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Jaeschke H, Ramachandran A. The multiple mechanisms and modes of cell death after acetaminophen overdose. EXPLORATION OF DIGESTIVE DISEASES 2025; 4:100569. [PMID: 40364831 PMCID: PMC12074662 DOI: 10.37349/edd.2025.100569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Accepted: 03/25/2025] [Indexed: 05/15/2025]
Abstract
Acetaminophen (APAP)-induced liver injury and acute liver failure is a significant clinical problem worldwide; in addition, APAP overdoses in animals or in cell culture are used as popular models to study drug-induced liver injury mechanisms and test therapeutic interventions. Early assumptions that APAP toxicity is caused by a single mechanism resulting in a defined mode of cell death in hepatocytes had to be questioned when over the years many different mechanisms and modes of cell death were reported. Although many of the contradictory results and conclusions reported over the years can be attributed to lack of understanding of established mechanisms, methodological problems, and misinterpretation of data, it is increasingly recognized that some of the reported differences in signaling mechanisms and even a switch in the mode of cell death can be caused by variations in the experimental conditions. In this review, examples will be discussed how experimental conditions (dose, solvent, etc.), the experimental system (species, strain, and substrain in vivo, cell type, and in vitro conditions), and also adaptive responses and off-target effects of genetic manipulations and chemical interventions, can impact the mechanisms of cell death. Given that the conditions will determine the results, it is therefore of critical importance to keep in mind the translational aspect of the experiments, i.e., the conditions relevant to the human pathophysiology. Only the full appreciation of these issues will lead to reproducible and clinically relevant results that advance our understanding of all facets of the human pathophysiology and identify clinically relevant therapeutic targets.
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Affiliation(s)
- Hartmut Jaeschke
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Anup Ramachandran
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Fukunaga I, Takebe T. In vitro liver models for toxicological research. Drug Metab Pharmacokinet 2025; 62:101478. [PMID: 40203632 DOI: 10.1016/j.dmpk.2025.101478] [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: 12/19/2024] [Revised: 02/25/2025] [Accepted: 03/04/2025] [Indexed: 04/11/2025]
Abstract
Drug-induced liver injury (DILI) presents a major challenge not only in new drug development but also in post-marketing withdrawals and the safety of food, cosmetics, and chemicals. Experimental model organisms such as the rodents have been widely used for preclinical toxicological testing. However, the tension exists associated with the ethical and sustainable use of animals in part because animals do not necessarily inform the human-specific ADME (adsorption, dynamics, metabolism and elimination) profiling. To establish alternative models in humans, in vitro hepatic tissue models have been proposed, ranging from primary hepatocytes, immortal hepatocytes, to the development of new cell resources such as stem cell-derived hepatocytes. Given the evolving number of novel alternative methods, understanding possible combinations of cell sources and culture methods will be crucial to develop the context-of-use assays. This review primarily focuses on 3D liver organoid models for conducting. We will review the relevant cell sources, bioengineering methods, selection of training compounds, and biomarkers towards the rationale design of in vitro toxicology testing.
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Affiliation(s)
- Ichiro Fukunaga
- Center for Genomic and Regenerative Medicine, Juntendo University Graduate School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8431, Japan.
| | - Takanori Takebe
- Human Biology Research Unit, Institute of Integrated Research, Institute of Science Tokyo, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan; Department of Genome Biology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan; Divisions of Gastroenterology, Hepatology & Nutrition, Developmental Biology and Biomedical Informatics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229-3039, USA; Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH, 45229-3039, USA; Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229-3039, USA; Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), Osaka University, Suita, Osaka, 565-0871, Japan
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Umbaugh DS, Nguyen NT, Curry SC, Rule JA, Lee WM, Ramachandran A, Jaeschke H. The endothelial growth factor Angiopoietin-2 is an accurate prognostic biomarker in patients with acetaminophen-induced acute liver failure. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.02.19.25322567. [PMID: 40034764 PMCID: PMC11875305 DOI: 10.1101/2025.02.19.25322567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Background and Aims Acetaminophen (APAP) overdose is the leading individual cause of acute liver failure (ALF) in the United States, with many patients rapidly progressing to hyperacute liver failure. While hepatocytes are the main target of APAP toxicity, endothelial cells (ECs) are also affected. However, the efficacy of an endothelial-specific biomarker to predict patient outcomes remains unknown. This study aimed to evaluate angiopoietin-2 (ANGPT2) as a prognostic biomarker for poor outcomes in APAP-induced ALF. Approach and Results Using human and mouse single-cell RNA sequencing (scRNAseq) data, we found that ANGPT2 expression was significantly elevated in ECs following APAP exposure. We measured circulating ANGPT2 levels from two independent APAP-ALF cohorts: a Phoenix cohort (n=43) and a cohort from the ALF Study Group (n=80). In the Phoenix cohort, ANGPT2 levels were significantly higher in non-survivors with an AUROC of 0.938. In the ALFSG cohort, we stratified patients based on time of symptom onset finding that ANGPT2 had improved prognostic value in early-presenting patients, with day 1 and day 3 AUC values of 0.825 and 0.918, respectively. Lastly, we combined the patient cohorts (n=110) finding that ANGPT2 alone or in combination with MELD outperformed MELD alone based on AUC (ANGPT2: 0.87, MELD 0.83, ANGPT2+MELD 0.90). Conclusions ANGPT2 is a promising prognostic biomarker for APAP-induced ALF, reflecting endothelial stress and offering superior predictive value compared to MELD alone, especially in early-presenting patients. Its capacity for predicting poor outcomes underscores its value in improving patient prognosis and therapeutic intervention strategies in APAP overdose cases. Lay Summary Accidental or intentional overdosing on acetaminophen can cause liver injury and in severe cases acute liver failure. Under these circumstances, receiving a liver transplant may be the only remaining therapeutic option. However, a liver transplant is a major surgery and commits the patient to a lifetime of anti-rejection medication. Because there is only a limited time window to decide who will recover and who needs a transplant to survive, prognostic biomarkers are essential to identify transplant candidates as early as possible after the overdose. In this study we discovered that plasma levels of the endothelial growth factor angiopoietin-2 can accurately predict at the peak of injury who will need a liver transplant to survive. In addition, this biomarker can be rapidly measured, which allows the data to be available for clinical decision making. Highlights Acetaminophen-induced liver injury can cause hyper-acute liver failure within 3 to 7 days with a high probability of negative outcome.Under these conditions, a liver transplant may be the only therapeutic option.In two independent cohorts, angiopoietin 2 was identified as an early prognostic biomarker for poor outcome.Angiopoietin can more accurately inform clinical management during the initial stages of hospital presentation than the MELD score.
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Cardin R, Bizzaro D, Russo FP, D’Arcangelo F, Ideo F, Pelizzaro F, Carlotto C, Minotto M, Farinati F, Burra P, Germani G. Drug-Induced Liver Injury: Role of Circulating Liver-Specific microRNAs and Keratin-18. GASTROENTEROLOGY INSIGHTS 2024; 15:1093-1105. [DOI: 10.3390/gastroent15040075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/16/2025] Open
Abstract
Background and Objective: Drug-induced liver injury (DILI) is increasingly becoming a cause of acute hepatitis. The study evaluated the role of liver-specific microRNAs (miRNAs) and keratin-18 (K-18) markers M30 (apoptosis) and M65 (necrosis) as biomarkers of acute hepatitis. Methods: Sixty-eight patients were sub-grouped as DILI, HBV- and alcohol-related acute hepatitis. Five healthy controls were included. The expression of plasma miR-21-5p, miR-34a-5p and miR-122-5p was evaluated by RT-qPCR analysis using healthy volunteers as reference. M30 and M65 were determined with ELISA kits. Results: All markers were significantly higher in the acute liver disease patients compared to controls. In DILI, miRNA levels positively correlated with M30, M65 and ALT. miR-122-5p had the highest AUC of 0.73, sensitivity of 76.2 and specificity of 72.2 in identifying DILI from other groups. Patients with hepatocellular-pattern DILI showed higher miR-122-5p and miR-21-5p compared to patients with cholestatic or mixed pattern. A new score to discriminate DILI versus other causes of acute hepatitis was developed using the identified risk factors as follows: 0.012 × miR-34a-5p + 0.012 × miR-122-5p − 0.001 × M30 + 2.642 × 1 (if mixed pattern) + 0.014 × 1 (if hepatocellular pattern) + 1.887. The AUC of the score was 0.86, with a sensitivity and specificity of 81%, better than the values of the single markers. Conclusions: Liver-specific miRNAs and K-18 could be promising serum biomarkers of DILI, especially when used in combination.
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Affiliation(s)
- Romilda Cardin
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
| | - Debora Bizzaro
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
| | - Francesco Paolo Russo
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
| | - Francesca D’Arcangelo
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
| | - Francesco Ideo
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
| | - Filippo Pelizzaro
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
| | - Chiara Carlotto
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
| | - Milena Minotto
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
| | - Fabio Farinati
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
| | - Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
| | - Giacomo Germani
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
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Ramachandran A, Akakpo JY, Curry SC, Rumack BH, Jaeschke H. Clinically relevant therapeutic approaches against acetaminophen hepatotoxicity and acute liver failure. Biochem Pharmacol 2024; 228:116056. [PMID: 38346541 PMCID: PMC11315809 DOI: 10.1016/j.bcp.2024.116056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 01/15/2024] [Accepted: 02/09/2024] [Indexed: 02/17/2024]
Abstract
Liver injury and acute liver failure caused by an acetaminophen (APAP) overdose is a significant clinical problem in western countries. With the introduction of the mouse model of APAP hepatotoxicity in the 1970 s, fundamental mechanisms of cell death were discovered. This included the recognition that part of the APAP dose is metabolized by cytochrome P450 generating a reactive metabolite that is detoxified by glutathione. After the partial depletion of glutathione, the reactive metabolite will covalently bind to sulfhydryl groups of proteins, which is the initiating event of the toxicity. This insight led to the introduction of N-acetyl-L-cysteine, a glutathione precursor, as antidote against APAP overdose in the clinic. Despite substantial progress in our understanding of the pathomechanisms over the last decades viable new antidotes only emerged recently. This review will discuss the background, mechanisms of action, and the clinical prospects of the existing FDA-approved antidote N-acetylcysteine, of several new drug candidates under clinical development [4-methylpyrazole (fomepizole), calmangafodipir] and examples of additional therapeutic targets (Nrf2 activators) and regeneration promoting agents (thrombopoietin mimetics, adenosine A2B receptor agonists, Wharton's Jelly mesenchymal stem cells). Although there are clear limitations of certain therapeutic approaches, there is reason to be optimistic. The substantial progress in the understanding of the pathophysiology of APAP hepatotoxicity led to the consideration of several drugs for development as clinical antidotes against APAP overdose in recent years. Based on the currently available information, it is likely that this will result in additional drugs that could be used as adjunct treatment for N-acetylcysteine.
