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Jorgensen AL, Korver S, Schofield A, Howell L, Clarke JI, Walker LE, Brillant N, Goldring CEP, Pirmohamed M. Establishing reference ranges for circulating biomarkers of drug-induced liver injury in healthy human volunteers. Br J Clin Pharmacol 2025; 91:1361-1369. [PMID: 39676236 PMCID: PMC12035588 DOI: 10.1111/bcp.16371] [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: 06/12/2024] [Revised: 11/19/2024] [Accepted: 12/02/2024] [Indexed: 12/17/2024] Open
Abstract
AIMS The potential of mechanistic biomarkers to improve prediction of drug-induced liver injury (DILI) and hepatic regeneration is widely acknowledged. We sought to determine reference intervals for new biomarkers of DILI and regeneration, as well as to characterize their natural variability and impact of diurnal variation. METHODS Serum samples from 227 healthy volunteers were recruited as part of a cross-sectional study; of these, 25 subjects had weekly serial sampling over 3 weeks, while 23 had intensive blood sampling over a 24h period. Alanine aminotransferase (ALT), MicroRNA-122 (miR-122), High Mobility Group Box-1 (HMGB1), total Keratin-18 (K18), caspase-cleaved Keratin-18 (ccK18), Glutamate Dehydrogenase (GLDH) and Macrophage Colony-Stimulating Factor-1 (CSF-1) were assayed. RESULTS Reference intervals were established for each biomarker based on the 97.5% quantile (90% CI) following the assessment of fixed effects in univariate and multivariable models. Intra-individual variability was found to be non-significant, and there was no significant impact of diurnal variation. CONCLUSION Reference intervals for novel DILI biomarkers have been described. An upper limit of a reference range might represent the most appropriate mechanism to utilize these data. These data can now be used to interpret data from exploratory clinical DILI studies and to assist their further qualification as required by regulatory authorities.
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Affiliation(s)
- Andrea L. Jorgensen
- Department of Health Data Science, Institute of Population HealthUniversity of LiverpoolLiverpoolUK
| | - Samantha Korver
- Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Molecular & Clinical Pharmacology, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Amy Schofield
- Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Molecular & Clinical Pharmacology, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Lawrence Howell
- Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Molecular & Clinical Pharmacology, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Joanna I. Clarke
- Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Molecular & Clinical Pharmacology, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Lauren E. Walker
- Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Molecular & Clinical Pharmacology, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Nathalie Brillant
- Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Molecular & Clinical Pharmacology, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Chris E. P. Goldring
- Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Molecular & Clinical Pharmacology, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Munir Pirmohamed
- Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Molecular & Clinical Pharmacology, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
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Safi K, Pawlicka AJ, Pradhan B, Sobieraj J, Zhylko A, Struga M, Grąt M, Chrzanowska A. Perspectives and Tools in Liver Graft Assessment: A Transformative Era in Liver Transplantation. Biomedicines 2025; 13:494. [PMID: 40002907 PMCID: PMC11852418 DOI: 10.3390/biomedicines13020494] [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: 12/16/2024] [Revised: 02/07/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Liver transplantation is a critical and evolving field in modern medicine, offering life-saving treatment for patients with end-stage liver disease and other hepatic conditions. Despite its transformative potential, transplantation faces persistent challenges, including a global organ shortage, increasing liver disease prevalence, and significant waitlist mortality rates. Current donor evaluation practices often discard potentially viable livers, underscoring the need for refined graft assessment tools. This review explores advancements in graft evaluation and utilization aimed at expanding the donor pool and optimizing outcomes. Emerging technologies, such as imaging techniques, dynamic functional tests, and biomarkers, are increasingly critical for donor assessment, especially for marginal grafts. Machine learning and artificial intelligence, exemplified by tools like LiverColor, promise to revolutionize donor-recipient matching and liver viability predictions, while bioengineered liver grafts offer a future solution to the organ shortage. Advances in perfusion techniques are improving graft preservation and function, particularly for donation after circulatory death (DCD) grafts. While challenges remain-such as graft rejection, ischemia-reperfusion injury, and recurrence of liver disease-technological and procedural advancements are driving significant improvements in graft allocation, preservation, and post-transplant outcomes. This review highlights the transformative potential of integrating modern technologies and multidisciplinary approaches to expand the donor pool and improve equity and survival rates in liver transplantation.
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Affiliation(s)
- Kawthar Safi
- Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Poland; (K.S.)
| | | | - Bhaskar Pradhan
- Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Poland; (K.S.)
| | - Jan Sobieraj
- 1st Chair and Department of Cardiology, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Andriy Zhylko
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland
| | - Marta Struga
- Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Poland; (K.S.)
| | - Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland
| | - Alicja Chrzanowska
- Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Poland; (K.S.)
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Hörauf JA, Singh A, Voth M, Moheimani H, Schindler CR, Relja B, Leppik L, Marzi I, Henrich D. Limited Diagnostic Value of miRNAs in Early Trauma-Induced Liver Injury: Only miRNA-122 Emerges as a Late-Phase Marker. Diagnostics (Basel) 2025; 15:179. [PMID: 39857063 PMCID: PMC11764008 DOI: 10.3390/diagnostics15020179] [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: 11/30/2024] [Revised: 01/09/2025] [Accepted: 01/12/2025] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Liver injury is common after abdominal trauma. However, the established biomarkers of liver injury, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), lack accuracy. This study investigates whether specific liver-related microRNAs (miRNAs) are released into the circulation in trauma patients with liver injury and whether they can indicate liver damage in the early phase after major trauma. Methods: A retrospective analysis of prospectively collected data and blood samples from 26 trauma patients was conducted. The levels of miRNA-21-5p, -122-5p, -191-5p, -192-3p, and -212-3p were measured in patients with computed tomography-confirmed liver trauma (LT group, n = 12) and polytrauma patients without liver trauma (PT group, n = 14) upon emergency room (ER) admission, and 24 and 48 h after trauma. Additionally, liver-type fatty acid binding protein (L-FABP) was measured, as it has recently been discussed in the context of abdominal trauma. Results: Only miRNA-122-5p showed a significant increase in the LT group compared to the PT group, but only at the 48 h time point (p = 0.032). Conversely, L-FABP (p = 0.018) and ALT (p = 0.05) were significantly elevated in the LT group compared to the PT group at the time of ER admission. There was a moderate correlation between miRNA-122-5p and AISAbdomen (p = 0.056) and transfused red blood cell concentrates (p = 0.055). L-FABP correlated strongly with the ALT levels (p = 0.0009) and the length of stay in the ICU (p = 0.0086). Conclusions: In this study, the liver-specific miRNA-122-5p did not effectively indicate liver injury in the early acute post-traumatic phase. Future research with a large sample size should investigate whether other miRNAs can more accurately predict liver injury and the extent of hepatocellular injury, particularly in the acute post-traumatic phase.
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Affiliation(s)
- Jason-Alexander Hörauf
- Department of Trauma Surgery and Orthopedics, University Hospital Frankfurt, Goethe University Frankfurt, 60596 Frankfurt am Main, Germany
| | - Amit Singh
- Department of Trauma Surgery and Orthopedics, University Hospital Frankfurt, Goethe University Frankfurt, 60596 Frankfurt am Main, Germany
| | - Maika Voth
- Department of Trauma Surgery and Orthopedics, University Hospital Frankfurt, Goethe University Frankfurt, 60596 Frankfurt am Main, Germany
| | - Hamed Moheimani
- Pittsburgh Trauma Research Center, Division of Trauma and Acute Care Surgery, Pittsburgh, PA 15213, USA
| | - Cora Rebecca Schindler
- Department of Trauma Surgery and Orthopedics, University Hospital Frankfurt, Goethe University Frankfurt, 60596 Frankfurt am Main, Germany
| | - Borna Relja
- Department of Trauma, Hand, Plastic and Reconstructive Surgery, Translational and Experimental Trauma Research, University Hospital Ulm, Ulm University, 89081 Ulm, Germany
| | - Liudmila Leppik
- Department of Trauma Surgery and Orthopedics, University Hospital Frankfurt, Goethe University Frankfurt, 60596 Frankfurt am Main, Germany
| | - Ingo Marzi
- Department of Trauma Surgery and Orthopedics, University Hospital Frankfurt, Goethe University Frankfurt, 60596 Frankfurt am Main, Germany
| | - Dirk Henrich
- Department of Trauma Surgery and Orthopedics, University Hospital Frankfurt, Goethe University Frankfurt, 60596 Frankfurt am Main, Germany
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Shi Y, Wei J, Nie Y, Luo J, Chen T, Xi Q, Zhang Y, Sun J. Plant-derived miR166a-3p packaged into exosomes to cross-kingdom inhibit mammary cell proliferation and promote apoptosis by targeting APLNR gene. Int J Biol Macromol 2025; 286:138470. [PMID: 39645121 DOI: 10.1016/j.ijbiomac.2024.138470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Revised: 12/02/2024] [Accepted: 12/04/2024] [Indexed: 12/09/2024]
Abstract
Plant-derived microRNAs (miRNAs) have attracted significant attention for their potential in cross-kingdom gene regulation, but the mechanisms of their entry, stability, and function in animal bodies need further investigation. We provided an in-depth analysis of tissue-specific miRNA expression in dairy cows, identifying 347 miRNAs, including 16 novel candidates, across 21 normal tissues. Our findings revealed that specific miRNAs, such as miR-192, miR-143, miR-148a, miR-486, and miR-21-5p, showed distinct tissue enrichment. In addition, a total of 167 maize-derived miRNAs were identified in dairy cow tissues, particularly in the rumen, mammary glands, serum, and exosomes. These exogenous miRNAs, which are abundant and conserved among plants, may be absorbed by the SLC46A2 transporter in the rumen epithelium during feeding and distributed to other tissues via exosomal encapsulation. The maize-derived miR166a-3p was highly abundant. Transfection experiments confirmed that miR166a-3p reduces the expression of proliferation markers (PCNA, Cyclin D, and Cyclin E) and the anti-apoptotic gene Bcl2, while upregulating the pro-apoptotic gene Bax. Moreover, exosomes derived from bovine serum were found to mediate these effects, as miR166a-3p-enriched exosomes inhibited cell proliferation and promoted apoptosis, further supporting the cross-kingdom role of plant-derived miRNAs in regulating biological processes. This study enhances the understanding of miRNA regulatory mechanisms, particularly the absorption and systemic transport of plant-derived miRNAs in dairy cows. The findings underscore the potential for using exogenous miRNAs, like miR166a-3p, in agricultural and medical contexts, warranting further investigation into their functions and cross-species interactions.
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Affiliation(s)
- Yiru Shi
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Junjie Wei
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Ying Nie
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Junyi Luo
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Ting Chen
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Qianyun Xi
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Yongliang Zhang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Jiajie Sun
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China.
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Yang Y, Shang J, Xia Y, Gui Y. Fluorescent probes for sensing peroxynitrite: biological applications. Redox Rep 2024; 29:2430157. [PMID: 39581574 PMCID: PMC11587728 DOI: 10.1080/13510002.2024.2430157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2024] Open
Abstract
Peroxynitrite (ONOO-) is a quintessential reactive oxygen species (ROS) and reactive nitrogen species (RNS), renowned for its potent oxidizing and nitrifying capabilities. Under normal physiological conditions, a baseline level of ONOO- is present within the body. However, its production escalates significantly in response to oxidative stress. ONOO- is highly reactive with various biomolecules in vivo, particularly proteins, lipids, and nucleic acids, thereby playing a role in a spectrum of physiological and pathological processes, such as inflammation, cancer, neurodegenerative diseases, and cardiovascular diseases. Consequently, detecting ONOO- in vivo is of paramount importance for understanding the etiology of various diseases and facilitating early diagnosis. Fluorescent probes have become a staple in the identification of biomolecules due to their ease of use, convenience, and superior sensitivity and specificity. This review highlights the recent advancements in the development of fluorescent probes for the detection of ONOO- in diverse disease models and provides an in-depth examination of their design and application.
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Affiliation(s)
- Yan Yang
- Hubei Key Laboratory of Cognitive and Affective Disorders, Jianghan University, Wuhan, Hubei, People’s Republic of China
- Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, Hubei, People’s Republic of China
| | - Jinting Shang
- Hubei Key Laboratory of Cognitive and Affective Disorders, Jianghan University, Wuhan, Hubei, People’s Republic of China
- Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, Hubei, People’s Republic of China
| | - Yiyuan Xia
- Hubei Key Laboratory of Cognitive and Affective Disorders, Jianghan University, Wuhan, Hubei, People’s Republic of China
- Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, Hubei, People’s Republic of China
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, Hubei, People’s Republic of China
| | - Yuran Gui
- Hubei Key Laboratory of Cognitive and Affective Disorders, Jianghan University, Wuhan, Hubei, People’s Republic of China
- Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, Hubei, People’s Republic of China
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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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Sánchez-Monteagudo A, Ripollés E, Murillo O, Domènech S, Álvarez-Sauco M, Girona E, Sastre-Bataller I, Bono A, García-Villarreal L, Tugores A, García-García F, González-Aseguinolaza G, Berenguer M, Espinós C. Profile of plasma microRNAs as a potential biomarker of Wilson's disease. J Gastroenterol 2024; 59:921-931. [PMID: 39060521 PMCID: PMC11415402 DOI: 10.1007/s00535-024-02135-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024]
Abstract
BACKGROUND Wilson's disease (WD) is a rare condition resulting from autosomal recessive mutations in ATP7B, a copper transporter, manifesting with hepatic, neurological, and psychiatric symptoms. Timely diagnosis and appropriate treatment yield a positive prognosis, while delayed identification and/or insufficient therapy lead to a poor outcome. Our aim was to establish a prognostic method for WD by characterising biomarkers based on circulating microRNAs. METHODS We conducted investigations across three cohorts: discovery, validation (comprising unrelated patients), and follow-up (revisiting the discovery cohort 3 years later). All groups were compared to age- and gender-matched controls. Plasma microRNAs were analysed via RNA sequencing in the discovery cohort and subsequently validated using quantitative PCR in all three cohorts. To assess disease progression, we examined the microRNA profile in Atp7b-/- mice, analysing serum samples from 6 to 44 weeks of age and liver samples at three time points: 20, 30, and 40 weeks of age. RESULTS In patients, elevated levels of the signature microRNAs (miR-122-5p, miR-192-5p, and miR-885-5p) correlated with serum activities of aspartate transaminase, alanine aminotransferase and gamma-glutamyl transferase. In Atp7b-/- mice, levels of miR-122-5p and miR-192-5p (miR-885-5p lacking a murine orthologue) increased from 12 weeks of age in serum, while exhibiting fluctuations in the liver, possibly attributable to hepatocyte regenerative capacity post-injury and the release of hepatic microRNAs into the bloodstream. CONCLUSIONS The upregulation of the signature miR-122-5p, miR-192-5p, and miR-885-5p in patients and their correlation with liver disease progression in WD mice support their potential as biomarkers of WD.
