Martinez-Llordella M, Sanchez-Fueyo A. Impact of liver failure on the circulating extracellular vesicle miRNA repertoire. Hepatol Res 2023; 53:771-785. [PMID: 37060575 DOI: 10.1111/hepr.13909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 03/19/2023] [Accepted: 04/05/2023] [Indexed: 04/16/2023]
Abstract
BACKGROUND & AIMS Cell-derived small extracellular vesicles (sEVs) participate in cell-cell communication via the transfer of molecular cargo including selectively enriched microRNAs (miRNAs). Utilizing advances in sEV isolation and characterization, this study investigates the impact of liver injury and dysfunction on the circulating EV-miRNA profile. METHODS High-throughput screening of 799 sEV-miRNAs isolated from plasma was performed in patients across a spectrum of liver disorders including compensated and decompensated chronic liver disease, acute-on-chronic liver failure (ACLF), and acute liver failure, in addition to healthy controls and those with severe sepsis. miRNA levels were compared with clinical and biochemical parameters, composite scores of liver disease, and patient outcomes. RESULTS miRNA screening revealed the degree of hepatic dysfunction to be the main determinant of changes in circulating sEV-miRNA profile, with liver-specific miRNA-122 being among the most highly dysregulated in severe injury. Principal components analyses of the 215 differentially expressed miRNAs showed differing profiles, particularly among those with acute liver injury and ACLF. A distinct profile of dysregulated miRNA, but not circulating cytokines, was shown to characterize ACLF, with four consensus miRNAs identified-miR-320e, miR-374-5p, miR-202-3p, and miR-1910-5p. High miR-320e was associated with poorer 90-day survival (p = 0.014) and regulated the functional gene targets IK, RPS5, MANBAL, and PEBP1. CONCLUSIONS This first comprehensive analysis to the best of our knowledge of patients with varying degrees and stages of liver failure demonstrates miRNA profiles specifically within the sEV compartment to be significantly altered in progressive liver disease and highlights the diagnostic and prognostic potential of sEV-miRNA in ACLF while also establishing downstream gene targets.
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Affiliation(s)
- Sotiris Mastoridis
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Vishal Patel
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK
- The Roger Williams Institute of Hepatology (Foundation for Liver Research), London, UK
| | - Sofia Christakoudi
- Department of Epidemiology and Biostatistics, Imperial College London, London, UK
- Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Juan Jose Lozano
- Bioinformatic Platform, Biomedical Research Centre in Hepatic and Digestive Diseases, Instituto de Salud Carlos III, Madrid, Spain
| | - Siamak Salehi
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Ada Kurt
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Cathleen Grossart
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Elisavet Kodela
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK
| | - Marc Martinez-Llordella
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK
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15
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Gholizadeh M, Łapczuk-Romańska J, Post M, Komaniecka N, Mazlooman SR, Kaderali L, Droździk M. A Mixture Method for Robust Detection HCV Early Diagnosis Biomarker with ML Approach and Molecular Docking. Int J Mol Sci 2023; 24:ijms24087207. [PMID: 37108370 PMCID: PMC10138470 DOI: 10.3390/ijms24087207] [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: 03/15/2023] [Revised: 03/30/2023] [Accepted: 04/11/2023] [Indexed: 04/29/2023] Open
Abstract
Given the substantial correlation between early diagnosis and prolonged patient survival in HCV patients, it is vital to identify a reliable and accessible biomarker. The purpose of this research was to identify accurate miRNA biomarkers to aid in the early diagnosis of HCV and to identify key target genes for anti-hepatic fibrosis therapeutics. The expression of 188 miRNAs in 42 HCV liver patients with different functional states and 23 normal livers were determined using RT-qPCR. After screening out differentially expressed miRNA (DEmiRNAs), the target genes were predicted. To validate target genes, an HCV microarray dataset was subjected to five machine learning algorithms (Random Forest, Adaboost, Bagging, Boosting, XGBoost) and then, based on the best model, importance features were selected. After identification of hub target genes, to evaluate the potency of compounds that might hit key hub target genes, molecular docking was performed. According to our data, eight DEmiRNAs are associated with early stage and eight DEmiRNAs are linked to a deterioration in liver function and an increase in HCV severity. In the validation phase of target genes, model evaluation revealed that XGBoost (AUC = 0.978) outperformed the other machine learning algorithms. The results of the maximal clique centrality algorithm determined that CDK1 is a hub target gene, which can be hinted at by hsa-miR-335, hsa-miR-140, hsa-miR-152, and hsa-miR-195. Because viral proteins boost CDK1 activation for cell mitosis, pharmacological inhibition may have anti-HCV therapeutic promise. The strong affinity binding of paeoniflorin (-6.32 kcal/mol) and diosmin (-6.01 kcal/mol) with CDK1 was demonstrated by molecular docking, which may result in attractive anti-HCV compounds. The findings of this study may provide significant evidence, in the context of the miRNA biomarkers, for early-stage HCV diagnosis. In addition, recognized hub target genes and small molecules with high binding affinity may constitute a novel set of therapeutic targets for HCV.