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Affiliation(s)
- Anup Ramachandran
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Jephte Y Akakpo
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Steven C Curry
- Department of Medical Toxicology, Banner - University Medical Center Phoenix, Phoenix, AZ, USA; Department of Medicine, and Division of Clinical Data Analytics and Decision Support, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
| | - Barry H Rumack
- Department of Emergency Medicine and Pediatrics, University of Colorado School of Medicine, Denver, CO, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
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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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de Oliveira HD, Batista CN, Lima MN, Lima AC, Dos Passos BABR, Freitas RJRX, Silva JD, Xisto DG, Rangel-Ferreira MV, Pelajo M, Rocco PRM, Ribeiro-Gomes FL, de Castro Faria-Neto HC, Maron-Gutierrez T. Acetylsalicylic acid and dihydroartemisinin combined therapy on experimental malaria-associated acute lung injury: analysis of lung function and the inflammatory process. Malar J 2024; 23:285. [PMID: 39300444 DOI: 10.1186/s12936-024-05017-7] [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: 04/09/2024] [Accepted: 06/16/2024] [Indexed: 09/22/2024] Open
Abstract
BACKGROUND Severe malaria can cause respiratory symptoms, which may lead to malaria-acute lung injury (MA-ALI) due to inflammation and damage to the blood-gas barrier. Patients with severe malaria also often present thrombocytopenia, and the use of acetylsalicylic acid (ASA), a commonly used non-steroidal anti-inflammatory drug with immunomodulatory and antiplatelet effects, may pose a risk in regions where malaria is endemic. Thus, this study aimed to investigate the systemic impact of ASA and dihydroartemisinin (DHA) on ALI induced in mice by Plasmodium berghei NK65 (PbNK65). METHODS C57BL/6 mice were randomly divided into control (C) and PbNK65 infected groups and were inoculated with uninfected or 104 infected erythrocytes, respectively. Then, the animals were treated with DHA (3 mg/kg) or vehicle (DMSO) at the 8-day post-infection (dpi) for 7 days and with ASA (100 mg/kg, single dose), and analyses were performed at 9 or 15 dpi. Lung mechanics were performed, and lungs were collected for oedema evaluation and histological analyses. RESULTS PbNK65 infection led to lung oedema, as well as increased lung static elastance (Est, L), resistive (ΔP1, L) and viscoelastic (ΔP2, L) pressures, percentage of mononuclear cells, inflammatory infiltrate, hemorrhage, alveolar oedema, and alveolar thickening septum at 9 dpi. Mice that received DHA or DHA + ASA had an increase in Est, L, and CD36 expression on inflammatory monocytes and higher protein content on bronchoalveolar fluid (BALF). However, only the DHA-treated group presented a percentage of inflammatory monocytes similar to the control group and a decrease in ΔP1, L and ΔP2, L compared to Pb + DMSO. Also, combined treatment with DHA + ASA led to an impairment in diffuse alveolar damage score and lung function at 9 dpi. CONCLUSIONS Therapy with ASA maintained lung morpho-functional impairment triggered by PbNK65 infection, leading to a large influx of inflammatory monocytes to the lung tissue. Based on its deleterious effects in experimental MA-ALI, ASA administration or its treatment maintenance might be carefully reconsidered and further investigated in human malaria cases.
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Affiliation(s)
- Helena D'Anunciação de Oliveira
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Av. Brasil, 4036 - Bloco 2. Manguinhos, Rio de Janeiro, RJ, 21040-361, Brazil
| | - Camila Nunes Batista
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Av. Brasil, 4036 - Bloco 2. Manguinhos, Rio de Janeiro, RJ, 21040-361, Brazil
| | - Maiara Nascimento Lima
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Av. Brasil, 4036 - Bloco 2. Manguinhos, Rio de Janeiro, RJ, 21040-361, Brazil
| | - Ana Carolina Lima
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Av. Brasil, 4036 - Bloco 2. Manguinhos, Rio de Janeiro, RJ, 21040-361, Brazil
| | | | - Rodrigo Jose Rocha Xavier Freitas
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Av. Brasil, 4036 - Bloco 2. Manguinhos, Rio de Janeiro, RJ, 21040-361, Brazil
| | - Johnatas Dutra Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Debora Gonçalves Xisto
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Marcelo Pelajo
- Laboratory of Pathology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil
| | - Patricia Rieken Macedo Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Hugo Caire de Castro Faria-Neto
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Av. Brasil, 4036 - Bloco 2. Manguinhos, Rio de Janeiro, RJ, 21040-361, Brazil
| | - Tatiana Maron-Gutierrez
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Av. Brasil, 4036 - Bloco 2. Manguinhos, Rio de Janeiro, RJ, 21040-361, Brazil.
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Cui Y, Wu J, Zhang D, Li D, Zhang J, Li W, Wang C, Yuan C, Liu Z. Changes in chemical components and hepatoprotective effect of red Panax notoginseng processed by aspartic acid impregnation treatment. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2024; 104:6085-6099. [PMID: 38445528 DOI: 10.1002/jsfa.13440] [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: 12/10/2023] [Revised: 02/28/2024] [Accepted: 03/06/2024] [Indexed: 03/07/2024]
Abstract
BACKGROUND Red Panax notoginseng (RPN) is one of the major processed products of P. notoginseng (PN), with more effective biological activities. However, the traditional processing method of RPN has some disadvantages, such as low conversion rate of ginsenosides and long processing time. RESULTS In this work, we developed a green, safe, and efficient approach for RPN processing by aspartic acid impregnation pretreatment. Our results showed that the optimized temperature, steaming time, and concentration of aspartic acid were 120 °C, 1 h, and 3% respectively. The original ginsenosides in PN treated by aspartic acid (Asp-PN) were completely converted to rare saponins at 120 °C within just 1 h. The concentration of the rare ginsenosides in Asp-PN was two times higher than that in untreated RPN. In addition, we examined the protective effect of RPN and Asp-PN on acetaminophen-induced liver injury in a mouse model. The results showed that Asp-PN has significantly more potent hepatoprotective action than the RPN. The hepatoprotection of Asp-PN in acetaminophen-induced hepatotoxicity may be due to its anti-oxidative stress, anti-apoptotic, and anti-inflammatory activities. CONCLUSION These results indicated that aspartic acid impregnation pretreatment may provide an effective method to shorten the steaming time, improve the conversion rate of ginsenosides, and enhance hepatoprotective activity of RPN. © 2024 Society of Chemical Industry.
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Affiliation(s)
- Ying Cui
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, China
| | - Jianfa Wu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, China
| | - Danli Zhang
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, China
| | - Dan Li
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, China
| | - Jing Zhang
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, China
- Jilin Provincial International Joint Research Center for the Development and Utilization of Authentic Medicinal Materials, Changchun, China
| | - Wei Li
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, China
- Jilin Provincial International Joint Research Center for the Development and Utilization of Authentic Medicinal Materials, Changchun, China
| | - Chongzhi Wang
- Tang Center for Herbal Medicine Research and The Pritzker School of Medicine, University of Chicago, Chicago, IL, USA
| | - Chunsu Yuan
- Tang Center for Herbal Medicine Research and The Pritzker School of Medicine, University of Chicago, Chicago, IL, USA
| | - Zhi Liu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, China
- Jilin Provincial International Joint Research Center for the Development and Utilization of Authentic Medicinal Materials, Changchun, China
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Laddha AP, Wu H, Manautou JE. Deciphering Acetaminophen-Induced Hepatotoxicity: The Crucial Role of Transcription Factors like Nuclear Factor Erythroid 2-Related Factor 2 as Genetic Determinants of Susceptibility to Drug-Induced Liver Injury. Drug Metab Dispos 2024; 52:740-753. [PMID: 38857948 DOI: 10.1124/dmd.124.001282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 05/20/2024] [Accepted: 06/06/2024] [Indexed: 06/12/2024] Open
Abstract
Acetaminophen (APAP) is the most commonly used over-the-counter medication throughout the world. At therapeutic doses, APAP has potent analgesic and antipyretic effects. The efficacy and safety of APAP are influenced by multifactorial processes dependent upon dosing, namely frequency and total dose. APAP poisoning by repeated ingestion of supratherapeutic doses, depletes glutathione stores in the liver and other organs capable of metabolic bioactivation, leading to hepatocellular death due to exhausted antioxidant defenses. Numerous genes, encompassing transcription factors and signaling pathways, have been identified as playing pivotal roles in APAP toxicity, with the liver being the primary organ studied due to its central role in APAP metabolism and injury. Nuclear factor erythroid 2-related factor 2 (NRF2) and its array of downstream responsive genes are crucial in counteracting APAP toxicity. NRF2, along with its negative regulator Kelch-like ECH-associated protein 1, plays a vital role in regulating intracellular redox homeostasis. This regulation is significant in modulating the oxidative stress, inflammation, and hepatocellular death induced by APAP. In this review, we provide an updated overview of the mechanisms through which NRF2 activation and signaling critically influence the threshold for developing APAP toxicity. We also describe how genetically modified rodent models for NRF2 and related genes have been pivotal in underscoring the significance of this antioxidant response pathway. While NRF2 is a primary focus, the article comprehensively explores other genetic factors involved in phase I and phase II metabolism of APAP, inflammation, oxidative stress, and related pathways that contribute to APAP toxicity, thereby providing a holistic understanding of the genetic landscape influencing susceptibility to this condition. SIGNIFICANCE STATEMENT: This review summarizes the genetic elements and signaling pathways underlying APAP-induced liver toxicity, focusing on the crucial protective role of the transcription factor NRF2. This review also delves into the genetic intricacies influencing APAP safety and potential liver harm. It also emphasizes the need for deeper insight into the molecular mechanisms of hepatotoxicity, especially the interplay of NRF2 with other pathways.