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Affiliation(s)
- Ana Sánchez-Monteagudo
- Unit of Rare Neurodegenerative Diseases, Valencia Biomedical Research Foundation-Centro de Investigación Príncipe Felipe (CIPF), Calle Eduardo Primo Yúfera No. 13, 46012, Valencia, Spain
| | - Edna Ripollés
- Unit of Rare Neurodegenerative Diseases, Valencia Biomedical Research Foundation-Centro de Investigación Príncipe Felipe (CIPF), Calle Eduardo Primo Yúfera No. 13, 46012, Valencia, Spain
- Rare Diseases Joint Unit, CIPF-IIS La Fe, Valencia, Spain
| | - Oihana Murillo
- DNA@RNA Medicine Division, Centro de Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain
| | - Sofia Domènech
- Unit of Rare Neurodegenerative Diseases, Valencia Biomedical Research Foundation-Centro de Investigación Príncipe Felipe (CIPF), Calle Eduardo Primo Yúfera No. 13, 46012, Valencia, Spain
- Rare Diseases Joint Unit, CIPF-IIS La Fe, Valencia, Spain
| | - María Álvarez-Sauco
- Department of Neurology, Hospital General Universitari d'Elx, Alicante, Spain
| | - Eva Girona
- Department of Internal Medicine, Hospital General Universitari d'Elx, Alicante, Spain
| | - Isabel Sastre-Bataller
- Rare Diseases Joint Unit, CIPF-IIS La Fe, Valencia, Spain
- Department of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - Ariadna Bono
- Rare Diseases Joint Unit, CIPF-IIS La Fe, Valencia, Spain
- Hepatology-Liver Transplantation Unit, Digestive Medicine Service, IIS La Fe and CIBER-EHD, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - Luis García-Villarreal
- Research Unit, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain
| | - Antonio Tugores
- Research Unit, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain
| | - Francisco García-García
- Rare Diseases Joint Unit, CIPF-IIS La Fe, Valencia, Spain
- Unit of Bioinformatics and Biostatistics, Valencia Biomedical Research Foundation-Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain
| | - Gloria González-Aseguinolaza
- DNA@RNA Medicine Division, Centro de Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain
- Vivet Therapeutics S.L., Pamplona, Spain
| | - Marina Berenguer
- Rare Diseases Joint Unit, CIPF-IIS La Fe, Valencia, Spain
- Hepatology-Liver Transplantation Unit, Digestive Medicine Service, IIS La Fe and CIBER-EHD, Hospital Universitari i Politècnic La Fe, Valencia, Spain
- Department of Medicine, Universitat de València, Valencia, Spain
| | - Carmen Espinós
- Unit of Rare Neurodegenerative Diseases, Valencia Biomedical Research Foundation-Centro de Investigación Príncipe Felipe (CIPF), Calle Eduardo Primo Yúfera No. 13, 46012, Valencia, Spain.
- Rare Diseases Joint Unit, CIPF-IIS La Fe, Valencia, Spain.
- Biotechnology Department, Universitat Politècnica de València, Valencia, Spain.
- Rare Diseases Networking Biomedical Research Centre (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
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Zhang X, Wang T, Fan X, Wang M, Duan Z, He F, Wang HH, Li Z. Development of a Modular miRNA-Responsive Biosensor for Organ-Specific Evaluation of Liver Injury. BIOSENSORS 2024; 14:450. [PMID: 39329825 PMCID: PMC11430419 DOI: 10.3390/bios14090450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 09/01/2024] [Accepted: 09/19/2024] [Indexed: 09/28/2024]
Abstract
MicroRNAs (miRNAs) are increasingly being considered essential diagnostic biomarkers and therapeutic targets for multiple diseases. In recent years, researchers have emphasized the need to develop probes that can harness extracellular miRNAs as input signals for disease diagnostics. In this study, we introduce a novel miRNA-responsive biosensor (miR-RBS) designed to achieve highly sensitive and specific detection of miRNAs, with a particular focus on targeted organ-specific visualization. The miR-RBS employs a Y-structured triple-stranded DNA probe (Y-TSDP) that exhibits a fluorescence-quenched state under normal physiological conditions. The probe switches to an activated state with fluorescence signals in the presence of high miRNA concentrations, enabling rapid and accurate disease reporting. Moreover, the miR-RBS probe had a modular design, with a fluorescence-labeled strand equipped with a functional module that facilitates specific binding to organs that express high levels of the target receptors. This allowed the customization of miRNA detection and cell targeting using aptameric anchors. In a drug-induced liver injury model, the results demonstrate that the miR-RBS probe effectively visualized miR-122 levels, suggesting it has good potential for disease diagnosis and organ-specific imaging. Together, this innovative biosensor provides a versatile tool for the early detection and monitoring of diseases through miRNA-based biomarkers.
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Affiliation(s)
- Xinxin Zhang
- College of Biology, Hunan University, No. 27 Tianma Road, Yuelu District, Changsha 410082, China
| | - Tingting Wang
- College of Biology, Hunan University, No. 27 Tianma Road, Yuelu District, Changsha 410082, China
| | - Xiangqing Fan
- College of Biology, Hunan University, No. 27 Tianma Road, Yuelu District, Changsha 410082, China
| | - Meixia Wang
- College of Biology, Hunan University, No. 27 Tianma Road, Yuelu District, Changsha 410082, China
| | - Zhixi Duan
- Department of Emergency Medicine, The Second Xiangya Hospital of Central South University, Changsha 410011, China
- Department of Trauma Center, The Second Xiangya Hospital of Central South University, Changsha 410011, China
- FuRong Laboratory, Changsha 410078, China
| | - Fang He
- College of Biology, Hunan University, No. 27 Tianma Road, Yuelu District, Changsha 410082, China
| | - Hong-Hui Wang
- College of Biology, Hunan University, No. 27 Tianma Road, Yuelu District, Changsha 410082, China
| | - Zhihong Li
- Department of Trauma Center, The Second Xiangya Hospital of Central South University, Changsha 410011, China
- FuRong Laboratory, Changsha 410078, China
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha 410011, China
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10
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Dong W, Yan W, Xu Y, Shang X, Wang W, Qiu J, Wang B, Wang H, Zhang Z, Zhao T. Multiplex Profiling of miR-122 for Preclinical and Clinical Evaluation of Drug-Induced Liver Injury by a Full-Scale Platform. ACS NANO 2024; 18:24860-24871. [PMID: 39195723 DOI: 10.1021/acsnano.4c05081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/29/2024]
Abstract
Diagnostic and monitoring for drug-induced liver injury (DILI) predominantly rely on serum aminotransferases. However, owing to their widespread expression across multiple organs, a significant challenge emerges from the absence of reliable biomarkers for DILI diagnosis. Herein, we introduce a concept for DILI detection, circumventing the nonspecific elevation and delayed release of aminotransferases and then straightforwardly focusing on the core feature of DILI, abnormal gene expression caused by drug overdose. The developed full-scale platform integrates the properties of spherical nucleic acids with elaborately designed fluorescence in situ hybridization sequences, enabling the sensitive and specific profiling of drug-overdosed miR-122 expression alterations across molecular, cellular, organismal, and clinical scales and effectively bypassing the phenotypic features of disease. Furthermore, the diagnostic efficacies of serum and total RNA extracted from both mouse and human blood samples for DILI diagnosis were analyzed using the receiver operating characteristic curve and principal component analysis. We anticipate that this universal platform holds potential in facilitating DILI diagnosis, therapeutic evaluation, and prognosis.
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Affiliation(s)
- Wuqi Dong
- School of Basic Medical Sciences, Biopharmaceutical Research Institute, Anhui Provincial Institute of Translational Medicine, Anhui Medical University, Hefei, Anhui 230032, China
| | - Weizhen Yan
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yuechen Xu
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230032, China
| | - Xiaofei Shang
- School of Basic Medical Sciences, Biopharmaceutical Research Institute, Anhui Provincial Institute of Translational Medicine, Anhui Medical University, Hefei, Anhui 230032, China
| | - Wanrong Wang
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230032, China
| | - Jie Qiu
- School of Basic Medical Sciences, Biopharmaceutical Research Institute, Anhui Provincial Institute of Translational Medicine, Anhui Medical University, Hefei, Anhui 230032, China
| | - Baoxin Wang
- School of Basic Medical Sciences, Biopharmaceutical Research Institute, Anhui Provincial Institute of Translational Medicine, Anhui Medical University, Hefei, Anhui 230032, China
| | - Hua Wang
- The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230032, China
| | - Zhongping Zhang
- School of Chemistry and Chemical Engineering, Anhui University, Hefei, Anhui 230601, China
| | - Tingting Zhao
- School of Basic Medical Sciences, Biopharmaceutical Research Institute, Anhui Provincial Institute of Translational Medicine, Anhui Medical University, Hefei, Anhui 230032, China
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11
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Besaratinia A, Tommasi S. The Untapped Biomarker Potential of MicroRNAs for Health Risk-Benefit Analysis of Vaping vs. Smoking. Cells 2024; 13:1330. [PMID: 39195220 PMCID: PMC11352591 DOI: 10.3390/cells13161330] [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: 07/23/2024] [Revised: 08/08/2024] [Accepted: 08/09/2024] [Indexed: 08/29/2024] Open
Abstract
Despite the popularity of electronic cigarettes (e-cigs) among adolescent never-smokers and adult smokers seeking a less pernicious substitute for tobacco cigarettes, the long-term health impact of vaping is largely unknown. Like cigarette smoke, e-cig vapor contains harmful and potentially harmful compounds, although in fewer numbers and at substantially lower concentrations. Many of the same constituents of e-cig vapor and cigarette smoke induce epigenetic changes that can lead to the dysregulation of disease-related genes. MicroRNAs (MiRNAs) are key regulators of gene expression in health and disease states. Extensive research has shown that miRNAs play a prominent role in the regulation of genes involved in the pathogenesis of smoking-related diseases. However, the use of miRNAs for investigating the disease-causing potential of vaping has not been fully explored. This review article provides an overview of e-cigs as a highly consequential electronic nicotine delivery system, describes trends in e-cig use among adolescents and adults, and discusses the ongoing debate on the public health impact of vaping. Highlighting the significance of miRNAs in cell biology and disease, it summarizes the published and ongoing research on miRNAs in relation to gene regulation and disease pathogenesis in e-cig users and in vitro experimental settings. It identifies gaps in knowledge and priorities for future research while underscoring the need for empirical evidence that can inform the regulation of tobacco products to protect youth and promote public health.
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Affiliation(s)
- Ahmad Besaratinia
- Department of Population & Public Health Sciences, USC Keck School of Medicine, University of Southern California, M/C 9603, Los Angeles, CA 90033, USA;
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12
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Yang D, Jeong H, Kim MS, Oh SI, Lee K, Kim JW, Kim B. Prenatal cigarette smoke exposure sensitizes acetaminophen-induced liver injury by modulating miR-34a-5p in male offspring mice. Front Cell Dev Biol 2024; 12:1393618. [PMID: 39139452 PMCID: PMC11319911 DOI: 10.3389/fcell.2024.1393618] [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: 02/29/2024] [Accepted: 07/01/2024] [Indexed: 08/15/2024] Open
Abstract
Introduction: Cigarette smoke (CS) exacerbates the severity of diseases not only in lungs, but also in systemic organs having no direct contact with smoke. In addition, smoking during pregnancy can have severe health consequences for both the mother and the fetus. Therefore, our aim was to evaluate effects of prenatal exposure to CS on acetaminophen (APAP)-induced acute liver injury (ALI) in offspring. Methods: Female C57BL/6 mice on day 6 of gestation were exposed to mainstream CS (MSCS) at 0, 150, 300, or 600 μg/L for 2 h a day, 5 days a week for 2 weeks using a nose-only exposure system. At four weeks old, male offspring mice were injected intraperitoneally with a single dose of APAP at 300 mg/kg body weight to induce ALI. Results: Maternal MSCS exposure significantly amplified pathological effects associated with ALI as evidenced by elevated serum alanine aminotransferase levels, increased hepatocellular apoptosis, higher oxidative stress, and increased inflammation. Interestingly, maternal MSCS exposure reduced microRNA (miR)-34a-5p expression in livers of offspring. Moreover, treatment with a miR-34a-5p mimic significantly mitigated the severity of APAP-induced hepatotoxicity. Overexpression of miR-34a-5p completely abrogated adverse effects of maternal MSCS exposure in offspring with ALI. Mechanistically, miR-34a-5p significantly decreased expression levels of hepatocyte nuclear factor 4 alpha, leading to down-regulated expression of cytochrome P450 (CYP)1A2 and CYP3A11. Discussion: Prenatal exposure to MSCS can alter the expression of miRNAs, even in the absence of additional MSCS exposure, potentially increasing susceptibility to APAP exposure in male offspring mice.