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Affiliation(s)
- Maryam Gholizadeh
- Institute for Bioinformatics, University Medicine Greifswald, 17475 Greifswald, Germany
| | - Joanna Łapczuk-Romańska
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Mariola Post
- Department of General and Transplantation Surgery, County Hospital, 71-455 Szczecin, Poland
| | - Nina Komaniecka
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Seyed Reza Mazlooman
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, 17475 Greifswald, Germany
| | - Lars Kaderali
- Institute for Bioinformatics, University Medicine Greifswald, 17475 Greifswald, Germany
| | - Marek Droździk
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, 70-111 Szczecin, Poland
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Selvakumar SC, Auxzilia Preethi K, Veeraiyan DN, Sekar D. The role of microRNAs on the pathogenesis, diagnosis and management of portal hypertension in patients with chronic liver disease. Expert Rev Gastroenterol Hepatol 2022; 16:941-951. [PMID: 36315408 DOI: 10.1080/17474124.2022.2142562] [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: 03/25/2022] [Accepted: 10/28/2022] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Portal hypertension (PH) is the elevated pressure in the portal vein, which results in poor functioning of the liver and is influenced by various factors like liver cirrhosis, nonalcoholic fatty liver disease, schistosomiasis, thrombosis, and angiogenesis. Though the diagnosis and treatment have been advanced, early diagnosis of the disease remains a challenge, and the diagnosis methods are often invasive. Hence, the clear understanding of the molecular mechanisms of PH can give rise to the development of novel biomarkers which can pave way for early diagnosis in noninvasive methods, and also the identification of target genes can elucidate an efficient therapeutic target. AREAS COVERED PubMed and Embase database was used to search articles with search terms 'Portal Hypertension' or 'pathophysiology' and 'diagnosis' and 'treatment' or "role of miRNAs in portal hypertension. EXPERT OPINION Interestingly, biomarkers like microRNAs (miRNAs) have been studied for their potential role in various diseases including hypertension. In recent years, miRNAs have been proved to be an efficient biomarker and therapeutic target and few studies have assessed the roles of miRNAs in PH. The present paper highlights the potential roles of miRNAs in PH.