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Affiliation(s)
- Ankit P Laddha
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut
| | - Hangyu Wu
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut
| | - José E Manautou
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut
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10
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Jaeschke H, Ramachandran A. Central Mechanisms of Acetaminophen Hepatotoxicity: Mitochondrial Dysfunction by Protein Adducts and Oxidant Stress. Drug Metab Dispos 2024; 52:712-721. [PMID: 37567742 PMCID: PMC11257690 DOI: 10.1124/dmd.123.001279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/02/2023] [Accepted: 08/04/2023] [Indexed: 08/13/2023] Open
Abstract
Acetaminophen (APAP) is an analgesic and antipyretic drug used worldwide, which is safe at therapeutic doses. However, an overdose can induce liver injury and even liver failure. Mechanistic studies in mice beginning with the seminal papers published by B.B. Brodie's group in the 1970s have resulted in important insight into the pathophysiology. Although the metabolic activation of APAP with generation of a reactive metabolite, glutathione depletion, and protein adduct formation are critical initiating events, more recently, mitochondria have come into focus as an important target and decision point of cell death. This review provides a comprehensive overview of the induction of mitochondrial superoxide and peroxynitrite formation and its propagation through a mitogen-activated protein kinase cascade, the mitochondrial permeability transition pore opening caused by iron-catalyzed protein nitration, and the mitochondria-dependent nuclear DNA fragmentation. In addition, the role of adaptive mechanisms that can modulate the pathophysiology, including autophagy, mitophagy, nuclear erythroid 2 p45-related factor 2 activation, and mitochondrial biogenesis, are discussed. Importantly, it is outlined how the mechanisms elucidated in mice translate to human hepatocytes and APAP overdose patients, and how this mechanistic insight explains the mechanism of action of the clinically approved antidote N-acetylcysteine and led to the recent discovery of a novel compound, fomepizole, which is currently under clinical development. SIGNIFICANCE STATEMENT: Acetaminophen (APAP)-induced liver injury is the most frequent cause of acute liver failure in western countries. Extensive mechanistic research over the last several decades has revealed a central role of mitochondria in the pathophysiology of APAP hepatotoxicity. This review article provides a comprehensive discussion of a) mitochondrial protein adducts and oxidative/nitrosative stress, b) mitochondria-regulated nuclear DNA fragmentation, c) adaptive mechanisms to APAP-induced cellular stress, d) translation of cell death mechanisms to overdose patients, and e) mechanism-based antidotes against APAP-induced liver injury.
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Affiliation(s)
- Hartmut Jaeschke
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Anup Ramachandran
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
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Cai S, Su Y, Shi M, Wang D, Chen DDY, Yan B. Simultaneous quantification of six proteins related to liver injury using nano liquid chromatography-tandem mass spectrometry. RAPID COMMUNICATIONS IN MASS SPECTROMETRY : RCM 2024; 38:e9754. [PMID: 38605420 DOI: 10.1002/rcm.9754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 03/19/2024] [Accepted: 03/21/2024] [Indexed: 04/13/2024]
Abstract
RATIONALE In clinical diagnosis of liver injury, which is an important health concern, serum aminotransferase assays have been the go-to method used worldwide. However, the measurement of serum enzyme activity has limitations, including inadequate disease specificity and enzyme specificity. METHODS With the high selectivity and specificity provided by nano liquid chromatography-tandem mass spectrometry (LC/MS/MS), this work describes a method for the simultaneous determination of six proteins in liver that can be potentially used as biomarkers for liver injury: glutamic-pyruvic transaminase 1 (GPT1), glutamic oxaloacetic transaminase 1 (GOT1), methionine adenosyl transferase 1A (MAT1A), glutathione peroxidase 1 (GPX1), cytokeratin 18 (KRT18) and apolipoprotein E (APOE). RESULTS In validation, the method was shown to have good selectivity and sensitivity (limits of detection at pg/mL level). The analytical method revealed that, compared with normal mice, in carbon tetrachloride-induced acute liver injury mice, liver MAT1A and GPX1 were significantly lower (p < 0.01 and p < 0.05, respectively), KRT18 was significantly higher (p < 0.05) and APOE and GPT1 were marginally significantly lower (p between 0.05 and 0.1). This is the first work reporting the absolute contents of GPT1, GOT1, MAT1A, GPX1 and KRT18 proteins based on LC/MS. CONCLUSIONS The proposed method provides a basis for establishing more specific diagnostic indicators of liver injury.
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Affiliation(s)
- Siyu Cai
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, China
| | - Yuan Su
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, China
| | - Mengtian Shi
- College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, China
| | - Dandan Wang
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, China
| | - David Da Yong Chen
- Department of Chemistry, University of British Columbia, Vancouver, BC, Canada
| | - Binjun Yan
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, China
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12
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Hu T, Liu CH, Zheng Y, Ji J, Zheng Y, He SK, Wu D, Jiang W, Zeng Q, Zhang N, Tang H. miRNAs in patients with alcoholic liver disease: a systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol 2024; 18:283-292. [PMID: 38937981 DOI: 10.1080/17474124.2024.2374470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Accepted: 06/26/2024] [Indexed: 06/29/2024]
Abstract
INTRODUCTION Alcoholic liver disease (ALD) encompasses a spectrum of liver conditions, including liver steatosis, alcoholic hepatitis (AH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). microRNAs (miRNAs) have garnered significant interest as potential biomarkers for ALD. METHODS We searched PubMed, Embase, Web of Science and Cochrane Central Register of Controlled Trials (CENTRAL) systemically from inception to June 2024. All extracted data was stratified according to the stages of ALD. The vote-counting strategy performed a meta-analysis on miRNA expression profiles. RESULTS We included 40 studies. In serum of individuals with alcohol-use vs. no alcohol-use, miRNA-122 and miRNA-155 were upregulated, and miRNA-146a was downregulated. In patients with ALD vs. healthy controls, miRNA-122 and miRNA-155 were also upregulated, and miRNA-146a was downregulated. However, in patients with AH vs. healthy individuals, only the serum miRNA-122 level was upregulated. Due to insufficient data on diagnostic accuracy, we failed to conclude the ability of miRNAs to distinguish between different stages of ALD-related liver fibrosis. The results for ALD-related HCC were also insufficient and controversial. CONCLUSIONS Circulating miRNA-122 was the most promising biomarker to manage individuals with ALD. More studies were needed for the diagnostic accuracy of miRNAs in ALD. REGISTRATION This protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (www.crd.york.ac.uk/prospero/) with registration number CRD42023391931.
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Affiliation(s)
- Tengyue Hu
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institution of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Chang Hai Liu
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institution of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Yurong Zheng
- West China School of Public Health, Sichuan University, Chengdu, China
| | - Jialin Ji
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Yantong Zheng
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Si-Ke He
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Dongbo Wu
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institution of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Wei Jiang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institution of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Qingmin Zeng
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institution of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Nannan Zhang
- National Center for Birth Defect Monitoring, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institution of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
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Thakur S, Kumar V, Das R, Sharma V, Mehta DK. Biomarkers of Hepatic Toxicity: An Overview. CURRENT THERAPEUTIC RESEARCH 2024; 100:100737. [PMID: 38860148 PMCID: PMC11163176 DOI: 10.1016/j.curtheres.2024.100737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 01/31/2024] [Indexed: 06/12/2024]
Abstract
Background Hepatotoxicity is the foremost issue for clinicians and the primary reason for pharmaceutical product recalls. A biomarker is a measurable and quantifiable attribute used to evaluate the efficacy of a treatment or to diagnose a disease. There are various biomarkers which are used for the detection of liver disease and the intent of liver damage. Objective This review aims to investigate the current state of hepatotoxicity biomarkers and their utility in clinical settings. Using hepatic biomarkers, the presence of liver injury, its severity, prognosis, causative agent, and type of hepatotoxicity can all be determined. Methods Relevant published articles up to 2022 were systematically retrieved from MEDLINE/PubMed, SCOPUS, EMBASE, and WOS databases using keywords such as drug toxicity, hepatotoxicity biomarkers, biochemical parameters, and nonalcoholic fatty liver disease. Results In clinical trials and everyday practice, biomarkers of drug-induced liver injury are essential for spotting the most severe cases of hepatotoxicity. Hence, developing novel biomarker approaches to enhance hepatotoxicity diagnosis will increase specificity and/or identify the person at risk. Importantly, early clinical studies on patients with liver illness have proved that some biomarkers such as aminotransferase, bilirubin, albumin, and bile acids are even therapeutically beneficial. Conclusions By assessing the unique signs of liver injury, health care professionals can rapidly and accurately detect liver damage and evaluate its severity. These measures contribute to ensuring prompt and effective medical intervention, hence reducing the risk of long-term liver damage and other major health concerns.
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Affiliation(s)
- Simran Thakur
- Department of Pharmacy Practice, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
| | - Vishal Kumar
- Department of Pharmacy Practice, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
| | - Rina Das
- Department of Pharmaceutical Chemistry, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
| | - Vishal Sharma
- Department of Pharmaceutical Chemistry, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
| | - Dinesh Kumar Mehta
- Department of Pharmaceutical Chemistry, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
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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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15
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Maina A, Foster GR. Hepatitis after gene therapy, what are the possible causes? J Viral Hepat 2024; 31 Suppl 1:14-20. [PMID: 38606951 DOI: 10.1111/jvh.13919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 12/06/2023] [Accepted: 01/03/2024] [Indexed: 04/13/2024]
Abstract
Hepatitis is a common adverse event following gene therapy for haemophilia, often associated with a loss of transgene expression. Investigating the potential causes and implications of this is crucial for the overall success of treatment. Gene therapy trials using adeno-associated virus (AAV) vectors have demonstrated promising results marked by increases in factor FVIII and FIX levels and reductions in episodes of bleeding. However, hepatocellular injury characterised by elevations in alanine aminotransferases (ALT) has been noted. This liver injury is typically transient and asymptomatic, posing challenges in determining its clinical significance. Proposed causes encompass immune-mediated responses, notably T cell cytotoxicity in response to the AAV vector, direct liver injury from the viral capsid or transcribed protein via the unfolded protein response and pre-existing liver conditions. Liver biopsy data conducted years post-gene therapy infusion has shown sinusoidal infiltration without significant inflammation. The overall safety profile of gene therapy remains favourable with no evidence drug-induced liver injury (DILI) based on Hy's Law criteria. Essential pre-therapy monitoring and identifying patients at high risk of liver injury should involve liver function tests and non-invasive fibroscans, while novel blood-based biomarkers are under exploration. Further research is required to comprehend the mechanisms underlying transaminitis, loss of transgene expression and long-term effects on the liver, providing insights for optimising gene therapy for haemophilia.