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Affiliation(s)
- Daram Yang
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Republic of Korea
| | - Hyuneui Jeong
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Republic of Korea
| | - Min-Seok Kim
- Inhalation Toxicology Center, Jeonbuk Department of Inhalation Research, Korea Institute of Toxicology, Jeongeup, Jeonbuk, Republic of Korea
| | - Sang-Ik Oh
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Republic of Korea
| | - Kyuhong Lee
- Inhalation Toxicology Center, Jeonbuk Department of Inhalation Research, Korea Institute of Toxicology, Jeongeup, Jeonbuk, Republic of Korea
| | - Jong-Won Kim
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Republic of Korea
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, United States
| | - Bumseok Kim
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, Iksan, Republic of Korea
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13
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Cui J, Piao J, Han H, Peng W, Lin M, Zhou D, Zhu C, Gong X. Semiarbitrary qPCR for Sensitive Detection of Circulating miRNA via Terminal Deoxynucleotidyl Transferase-Assisted RNA-Primed DNA Polymerization. Anal Chem 2024; 96:10496-10505. [PMID: 38896549 DOI: 10.1021/acs.analchem.3c05723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Circulating microRNAs (miRNAs) have recently emerged as noninvasive disease biomarkers. Quantitative detection of circulating miRNAs could offer significant information for clinical diagnosis due to its significance in the development of biological processes. In response to the current challenges of circulating miRNA detection, we introduce a sensitive, selective, and versatile circulating miRNA detection strategy using terminal deoxynucleotidyl transferase (TdT)-catalyzed RNA-primed DNA polymerization (TCRDP) coupled with semiarbitrary qPCR (SAPCR). Semiarbitrary qPCR was first developed here to detect long fragment targets with only a short-known sequence or to detect a short fragment target after extension with terminal transferase. Besides, the subsequent results show that TdT has a preference for RNA, particularly for extending RNAs with purine-rich and unstructured ends. Consequently, utilizing this assay, we have successfully applied it to the quantitative analysis of circulating miR-122 in animal models, a sensitive and informative biomarker for drug-induced liver injury, and as low as 200 zmol of the target is detected with desirable specificity and sensitivity, indicating that the TCRDP-SAPCR can offer a promising platform for nucleic acids analysis.
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Affiliation(s)
- Jingyu Cui
- Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
| | - Jiafang Piao
- Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China
| | - Houyu Han
- Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China
| | - Weipan Peng
- Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China
| | - Mengyao Lin
- Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China
| | - Dianming Zhou
- Tianjin Centers for Disease Control and Prevention, Tianjin 300011, China
| | - Cheng Zhu
- Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China
| | - Xiaoqun Gong
- Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin 300072, China
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Wang QL, Meng LC, Zhao Z, Du JF, Li P, Jiang Y, Li HJ. Ultrasensitive upconverting nanoprobes for in situ imaging of drug-induced liver injury using miR-122 as the biomarker. Talanta 2024; 274:126108. [PMID: 38640602 DOI: 10.1016/j.talanta.2024.126108] [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: 10/01/2023] [Revised: 01/09/2024] [Accepted: 04/12/2024] [Indexed: 04/21/2024]
Abstract
Drug-induced liver injury (DILI) is a frequent adverse drug reaction. The current clinical diagnostic methods are inadequate for accurate and early detection of DILI due to the lack of effective diagnostic biomarkers. Hepatocyte-specific miR-122 is released from injured hepatocytes promptly and its efflux is significantly correlated with the progression of DILI. Therefore, achieving precise in situ detection of miR-122 with high sensitivity is vital for early visualization of DILI. Herein, a new nanoprobe, consisting of miR-122 aptamer, upconversion nanoparticles (UCNPs) and Prussian blue nanoparticles (PBNPs) was introduced for the early and sensitive detection of DILI in situ. As the nanoprobes reached in the liver, miR-122 aptamer-based entropy-driven strand displacement (ESDR) signal amplification reaction was triggered and luminescence resonance energy transfer (LRET) between UCNPs and PBNPs was responded to achieve the high-fidelity detection of DILI. A negative correlation was observed between the intensity of upconversion luminescence (UCL) and the concentration of miR-122. UCL imaging conducted both in vivo and ex vivo indicated that a reduction in miR-122 concentration led to an increase in UCL intensity, revealing a precise state of DILI. The detection technique demonstrated a positive correlation between signal intensity and severity, offering a more straightforward and intuitive method of visualizing DILI.
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Affiliation(s)
- Qiao-Lei Wang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Ling-Chang Meng
- Institute of Chinese Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University, Nanjing, China
| | - Zhen Zhao
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Jin-Fa Du
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Ping Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Yan Jiang
- College of Chemical Engineering, Nanjing Forestry University, Nanjing, 210037, China.
| | - Hui-Jun Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
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15
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Scullion KM, MacIntyre IM, Sloan-Dennison S, Clark B, Fineran P, Mair J, Creasey D, Rathmell C, Faulds K, Graham D, Webb DJ, Dear JW. Cytokeratin-18 is a sensitive biomarker of alanine transaminase increase in a placebo-controlled, randomized, crossover trial of therapeutic paracetamol dosing (PATH-BP biomarker substudy). Toxicol Sci 2024; 199:203-209. [PMID: 38521541 PMCID: PMC11131027 DOI: 10.1093/toxsci/kfae031] [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] [Indexed: 03/25/2024] Open
Abstract
Drug-induced liver injury (DILI) is a challenge in clinical medicine and drug development. Highly sensitive novel biomarkers have been identified for detecting DILI following a paracetamol overdose. The study objective was to evaluate biomarker performance in a 14-day trial of therapeutic dose paracetamol. The PATH-BP trial was a double-blind, placebo-controlled, crossover study. Individuals (n = 110) were randomized to receive 1 g paracetamol 4× daily or matched placebo for 2 weeks followed by a 2-week washout before crossing over to the alternate treatment. Blood was collected on days 0 (baseline), 4, 7, and 14 in both arms. Alanine transaminase (ALT) activity was measured in all patients. MicroRNA-122 (miR-122), cytokeratin-18 (K18), and glutamate dehydrogenase (GLDH) were measured in patients who had an elevated ALT on paracetamol treatment (≥50% from baseline). ALT increased in 49 individuals (45%). All 3 biomarkers were increased at the time of peak ALT (K18 paracetamol arm: 18.9 ± 9.7 ng/ml, placebo arm: 11.1 ± 5.4 ng/ml, ROC-AUC = 0.80, 95% CI 0.71-0.89; miR-122: 15.1 ± 12.9fM V 4.9 ± 4.7fM, ROC-AUC = 0.83, 0.75-0.91; and GLDH: 24.6 ± 31.1U/l V 12.0 ± 11.8U/l, ROC-AUC = 0.66, 0.49-0.83). All biomarkers were correlated with ALT (K18 r = 0.68, miR-122 r = 0.67, GLDH r = 0.60). To assess sensitivity, biomarker performance was analyzed on the visit preceding peak ALT (mean 3 days earlier). K18 identified the subsequent ALT increase (K18 ROC-AUC = 0.70, 0.59-0.80; miR-122 ROC-AUC = 0.60, 0.49-0.72, ALT ROC-AUC = 0.59, 0.48-0.70; GLDH ROC-AUC = 0.70, 0.50-0.90). Variability was lowest for ALT and K18. In conclusion, K18 was more sensitive than ALT, miR-122, or GLDH and has potential significant utility in the early identification of DILI in trials and clinical practice.
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Affiliation(s)
- Kathleen M Scullion
- Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh EH16 4TJ, UK
| | - Iain M MacIntyre
- Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh EH16 4TJ, UK
| | - Sian Sloan-Dennison
- Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of Strathclyde, Glasgow G1 1RD, UK
| | - Benjamin Clark
- Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of Strathclyde, Glasgow G1 1RD, UK
| | - Paul Fineran
- Centre for Inflammation Research, University of Edinburgh, Institute for Regeneration and Repair, Edinburgh EH16 4UU, UK
| | - Joanne Mair
- Centre for Inflammation Research, University of Edinburgh, Institute for Regeneration and Repair, Edinburgh EH16 4UU, UK
| | - David Creasey
- Wasatch Photonics, Morrisville, North Carolina 27560, USA
| | | | - Karen Faulds
- Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of Strathclyde, Glasgow G1 1RD, UK
| | - Duncan Graham
- Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of Strathclyde, Glasgow G1 1RD, UK
| | - David J Webb
- Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh EH16 4TJ, UK
| | - James W Dear
- Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh EH16 4TJ, UK
- Centre for Precision Cell Therapy for the Liver, Lothian Health Board, Queen’s Medical Research Institute, Edinburgh EH16 4TJ, UK
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16
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Cirronis M, Schneemann S, Pettie J, Mannaioni G, Dear JW. Evaluation of capillary miR-122 as a prognostic biomarker of paracetamol-induced liver toxicity. Mol Biol Rep 2024; 51:548. [PMID: 38642142 DOI: 10.1007/s11033-024-09327-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 02/07/2024] [Indexed: 04/22/2024]
Abstract
INTRODUCTION Paracetamol (acetaminophen) overdose is a leading cause of acute liver failure in many Western countries. Diagnostic tools for this poisoning may be suboptimal in some cases and new biomarkers have been investigated. We investigated the role of capillary microRNA-122 (miR-122) as a prognostic biomarker of liver injury in the clinical management of patients with paracetamol overdose. METHODS In a paracetamol overdose patient cohort, miR-122 was measured by quantitative polymerase chain reaction in a blood drop obtained by a finger prick at the end of an antidote cycle treatment with N-acetylcysteine treatment (12 h). Liver injury was defined as serum alanine aminotransferase (ALT) activity > 100 IU/L collected at 10 or 20 h after the start of treatment. Pearson's correlation analyses were performed. RESULTS In patients with paracetamol overdose, capillary miR-122 was positively correlated with ALT measured at 10 h and at 20 h (r = 0.83, P < 0.0001; r = 0.96, P < 0.0001, respectively). CONCLUSION This work supports the potential use of capillary miR-122 as a prognostic biomarker of liver injury throughout clinical management of patients with paracetamol overdose. Capillary miR-122 can be measured in a blood drop collected by a finger prick, a minimally invasive diagnostic test for patient stratification.
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Affiliation(s)
- Marco Cirronis
- Edinburgh Clinical Toxicology, Royal Infirmary of Edinburgh, Edinburgh, UK.
- Department of Neuroscience, Psychiatry, Drug Area and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Florence, Italy.
- Bergamo Poison Control Center & Teratology Information Service, ASST Papa Giovanni XXXIII Hospital, Bergamo, Italy.
| | - Sarah Schneemann
- Edinburgh Clinical Toxicology, Royal Infirmary of Edinburgh, Edinburgh, UK
- Julius Center for Health Sciences and Primary Care, Department of Medical Humanities, University Medical Center Utrecht, 3508 GA, Utrecht, Netherlands
| | - Janice Pettie
- Edinburgh Clinical Toxicology, Royal Infirmary of Edinburgh, Edinburgh, UK
- Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, Edinburgh University, Edinburgh, UK
| | - Guido Mannaioni
- Department of Neuroscience, Psychiatry, Drug Area and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Florence, Italy
| | - James W Dear
- Edinburgh Clinical Toxicology, Royal Infirmary of Edinburgh, Edinburgh, UK
- Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, Edinburgh University, Edinburgh, UK
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Atteia HH. MicroRNAs in Anticancer Drugs Hepatotoxicity: From Pathogenic Mechanism and Early Diagnosis to Therapeutic Targeting by Natural Products. Curr Pharm Biotechnol 2024; 25:1791-1806. [PMID: 38178678 DOI: 10.2174/0113892010282155231222071903] [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: 09/13/2023] [Revised: 11/11/2023] [Accepted: 11/24/2023] [Indexed: 01/06/2024]
Abstract
Patients receiving cancer therapies experience severe adverse effects, including hepatotoxicity, even at therapeutic doses. Consequently, monitoring patients on cancer therapy for hepatic functioning is necessary to avoid permanent liver damage. Several pathways of anticancer drug-induced hepatotoxicity involve microRNAs (miRNAs) via targeting mRNAs. These short and non-coding RNAs undergo rapid modulation in non-targeted organs due to cancer therapy insults. Recently, there has been an interest for miRNAs as useful and promising biomarkers for monitoring toxicity since they have conserved sequences across species and are cellular-specific, stable, released during injury, and simple to analyze. Herein, we tried to review the literature handling miRNAs as mediators and biomarkers of anticancer drug-induced hepatotoxicity. Natural products and phytochemicals are suggested as safe and effective candidates in treating cancer. There is also an attempt to combine anticancer drugs with natural compounds to enhance their efficiencies and reduce systemic toxicities. We also discussed natural products protecting against chemotherapy hepatotoxicity via modulating miRNAs, given that miRNAs have pathogenic and diagnostic roles in chemotherapy-induced hepatotoxicity and that many natural products can potentially regulate their expression. Future studies should integrate these findings into clinical trials by formulating suitable therapeutic dosages of natural products to target miRNAs involved in anticancer drug hepatotoxicity.