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Affiliation(s)
- Sushmaa Chandralekha Selvakumar
- Centre for Cellular and Molecular Research, Saveetha Dental College & Hospitals, Saveetha Institute of Medical & Technical Sciences (SIMATS), Saveetha University, Chennai, India
| | - K Auxzilia Preethi
- Centre for Cellular and Molecular Research, Saveetha Dental College & Hospitals, Saveetha Institute of Medical & Technical Sciences (SIMATS), Saveetha University, Chennai, India
| | - Deepak Nallaswamy Veeraiyan
- Department of Prosthodontics, Saveetha Dental College & Hospitals, Saveetha Institute of Medical & Technical Sciences (SIMATS), Saveetha University, Chennai, India
| | - Durairaj Sekar
- Centre for Cellular and Molecular Research, Saveetha Dental College & Hospitals, Saveetha Institute of Medical & Technical Sciences (SIMATS), Saveetha University, Chennai, India
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During HCV DAA Therapy Plasma Mip1B, IP10, and miRNA Profile Are Distinctly Associated with Subsequent Diagnosis of Hepatocellular Carcinoma: A Pilot Study. BIOLOGY 2022; 11:biology11091262. [PMID: 36138741 PMCID: PMC9495750 DOI: 10.3390/biology11091262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/11/2022] [Accepted: 08/13/2022] [Indexed: 01/07/2023]
Abstract
Background: Hepatitis C virus (HCV) therapy lowers risk of hepatocellular carcinoma (HCC). Little is known about factors driving/preceding HCC in treated persons. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) regulate host response and pathogenesis of disease. We investigated plasma levels of these RNAs and select serum markers before, during, and after HCV therapy, preceding HCC. Methods: Of 187 DAA treated HCV patients where therapy oriented longitudinal sampling was performed at a time without HCC diagnosis, 9 were subsequently diagnosed with HCC within 2 years of therapy. They were matched with 7 patients not diagnosed with HCC over the same time period. RNASeq was performed on plasma, and serum was assessed for biomarkers of inflammation by ELISA. Results: HCC diagnosis was 19 months (6-28) after therapy start in the HCC group. 73 and 63 miRs were differentially expressed at baseline (before DAA therapy) and 12 weeks after DAA therapy comparing HCC and non-HCC groups. Several lncRNA- showed differential expression as well. Several miRNA suppressors of cancer-related pathways, lncRNA- and mRNA-derived stabilized short RNAs were consistently absent in the plasma of patients who developed HCC. Serum IP10, and MCP-1 level was higher in the HCC group 12 weeks after therapy, and distinct miRNAs correlated with IP10 and MCP-1. Finally, in a focused analysis of 8 miRNAs best associated with HCC we observed expression of mi576 and mi-5189 correlation with expression of a select group of PBMC mRNA. Conclusions: These results are consistent with complex interplay between RNA-mediated host immune regulation and cancer suppression, strikingly skewed 12 weeks following therapy, prior to HCC diagnosis.
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Bioinformatics analyses of potential ACLF biological mechanisms and identification of immune-related hub genes and vital miRNAs. Sci Rep 2022; 12:14052. [PMID: 35982134 PMCID: PMC9388648 DOI: 10.1038/s41598-022-18396-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 08/10/2022] [Indexed: 11/08/2022] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a critical and refractory disease and a hepatic disorder accompanied by immune dysfunction. Thus, it is essential to explore key immune-related genes of ACLF and investigate its mechanisms. We used two public datasets (GSE142255 and GSE168048) to perform various bioinformatics analyses, including WGCNA, CIBERSORT, and GSEA. We also constructed an ACLF immune-related protein-protein interaction (PPI) network to obtain hub differentially expressed genes (DEGs) and predict corresponding miRNAs. Finally, an ACLF rat model was established to verify the results. A total of 388 DEGs were identified in ACLF, including 162 upregulated and 226 downregulated genes. The enrichment analyses revealed that these DEGs were mainly involved in inflammatory-immune responses and biosynthetic metabolic pathways. Twenty-eight gene modules were obtained using WGCNA and the coral1 and darkseagreen4 modules were highly correlated with M1 macrophage polarization. As a result, 10 hub genes and 2 miRNAs were identified to be significantly altered in ACLF. The bioinformatics analyses of the two datasets presented valuable insights into the pathogenesis and screening of hub genes of ACLF. These results might contribute to a better understanding of the potential molecular mechanisms of ACLF. Finally, further studies are required to validate our current findings.
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Clària J. Leveraging omics to understand the molecular basis of acute-on-chronic liver failure. ADVANCES IN LABORATORY MEDICINE 2021; 2:516-540. [PMID: 37360898 PMCID: PMC10197663 DOI: 10.1515/almed-2021-0023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 07/01/2021] [Indexed: 06/28/2023]
Abstract
Acute-on-chronic liver failure (ACLF) is a complex syndrome that develops in patients with acutely decompensated cirrhosis. In this condition, dysbalanced immune function and excessive systemic inflammation are closely associated with organ failure and high short-term mortality. In this review, we describe how omic technologies have contributed to the characterization of the hyperinflammatory state in patients with acutely decompensated cirrhosis developing ACLF, with special emphasis on the role of metabolomics, lipidomics and transcriptomics in profiling the triggers (pathogen- and damage-associated molecular patterns [PAMPs and DAMPs]) and effector molecules (cytokines, chemokines, growth factors and bioactive lipid mediators) that lead to activation of the innate immune system. This review also describes how omic approaches can be invaluable tools to accelerate the identification of novel biomarkers that could guide the implementation of novel therapies/interventions aimed at protecting these patients from excessive systemic inflammation and organ failure.