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Eluu SC, Obayemi JD, Salifu AA, Yiporo D, Oko AO, Aina T, Oparah JC, Ezeala CC, Etinosa PO, Ugwu CM, Esimone CO, Soboyejo WO. In-vivo studies of targeted and localized cancer drug release from microporous poly-di-methyl-siloxane (PDMS) devices for the treatment of triple negative breast cancer. Sci Rep 2024; 14:31. [PMID: 38167999 PMCID: PMC10761815 DOI: 10.1038/s41598-023-50656-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 12/22/2023] [Indexed: 01/05/2024] Open
Abstract
Triple-negative breast cancer (TNBC) treatment is challenging and frequently characterized by an aggressive phenotype and low prognosis in comparison to other subtypes. This paper presents fabricated implantable drug-loaded microporous poly-di-methyl-siloxane (PDMS) devices for the delivery of targeted therapeutic agents [Luteinizing Hormone-Releasing Hormone conjugated paclitaxel (PTX-LHRH) and Luteinizing Hormone-Releasing Hormone conjugated prodigiosin (PG-LHRH)] for the treatment and possible prevention of triple-negative cancer recurrence. In vitro assessment using the Alamar blue assay demonstrated a significant reduction (p < 0.05) in percentage of cell growth in a time-dependent manner in the groups treated with PG, PG-LHRH, PTX, and PTX-LHRH. Subcutaneous triple-negative xenograft breast tumors were then induced in athymic female nude mice that were four weeks old. Two weeks later, the tumors were surgically but partially removed, and the device implanted. Mice were observed for tumor regrowth and organ toxicity. The animal study revealed that there was no tumor regrowth, six weeks post-treatment, when the LHRH targeted drugs (LHRH-PTX and LHRH-PGS) were used for the treatment. The possible cytotoxic effects of the released drugs on the liver, kidney, and lung are assessed using quantitative biochemical assay from blood samples of the treatment groups. Ex vivo histopathological results from organ tissues showed that the targeted cancer drugs released from the implantable drug-loaded device did not induce any adverse effect on the liver, kidneys, or lungs, based on the results of qualitative toxicity studies. The implications of the results are discussed for the targeted and localized treatment of triple negative breast cancer.
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Affiliation(s)
- S C Eluu
- Department of Pharmaceutical Microbiology and Biotechnology, Nnamdi Azikiwe University, Ifite Awka, 420110, Anambra State, Nigeria
| | - J D Obayemi
- Department of Mechanical Engineering, Higgins Lab, Worcester Polytechnic Institute (WPI), 100 Institute Road, Worcester, MA, 01609, USA
- Department of Biomedical Engineering, Gateway Park Life Sciences and Bioengineering Centre, Worcester Polytechnic Institute, 60 Prescott Street, Worcester, MA, 01609, USA
| | - A A Salifu
- Department of Engineering, Morrissey College of Arts and Science, Boston College, Boston, USA
| | - D Yiporo
- Department of Mechanical Engineering, Ashesi University, Berekuso, Ghana
| | - A O Oko
- Department of Biology and Biotechnology, David Umahi Federal, University of Health Sciences, Uburu, Nigeria
| | - T Aina
- Department of Material Science, African University of Science and Technology, Km 10 Airport Road, Abuja, Nigeria
| | - J C Oparah
- Department of Material Science, African University of Science and Technology, Km 10 Airport Road, Abuja, Nigeria
| | - C C Ezeala
- Department of Material Science, African University of Science and Technology, Km 10 Airport Road, Abuja, Nigeria
| | - P O Etinosa
- Department of Mechanical Engineering, Higgins Lab, Worcester Polytechnic Institute (WPI), 100 Institute Road, Worcester, MA, 01609, USA
| | - C M Ugwu
- Department of Pharmaceutical Microbiology and Biotechnology, Nnamdi Azikiwe University, Ifite Awka, 420110, Anambra State, Nigeria
| | - C O Esimone
- Department of Pharmaceutical Microbiology and Biotechnology, Nnamdi Azikiwe University, Ifite Awka, 420110, Anambra State, Nigeria
| | - W O Soboyejo
- Department of Mechanical Engineering, Higgins Lab, Worcester Polytechnic Institute (WPI), 100 Institute Road, Worcester, MA, 01609, USA.
- Department of Biomedical Engineering, Gateway Park Life Sciences and Bioengineering Centre, Worcester Polytechnic Institute, 60 Prescott Street, Worcester, MA, 01609, USA.
- Department of Engineering, SUNY Polytechnic Institute, 100 Seymour Rd, Utica, NY, 13502, USA.
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17
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Prescott LF. Paracetamol (acetaminophen) poisoning: The early years. Br J Clin Pharmacol 2024; 90:127-134. [PMID: 37683599 DOI: 10.1111/bcp.15903] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/29/2023] [Accepted: 09/03/2023] [Indexed: 09/10/2023] Open
Abstract
Paracetamol (acetaminophen) was marketed in the 1950s as a nonprescription analgesic/antipyretic without any preclinical toxicity studies. It became used increasingly for self-poisoning, particularly in the UK and was belatedly found to cause acute liver damage, which could be fatal. Management of poisoned patients was difficult as maximum abnormalities of liver function were delayed for 3 days or more after an overdose. There was no treatment and the mechanism of hepatotoxicity was not known. The paracetamol half-life was prolonged with liver damage occurring when it exceeded 4 h and the Rumack-Matthew nomogram was an important advance that allowed stratification of patients into separate zones of risk. It is used to guide prognosis and treatment and its predictive value could be increased by combining it with the paracetamol half-life. The problems of a sheep farmer in Australia in the early 1970s led to the discovery of the mechanism of paracetamol hepatotoxicity, and the first effective treatment of overdosage with intravenous (IV) cysteamine. This had unpleasant side effects and administration was difficult. N-acetylcysteine soon became the treatment of choice for paracetamol overdose and given early it was very effective when administered either IV or orally. N-acetylcysteine could cause anaphylactoid reactions, particularly early during IV administration when the concentrations were highest. Simpler and shorter regimes with slower initial rates of infusion have now been introduced with a reduced incidence of these adverse effects. In addition, there has been a move to use larger doses of N-acetylcysteine given over longer periods for patients who are more severely poisoned and those with risk factors. There has been much interest recently in the search for novel biomarkers such as microRNAs, procalcitonin and cyclophilin that promise to have greater specificity and sensitivity than transaminases. Paracetamol-protein adducts predict hepatotoxicity and are specific biomarkers of toxic paracetamol metabolite exposure. Another approach would be measurement of the plasma levels of cysteine and inorganic sulfate. It is 50 years since the first effective treatment for paracetamol poisoning and, apart from liver transplantation, there is still no effective treatment for patients who present late.
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Affiliation(s)
- Laurie F Prescott
- Emeritus Professor of Clinical Pharmacology, University of Edinburgh, Edinburgh, UK
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18
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Kandori H, Aoki M, Miyamoto Y, Nakamura S, Kobayashi R, Matsumoto M, Yokoyama K. Lobular distribution of enhanced expression levels of heat shock proteins using in-situ hybridization in the mouse liver treated with a single administration of CCl4. J Toxicol Pathol 2024; 37:29-37. [PMID: 38283376 PMCID: PMC10811382 DOI: 10.1293/tox.2023-0053] [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: 04/12/2023] [Accepted: 10/13/2023] [Indexed: 01/30/2024] Open
Abstract
This study was conducted to visualize the lobular distribution of enhanced mRNA expression levels of heat shock proteins (HSPs) in liver samples from carbon tetra chloride (CCl4)-treated mice using in-situ hybridization (ISH). Male BALB/c mice given a single oral administration of CCl4 were euthanized 6 hours or 1 day after the administration (6 h or 1 day). Paraffin-embedded liver samples were obtained, ISH for HSPs was conducted, as well as hematoxylin-eosin staining and immunohistochemistry (IHC). At 6 h, centrilobular hepatocellular vacuolization was observed, and increased signals for Hspa1a, Hspa1b, and Grp78, which are HSPs, were noted in the centrilobular area using ISH. At 1 day, zonal hepatocellular necrosis was observed in the centrilobular area, but mRNA signal increases for HSPs were no longer observed there. Some discrepancies between ISH and IHC for HSPs were observed, and they might be partly caused by post-transcriptional gene regulation, including the ribosome quality control mechanisms. It is known that CCl4 damages centrilobular hepatocytes through metabolization by cytochrome P450, mainly located in the centrilobular region, and HSPs are induced under cellular stress. Therefore, our ISH results visualized increased mRNA expression levels of HSPs in the centrilobular hepatocytes of mice 6 hours after a single administration of CCl4 as a response to cellular stress, and it disappeared 1 day after the treatment when remarkable necrosis was observed there.