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Affiliation(s)
- Hebatallah Husseini Atteia
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Sharkia, 44519, Egypt
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Naume MM, Zhao Q, Haslund-Krog SS, Krag T, Winter BCMD, Revsbech KL, Vissing J, Holst H, Møller MH, Hornsyld TM, Dunø M, Hoei-Hansen CE, Born AP, Bo Jensen P, Cathrine Ørngreen M. Acetaminophen treatment in children and adults with spinal muscular atrophy: a lower tolerance and higher risk of hepatotoxicity. Neuromuscul Disord 2024; 34:9-18. [PMID: 38052667 DOI: 10.1016/j.nmd.2023.11.005] [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: 09/26/2023] [Revised: 10/31/2023] [Accepted: 11/12/2023] [Indexed: 12/07/2023]
Abstract
Acute liver failure has been reported sporadically in patients with spinal muscular atrophy (SMA) and other neuromuscular disorders with low skeletal muscle mass receiving recommended dosages of acetaminophen. It is suggested that low skeletal muscle mass may add to the risk of toxicity. We aimed to describe the pharmacokinetics and safety of acetaminophen in patients with SMA. We analyzed acetaminophen metabolites and liver biomarkers in plasma from SMA patients and healthy controls (HC) every hour for six or eight hours on day 1 and day 3 of treatment with therapeutic doses of acetaminophen. Twelve patients with SMA (six adults and six children) and 11 HC participated in the study. Adult patients with SMA had significantly lower clearance of acetaminophen compared to HC (14.1 L/h vs. 21.5 L/h). Formation clearance of acetaminophen metabolites, glucuronide, sulfate, and oxidative metabolites were two-fold lower in the patients compared to HC. The liver transaminases and microRNAs increased nine-fold in one adult SMA patient after two days of treatment. The other patients and HC did not develop abnormal liver biomarkers. In this study, patients with SMA had lower clearance and slower metabolism of acetaminophen, and one patient developed liver involvement. We recommend giving 15 mg/kg/dose to SMA adults (with a maximum of 4000 mg/day) and monitoring standard liver biomarkers 48 h after first-time treatment of acetaminophen.
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Affiliation(s)
- Marie Mostue Naume
- Copenhagen Neuromuscular Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.
| | - Qiaolin Zhao
- Department of Hospital Pharmacy, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands; Rotterdam Clinical Pharmacometrics Group, the Netherlands
| | | | - Thomas Krag
- Copenhagen Neuromuscular Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Brenda C M de Winter
- Department of Hospital Pharmacy, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands; Rotterdam Clinical Pharmacometrics Group, the Netherlands
| | - Karoline Lolk Revsbech
- Copenhagen Neuromuscular Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - John Vissing
- Copenhagen Neuromuscular Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark
| | - Helle Holst
- Rare disease and advance therapies, Novo Nordisk, Denmark
| | - Morten Hylander Møller
- Department of Intensive Care, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark
| | - Tessa Munkeboe Hornsyld
- Copenhagen Neuromuscular Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Morten Dunø
- Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Christina Engel Hoei-Hansen
- Department of Clinical Medicine, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark; Department of Pediatric and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Alfred Peter Born
- Department of Pediatric and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Per Bo Jensen
- Department of Clinical Biochemistry, Bispebjerg Hospital, Copenhagen, Denmark
| | - Mette Cathrine Ørngreen
- Copenhagen Neuromuscular Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Pediatric and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
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19
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McGill MR, Curry SC. The Evolution of Circulating Biomarkers for Use in Acetaminophen/Paracetamol-Induced Liver Injury in Humans: A Scoping Review. LIVERS 2023; 3:569-596. [PMID: 38434489 PMCID: PMC10906739 DOI: 10.3390/livers3040039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/05/2024] Open
Abstract
Acetaminophen (APAP) is a widely used drug, but overdose can cause severe acute liver injury. The first reports of APAP hepatotoxicity in humans were published in 1966, shortly after the development of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as the first biomarkers of liver injury as opposed to liver function. Thus, the field of liver injury biomarkers has evolved alongside the growth in APAP hepatotoxicity incidence. Numerous biomarkers have been proposed for use in the management of APAP overdose patients in the intervening years. Here, we comprehensively review the development of these markers from the 1960s to the present day and briefly discuss possible future directions.
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Affiliation(s)
- Mitchell R McGill
- Dept. of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR 72212, USA
- Dept. of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72212, USA
- Dept. of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72212, USA
| | - Steven C Curry
- Division of Clinical Data Analytics and Decision Support, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85006, USA
- Department of Medical Toxicology, Banner-University Medical Center Phoenix, Phoenix, AZ 85006, USA
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20
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Chiew AL, Isbister GK. Advances in the understanding of acetaminophen toxicity mechanisms: a clinical toxicology perspective. Expert Opin Drug Metab Toxicol 2023; 19:601-616. [PMID: 37714812 DOI: 10.1080/17425255.2023.2259787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 08/02/2023] [Accepted: 09/13/2023] [Indexed: 09/17/2023]
Abstract
INTRODUCTION Acetaminophen (paracetamol) is a commonly used analgesic and antipyretic agent, which is safe in therapeutic doses. Acetaminophen poisoning due to self-harm or repeated supratherapeutic ingestion is a common cause of acute liver injury. Acetylcysteine has been a mainstay of treatment for acetaminophen poisoning for decades and is efficacious if administered early. However, treatment failures occur if administered late, in 'massive' overdoses or in high-risk patients. AREAS COVERED This review provides an overview of the mechanisms of toxicity of acetaminophen poisoning (metabolic and oxidative phase) and how this relates to the assessment and treatment of the acetaminophen poisoned patient. The review focuses on how these advances offer further insight into the utility of novel biomarkers and the role of proposed adjunct treatments. EXPERT OPINION Advances in our understanding of acetaminophen toxicity have allowed the development of novel biomarkers and a better understanding of how adjunct treatments may prevent acetaminophen toxicity. Newly proposed adjunct treatments like fomepizole are being increasingly used without robust clinical trials. Novel biomarkers (not yet clinically available) may provide better assessment of these newly proposed adjunct treatments, particularly in clinical trials. These advances in our understanding of acetaminophen toxicity and liver injury hold promise for improved diagnosis and treatment.
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Affiliation(s)
- Angela L Chiew
- Department of Clinical Toxicology, Prince of Wales Hospital, Randwick, NSW, Australia
- Faculty of Medicine, The University of New South Wales, Sydney, New South Wales, Australia
- New South Wales Poisons Information Centre, Sydney Children's Hospital, Sydney, New South Wales, Australia
| | - Geoffrey K Isbister
- New South Wales Poisons Information Centre, Sydney Children's Hospital, Sydney, New South Wales, Australia
- Clinical Toxicology Research Group, University of Newcastle, Callaghan, NSW, Australia
- Department of Clinical Toxicology, Calvary Mater Newcastle, Waratah, NSW, Australia
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21
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Liu Y, Guan H, Feng M, Du C, Zhang Q, Shou Y, Qi G, Yu D, Jin Y. MiR-766-3p and miR-671-5p attenuate aristolochic acid-induced hepatotoxicity by directly targeting the key bioactivating enzyme NQO1. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 261:115103. [PMID: 37285672 DOI: 10.1016/j.ecoenv.2023.115103] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 05/23/2023] [Accepted: 06/01/2023] [Indexed: 06/09/2023]
Abstract
Aristolochic acid (AA) as an emerging contaminant in herbal medicines or crops has been well-recognized for causing nephropathy since 1990s. Over the last decade, mounting evidence has linked AA to liver injury; however, the underlying mechanism is poorly elucidated. MicroRNAs respond to environmental stress and mediate multiple biological processes, thus showing biomarker potentials prognostically or diagnostically. In the present study, we investigated the role of miRNAs in AA-induced hepatotoxicity, specifically in regulating NQO1, the key enzyme responsible for AA bioactivation. In silico analysis showed that hsa-miR-766-3p and hsa-miR-671-5p were significantly associated with AAI exposure as well as NQO1 induction. A 28-day rat experiment of 20 mg/kg AA exposure demonstrated a 3-fold increase of NQO1 and an almost 50 % decrease of the homologous miR-671 that were accompanied with liver injury, which was consistent with in silico prediction. Further mechanistic investigation using Huh7 cells with IC50 of AAI at 146.5 µM showed both hsa-miR-766-3p and hsa-miR-671-5p were able to directly bind to and down-regulate NQO1 basal expression. In addition, both miRNAs were shown to suppress AAI-induced NQO1 upregulation in Huh7 cells at a cytotoxic concentration of 70 μM, and consequently alleviate AAI-induced cellular effects, including cytotoxicity and oxidative stress. Together, these data illustrate that miR-766-3p and miR-671-5p attenuate AAI-induced hepatotoxicity, and thus have monitoring and diagnostic potentials.
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Affiliation(s)
- Yuzhen Liu
- School of Public Health, Qingdao University, Qingdao, China
| | - Heyuan Guan
- School of Public Health, Qingdao University, Qingdao, China
| | - Meiyao Feng
- Department of Environmental Health, Qingdao Municipal Center for Disease Control and Prevention, Qingdao Institute of Preventive Medicine, Qingdao, China
| | - Chenlong Du
- School of Public Health, Qingdao University, Qingdao, China
| | - Qianqian Zhang
- School of Public Health, Qingdao University, Qingdao, China
| | - Yingqing Shou
- School of Public Health, Qingdao University, Qingdao, China
| | - Guangshuai Qi
- School of Public Health, Qingdao University, Qingdao, China
| | - Dianke Yu
- School of Public Health, Qingdao University, Qingdao, China
| | - Yuan Jin
- School of Public Health, Qingdao University, Qingdao, China.
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22
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Zhang Y, Li Y, Liu Y, Wang H, Chen Y, Zhang B, Song M, Song L, Ding Q, Qiu J, Fan M, Qu L, Wang Z. Alcoholic Setdb1 suppression promotes hepatosteatosis in mice by strengthening Plin2. Metabolism 2023:155656. [PMID: 37419179 DOI: 10.1016/j.metabol.2023.155656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/25/2023] [Accepted: 07/04/2023] [Indexed: 07/09/2023]
Abstract
BACKGROUND AND AIMS Hepatosteatosis is one of the early features of alcoholic liver disease (ALD) and pharmaceutical or genetic interfering of the development of hepatosteatosis will efficiently alleviate the progression of ALD. Currently, the role of histone methyltransferase Setdb1 in ALD is not yet well understood. METHOD Lieber-De Carli diet mice model and NIAAA mice model were constructed to confirm the expression of Setdb1. The hepatocyte-specific Setdb1-knockout (Setdb1-HKO) mice was established to determine the effects of Setdb1 in vivo. Adenovirus-Setdb1 were produced to rescue the hepatic steatosis in both Setdb1-HKO and Lieber-De Carli mice. The enrichment of H3k9me3 in the upstream sequence of Plin2 and the chaperone-mediated autophagy (CMA) of Plin2 were identified by ChIP and co-IP. Dual-luciferase reporter assay was used to detect the interaction of Setdb1 3'UTR and miR216b-5p in AML12 or HEK 293 T cells. RESULTS We found that Setdb1 was downregulated in the liver of alcohol-fed mice. Setdb1 knockdown promoted lipid accumulation in AML12 hepatocytes. Meanwhile, hepatocyte-specific Setdb1-knockout (Setdb1-HKO) mice exhibited significant lipid accumulation in the liver. Overexpression of Setdb1 was performed with an adenoviral vector through tail vein injection, which ameliorated hepatosteatosis in both Setdb1-HKO and alcoholic diet-fed mice. Mechanistically, downregulated Setdb1 promoted the mRNA expression of Plin2 by desuppressing H3K9me3-mediated chromatin silencing in its upstream sequence. Pin2 acts as a critical membrane surface-associated protein to maintain lipid droplet stability and inhibit lipase degradation. The downregulation of Setdb1 also maintained the stability of Plin2 protein through inhibiting Plin2-recruited chaperone-mediated autophagy (CMA). To explore the reasons for Setdb1 suppression in ALD, we found that upregulated miR-216b-5p bound to the 3'UTR of Setdb1 mRNA, disturbed its mRNA stability, and eventually aggravated hepatic steatosis. CONCLUSIONS Setdb1 suppression plays an important role in the progression of alcoholic hepatosteatosis via elevating the expression of Plin2 mRNA and maintaining the stability of Plin2 protein. Targeting hepatic Setdb1 might be a promising diagnostic or therapeutic strategy for ALD.
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Affiliation(s)
- Yi Zhang
- College of Medical Laboratory Science and Technology, Harbin Medical University-Daqing Campus, Daqing, China; Departments of Laboratory Diagnosis, The Fifth Affiliated Hospital of Harbin Medical University, Daqing, China
| | - Yanhui Li
- College of Medical Laboratory Science and Technology, Harbin Medical University-Daqing Campus, Daqing, China
| | - Yang Liu
- Clinical Laboratory, The First Hospital of Harbin, Harbin, China
| | - Hongzhi Wang
- Departments of Laboratory Diagnosis, The Fifth Affiliated Hospital of Harbin Medical University, Daqing, China
| | - Yingli Chen
- College of Medical Laboratory Science and Technology, Harbin Medical University-Daqing Campus, Daqing, China
| | - Bing Zhang
- College of Medical Laboratory Science and Technology, Harbin Medical University-Daqing Campus, Daqing, China
| | - Meiqi Song
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, KingMed School of Laboratory Medicine, China
| | - Lei Song
- Department of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, China
| | - Qinchao Ding
- College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Jiannan Qiu
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Mingjian Fan
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, KingMed School of Laboratory Medicine, China
| | - Lihui Qu
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Zhigang Wang
- College of Medical Laboratory Science and Technology, Harbin Medical University-Daqing Campus, Daqing, China; Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, KingMed School of Laboratory Medicine, China.