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Affiliation(s)
- Joan Clària
- Biochemistry and Molecular Genetics Service, Hospital Clínic – IDIBAPS, Barcelona, Spain
- Department of Biomedical Sciences, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain
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Garcia Garcia de Paredes A, Villanueva C, Blanco C, Genescà J, Manicardi N, Garcia-Pagan JC, Calleja JL, Aracil C, Morillas RM, Poca M, Peñas B, Augustin S, Abraldes JG, Alvarado E, Royo F, Garcia-Bermejo ML, Falcon-Perez JM, Bañares R, Bosch J, Gracia-Sancho J, Albillos A. Serum miR-181b-5p predicts ascites onset in patients with compensated cirrhosis. JHEP Rep 2021; 3:100368. [PMID: 34712934 PMCID: PMC8531668 DOI: 10.1016/j.jhepr.2021.100368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/19/2021] [Accepted: 09/08/2021] [Indexed: 11/30/2022] Open
Abstract
Background & Aims Treatment with non-selective beta-blockers (NSBBs) reduces the risk of ascites, which is the most common decompensating event in cirrhosis. This study aimed to assess the ability of a serum microRNA (miRNA) signature to predict ascites formation and the hemodynamic response to NSBBs in compensated cirrhosis. Methods Serum levels of miR-452-5p, miR-429, miR-885-5p, miR-181b-5p, and miR-122-5p were analyzed in patients with compensated cirrhosis (N = 105). Hepatic venous pressure gradient (HVPG) was measured at baseline, after intravenous propranolol, and 1 year after randomization to NSBBs (n = 52) or placebo (n = 53) (PREDESCI trial). miRNAs were analyzed at baseline and at 1 year. Results Nineteen patients (18%) developed ascites, of whom 17 developed ascites after 1 year. miR-181b-5p levels at 1 year, but not at baseline, were higher in patients that developed ascites. The AUC of miR-181b-5p at 1 year to predict ascites was 0.7 (95% CI 0.59–0.78). miR-429 levels were lower at baseline in acute HVPG responders to NSBBs (AUC 0.65; 95% CI, 0.53–0.76), but levels at baseline and at 1 year were not associated with the HVPG response to NSBBs at 1 year. Conclusions Serum miR-181b-5p is a promising non-invasive biomarker to identify patients with compensated cirrhosis at risk of ascites development. Lay summary Ascites marks the transition from the compensated to decompensated stage in cirrhosis and indicates a worsening in prognosis. There are currently no easily accessible tools to identify patients with compensated cirrhosis at risk of developing ascites. We evaluated the levels of novel molecules termed microRNAs in the blood of patients with compensated cirrhosis and observed that miR-181b-5p can predict which patients are going to develop ascites.
miR-181b-5p appears to be a useful serum biomarker to anticipate ascites onset. Low serum miR-181b-5p indicates low risk of ascites in compensated cirrhosis. Low serum miR-429 reflects acute hemodynamic response to non-selective beta-blockers.