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Affiliation(s)
- Hitoshi Kandori
- Integrated Pathology, Frontier Technology, Integrated &
Translational Science, Axcelead Drug Discovery Partners, Inc., 26-1 Muraoka-Higashi
2-chome, Fujisawa-shi, Kanagawa 251-0012, Japan
| | - Masami Aoki
- Integrated Pathology, Frontier Technology, Integrated &
Translational Science, Axcelead Drug Discovery Partners, Inc., 26-1 Muraoka-Higashi
2-chome, Fujisawa-shi, Kanagawa 251-0012, Japan
| | - Yumiko Miyamoto
- Integrated Pathology, Frontier Technology, Integrated &
Translational Science, Axcelead Drug Discovery Partners, Inc., 26-1 Muraoka-Higashi
2-chome, Fujisawa-shi, Kanagawa 251-0012, Japan
| | - Sayuri Nakamura
- Integrated Pathology, Frontier Technology, Integrated &
Translational Science, Axcelead Drug Discovery Partners, Inc., 26-1 Muraoka-Higashi
2-chome, Fujisawa-shi, Kanagawa 251-0012, Japan
| | - Ryosuke Kobayashi
- Integrated Pathology, Frontier Technology, Integrated &
Translational Science, Axcelead Drug Discovery Partners, Inc., 26-1 Muraoka-Higashi
2-chome, Fujisawa-shi, Kanagawa 251-0012, Japan
| | - Mitsuharu Matsumoto
- Integrated Biology, Kidney/Liver Disease, Integrated &
Translational Science, Axcelead Drug Discovery Partners, Inc., 26-1 Muraoka-Higashi
2-chome, Fujisawa-shi, Kanagawa 251-0012, Japan
| | - Kotaro Yokoyama
- Integrated Pathology, Frontier Technology, Integrated &
Translational Science, Axcelead Drug Discovery Partners, Inc., 26-1 Muraoka-Higashi
2-chome, Fujisawa-shi, Kanagawa 251-0012, Japan
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Orzeł-Gajowik K, Milewski K, Zielińska M. miRNA-ome plasma analysis unveils changes in blood-brain barrier integrity associated with acute liver failure in rats. Fluids Barriers CNS 2023; 20:92. [PMID: 38066639 PMCID: PMC10709860 DOI: 10.1186/s12987-023-00484-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 10/30/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND Hepatic encephalopathy (HE) symptoms associated with liver insufficiency are linked to the neurotoxic effects of ammonia and other toxic metabolites reaching the brain via the blood-brain barrier (BBB), further aggravated by the inflammatory response. Cumulative evidence documents that the non-coding single-stranded RNAs, micro RNAs (miRs) control the BBB functioning. However, miRs' involvement in BBB breakdown in HE is still underexplored. Here, we hypothesized that in rats with acute liver failure (ALF) or rats subjected to hyperammonemia, altered circulating miRs affect BBB composing proteins. METHODS Transmission electron microscopy was employed to delineate structural alterations of the BBB in rats with ALF (thioacetamide (TAA) intraperitoneal (ip.) administration) or hyperammonemia (ammonium acetate (OA) ip. administration). The BBB permeability was determined with Evans blue dye and sodium fluorescein assay. Plasma MiRs were profiled by Next Generation Sequencing (NGS), followed by in silico analysis. Selected miRs, verified by qRT-PCR, were examined in cultured rat brain endothelial cells. Targeted protein alterations were elucidated with immunofluorescence, western blotting, and, after selected miR mimics transfection, through an in vitro resistance measurement. RESULTS Changes in BBB structure and increased permeability were observed in the prefrontal cortex of TAA rats but not in the brains of OA rats. The NGS results revealed divergently changed miRNA-ome in the plasma of both rat models. The in silico analysis led to the selection of miR-122-5p and miR-183-5p with their target genes occludin and integrin β1, respectively, as potential contributors to BBB alterations. Both proteins were reduced in isolated brain vessels and cortical homogenates in TAA rats. We documented in cultured primary brain endothelial cells that ammonia alone and, in combination with TNFα increases the relative expression of NGS-selected miRs with a less pronounced effect of TNFα when added alone. The in vitro study also confirmed miR-122-5p-dependent decrease in occludin and miR-183-5p-related reduction in integrin β1 expression. CONCLUSION This work identified, to our knowledge for the first time, potential functional links between alterations in miRs residing in brain endothelium and BBB dysfunction in ALF.
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Affiliation(s)
- Karolina Orzeł-Gajowik
- Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego St. 5, 02-106, Warsaw, Poland
| | - Krzysztof Milewski
- Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego St. 5, 02-106, Warsaw, Poland
- Laboratory of Cellular Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteura St. 3, 02-093, Warsaw, Poland
| | - Magdalena Zielińska
- Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego St. 5, 02-106, Warsaw, Poland.
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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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Li X, Ni J, Chen L. Advances in the study of acetaminophen-induced liver injury. Front Pharmacol 2023; 14:1239395. [PMID: 37601069 PMCID: PMC10436315 DOI: 10.3389/fphar.2023.1239395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 07/28/2023] [Indexed: 08/22/2023] Open
Abstract
Acetaminophen (APAP) overdose is a significant cause of drug-induced liver injury and acute liver failure. The diagnosis, screening, and management of APAP-induced liver injury (AILI) is challenging because of the complex mechanisms involved. Starting from the current studies on the mechanisms of AILI, this review focuses on novel findings in the field of diagnosis, screening, and management of AILI. It highlights the current issues that need to be addressed. This review is supposed to summarize the recent research progress and make recommendations for future research.
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Affiliation(s)
- Xinghui Li
- West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Jiaqi Ni
- West China School of Pharmacy, Sichuan University, Chengdu, China
- Department of Pharmacy, Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
| | - Li Chen
- Department of Pharmacy, Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
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22
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Bakshi S, Kaur M, Verma A, Sharma S. Molecular and cellular remodeling of HepG2 cells upon treatment with antitubercular drugs. J Biochem Mol Toxicol 2023; 37:e23386. [PMID: 37254945 DOI: 10.1002/jbt.23386] [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: 06/13/2022] [Revised: 02/20/2023] [Accepted: 05/17/2023] [Indexed: 06/01/2023]
Abstract
Drug-induced liver injury (DILI) is an adverse outcome of the currently used tuberculosis treatment regimen, which results in patient noncompliance, poor treatment outcomes, and the emergence of drug-resistant tuberculosis. DILI is primarily caused by the toxicity of the drugs and their metabolites, which affect liver cells, biliary epithelial cells, and liver vasculature. However, the precise mechanism behind the cellular damage attributable to first-line antitubercular drugs (ATDs), as well as the effect of toxicity on the cell survival strategies, is yet to be elucidated. In the current study, HepG2 cells upon treatment with a high concentration of ATDs showed increased perforation within the cell, cuboidal shape, and membrane blebbing as compared with control/untreated cells. It was observed that ATD-induced toxicity in HepG2 cells leads to altered mitochondrial membrane permeability, which was depicted by the decreased fluorescence intensity of the MitoRed tracker dye at higher drug concentrations. In addition, high doses of ATDs caused cell damage through an increase in reactive oxygen species production in HepG2 cells and a simultaneous reduction in glutathione levels. Further, high dose of isoniazid (50-200 mM), pyrazinamide (50-200 mM), and rifampicin (20-100 µM) causes cell apoptosis and affects cell survival during toxic conditions by decreasing the expression of potent autophagy markers Atg5, Atg7, and LC3B. Thus, ATD-mediated toxicity contributes to the reduced ability of hepatocytes to tolerate cellular damage caused by altered mitochondrial membrane permeability, increased apoptosis, and decreased autophagy. These findings further emphasize the need to develop adjuvant therapies that can mitigate ATD-induced toxicity for the effective treatment of tuberculosis.
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Affiliation(s)
- Shikha Bakshi
- Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Maninder Kaur
- Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Arpana Verma
- Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Sadhna Sharma
- Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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Zeng G, Eslick GD, Weltman M. Systematic review and meta-analysis: Comparing hepatocellular and cholestatic patterns of drug-induced liver injury. ILIVER 2023; 2:122-129. [DOI: 10.1016/j.iliver.2023.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
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24
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Sun M, Chen P, Xiao K, Zhu X, Zhao Z, Guo C, He X, Shi T, Zhong Q, Jia Y, Tao Y, Li M, Leong KW, Shao D. Circulating Cell-Free DNAs as a Biomarker and Therapeutic Target for Acetaminophen-Induced Liver Injury. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2206789. [PMID: 37035952 PMCID: PMC10238175 DOI: 10.1002/advs.202206789] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 01/08/2023] [Indexed: 06/04/2023]
Abstract
Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury and acute liver failure, while the detection, prognosis prediction, and therapy for APAP-induced liver injury (AILI) remain improved. Here, it is determined that the temporal pattern of circulating cell-free DNA (cfDNA) is strongly associated with damage and inflammation parameters in AILI. CfDNA is comparable to alanine aminotransferase (ALT) in predicting mortality and outperformed ALT when combined with ALT in AILI. The depletion of cfDNA or neutrophils alleviates liver damage, while the addition of cfDNA or adoptive transfer of neutrophils exacerbates the damage. The combination of DNase I and N-acetylcysteine attenuates AILI significantly. This study establishes that cfDNA is a mechanistic biomarker to predict mortality in AILI mice. The combination of scavenging cfDNA and reducing oxidative damage provides a promising treatment for AILI.