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23
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Moosa MS, Russomanno G, Dorfman JR, Gunter H, Patel C, Costello E, Carr D, Maartens G, Pirmohamed M, Goldring C, Cohen K. Analysis of serum microRNA-122 in a randomized controlled trial of N-acetylcysteine for treatment of antituberculosis drug-induced liver injury. Br J Clin Pharmacol 2023; 89:1844-1851. [PMID: 36639145 PMCID: PMC10952339 DOI: 10.1111/bcp.15661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/30/2022] [Accepted: 01/04/2023] [Indexed: 01/15/2023] Open
Abstract
AIM Serum microRNA-122 (miR-122) is a novel biomarker for drug-induced liver injury, with good sensitivity in the early diagnosis of paracetamol-induced liver injury. We describe miR-122 concentrations in participants with antituberculosis drug-induced liver injury (AT-DILI). We explored the relationship between miR-122 and alanine aminotransferase (ALT) concentrations and the effect of N-acetylcysteine (NAC) on miR-122 concentrations. METHODS We included participants from a randomized placebo-controlled trial of intravenous NAC in AT-DILI. ALT and miR-122 concentrations were quantified before and after infusion of NAC/placebo. We assessed correlations between ALT and miR-122 concentrations and described changes in ALT and miR-122 concentrations between sampling occasions. RESULTS We included 45 participants; mean age (± standard deviation) 38 (±10) years, 58% female and 91% HIV positive. The median (interquartile range) time between pre- and post-infusion biomarker specimens was 68 h (47-77 h). The median pre-infusion ALT and miR-122 concentrations were 420 U/L (238-580) and 0.58 pM (0.18-1.47), respectively. Pre-infusion ALT and miR-122 concentrations were correlated (Spearman's ρ = .54, P = .0001). Median fold-changes in ALT and miR-122 concentrations between sampling were 0.56 (0.43-0.69) and 0.75 (0.23-1.53), respectively, and were similar in the NAC and placebo groups (P = .40 and P = .68 respectively). CONCLUSIONS miR-122 concentrations in our participants with AT-DILI were considerably higher than previously reported in healthy volunteers and in patients on antituberculosis therapy without liver injury. We did not detect an effect of NAC on miR-122 concentrations. Further research is needed to determine the utility of miR-122 in the diagnosis and management of AT-DILI.
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Affiliation(s)
- Muhammed Shiraz Moosa
- New Somerset Hospital, Department of MedicineUniversity of Cape TownCape TownSouth Africa
| | - Giusy Russomanno
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Jeffrey R. Dorfman
- Division of Medical Virology, Department of PathologyUniversity of StellenboschCape TownSouth Africa
| | - Hannah Gunter
- Division of Clinical Pharmacology, Department of MedicineUniversity of Cape TownCape TownSouth Africa
| | - Chandni Patel
- Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Eithne Costello
- Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Dan Carr
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Gary Maartens
- Division of Clinical Pharmacology, Department of MedicineUniversity of Cape TownCape TownSouth Africa
| | - Munir Pirmohamed
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Christopher Goldring
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Karen Cohen
- Division of Clinical Pharmacology, Department of MedicineUniversity of Cape TownCape TownSouth Africa
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24
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Nakajima M, Tamai I. Roles and Application of Extracellular Vesicles Occurring Endogenously and Naturally. Pharm Res 2023; 40:793-794. [PMID: 37079150 DOI: 10.1007/s11095-023-03519-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/21/2023]
Affiliation(s)
- Miki Nakajima
- Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
- WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa, Japan
| | - Ikumi Tamai
- Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
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25
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Liu L, Xiao F, Sun J, Wang Q, Wang A, Zhang F, Li Z, Wang X, Fang Z, Qiao Y. Hepatocyte-derived extracellular vesicles miR-122-5p promotes hepatic ischemia reperfusion injury by regulating Kupffer cell polarization. Int Immunopharmacol 2023; 119:110060. [PMID: 37044034 DOI: 10.1016/j.intimp.2023.110060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 03/17/2023] [Accepted: 03/17/2023] [Indexed: 04/14/2023]
Abstract
Ischemia reperfusion injury remains a major barrier to liver transplantation, especially using grafts from donation after circulatory death, and it is also a pressing issue to be solved in clinical practice. Kupffer cell polarization toward a proinflammatory M1 phenotype is an early trigger of liver ischemia-reperfusion injury. However, the molecular mechanism regulating Kupffer cell polarization has not yet been fully elucidated. We induced liver ischemia reperfusion injury in mice and obtained samples from patients undergoing liver transplantation, serum and hepatocytes-derived extracellular vesicles were isolated by differential ultracentrifugation. Kupffer cell polarization was examined by flow cytometry and immunofluorescence histochemistry. RNA-seq was conducted to detect the differentially expressed miRNAs in extracellular vesicles. The role and mechanism of exosomal miR-122-5p in liver ischemia-reperfusion injury were determined both in vitro and in vivo. We identified ischemia reperfusion induced extracellular vesicles as a major cause of hepatic inflammation and tissue damage using adoptive transfer and release inhibition. The study also demonstrated that hepatocyte-derived exosomal miR-122-5p mediates liver ischemia reperfusion injury by polarizing Kupffer cell via PPARδ down-regulation and NF-κB pathway activation using profiling and functional analysis. Moreover, inhibiting miR-122-5p with antagomir suppressed Kupffer cell M1 polarization and attenuated liver ischemia reperfusion injury. Overall, our study demonstrated that hepatocyte-derived exosomal miR-122-5p played a critical role in promoting hepatic ischemia reperfusion injury through modulating PPARδ signaling and NF-κB pathway to introduce M1 polarization of Kupffer cell. Inhibition of miR-122-5p exhibited a protective effect against liver ischemia reperfusion injury, suggesting a potential therapeutic target for liver transplantation.
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Affiliation(s)
- Long Liu
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Zhejiang University, Linhai, Zhejiang 317000, China
| | - Fei Xiao
- Department of Organ Transplantation, Liaocheng People's Hospital, Liaocheng, Shandong 252000, China
| | - Jie Sun
- Medical Records Department, Liaocheng People's Hospital, Liaocheng, Shandong 252000, China
| | - Qi Wang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang 317000, China
| | - Aidong Wang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang 317000, China.
| | - Fabiao Zhang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang 317000, China
| | - Zhu Li
- Department of Organ Transplantation, Liaocheng People's Hospital, Liaocheng, Shandong 252000, China
| | - Xuequan Wang
- Department of Radiation Oncology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang 317000, China
| | - Zheping Fang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Zhejiang University, Linhai, Zhejiang 317000, China; Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang 317000, China.
| | - Yingli Qiao
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang 317000, China; Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province, Linhai, Zhejiang 317000, China.
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26
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Roychoudhury A, Dear JW, Kersaudy-Kerhoas M, Bachmann TT. Amplification-free electrochemical biosensor detection of circulating microRNA to identify drug-induced liver injury. Biosens Bioelectron 2023; 231:115298. [PMID: 37054598 DOI: 10.1016/j.bios.2023.115298] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 03/23/2023] [Accepted: 04/04/2023] [Indexed: 04/15/2023]
Abstract
Drug-induced liver injury (DILI) is a major challenge in clinical medicine and drug development. There is a need for rapid diagnostic tests, ideally at point-of-care. MicroRNA 122 (miR-122) is an early biomarker for DILI which is reported to increase in the blood before standard-of-care markers such as alanine aminotransferase activity. We developed an electrochemical biosensor for diagnosis of DILI by detecting miR-122 from clinical samples. We used electrochemical impedance spectroscopy (EIS) for direct, amplification free detection of miR-122 with screen-printed electrodes functionalised with sequence specific peptide nucleic acid (PNA) probes. We studied the probe functionalisation using atomic force microscopy and performed elemental and electrochemical characterisations. To enhance the assay performance and minimise sample volume requirements, we designed and characterised a closed-loop microfluidic system. We presented the EIS assay's specificity for wild-type miR-122 over non-complementary and single nucleotide mismatch targets. We successfully demonstrated a detection limit of 50 pM for miR-122. Assay performance could be extended to real samples; it displayed high selectivity for liver (miR-122 high) comparing to kidney (miR-122 low) derived samples extracted from murine tissue. Finally, we successfully performed an evaluation with 26 clinical samples. Using EIS, DILI patients were distinguished from healthy controls with a ROC-AUC of 0.77, a comparable performance to qPCR detection of miR-122 (ROC-AUC: 0.83). In conclusion, direct, amplification free detection of miR-122 using EIS was achievable at clinically relevant concentrations and in clinical samples. Future work will focus on realising a full sample-to-answer system which can be deployed for point-of-care testing.
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Affiliation(s)
- Appan Roychoudhury
- Infection Medicine, Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK
| | - James W Dear
- Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
| | - Maïwenn Kersaudy-Kerhoas
- Infection Medicine, Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK; Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University, Edinburgh, EH14 4AS, UK
| | - Till T Bachmann
- Infection Medicine, Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
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27
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Tang F, Wang Z, Zhou J, Yao J. Salvianolic Acid A Protects against Acetaminophen-Induced Hepatotoxicity via Regulation of the miR-485-3p/SIRT1 Pathway. Antioxidants (Basel) 2023; 12:antiox12040870. [PMID: 37107244 PMCID: PMC10135683 DOI: 10.3390/antiox12040870] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/28/2023] [Accepted: 03/30/2023] [Indexed: 04/07/2023] Open
Abstract
The vast majority of drug-induced liver injury is mainly attributed to acetaminophen (APAP) overdose. Salvianolic acid A (Sal A), a powerful water-soluble compound obtained from Salvia miltiorrhiza, has been confirmed to exert hepatoprotective effects. However, the beneficial effects and the exact mechanisms of Sal A on APAP-induced hepatotoxicity remain unclear. In this study, APAP-induced liver injury with or without Sal A treatment was examined in vitro and in vivo. The results showed that Sal A could alleviate oxidative stress and inflammation by regulating Sirtuin 1 (SIRT1). Furthermore, miR-485-3p could target SIRT1 after APAP hepatotoxicity and was regulated by Sal A. Importantly, inhibiting miR-485-3p had a hepatoprotective effect similar to that of Sal A on APAP-exposed AML12 cells. These findings suggest that regulating the miR-485-3p/SIRT1 pathway can alleviate oxidative stress and inflammation induced by APAP in the context of Sal A treatment.
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Affiliation(s)
- Fan Tang
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Zhecheng Wang
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Junjun Zhou
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Jihong Yao
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
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28
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Ali FE, Abd El-Aziz MK, Sharab EI, Bakr AG. Therapeutic interventions of acute and chronic liver disorders: A comprehensive review. World J Hepatol 2023; 15:19-40. [PMID: 36744165 PMCID: PMC9896501 DOI: 10.4254/wjh.v15.i1.19] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/17/2022] [Accepted: 12/21/2022] [Indexed: 01/16/2023] Open
Abstract
Liver disorders are one of the most common pathological problems worldwide. It affects more than 1.5 billion worldwide. Many types of hepatic cells have been reported to be involved in the initiation and propagation of both acute and chronic liver diseases, including hepatocytes, Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells (HSCs). In addition, oxidative stress, cytokines, fibrogenic factors, microRNAs, and autophagy are also involved. Understanding the molecular mechanisms of liver diseases leads to discovering new therapeutic interventions that can be used in clinics. Recently, antioxidant, anti-inflammatory, anti-HSCs therapy, gene therapy, cell therapy, gut microbiota, and nanoparticles have great potential for preventing and treating liver diseases. Here, we explored the recent possible molecular mechanisms involved in the pathogenesis of acute and chronic liver diseases. Besides, we overviewed the recent therapeutic interventions that targeted liver diseases and summarized the recent studies concerning liver disorders therapy.
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Affiliation(s)
- Fares Em Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt.
| | | | - Elham I Sharab
- Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
| | - Adel G Bakr
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
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29
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Abdel Halim AS, Rudayni HA, Chaudhary AA, Ali MAM. MicroRNAs: Small molecules with big impacts in liver injury. J Cell Physiol 2023; 238:32-69. [PMID: 36317692 DOI: 10.1002/jcp.30908] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/30/2022] [Accepted: 10/14/2022] [Indexed: 11/07/2022]
Abstract
A type of small noncoding RNAs known as microRNAs (miRNAs) fine-tune gene expression posttranscriptionally by binding to certain messenger RNA targets. Numerous physiological processes in the liver, such as differentiation, proliferation, and apoptosis, are regulated by miRNAs. Additionally, there is growing evidence that miRNAs contribute to liver pathology. Extracellular vesicles like exosomes, which contain secreted miRNAs, may facilitate paracrine and endocrine communication between various tissues by changing the gene expression and function of distal cells. The use of stable miRNAs as noninvasive biomarkers was made possible by the discovery of these molecules in body fluids. Circulating miRNAs reflect the conditions of the liver that are abnormal and may serve as new biomarkers for the early detection, prognosis, and evaluation of liver pathological states. miRNAs are appealing therapeutic targets for a range of liver disease states because altered miRNA expression is associated with deregulation of the liver's metabolism, liver damage, liver fibrosis, and tumor formation. This review provides a comprehensive review and update on miRNAs biogenesis pathways and mechanisms of miRNA-mediated gene silencing. It also outlines how miRNAs affect hepatic cell proliferation, death, and regeneration as well as hepatic detoxification. Additionally, it highlights the diverse functions that miRNAs play in the onset and progression of various liver diseases, including nonalcoholic fatty liver disease, alcoholic liver disease, fibrosis, hepatitis C virus infection, and hepatocellular carcinoma. Further, it summarizes the diverse liver-specific miRNAs, illustrating the potential merits and possible caveats of their utilization as noninvasive biomarkers and appealing therapeutic targets for liver illnesses.