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Affiliation(s)
- Ana Garcia Garcia de Paredes
- Gastroenterology and Hepatology Department, Hospital Universitario Ramon y Cajal, Instituto Ramon y Cajal de Investigacion Sanitaria (IRYCIS), Universidad de Alcala, Madrid, Spain
| | - Càndid Villanueva
- Hospital of Santa Creu and Sant Pau, Autonomous University of Barcelona, Hospital Sant Pau Biomedical Research Institute (IIB Sant Pau) Barcelona, Spain.,Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Spain
| | - Carolina Blanco
- Biomarkers and Therapeutic Targets Group, Instituto Ramon y Cajal de Investigacion Sanitaria (IRYCIS), Madrid, Spain
| | - Joan Genescà
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Spain.,Liver Unit, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Research (VHIR), Vall d'Hebron Barcelona Hospital campus, Autonomous University of Barcelona, Barcelona, Spain
| | - Nicolo Manicardi
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, Barcelona, Spain
| | - Juan Carlos Garcia-Pagan
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Spain.,Barcelona Hepatic Haemodynamic Laboratory, Liver Unit, Institute of Digestive and Metabolic Diseases, August Pi i Sunyer Institute of Biomedical Research, Hospital Clínic, Barcelona, Spain
| | - Jose Luis Calleja
- Gastroenterology and Hepatology Department, Hospital Universitario Puerta de Hierro, Puerta de Hierro Hospital Research Institute, Autonomous University of Madrid, Madrid, Spain
| | - Carlos Aracil
- Institute of Biomedical Research, Arnau de Vilanova University Hospital (IRB Lleida), Lleida, Spain
| | - Rosa M Morillas
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Spain.,Liver Section, Hospital Universitari Germans Trias i Pujol, IGTP, Badalona, Spain.,Universitat Autònoma de Barcelona, Spain
| | - Maria Poca
- Hospital of Santa Creu and Sant Pau, Autonomous University of Barcelona, Hospital Sant Pau Biomedical Research Institute (IIB Sant Pau) Barcelona, Spain
| | - Beatriz Peñas
- Gastroenterology and Hepatology Department, Hospital Universitario Ramon y Cajal, Instituto Ramon y Cajal de Investigacion Sanitaria (IRYCIS), Universidad de Alcala, Madrid, Spain
| | - Salvador Augustin
- Liver Unit, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Research (VHIR), Vall d'Hebron Barcelona Hospital campus, Autonomous University of Barcelona, Barcelona, Spain
| | - Juan G Abraldes
- Barcelona Hepatic Haemodynamic Laboratory, Liver Unit, Institute of Digestive and Metabolic Diseases, August Pi i Sunyer Institute of Biomedical Research, Hospital Clínic, Barcelona, Spain.,Liver Unit, Division of Gastroenterology, University of Alberta, Edmonton, Canada
| | - Eldimar Alvarado
- Hospital of Santa Creu and Sant Pau, Autonomous University of Barcelona, Hospital Sant Pau Biomedical Research Institute (IIB Sant Pau) Barcelona, Spain
| | - Félix Royo
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Spain.,Exosomes Laboratory, Center for Cooperative Research in Biosciencies (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Bizkaia, 48160, Spain
| | - Maria Laura Garcia-Bermejo
- Biomarkers and Therapeutic Targets Group, Instituto Ramon y Cajal de Investigacion Sanitaria (IRYCIS), Madrid, Spain
| | - Juan Manuel Falcon-Perez
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Spain.,Exosomes Laboratory, Center for Cooperative Research in Biosciencies (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Bizkaia, 48160, Spain
| | - Rafael Bañares
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Spain.,Gastroenterology and Hepatology Department, Hospital Universitario Gregorio Marañon, Instituto de Investigacion Sanitaria Gregorio Marañon (IiSGM), Universidad Complutense de Madrid, Madrid, Spain
| | - Jaime Bosch
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Spain.,Barcelona Hepatic Haemodynamic Laboratory, Liver Unit, Institute of Digestive and Metabolic Diseases, August Pi i Sunyer Institute of Biomedical Research, Hospital Clínic, Barcelona, Spain.,Department of Biomedical Research and University Clinic for Visceral Medicine and Surgery, Inselspital, Bern, Switzerland
| | - Jordi Gracia-Sancho
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Spain.,Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, Barcelona, Spain
| | - Agustin Albillos
- Gastroenterology and Hepatology Department, Hospital Universitario Ramon y Cajal, Instituto Ramon y Cajal de Investigacion Sanitaria (IRYCIS), Universidad de Alcala, Madrid, Spain.,Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Spain
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The third year. JHEP Rep 2021; 3:100259. [PMID: 33898957 PMCID: PMC8053695 DOI: 10.1016/j.jhepr.2021.100259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 02/16/2021] [Indexed: 11/24/2022] Open
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