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Affiliation(s)
- Madi Sun
- School of Biomedical Sciences and EngineeringSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
- National Engineering Research Center for Tissue Restoration and ReconstructionSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
| | - Peiyu Chen
- School of Biomedical Sciences and EngineeringSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
- National Engineering Research Center for Tissue Restoration and ReconstructionSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
| | - Kai Xiao
- National Engineering Research Center for Tissue Restoration and ReconstructionSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
- School of MedicineSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510006China
| | - Xiang Zhu
- Laboratory of Biomaterials and Translational MedicineThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510006China
| | - Zhibin Zhao
- School of MedicineSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510006China
| | - Chenyang Guo
- School of Biomedical Sciences and EngineeringSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
- National Engineering Research Center for Tissue Restoration and ReconstructionSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
| | - Xuan He
- School of Biomedical Sciences and EngineeringSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
- National Engineering Research Center for Tissue Restoration and ReconstructionSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
| | - Tongfei Shi
- School of Biomedical Sciences and EngineeringSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
- National Engineering Research Center for Tissue Restoration and ReconstructionSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
| | - Qingguo Zhong
- Laboratory of Biomaterials and Translational MedicineThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510006China
| | - Yong Jia
- School of NursingJilin UniversityChangchunJilin130021China
| | - Yu Tao
- Laboratory of Biomaterials and Translational MedicineThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510006China
| | - Mingqiang Li
- Laboratory of Biomaterials and Translational MedicineThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhouGuangdong510006China
| | - Kam W. Leong
- Department of Systems BiologyColumbia UniversityNew YorkNY10032USA
| | - Dan Shao
- School of Biomedical Sciences and EngineeringSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
- National Engineering Research Center for Tissue Restoration and ReconstructionSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510630China
- Guangdong Provincial Key Laboratory of Biomedical EngineeringKey Laboratory of Biomedical Materials and Engineering of the Ministry of EducationSouth China University of TechnologyGuangzhouGuangdong510006China
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25
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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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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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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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miR-122 dysregulation is associated with type 2 diabetes mellitus-induced dyslipidemia and hyperglycemia independently of its rs17669 variant. Mol Biol Rep 2023; 50:4217-4224. [PMID: 36899278 DOI: 10.1007/s11033-023-08344-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 02/15/2023] [Indexed: 03/12/2023]
Abstract
BACKGROUND miR-122 is a liver specific micro-RNA that participates in the regulation of carbohydrate and lipid metabolism. The rs17669 variant of miR-122 is positioned at the flanking region of miR-122 and may affect its stability and maturation. Therefore, this study was aimed to investigate the association of the rs17669 polymorphism with the miR-122 circulating level, risk of type 2 diabetes mellitus (T2DM) development, and biochemical parameters in T2DM patients and matched healthy controls. METHODS AND RESULTS This study involved 295 subjects (controls: n = 145 and T2DM: n = 150). The rs17669 variant genotyping was done by ARMS-PCR. Serum biochemical parameters including lipid profile, small-dense low density lipoprotein (sdLDL) and glucose were measured by colorimetric kits. Insulin and Glycated hemoglobin (HbA1c) were assayed using ELISA and capillary electrophoresis methods, respectively. miR-122 expression was measured by real-time PCR. There was no significant difference between study groups in terms of allele and genotype distribution (P > 0.05). The rs17669 variant did not have any significant association with miR-122 gene expression and biochemical parameters (P > 0.05). miR-122 expression level in T2DM patients was significantly higher than that in control subjects (5.7 ± 2.4 vs. 1.4 ± 0.78) (P < 0.001). Furthermore, miR-122 fold change had a positive and significant correlation with low-density lipoprotein cholesterol (LDL-C), sdLDL, fasting blood sugar (FBS), and insulin resistance (P < 0.05). CONCLUSION It can be concluded that the rs17669 variant of miR-122 is not associated with the miR-122 expression and T2DM-associated serum parameters. Furthermore, it can be suggested that miR-122 dysregulation is involved in T2DM development through inducing dyslipidemia, hyperglycemia, and resistance to insulin.
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Fontana RJ, Liou I, Reuben A, Suzuki A, Fiel MI, Lee W, Navarro V. AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury. Hepatology 2023; 77:1036-1065. [PMID: 35899384 PMCID: PMC9936988 DOI: 10.1002/hep.32689] [Citation(s) in RCA: 76] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 07/07/2022] [Indexed: 12/14/2022]
Affiliation(s)
- Robert J. Fontana
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Iris Liou
- University of Washington, Seattle, Washington, USA
| | - Adrian Reuben
- Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Ayako Suzuki
- Division of Gastroenterology, Duke University, Durham, North Carolina, USA
| | - M. Isabel Fiel
- Department of Pathology, Mount Sinai School of Medicine, New York City, New York, USA
| | - William Lee
- Division of Gastroenterology, University of Texas Southwestern, Dallas, Texas, USA
| | - Victor Navarro
- Department of Medicine, Einstein Healthcare Network, Philadelphia, Pennsylvania, USA
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Chidiac AS, Buckley NA, Noghrehchi F, Cairns R. Paracetamol (acetaminophen) overdose and hepatotoxicity: mechanism, treatment, prevention measures, and estimates of burden of disease. Expert Opin Drug Metab Toxicol 2023; 19:297-317. [PMID: 37436926 DOI: 10.1080/17425255.2023.2223959] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 06/05/2023] [Indexed: 07/14/2023]
Abstract
INTRODUCTION Paracetamol is one of the most used medicines worldwide and is the most common important poisoning in high-income countries. In overdose, paracetamol causes dose-dependent hepatotoxicity. Acetylcysteine is an effective antidote, however despite its use hepatotoxicity and many deaths still occur. AREAS COVERED This review summarizes paracetamol overdose and toxicity (including mechanisms, risk factors, risk assessment, and treatment). In addition, we summarize the epidemiology of paracetamol overdose worldwide. A literature search on PubMed for poisoning epidemiology and mortality from 1 January 2017 to 26 October 2022 was performed to estimate rates of paracetamol overdose, liver injury, and deaths worldwide. EXPERT OPINION Paracetamol is widely available and yet is substantially more toxic than other analgesics available without prescription. Where data were available, we estimate that paracetamol is involved in 6% of poisonings, 56% of severe acute liver injury and acute liver failure, and 7% of drug-induced liver injury. These estimates are limited by lack of available data from many countries, particularly in Asia, South America, and Africa. Harm reduction from paracetamol is possible through better identification of high-risk overdoses, and better treatment regimens. Large overdoses and those involving modified-release paracetamol are high-risk and can be targeted through legislative change.
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Affiliation(s)
- Annabelle S Chidiac
- Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Sydney, Australia
- New South Wales Poisons Information Centre, The Children's Hospital at Westmead, Sydney, Australia
| | - Nicholas A Buckley
- New South Wales Poisons Information Centre, The Children's Hospital at Westmead, Sydney, Australia
- Faculty of Medicine and Health, School of Medical Sciences, Discipline of Biomedical Informatics and Digital Health, The University of Sydney, Sydney, Australia
| | - Firouzeh Noghrehchi
- Faculty of Medicine and Health, School of Medical Sciences, Discipline of Biomedical Informatics and Digital Health, The University of Sydney, Sydney, Australia
| | - Rose Cairns
- Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Sydney, Australia
- New South Wales Poisons Information Centre, The Children's Hospital at Westmead, Sydney, Australia
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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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Lin J, Li M, Mak W, Shi Y, Zhu X, Tang Z, He Q, Xiang X. Applications of In Silico Models to Predict Drug-Induced Liver Injury. TOXICS 2022; 10:788. [PMID: 36548621 PMCID: PMC9785299 DOI: 10.3390/toxics10120788] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/09/2022] [Accepted: 12/13/2022] [Indexed: 06/17/2023]
Abstract
Drug-induced liver injury (DILI) is a major cause of the withdrawal of pre-marketed drugs, typically attributed to oxidative stress, mitochondrial damage, disrupted bile acid homeostasis, and innate immune-related inflammation. DILI can be divided into intrinsic and idiosyncratic DILI with cholestatic liver injury as an important manifestation. The diagnosis of DILI remains a challenge today and relies on clinical judgment and knowledge of the insulting agent. Early prediction of hepatotoxicity is an important but still unfulfilled component of drug development. In response, in silico modeling has shown good potential to fill the missing puzzle. Computer algorithms, with machine learning and artificial intelligence as a representative, can be established to initiate a reaction on the given condition to predict DILI. DILIsym is a mechanistic approach that integrates physiologically based pharmacokinetic modeling with the mechanisms of hepatoxicity and has gained increasing popularity for DILI prediction. This article reviews existing in silico approaches utilized to predict DILI risks in clinical medication and provides an overview of the underlying principles and related practical applications.
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Affiliation(s)
| | | | | | | | | | | | - Qingfeng He
- Correspondence: (Q.H.); (X.X.); Tel.: +86-21-51980024 (X.X.)
| | - Xiaoqiang Xiang
- Correspondence: (Q.H.); (X.X.); Tel.: +86-21-51980024 (X.X.)
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Umbaugh DS, Soder RP, Nguyen NT, Adelusi O, Robarts DR, Woolbright B, Duan L, Abhyankar S, Dawn B, Apte U, Jaeschke H, Ramachandran A. Human Wharton's Jelly-derived mesenchymal stem cells prevent acetaminophen-induced liver injury in a mouse model unlike human dermal fibroblasts. Arch Toxicol 2022; 96:3315-3329. [PMID: 36057886 PMCID: PMC9773902 DOI: 10.1007/s00204-022-03372-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 08/25/2022] [Indexed: 12/24/2022]
Abstract
The persistence of hepatotoxicity induced by N-acetyl-para-aminophenol (Acetaminophen or Paracetamol, abbreviated as APAP) as the most common cause of acute liver failure in the United States, despite the availability of N-acetylcysteine, illustrates the clinical relevance of additional therapeutic approaches. While human mesenchymal stem cells (MSCs) have shown protection in mouse models of liver injury, the MSCs used are generally not cleared for human use and it is unclear whether these effects are due to xenotransplantation. Here we evaluated GMP manufactured clinical grade human Wharton's Jelly mesenchymal stem cells (WJMSCs), which are currently being investigated in human clinical trials, in a mouse model of APAP hepatotoxicity in comparison to human dermal fibroblasts (HDFs) to address these issues. C57BL6J mice were treated with a moderate APAP overdose (300 mg/kg) and WJMSCs were administered 90 min later. Liver injury was evaluated at 6 and 24 h after APAP. WJMSCs treatment reduced APAP-induced liver injury at both time points unlike HDFs, which showed no protection. APAP-induced JNK activation as well as AIF and Smac release from mitochondria were prevented by WJMSCs treatment without influencing APAP bioactivation. Mechanistically, WJMSCs treatment upregulated expression of Gclc and Gclm to enhance recovery of liver GSH levels to attenuate mitochondrial dysfunction and accelerated recovery of pericentral hepatocytes to re-establish liver zonation and promote liver homeostasis. Notably, preventing GSH resynthesis with buthionine sulfoximine prevented the protective effects of WJMSCs. These data indicate that these GMP-manufactured WJMCs could be a clinically relevant therapeutic approach in the management of APAP hepatotoxicity in humans.
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Affiliation(s)
- David S Umbaugh
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA
| | - Rupal P Soder
- Midwest Stem Cell Therapy Center, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1075, Kansas City, KS, 66160, USA
| | - Nga T Nguyen
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA
| | - Olamide Adelusi
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA
| | - Dakota R Robarts
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA
| | - Ben Woolbright
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA
| | - Luqi Duan
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA
| | - Sunil Abhyankar
- Midwest Stem Cell Therapy Center, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1075, Kansas City, KS, 66160, USA
- Blood and Marrow Transplant Program, Division of Hematologic Malignancies and Cellular Therapeutics Center, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA
| | - Buddhadeb Dawn
- Midwest Stem Cell Therapy Center, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1075, Kansas City, KS, 66160, USA
- Department of Internal Medicine, Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas, USA
| | - Udayan Apte
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA
| | - Anup Ramachandran
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA.