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Affiliation(s)
- Alyaa S Abdel Halim
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hassan Ahmed Rudayni
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Anis Ahmad Chaudhary
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Mohamed A M Ali
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.,Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
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Cione E, Abrego Guandique DM, Caroleo MC, Luciani F, Colosimo M, Cannataro R. Liver Damage and microRNAs: An Update. Curr Issues Mol Biol 2022; 45:78-91. [PMID: 36661492 PMCID: PMC9857663 DOI: 10.3390/cimb45010006] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/12/2022] [Accepted: 12/20/2022] [Indexed: 12/28/2022] Open
Abstract
One of the major organs in the body with multiple functions is the liver. It plays a central role in the transformation of macronutrients and clearance of chemicals and drugs. The serum biomarkers often used to indicate liver damage are not specifically for drug-induced liver injury (DILI) or liver injury caused by other xenobiotics, nor for viral infection. In this case, microRNAs (miRNAs) could play an exciting role as biomarkers of specific liver damage. In this review, we aimed to update the current literature on liver damage induced by drugs, as acute conditions and viral infections mediated by the hepatitis B virus (HBV) linked these two conditions to advanced research, with a focus on microRNAs as early biomarkers for liver damage. The undoubtable evidence that circulating miR-122 could be used as a human biomarker of DILI came from several studies in which a strong increase of it was linked with the status of liver function. In infancy, there is the possibility of an early miRNA detection for hepatitis B virus infection, but there are a lack of solid models for studying the HVB molecular mechanism of infection in detail, even if miRNAs do hold unrealized potential as biomarkers for early detection of hepatitis B virus infection mediated by HBV.
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Affiliation(s)
- Erika Cione
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
- Galascreen Laboratories, University of Calabria, 87036 Rende, Italy
| | - Diana Marisol Abrego Guandique
- Galascreen Laboratories, University of Calabria, 87036 Rende, Italy
- Department of Health Sciences, University of Magna Graecia Catanzaro, 88100 Catanzaro, Italy
| | - Maria Cristina Caroleo
- Galascreen Laboratories, University of Calabria, 87036 Rende, Italy
- Department of Health Sciences, University of Magna Graecia Catanzaro, 88100 Catanzaro, Italy
| | - Filippo Luciani
- Infectious Disease Unit Annunziata Hospital, 87100 Cosenza, Italy
| | - Manuela Colosimo
- Microbiology Unit Pugliese Ciaccio Hospital, 88100 Catanzaro, Italy
| | - Roberto Cannataro
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
- Galascreen Laboratories, University of Calabria, 87036 Rende, Italy
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Pansa CC, Molica LR, Moraes KCM. Non-alcoholic fatty liver disease establishment and progression: genetics and epigenetics as relevant modulators of the pathology. Scand J Gastroenterol 2022; 58:521-533. [PMID: 36426638 DOI: 10.1080/00365521.2022.2148835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) results from metabolic dysfunctions that affect more than one-third of the world population. Over the last decades, scientific investigations have clarified many details on the pathology establishment and development; however, effective therapeutics approaches are still evasive. In addition, studies demonstrated that NAFLD establishment and progression are related to several etiologies. Recently, genetics and epigenetics backgrounds have emerged as relevant elements to the pathology onset, and, hence, deserve deep investigation to clarify molecular details on NAFLD signaling, which may be correlated with population behavior. Thus, to minimize the global problem, public health and public policies should take advantage of studies on NAFLD over the next following decades. METHODS In this context, we have performed a selective literature review focusing on biochemistry of lipid metabolism, genetics, epigenetics, and the ethnicity as strong elements that drive NAFLD establishment. RESULTS Considering the etiological agents that acts on NAFLD development and progression, the genetics and the epigenetics emerged as relevant factors. Genetics acts as a powerful element in the establishment and progression of the NAFLD. Over the last decades, details concerning genes and their polymorphisms, as well as epigenetics, have been considered relevant elements in the systems biology of diseases, and their effects on NAFLD should be considered in-depth, as well as the ethnicity, clarifying whether people are susceptible to liver diseases. Moreover, the endemicity and social problems of hepatic disfunction are far to be solved, which require a combined effort of various sectors of society. CONCLUSION Hence, the elements presented and discussed in this short review demonstrated their relevance to the physiological control of NAFLD, opening perspectives for research to develop new strategy to treat fatty liver diseases.
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Affiliation(s)
- Camila Cristiane Pansa
- Departamento de Biologia Geral e Aplicada, Cellular Signalling and Gene Expression Laboratory, Universidade Estadual Paulista "Júlio de Mesquita Filho", Instituto de Biociências, Rio Claro, Brazil
| | - Letícia Ramos Molica
- Departamento de Biologia Geral e Aplicada, Cellular Signalling and Gene Expression Laboratory, Universidade Estadual Paulista "Júlio de Mesquita Filho", Instituto de Biociências, Rio Claro, Brazil
| | - Karen C M Moraes
- Departamento de Biologia Geral e Aplicada, Cellular Signalling and Gene Expression Laboratory, Universidade Estadual Paulista "Júlio de Mesquita Filho", Instituto de Biociências, Rio Claro, Brazil
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Khurana A, Navik U, Allawadhi P, Yadav P, Weiskirchen R. Spotlight on liver macrophages for halting liver disease progression and injury. Expert Opin Ther Targets 2022; 26:707-719. [PMID: 36202756 DOI: 10.1080/14728222.2022.2133699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/06/2022]
Abstract
INTRODUCTION Over the past two decades, understanding of hepatic macrophage biology has provided astounding details of their role in the progression and regression of liver diseases. The hepatic macrophages constitute resident macrophages, Kupffer cells, and circulating bone marrow monocyte-derived macrophages, which play a diverse role in liver injury and repair. Imbalance in the macrophage population leads to pathological consequences and is responsible for the initiation and progression of acute and chronic liver injuries. Further, distinct populations of hepatic macrophages and their high heterogeneity make their complex role enigmatic. The unique features of distinct phenotypes of macrophages have provided novel biomarkers for defining the stages of liver diseases. The distinct mechanisms of hepatic macrophages polarization and recruitment have been at the fore front of research. In addition, the secretome of hepatic macrophages and their immune regulation has provided clinically relevant therapeutic targets. AREAS COVERED Herein we have highlighted the current understanding in the area of hepatic macrophages, and their role in the progression of liver injury. EXPERT OPINION It is essential to ascertain the physiological and pathological role of evolutionarily conserved distinct macrophage phenotypes in different liver diseases before viable approaches may see a clinical translation.
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Affiliation(s)
- Amit Khurana
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital, Pauwelsstr. 30, D-52074, Aachen, Germany
| | - Umashanker Navik
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda - 151401, Punjab, India
| | - Prince Allawadhi
- Department of Pharmacy, Vaish Institute of Pharmaceutical Education and Research (VIPER), Pandit Bhagwat Dayal Sharma University of Health Sciences (Pt. B. D. S. UHS), Rohtak - 124001, Haryana, India
| | - Poonam Yadav
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda - 151401, Punjab, India
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital, Pauwelsstr. 30, D-52074, Aachen, Germany
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Roychoudhury A, Dear JW, Bachmann TT. Proximity sensitive detection of microRNAs using electrochemical impedance spectroscopy biosensors. Biosens Bioelectron 2022; 212:114404. [DOI: 10.1016/j.bios.2022.114404] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 05/03/2022] [Accepted: 05/17/2022] [Indexed: 12/12/2022]
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Zajkowska M, Mroczko B. Chemokines in Primary Liver Cancer. Int J Mol Sci 2022; 23:ijms23168846. [PMID: 36012108 PMCID: PMC9408270 DOI: 10.3390/ijms23168846] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/04/2022] [Accepted: 08/08/2022] [Indexed: 11/16/2022] Open
Abstract
The liver is responsible for extremely important functions in the human body. In the liver’s structure, we distinguish between connective tissue (stroma) and parenchyma, the latter of which is formed from the basic structural and functional units of the liver—hepatocytes. There are many factors, that negatively affect the liver cells, contributing to their damage. This may lead to fibrosis, liver failure and, in consequence, primary liver cancer, which is the sixth most commonly diagnosed malignancy and the fourth leading cause of cancer death worldwide. Chemokines are a large family of secreted proteins. Their main role is to direct the recruitment and migration of cells to sites of inflammation or injury. Some authors suggest that these proteins might play a potential role in the development of many malignancies, including primary liver cancer. The aim of this study was to evaluate and summarize the knowledge regarding liver diseases, especially primary liver cancer (HCC) and the participation of chemokines in the development of this malignancy. Chemokines involved in the initiation of this type of tumor belong mainly to the CC and CXC chemokines. Their significant role in the course of hepatocellular carcinoma proves their usefulness in detecting and monitoring the course and treatment in patients with this disease.
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Affiliation(s)
- Monika Zajkowska
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
- Correspondence: ; Tel.: +48-686-5168; Fax: +48-686-5169
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
- Department of Biochemical Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
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Chen Y, Guan S, Guan Y, Tang S, Zhou Y, Wang X, Bi H, Huang M. Novel Clinical Biomarkers for Drug-Induced Liver Injury. Drug Metab Dispos 2022; 50:671-684. [PMID: 34903588 DOI: 10.1124/dmd.121.000732] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 12/07/2021] [Indexed: 11/22/2022] Open
Abstract
Drug-induced liver injury (DILI) remains a critical clinical issue and has been a treatment challenge today as it was in the past. However, the traditional biomarkers or indicators are insufficient to predict the risks and outcome of patients with DILI due to its poor specificity and sensitivity. Recently, the development of high-throughput technologies, especially omics and multiomics has sparked growing interests in identification of novel clinical DILI biomarkers, many of which also provide a mechanistic insight. Accordingly, in this minireview, we summarize recent advances in novel clinical biomarkers for DILI prediction, diagnosis, and prognosis and highlight the limitations or challenges involved in biomarker discovery or its clinical translation. Although huge work has been done, most reported biomarkers lack comprehensive information and more specific DILI biomarkers are still needed to complement the traditional biomarkers such as alanine aminotransferase (ALT) or aspartate transaminase (AST) in clinical decision-making. SIGNIFICANCE STATEMENT: This current review outlines an overview of novel clinical biomarkers for drug-induced liver injury (DILI) identified in clinical retrospective or prospective clinical analysis. Many of these biomarkers provide a mechanistic insight and are promising to complement the traditional DILI biomarkers. This work also highlights the limitations or challenges involved in biomarker discovery or its clinical translation.
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Affiliation(s)
- Youhao Chen
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Shaoxing Guan
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Yanping Guan
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Siyuan Tang
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Yanying Zhou
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Xueding Wang
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Huichang Bi
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Min Huang
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
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Offor SJ, Amadi CN, Chijioke-Nwauche I, Manautou JE, Orisakwe OE. Potential deleterious effects of paracetamol dose regime used in Nigeria versus that of the United States of America. Toxicol Rep 2022; 9:1035-1044. [PMID: 36561959 PMCID: PMC9764198 DOI: 10.1016/j.toxrep.2022.04.025] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 04/21/2022] [Accepted: 04/23/2022] [Indexed: 12/25/2022] Open
Abstract
Paracetamol, also known as acetaminophen (N-acetyl-para-aminophenol, APAP) is the world's most used over-the-counter analgesic-antipyretic drug. Despite its good safety profile, acetaminophen can cause severe hepatotoxicity in overdose, and poisoning from paracetamol has become a major public health concern. Paracetamol is now the major cause of acute liver failure in the United States and Europe. This systematic review aims at examining the likelihood of paracetamol use in Nigeria causing more liver toxicity vis-à-vis the reduced maximum recommended daily adult dose of 3 g for the 500 mg tablet. Online searches were conducted in the databases of PubMed, Google Scholar and MEDLINE for publications using terms like "paracetamol toxicity," "acetaminophen and liver toxicity," "paracetamol and liver diseases in Nigeria," and other variants. Further search of related references in PubMed was carried out, and synthesis of all studies included in this review finalized. There were 94 studies that met the inclusion criteria. Evaluation of hepatic disorder was predicated mostly on a constellation of clinical features and limited clinical laboratory investigations. Determination of blood paracetamol concentration was rarely reported, thus excluding paracetamol poisoning as one of the likely causes of liver disorders in Nigeria. In Nigeria and elsewhere, several factors are known to increase paracetamol's predisposition to liver injury. They include: the over-the-counter status of paracetamol, use of fixed-dose combinations of paracetamol with other drugs, malnutrition, dose miscalculations, and chronic alcohol consumption. The tendency to exceed the new paracetamol maximum daily dose of 3 g in Nigeria may increase its risk for hepatotoxicity than observed in the United States of America known for emphasizing lower dose of the drug. In addition to recommending the new maximal daily paracetamol dose allowance, the historical maximum daily adult dose of 4 g should be de-emphasized in Nigeria.