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Janković SM. Acetaminophen toxicity and overdose: current understanding and future directions for NAC dosing regimens. Expert Opin Drug Metab Toxicol 2022; 18:745-753. [PMID: 36420805 DOI: 10.1080/17425255.2022.2151893] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
INTRODUCTION Although N-acetyl-cysteine (NAC) has long been used for the treatment of acetaminophen poisoning/overdose, the optimal NAC dosing regimen for varying patterns or severity of the poisoning/overdose is still unknown. AREAS COVERED Relevant literature was searched for in the MEDLINE (from 1964 until August 31st, 2022), SCOPUS (from 2004 until August 31st, 2022) and GOOGLE SCHOLAR (from 2004 until August 31st, 2022) databases, without restriction in terms of publication date. The inclusion criteria were: original clinical studies reporting results, and studies investigating efficacy and safety of NAC dosing regimens in case(s) of overdose or poisoning with acetaminophen. EXPERT OPINION For a more effective treatment of acetaminophen poisoning in the future, it will be crucial to advance the technology of measuring acetaminophen, its metabolites and NAC in the serum, preferably with the point-of-care technique, so that in real time it can be continuously assessed whether it is necessary to administer NAC, and further to increase the dose of NAC and extend the duration of its administration, or not.
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He Y, Zhang Y, Zhang J, Hu X. The Key Molecular Mechanisms of Sini Decoction Plus Ginseng Soup to Rescue Acute Liver Failure: Regulating PPARα to Reduce Hepatocyte Necroptosis? J Inflamm Res 2022; 15:4763-4784. [PMID: 36032938 PMCID: PMC9417306 DOI: 10.2147/jir.s373903] [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: 05/08/2022] [Accepted: 08/09/2022] [Indexed: 12/02/2022] Open
Abstract
Purpose This study aimed to investigate the improvement effect of Sini Decoction plus Ginseng Soup (SNRS) on the LPS/D-GalN-induced acute liver failure (ALF) mouse model and the molecular mechanism of the SNRS effect. Methods To study the protective effect of SNRS on ALF mice, the ICR mice were firstly divided into 4 groups: Control group (vehicle-treated), Model group (LPS/D-GalN), SNRS group (LPS/D-GalN+SNRS), and Silymarin group (LPS/D-GalN+Silymarin), the therapeutic drug was administered by gavage 48h, 24h before, and 10 min after LPS/D-GalN injection. On this basis, the peroxisome proliferator-activated receptor (PPAR) α agonist (WY14643) and inhibitor (GW6471) were added to verify whether the therapeutic mechanism of SNRS is related to its promoting effect on PPARα. The animals are grouped as follows: Control group (vehicle-treated), Model group (LPS/D-GalN+DMSO), SNRS group (LPS/D-GalN+SNRS+DMSO), Inhibitor group (LPS/D-GalN+GW6471), Agonist group (LPS/D-GalN+WY14643), and Inhibitor+SNRS group (LPS/D-GalN+GW6471+SNRS). Results The protective effect of SNRS on the ALF model is mainly reflected in the reduction of serum alanine aminotransaminase (ALT) and aspartate aminotransaminase (AST) as well as the ameliorated pathology of the liver tissue. The survival rate of ALF mice treated with SNRS was significantly increased. Further mechanism studies showed that SNRS significantly promoted the protein expression of PPARα and decreased the expression of necroptosis proteins (RIP3, MLKL, p-MLKL) in ALF mice. Reduced necroptosis resulted in decreased HMGB1 release, which in turn inhibited the activation of TLR4-JNK and NLRP3 inflammasome signaling pathways and the expression of NF-κB protein induced by LPS/D-GalN. The expression of CPT1A, a key enzyme involved in fatty acid β-oxidation, was found to be significantly up-regulated in the SNRS treated group, accompanied by an increased adenosine-triphosphate (ATP) level, which may be the relevant mechanism by which SNRS reduces necroptosis. Conclusion The potential therapeutic effect of SNRS on ALF may be through promoting the expression of PPARα and increasing the level of ATP in liver tissue, thereby inhibiting necroptosis of hepatocytes, reducing hepatocyte damage, and improving liver function.
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Affiliation(s)
- Ying He
- Department of Gastroenterology, Clinical Medical College and the First Affiliated Hospital of Chengdu Medical College, Chengdu, People's Republic of China.,Department of College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Yang Zhang
- Department of Infectious Disease, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Junli Zhang
- Department of College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Xiaoyu Hu
- Department of Infectious Disease, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
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Teng H, Zhou L, Wang C, Yuan Z, Cao Q, Wu X, Li M. Novel carvedilol-loaded pro-phytomicelles: formulation, characterization and enhanced protective efficacy against acetaminophen-inducedliverinjury in mice. Int J Pharm 2022; 625:122127. [PMID: 35995319 DOI: 10.1016/j.ijpharm.2022.122127] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 07/31/2022] [Accepted: 08/16/2022] [Indexed: 11/17/2022]
Abstract
The work describes a novel, small-molecule phytochemicals as nanomaterials based pro-micelles (pro-phytomicelles) drug delivery system, for oral delivery of carvedilol (CAR). This novel nanoformulation of CAR, named CAR pro-phytomicelles, was prepared with rebaudioside A (RA) and dipotassium glycyrrhizinate (DG) as mixed nanomaterials. The formulation was optimized, leading to a 502-fold increase in solubility of CAR in water as a result of encapsulation within mixed phytomicelles based on DG and RA. CAR pro-phytomicelles samples could be instantly dissolved into aqueous media to formulate clear phytomicelle solutions with CAR encapsulation efficiency of 99.67 ± 0.02 %, and small micelle size of 15.62 ± 0.27 nm. CAR pro-phytomicelles exhibited good storage stability, rapid in vitro release in simulated intestinal fluid, and improved in vitro antioxidant activity. CAR pro-phytomicelles had good biocompatibility. Protective efficacy evaluation revealed that acetaminophen overdose could induce high mortality and severe liver injury in mice, while CAR pro-phytomicelle treatment exhibited significant protective effect against acetaminophen overdose. This protective efficacy was due to a mechanism that involved the regulation of high-mobility group box 1 and its signaling-related proinflammatory cytokines. These results show that pro-phytomicelles could provide a new concept and promising therapeutics as nanomedicines for improving the activities of CAR against acetaminophen-induced liver injury.
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Affiliation(s)
- Hanzhang Teng
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, China; Qingdao Women and Children's Hospital, Qingdao 266034, China
| | - Liping Zhou
- Department of Clinical Laboratory, Qingdao Municipal Hospital, Qingdao, China
| | - Cuicui Wang
- Department of Clinical Laboratory, Qingdao Municipal Hospital, Qingdao, China
| | - Zhixin Yuan
- Qingdao Haier Biotech Co. Ltd, Qingdao, China
| | - Qilong Cao
- Qingdao Haier Biotech Co. Ltd, Qingdao, China
| | - Xianggen Wu
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, China.
| | - Mengshuang Li
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, China; Qingdao Women and Children's Hospital, Qingdao 266034, China.
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Liao C, Zhang L, Jiang R, Hu D, Xu J, Hu K, Jiang S, Li L, Yang Y, Huang J, Tang L, Li L. Nicotinamide adenine dinucleotide attenuates acetaminophen-induced acute liver injury via activation of PARP1, Sirt1, and Nrf2 in mice. Can J Physiol Pharmacol 2022; 100:796-805. [PMID: 35983933 DOI: 10.1139/cjpp-2022-0127] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The aim of this study was to investigate the protective effect of nicotinamide adenine dinucleotide (NAD+) against acute liver injury (ALI) induced by acetaminophen (APAP) overdose in mice. First, serum transaminases were used to assess the protective effect of NAD+, and the data revealed that NAD+ mitigated the APAP-induced ALI in a dose-dependent manner. Then, we performed hematoxylin-eosin staining of liver tissues and found that NAD+ alleviated the abnormalities of histopathology. Meanwhile, increase in the malondialdehyde content and decrease in glutathione, superoxide dismutase (SOD), and glutathione peroxidase were identified in the APAP group, which were partially prevented by the NAD+ pretreatment. Moreover, compared with the mice treated with APAP only, the expression of poly ADP-ribose polymerase 1 (PARP1), Sirtuin1 (Sirt1), SOD2, nuclear factor erythroid 2-related factor 2 (Nrf2), and hemoxygenase-1 was upregulated, while Kelch-like ECH-associated protein 1 and histone H2AX phosphorylated on Ser-139 were downregulated by NAD+ in NAD+ + APAP group. Conversely, NAD+ could not correct the elevated expression of phospho-Jun N-terminal kinase and phospho-extracellular signal-regulated kinase induced by APAP. Taken together, these findings suggest that NAD+ confers an anti-ALI effect to enhance the expression of PARP1 and Sirt1, and to simultaneously stimulate the Nrf2 anti-oxidant signaling pathway.