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Affiliation(s)
- Samuel James Offor
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Uyo, Uyo, Akwa Ibom State, Nigeria
| | - Cecilia Nwadiuto Amadi
- Department of Experimental Pharmacology & Toxicology, Faculty of Pharmacy, University of Port-Harcourt, Port-Harcourt, Rivers State, Nigeria
| | - Ifeyinwa Chijioke-Nwauche
- Department of Clinical Pharmacy, Faculty of Pharmacy, University of Port Harcourt, Port Harcourt 5323, Rivers State, Nigeria
| | - Jose E. Manautou
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Orish E. Orisakwe
- Department of Experimental Pharmacology & Toxicology, Faculty of Pharmacy, University of Port-Harcourt, Port-Harcourt, Rivers State, Nigeria
- African Centre of Excellence for Public Health and Toxicological Research (ACE-PUTOR), University of Port Harcourt, PMB, 5323 Port Harcourt, Choba, Nigeria
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Khafagy HF, AbuSeada AN, Shash AM, Elayashy M, El-Araby RE, Sabry OM, Montasser AY, Mohamed MS, Ebied RS, Samhan YM. Effects of Desflurane exposure and Laparotomy on genomic biomarkers and hepatic histopathology in an experimentally induced liver injury model: A pilot study. EGYPTIAN JOURNAL OF ANAESTHESIA 2022. [DOI: 10.1080/11101849.2022.2069219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Affiliation(s)
- Hanan F. Khafagy
- Department of Anesthesia and Surgical Intensive Care, Theodor Bilharz Research Institute, Ministry of Higher Education and Scientific Research, Giza, Egypt
| | - AbdulRahman N. AbuSeada
- Department of Anesthesia and Surgical Intensive Care, Theodor Bilharz Research Institute, Ministry of Higher Education and Scientific Research, Giza, Egypt
| | - Ahmed M. Shash
- Department of Anesthesia, Faculty of Medicine, Cairo University, Ministry of Higher Education and Scientific Research, Cairo, Egypt
| | - Mohamed Elayashy
- Department of Anesthesia, Faculty of Medicine, Cairo University, Ministry of Higher Education and Scientific Research, Cairo, Egypt
| | - Rady E. El-Araby
- Molecular Biology, Central Lab, Theodor Bilharz Research Institute, Ministry of Higher Education and Scientific Research, Giza, Egypt
| | - Omar M. Sabry
- Department of Hematology, Theodor Bilharz Research Institute, Ministry of Higher Education and Scientific Research, Giza, Egypt
| | - Ahmed Y. Montasser
- Department of Pathology, Theodor Bilharz Research Institute, Ministry of Higher Education and Scientific Research, Giza, Egypt
| | - Mohamed S. Mohamed
- Experimental Laboratory Unit Theodor Bilharz Research Institute, Ministry of Higher Education and Scientific Research, Giza, Egypt
| | - Reeham S. Ebied
- Department of Anesthesia and Surgical Intensive Care, Theodor Bilharz Research Institute, Ministry of Higher Education and Scientific Research, Giza, Egypt
| | - Yasser M. Samhan
- Department of Anesthesia and Surgical Intensive Care, Theodor Bilharz Research Institute, Ministry of Higher Education and Scientific Research, Giza, Egypt
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Kersaudy-Kerhoas M, Liga A, Roychoudhury A, Stamouli M, Grant R, Carrera DS, Schulze H, Mielczarek W, Oosthuyzen W, Quintana JF, Dickinson P, Buck AH, Leslie NR, Haas J, Bachmann TT, Dear JW. Microfluidic system for near-patient extraction and detection of miR-122 microRNA biomarker for drug-induced liver injury diagnostics. BIOMICROFLUIDICS 2022; 16:024108. [PMID: 35464137 PMCID: PMC9018095 DOI: 10.1063/5.0085078] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 04/06/2022] [Indexed: 06/14/2023]
Abstract
Drug-induced liver injury (DILI) results in over 100 000 hospital attendances per year in the UK alone and is a leading cause for the post-marketing withdrawal of new drugs, leading to significant financial losses. MicroRNA-122 (miR-122) has been proposed as a sensitive DILI marker although no commercial applications are available yet. Extracellular blood microRNAs (miRNAs) are promising clinical biomarkers but their measurement at point of care remains time-consuming, technically challenging, and expensive. For circulating miRNA to have an impact on healthcare, a key challenge to overcome is the development of rapid and reliable low-cost sample preparation. There is an acknowledged issue with miRNA stability in the presence of hemolysis and platelet activation, and no solution has been demonstrated for fast and robust extraction at the site of blood draw. Here, we report a novel microfluidic platform for the extraction of circulating miR-122 from blood enabled by a vertical approach and gravity-based bubble mixing. The performance of this disposable cartridge was verified by standard quantitative polymerase chain reaction analysis on extracted miR-122. The cartridge performed equivalently or better than standard bench extraction kits. The extraction cartridge was combined with electrochemical impedance spectroscopy to detect miR-122 as an initial proof-of-concept toward an application in point-of-care detection. This platform enables the standardization of sample preparation and the detection of miRNAs at the point of blood draw and in resource limited settings and could aid the introduction of miRNA-based assays into routine clinical practice.
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Affiliation(s)
| | | | - Appan Roychoudhury
- Infection Medicine, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, Scotland
| | - Marilena Stamouli
- Infection Medicine, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, Scotland
| | - Rhiannon Grant
- Infection Medicine, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, Scotland
| | - Damaso Sanchez Carrera
- Institute of Biological Chemistry, Biophysics and Bioengineering, School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, Scotland
| | - Holger Schulze
- Infection Medicine, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, Scotland
| | | | - Wilna Oosthuyzen
- Centre for Cardiovascular Science, Queen Mary Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, Scotland
| | - Juan F. Quintana
- School of Biological Sciences, Ashworth Laboratories, University of Edinburgh, Edinburgh, Scotland
| | - Paul Dickinson
- School of Biological Sciences, Ashworth Laboratories, University of Edinburgh, Edinburgh, Scotland
| | - Amy H. Buck
- School of Biological Sciences, Ashworth Laboratories, University of Edinburgh, Edinburgh, Scotland
| | - Nicholas R. Leslie
- Institute of Biological Chemistry, Biophysics and Bioengineering, School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, Scotland
| | - Jurgen Haas
- Infection Medicine, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, Scotland
| | - Till T. Bachmann
- Infection Medicine, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, Scotland
| | - James W. Dear
- Centre for Cardiovascular Science, Queen Mary Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, Scotland
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Forte G, Ventimiglia G, Pesaturo M, Petralia S. A highly sensitive PNA-microarray system for miRNA122 recognition. Biotechnol J 2022; 17:e2100587. [PMID: 35225426 DOI: 10.1002/biot.202100587] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 02/16/2022] [Accepted: 02/21/2022] [Indexed: 11/09/2022]
Abstract
Surface chemistry is a fundamental aspect of the development of the sensitive biosensor based on microarray technology. Here we described an advanced PNA-microarray system for the detection of miRNA, composed by a multilayered Si/Al/Agarose component. A straightforward optical signal enhancement is achieved thanks to a combination of the Al film mirror effect and the positive interference for the emission wavelength of the Cy5 fluorescent label tuned by the agarose film. The PNA-microarray was investigated for the detection of miRNA_122, resulting in a sensitivity of about 1.75 μM-1 and Limit of Detection in the range of 0.043 nM as a function of the capture probe sequence. The contribution, in terms of H-bonds amounts at 298 and 333 K, of the agarose coating to the dsPNA-RNA interactions was demonstrated by Molecular Dynamic simulations. These results pave the way for advanced sensing strategies suitable for the environmental monitoring and the public safety. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Giuseppe Forte
- Department of Drug Science and Health, University of Catania, via S. Sofia 64, 95125, Catania, Italy
| | - Giorgio Ventimiglia
- EM Microelectronic, Rue de Sors 3, 2074, Marin (Suisse), Marin-Epagnier, Switzerland
| | | | - Salvatore Petralia
- Department of Drug Science and Health, University of Catania, via S. Sofia 64, 95125, Catania, Italy
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Astaxanthin Attenuates the Changes in the Expression of MicroRNAs Involved in the Activation of Hepatic Stellate Cells. Nutrients 2022; 14:nu14050962. [PMID: 35267937 PMCID: PMC8912553 DOI: 10.3390/nu14050962] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 02/20/2022] [Accepted: 02/22/2022] [Indexed: 02/01/2023] Open
Abstract
We previously demonstrated that astaxanthin (ASTX), a xanthophyll carotenoid, has an antifibrogenic effect in hepatic stellate cells (HSC), primarily responsible for the accumulation of extracellular matrix protein during the development of liver fibrosis. Studies have shown that microRNAs (miRNAs) are involved in HSC activation. Therefore, we analyzed the expression of 84 miRNAs using miRNA arrays in primary mouse quiescent HSC (qHSC) and activated HSC (aHSC) treated with/without ASTX during their activation. Compared with qHSC, the expression of 14 miRNAs and 23 miRNAs was increased and decreased by more than 2-fold, respectively, in aHSC. Among the 14 miRNAs increased in aHSC, the expression of miR-192-5p, miR-382-5p, and miR-874-3p was reduced by ASTX. In addition, ASTX increased the expression of miR-19a-3p, miR-19b-3p, and miR-101a-3p among 23 miRNAs decreased in aHSC. Moreover, we confirmed miR-382-5p expression was ~15-fold higher in aHSC than qHSC, and ASTX markedly inhibited the induction measured by quantitative real-time PCR. We identified that the expression of Baz1a and Zfp462 from the predicted miR-382-5p target genes was significantly reduced in aHSC while increased by ASTX treatment similar to the levels in qHSC. The roles of Baz1a and Zfp462 in HSC activation and the antifibrogenic effect of ASTX need to be further investigated.
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Factors influencing circulating microRNAs as biomarkers for liver diseases. Mol Biol Rep 2022; 49:4999-5016. [DOI: 10.1007/s11033-022-07170-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 01/19/2022] [Indexed: 11/09/2022]
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Orzeł-Gajowik K, Milewski K, Zielińska M. Insight into microRNAs-Mediated Communication between Liver and Brain: A Possible Approach for Understanding Acute Liver Failure? Int J Mol Sci 2021; 23:224. [PMID: 35008650 PMCID: PMC8745738 DOI: 10.3390/ijms23010224] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 01/11/2023] Open
Abstract
Acute liver failure (ALF) is a life-threatening consequence of hepatic function rapid loss without preexisting liver disease. ALF may result in a spectrum of neuropsychiatric symptoms that encompasses cognitive impairment, coma, and often death, collectively defined as acute hepatic encephalopathy. Micro RNAs are small non-coding RNAs that modulate gene expression and are extensively verified as biomarker candidates in various diseases. Our systematic literature review based on the last decade's reports involving a total of 852 ALF patients, determined 205 altered circulating miRNAs, of which 25 miRNAs were altered in the blood, regardless of study design and methodology. Selected 25 miRNAs, emerging predominantly from the analyses of samples obtained from acetaminophen overdosed patients, represent the most promising biomarker candidates for a diagnostic panel for symptomatic ALF. We discussed the role of selected miRNAs in the context of tissue-specific origin and its possible regulatory role for molecular pathways involved in blood-brain barrier function. The defined several common pathways for 15 differently altered miRNAs were relevant to cellular community processes, indicating loss of intercellular, structural, and functional components, which may result in blood-brain barrier impairment and brain dysfunction. However, a causational relationship between circulating miRNAs differential expression, and particular clinical features of ALF, has to be demonstrated in a further study.
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Affiliation(s)
| | | | - Magdalena Zielińska
- Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawińskiego Str., 02-106 Warsaw, Poland; (K.O.-G.); (K.M.)
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Sakai K, Hiradate Y, Hara K, Tanemura K. Potential of sperm small non-coding RNAs as biomarkers of testicular toxicity in a doxorubicin-induced mouse model. Biochem Biophys Rep 2021; 28:101160. [PMID: 34729424 PMCID: PMC8545667 DOI: 10.1016/j.bbrep.2021.101160] [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: 09/16/2021] [Revised: 10/18/2021] [Accepted: 10/19/2021] [Indexed: 11/28/2022] Open
Abstract
Testicular toxicity is a major concern in cancer chemotherapy and drug development as it can result in infertility; however, there are no effective biomarkers for this adverse effect. To identify new biomarkers, we investigated the expression of small non-coding RNAs (sncRNAs) in a mouse model of doxorubicin (DXR)-induced testicular toxicity. First, we performed small RNA-seq analysis of sperm from DXR-treated or control mice and observed differential expression of many genome-derived sequences. We then performed real-time RT-PCR validation of these sequences and discovered that sncRNA detected by one primers, dxRN_3, showed similar differential expression as that seen in the RNA-seq experiment. These findings suggest that the sncRNAs present in sperm have potential as clinically acceptable biomarkers for testicular toxicity.
Testicular toxicity is a major concern in cancer chemotherapy and drug development. There is a lack of effective biomarkers to assess testicular toxicity. Small RNA-seq analysis was performed on sperm from doxorubicin-treated mice. Differential RNA expression analyses identified a small non-coding RNA. Small non-coding RNAs in sperm may be useful biomarkers for testicular toxicity.
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Affiliation(s)
- Kazuya Sakai
- Laboratory of Animal Reproduction and Development, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan
| | - Yuki Hiradate
- Laboratory of Animal Reproduction and Development, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan
| | - Kenshiro Hara
- Laboratory of Animal Reproduction and Development, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan
| | - Kentaro Tanemura
- Laboratory of Animal Reproduction and Development, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan
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Ji H, Li H, Zhang H, Cheng Z. Role of microRNA‑218‑5p in sevoflurane‑induced protective effects in hepatic ischemia/reperfusion injury mice by regulating GAB2/PI3K/AKT pathway. Mol Med Rep 2021; 25:1. [PMID: 34726254 PMCID: PMC8600399 DOI: 10.3892/mmr.2021.12517] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 05/20/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatic ischemia/reperfusion (I/R) injury (HIRI) often occurs following tissue resection, hemorrhagic shock or transplantation surgery. Previous investigations showed that sevoflurane (Sevo), an inhalation anesthetic, had protective properties against different organ damage in animal models including HIRI. This study is aimed to investigate the underlying mechanisms involved in the protective effects of Sevo on HIRI. The present study results showed that treatment with Sevo improved histologic damage, inflammatory response, oxidative stress and apoptosis after hepatic I/R, indicating the protective role of Sevo against liver I/R injury. Importantly, in order to determine the molecular mechanism of Sevo in HIRI, the focus of the study was on microRNA (miR) regulation. By retrieving the microarray data in the Gene Expression Omnibus dataset (GSE72315), miR-218-5p was found to be significantly downregulated by Sevo. Moreover, miR-218-5p overexpression using agomiR-218-5p reversed the protective roles of Sevo against HIRI. Furthermore, GAB2, a positive regulator of PI3K/AKT signaling pathway, was found as a target gene of miR-218-5p. It was also found that the Sevo-mediated protective effects may be dependent on the activation of GAB2/PI3K/AKT. Collectively, these data revealed that Sevo alleviated HIRI in mice by restraining apoptosis, relieving oxidative stress and inflammatory response through the miR-218-5p/GAB2/PI3K/AKT pathway, which helps in understanding the novel mechanism of the hepatic-protection of Sevo.
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Affiliation(s)
- Hui Ji
- Department of Anesthesiology, Xinhua Hospital, Chongming Branch, Shanghai 202150, P.R. China
| | - Hui Li
- Department of Anesthesiology, Xinhua Hospital, Chongming Branch, Shanghai 202150, P.R. China
| | - Haixia Zhang
- Department of Anesthesiology, Xinhua Hospital, Chongming Branch, Shanghai 202150, P.R. China
| | - Zhijun Cheng
- Department of Anesthesiology, Xinhua Hospital, Chongming Branch, Shanghai 202150, P.R. China
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Schofield AL, Brown JP, Brown J, Wilczynska A, Bell C, Glaab WE, Hackl M, Howell L, Lee S, Dear JW, Remes M, Reeves P, Zhang E, Allmer J, Norris A, Falciani F, Takeshita LY, Seyed Forootan S, Sutton R, Park BK, Goldring C. Systems analysis of miRNA biomarkers to inform drug safety. Arch Toxicol 2021; 95:3475-3495. [PMID: 34510227 PMCID: PMC8492583 DOI: 10.1007/s00204-021-03150-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023]
Abstract
microRNAs (miRNAs or miRs) are short non-coding RNA molecules which have been shown to be dysregulated and released into the extracellular milieu as a result of many drug and non-drug-induced pathologies in different organ systems. Consequently, circulating miRs have been proposed as useful biomarkers of many disease states, including drug-induced tissue injury. miRs have shown potential to support or even replace the existing traditional biomarkers of drug-induced toxicity in terms of sensitivity and specificity, and there is some evidence for their improved diagnostic and prognostic value. However, several pre-analytical and analytical challenges, mainly associated with assay standardization, require solutions before circulating miRs can be successfully translated into the clinic. This review will consider the value and potential for the use of circulating miRs in drug-safety assessment and describe a systems approach to the analysis of the miRNAome in the discovery setting, as well as highlighting standardization issues that at this stage prevent their clinical use as biomarkers. Highlighting these challenges will hopefully drive future research into finding appropriate solutions, and eventually circulating miRs may be translated to the clinic where their undoubted biomarker potential can be used to benefit patients in rapid, easy to use, point-of-care test systems.
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Affiliation(s)
- Amy L Schofield
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK
| | - Joseph P Brown
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK
| | - Jack Brown
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK
| | - Ania Wilczynska
- bit.bio, Babraham Research Campus, The Dorothy Hodgkin Building, Cambridge, CB22 3FH, UK
| | - Catherine Bell
- CVRM Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Warren E Glaab
- Merck & Co., Inc, 770 Sumneytown Pike, West Point, PA, 19486, USA
| | | | - Lawrence Howell
- GlaxoSmithKline (GSK), Stevenage, Greater Cambridge Area, UK
| | - Stephen Lee
- ABHI, 1 Duchess St, 4th Floor, Suite 2, London, W1W 6AN, UK
| | - James W Dear
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
| | - Mika Remes
- Genomics EMEA, QIAGEN Aarhus, Prismet, Silkeborgvej 2, 8000, Aarhus C, Denmark
| | - Paul Reeves
- Arcis Biotechnology Limited, Suite S07, Techspace One, Sci-tech Daresbury, Keckwick Lane, Daresbury, Warrington, WA4 4AB, UK
| | - Eunice Zhang
- Wolfson Centre for Personalised Medicine, Department of Pharmacology and Therapeutics, University of Liverpool, Crown Street, Liverpool, L69 3BX, UK
| | - Jens Allmer
- Applied Bioinformatics, Bioscience, Wageningen University and Research, Droevendaalsesteeg 4, 6708 PB, Wageningen, The Netherlands
| | - Alan Norris
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK
| | - Francesco Falciani
- Computational Biology Facility, MerseyBio, University of Liverpool, Crown Street, Liverpool, L69 7ZB, UK
| | - Louise Y Takeshita
- Computational Biology Facility, MerseyBio, University of Liverpool, Crown Street, Liverpool, L69 7ZB, UK
| | - Shiva Seyed Forootan
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK
| | - Robert Sutton
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Biosciences Building, Crown Street, Liverpool, L69 7BE, UK
| | - B Kevin Park
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK
| | - Chris Goldring
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK.
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Barrera-Saldaña HA, Fernández-Garza LE, Barrera-Barrera SA. Liquid biopsy in chronic liver disease. Ann Hepatol 2021; 20:100197. [PMID: 32444248 DOI: 10.1016/j.aohep.2020.03.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 03/25/2020] [Indexed: 02/04/2023]
Abstract
Chronic liver diseases account for a considerable toll of incapacities, suffering, deaths, and resources of the nation's health systems. They can be prevented, treated or even cured when the diagnosis is made on time. Traditional liver biopsy remains the gold standard to diagnose liver diseases, but it has several limitations. Liquid biopsy is emerging as a superior alternative to surgical biopsy given that it surpasses the limitations: it is more convenient, readily and repeatedly accessible, safe, cheap, and provides a more detailed molecular and cellular representation of the individual patient's disease. Progress in understanding the molecular and cellular bases of diseased tissues and organs that normally release cells and cellular components into the bloodstream is catapulting liquid biopsy as a source of biomarkers for diagnosis, prognosis, and prediction of therapeutic response, thus supporting the realization of the promises of precision medicine. The review aims to summarize the evidence of the usefulness of liquid biopsy in liver diseases, including the presence of different biomarkers as circulating epithelial cells, cell-free nucleic acids, specific species of DNA and RNA, and the content of extracellular vesicles.
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Affiliation(s)
- Hugo A Barrera-Saldaña
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico; Center for Biotechnological Genomics of National Polytechnical Institute, Reynosa, Tamps., Mexico.
| | - Luis E Fernández-Garza
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico
| | - Silvia A Barrera-Barrera
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico; National Institute of Pediatrics, Mexico City, Mexico
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Lebin JA, Mudan A, Zhang Y, Wu AHB, Smollin CG. Circulating miR-122 in patients with non-toxic acute acetaminophen ingestions. Clin Toxicol (Phila) 2021; 60:527-529. [PMID: 34528842 DOI: 10.1080/15563650.2021.1978477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Introduction: MicroRNA-122 (miR-122) is a novel biomarker of liver injury and has been proposed as an early predictor of acetaminophen-associated hepatotoxicity. However, there is little data on miR-122 in patients with nontoxic acute acetaminophen ingestions.Methods: This was an observational study of patients with a history of acute acetaminophen ingestion and measured acetaminophen concentrations below the treatment nomogram and who did not receive antidotal treatment. Fold increase in miR-122 expression was measured from the remnant sample corresponding with the timed serum acetaminophen concentration used to determine need for antidotal treatment.Results: Ten patients met inclusion criteria with a four-hour acetaminophen concentration below the nomogram line (mean: 73.4 µg/mL). There was no significant difference in mean fold change of miR-122 expression between the acetaminophen exposed patients and negative controls [(0.82, IQR: 0.27, 0.77) vs (1.24, IQR: 0.54, 1.98), p = 0.33].Conclusion: miR-122 was not elevated in patients with acute acetaminophen ingestions with timed acetaminophen concentrations below the nomogram line. These data help to further characterize patterns of miR-122 in patients with acute acetaminophen exposures.
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Affiliation(s)
- Jacob A Lebin
- Department of Emergency Medicine, University of California, San Francisco, CA, USA
| | - Anita Mudan
- Department of Emergency Medicine, University of California, San Francisco, CA, USA
| | - Yu Zhang
- Department of Laboratory Medicine, University of California, San Francisco, CA, USA
| | - Alan H B Wu
- Department of Laboratory Medicine, University of California, San Francisco, CA, USA
| | - Craig G Smollin
- Department of Emergency Medicine, University of California, San Francisco, CA, USA
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A Review of the Clinical and Therapeutic Implications of Neuropathic Pain. Biomedicines 2021; 9:biomedicines9091239. [PMID: 34572423 PMCID: PMC8465811 DOI: 10.3390/biomedicines9091239] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/12/2021] [Accepted: 09/14/2021] [Indexed: 02/08/2023] Open
Abstract
Understanding neuropathic pain presents several challenges, given the various mechanisms underlying its pathophysiological classification and the lack of suitable tools to assess its diagnosis. Furthermore, the response of this pathology to available drugs is still often unpredictable, leaving the treatment of neuropathic pain still questionable. In addition, the rise of personalized treatments further extends the ramified classification of neuropathic pain. While a few authors have focused on neuropathic pain clustering, by analyzing, for example, the presence of specific TRP channels, others have evaluated the presence of alterations in microRNAs to find tailored therapies. Thus, this review aims to synthesize the available evidence on the topic from a clinical perspective and provide a list of current demonstrations on the treatment of this disease.
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Identification of miR-199a-5p, miR-214-3p and miR-99b-5p as Fibrosis-Specific Extracellular Biomarkers and Promoters of HSC Activation. Int J Mol Sci 2021; 22:ijms22189799. [PMID: 34575957 PMCID: PMC8464755 DOI: 10.3390/ijms22189799] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 08/27/2021] [Accepted: 09/07/2021] [Indexed: 12/14/2022] Open
Abstract
Liver fibrosis is characterized by the accumulation of extracellular matrix (ECM) resulting in the formation of fibrous scars. In the clinic, liver biopsies are the standard diagnostic method despite the potential for clinical complications. miRNAs are single-stranded, non-coding RNAs that can be detected in tissues, body fluids and cultured cells. The regulation of many miRNAs has been linked to tissue damage, including liver fibrosis in patients, resulting in aberrant miRNA expression/release. Experimental evidence also suggests that miRNAs are regulated in a similar manner in vitro and could thus serve as translational in vitro–in vivo biomarkers. In this work, we set out to identify and characterize biomarkers for liver fibrosis that could be used in vitro and clinically for research and diagnostic purposes. We focused on miRNAs released from hepatic 3D cultures exposed to methotrexate (MTX), which causes fibrosis, and acetaminophen (APAP), an acute hepatotoxicant with no clinically relevant association to liver fibrosis. Using a 3D in vitro model, we corroborated compound-specific responses as we show MTX induced a fibrotic response, and APAP did not. Performing miRNA-seq of cell culture supernatants, we identified potential miRNA biomarkers (miR-199a-5p, miR-214-3p, niRNA-125a-5p and miR-99b-5p) that were associated with a fibrotic phenotype and not with hepatocellular damage alone. Moreover, transfection of HSC with miR-199a-5p led to decreased expression of caveolin-1 and increased α-SMA expression, suggesting its role in HSC activation. In conclusion, we propose that extracellular miR-214-3p, miR-99b-5p, miR-125a-5p and specifically miR-199a-5p could contribute towards a panel of miRNAs for identifying liver fibrosis and that miR-199a-5p, miR-214-3p and miR-99b-5p are promoters of HSC activation.
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Chang Y, Han JA, Kang SM, Jeong SW, Ryu T, Park HS, Yoo JJ, Lee SH, Kim SG, Kim YS, Kim HS, Jin SY, Ryu S, Jang JY. Clinical impact of serum exosomal microRNA in liver fibrosis. PLoS One 2021; 16:e0255672. [PMID: 34506494 PMCID: PMC8432846 DOI: 10.1371/journal.pone.0255672] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 07/22/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIM We investigated alterations in the expression of serum exosomal miRNAs with the progression of liver fibrosis and evaluated their clinical applicability as biomarkers. METHODS This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. RESULTS NGS data revealed that exosomal miR-660-5p, miR-125a-5p, and miR-122 expression were changed significantly with the progression of liver fibrosis, of which miR-122 exhibited high read counts enough to be used as a biomarker. The level of exosomal miR-122 decreased as the pathologic fibrosis grade progressed and patients with biopsy-proven advanced fibrosis had significantly lower levels of exosomal miR-122 (P < 0.001) than those without advanced fibrosis. Exosomal miR-122 exhibited a fair performance in discriminating advanced fibrosis especially in combination with fibrosis-4 score and transient elastography. In a subgroup of patients with a non-viral etiology of liver disease, the performance of exosomal miR-122 as a biomarker was greatly improved. Inhibition of miR-122 expression increased the proliferation of the human hepatic stellate cell line, LX-2, and upregulated the expression of various fibrosis related proteins. CONCLUSION Exosomal miR-122 may serve as a useful non-invasive biomarker for liver fibrosis, especially in patients with non-viral etiologies of chronic liver disease.
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Affiliation(s)
- Young Chang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Jae-A. Han
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Korea
| | - Suk Min Kang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Soung Won Jeong
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Tom Ryu
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Han Seul Park
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Jeong-Ju Yoo
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Young Seok Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Hong Soo Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - So Young Jin
- Department of Pathology, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Seongho Ryu
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Korea
| | - Jae Young Jang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
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