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Affiliation(s)
- Cuiting Liao
- Department of Pathophysiology, Basic Medicine College, Chongqing Medical University, Chongqing 400016, China.,Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Li Zhang
- Department of Pathophysiology, Basic Medicine College, Chongqing Medical University, Chongqing 400016, China.,Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Rong Jiang
- Department of Pathophysiology, Basic Medicine College, Chongqing Medical University, Chongqing 400016, China.,Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Da Hu
- Department of Pathophysiology, Basic Medicine College, Chongqing Medical University, Chongqing 400016, China.,Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Juanjuan Xu
- Department of Pathophysiology, Basic Medicine College, Chongqing Medical University, Chongqing 400016, China.,Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Kai Hu
- Department of Pathophysiology, Basic Medicine College, Chongqing Medical University, Chongqing 400016, China.,Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Shifang Jiang
- Department of Pathophysiology, Basic Medicine College, Chongqing Medical University, Chongqing 400016, China.,Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Longhui Li
- Center of Health Management, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 400000, China
| | - Yongqiang Yang
- Department of Pathophysiology, Basic Medicine College, Chongqing Medical University, Chongqing 400016, China.,Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Jiayi Huang
- Department of Pathophysiology, Basic Medicine College, Chongqing Medical University, Chongqing 400016, China.,Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Li Tang
- Department of Pathophysiology, Basic Medicine College, Chongqing Medical University, Chongqing 400016, China.,Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China
| | - Longjiang Li
- Department of Pathophysiology, Basic Medicine College, Chongqing Medical University, Chongqing 400016, China.,Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China
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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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Armstrong SK, Oosthuyzen W, Gow AG, Salavati Schmitz S, Dear JW, Mellanby RJ. Investigation of a relationship between serum concentrations of microRNA-122 and alanine aminotransferase activity in hospitalised cats. J Feline Med Surg 2022; 24:e289-e294. [PMID: 35703473 PMCID: PMC9315172 DOI: 10.1177/1098612x221100071] [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] [Indexed: 11/17/2022]
Abstract
OBJECTIVES Current blood tests to diagnose feline liver diseases are suboptimal. Serum concentrations of microRNA (miR)-122 have been shown in humans, dogs and rodents to be a sensitive and specific biomarker for liver injury. To explore the potential diagnostic utility of measuring serum concentrations of miR-122 in cats, miR-122 was measured in a cohort of ill, hospitalised cats with known serum alanine aminotransferase (ALT) activity. METHODS In this retrospective study, cats were grouped into those with an ALT activity within the reference interval (0-83 U/l; n = 38) and those with an abnormal ALT activity (>84 U/l; n = 25). Serum concentrations of miR-122 were measured by real-time quantitative PCR and the relationship between miR-122 and ALT was examined. RESULTS miR-122 was significantly higher in the group with high ALT activity than the ALT group, within normal reference limits (P <0.0004). There was also a moderately positive correlation between serum ALT activity and miR-122 concentrations (P <0.001; r = 0.52). CONCLUSIONS AND RELEVANCE Concentrations of miR-122 were reliably quantified in feline serum and were higher in a cohort of cats with increased ALT activity than in cats with normal ALT activity. This work highlights the potential diagnostic utility of miR-122 as a biomarker of liver damage in cats and encourages further investigation to determine the sensitivity and specificity of miR-122 as a biomarker of hepatocellular injury in this species.
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Affiliation(s)
- Susan K Armstrong
- The Royal (Dick) School of Veterinary Studies and the Roslin Institute, The Hospital for Small Animals, University of Edinburgh, Edinburgh, UK
- Pharmacology, Toxicology and Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | | | - Adam G Gow
- The Royal (Dick) School of Veterinary Studies and the Roslin Institute, The Hospital for Small Animals, University of Edinburgh, Edinburgh, UK
| | - Silke Salavati Schmitz
- The Royal (Dick) School of Veterinary Studies and the Roslin Institute, The Hospital for Small Animals, University of Edinburgh, Edinburgh, UK
| | - James W Dear
- Pharmacology, Toxicology and Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Richard J Mellanby
- The Royal (Dick) School of Veterinary Studies and the Roslin Institute, The Hospital for Small Animals, University of Edinburgh, Edinburgh, UK
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Caveolin-1 Alleviates Acetaminophen—Induced Hepatotoxicity in Alcoholic Fatty Liver Disease by Regulating the Ang II/EGFR/ERK Axis. Int J Mol Sci 2022; 23:ijms23147587. [PMID: 35886933 PMCID: PMC9317714 DOI: 10.3390/ijms23147587] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 07/02/2022] [Accepted: 07/05/2022] [Indexed: 01/18/2023] Open
Abstract
Acetaminophen (APAP) is a widely used antipyretic analgesic which can lead to acute liver failure after overdoses. Chronic alcoholic fatty liver disease (AFLD) appears to enhance the risk and severity of APAP-induced liver injury, and the level of angiotensin II (Ang II) increased sharply at the same time. However, the underlying mechanisms remain unclear. Caveolin-1 (CAV1) has been proven to have a protective effect on AFLD. This study aimed to examine whether CAV1 can protect the APAP-induced hepatotoxicity of AFLD by affecting Ang II or its related targets. In vivo, the AFLD model was established according to the chronic-plus-binge ethanol model. Liver injury and hepatic lipid accumulation level were determined. The levels of Angiotensin converting enzyme 2 (ACE2), Ang II, CAV1, and other relevant proteins were evaluated by western blotting. In vitro, L02 cells were treated with alcohol and oleic acid mixture and APAP. CAV1 and ACE2 expression was downregulated in APAP-treated AFLD mice compared to APAP-treated mice. The overexpression of CAV1 in mice and L02 cells alleviated APAP-induced hepatotoxicity in AFLD and downregulated Ang II, p-EGFR/EGFR and P-ERK/ERK expression. Immunofluorescence experiments revealed interactions between CAV1, Ang II, and EGFR. The application of losartan (an Ang II receptor antagonist) and PD98059 (an ERK1/2 inhibitor) alleviated APAP-induced hepatotoxicity in AFLD. In conclusion, our findings verified that CAV1 alleviates APAP-aggravated hepatotoxicity in AFLD by downregulating the Ang II /EGFR/ERK axis, which could be a novel therapeutic target for its prevention or treatment.
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Moreno-Torres M, Quintás G, Castell JV. The Potential Role of Metabolomics in Drug-Induced Liver Injury (DILI) Assessment. Metabolites 2022; 12:metabo12060564. [PMID: 35736496 PMCID: PMC9227129 DOI: 10.3390/metabo12060564] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/31/2022] [Accepted: 06/13/2022] [Indexed: 12/19/2022] Open
Abstract
Drug-induced liver injury (DILI) is one of the most frequent adverse clinical reactions and a relevant cause of morbidity and mortality. Hepatotoxicity is among the major reasons for drug withdrawal during post-market and late development stages, representing a major concern to the pharmaceutical industry. The current biochemical parameters for the detection of DILI are based on enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP)) and bilirubin serum levels that are not specific of DILI and therefore there is an increasing interest on novel, specific, DILI biomarkers discovery. Metabolomics has emerged as a tool with a great potential for biomarker discovery, especially in disease diagnosis, and assessment of drug toxicity or efficacy. This review summarizes the multistep approaches in DILI biomarker research and discovery based on metabolomics and the principal outcomes from the research performed in this field. For that purpose, we have reviewed the recent scientific literature from PubMed, Web of Science, EMBASE, and PubTator using the terms “metabolomics”, “DILI”, and “humans”. Despite the undoubted contribution of metabolomics to our understanding of the underlying mechanisms of DILI and the identification of promising novel metabolite biomarkers, there are still some inconsistencies and limitations that hinder the translation of these research findings into general clinical practice, probably due to the variability of the methods used as well to the different mechanisms elicited by the DILI causing agent.
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Affiliation(s)
- Marta Moreno-Torres
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria Hospital La Fe, 46026 Valencia, Spain
- CIBEREHD, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence: (M.M.-T.); (J.V.C.)
| | - Guillermo Quintás
- Unidad Analítica, Instituto de Investigación Sanitaria Hospital La Fe, 46026 Valencia, Spain;
- Health and Biomedicine, LEITAT Technological Center, 46026 Valencia, Spain
| | - José V. Castell
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria Hospital La Fe, 46026 Valencia, Spain
- CIBEREHD, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
- Correspondence: (M.M.-T.); (J.V.C.)
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Weber S, Gerbes AL. Challenges and Future of Drug-Induced Liver Injury Research-Laboratory Tests. Int J Mol Sci 2022; 23:ijms23116049. [PMID: 35682731 PMCID: PMC9181520 DOI: 10.3390/ijms23116049] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 05/22/2022] [Accepted: 05/24/2022] [Indexed: 02/04/2023] Open
Abstract
Drug-induced liver injury (DILI) is a rare but potentially severe adverse drug event, which is also a major cause of study cessation and market withdrawal during drug development. Since no acknowledged diagnostic tests are available, DILI diagnosis poses a major challenge both in clinical practice as well as in pharmacovigilance. Differentiation from other liver diseases and the identification of the causative agent in the case of polymedication are the main issues that clinicians and drug developers face in this regard. Thus, efforts have been made to establish diagnostic testing methods and biomarkers in order to safely diagnose DILI and ensure a distinguishment from alternative liver pathologies. This review provides an overview of the diagnostic methods used in differential diagnosis, especially with regards to autoimmune hepatitis (AIH) and drug-induced autoimmune hepatitis (DI-AIH), in vitro causality methods using individual blood samples, biomarkers for diagnosis and severity prediction, as well as experimental predictive models utilized in pre-clinical settings during drug development regimes.
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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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Cave MC, Pinkston CM, Rai SN, Wahlang B, Pavuk M, Head KZ, Carswell GK, Nelson GM, Klinge CM, Bell DA, Birnbaum LS, Chorley BN. Circulating MicroRNAs, Polychlorinated Biphenyls, and Environmental Liver Disease in the Anniston Community Health Survey. ENVIRONMENTAL HEALTH PERSPECTIVES 2022; 130:17003. [PMID: 34989596 PMCID: PMC8734566 DOI: 10.1289/ehp9467] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 11/05/2021] [Accepted: 11/10/2021] [Indexed: 05/19/2023]
Abstract
BACKGROUND Polychlorinated biphenyl (PCB) exposures have been associated with liver injury in human cohorts, and steatohepatitis with liver necrosis in model systems. MicroRNAs (miRs) maintain cellular homeostasis and may regulate the response to environmental stress. OBJECTIVES We tested the hypothesis that specific miRs are associated with liver disease and PCB exposures in a residential cohort. METHODS Sixty-eight targeted hepatotoxicity miRs were measured in archived serum from 734 PCB-exposed participants in the cross-sectional Anniston Community Health Survey. Necrotic and other liver disease categories were defined by serum keratin 18 (K18) biomarkers. Associations were determined between exposure biomarkers (35 ortho-substituted PCB congeners) and disease biomarkers (highly expressed miRs or previously measured cytokines), and Ingenuity Pathway Analysis was performed. RESULTS The necrotic liver disease category was associated with four up-regulated miRs (miR-99a-5p, miR-122-5p, miR-192-5p, and miR-320a) and five down-regulated miRs (let-7d-5p, miR-17-5p, miR-24-3p, miR-197-3p, and miR-221-3p). Twenty-two miRs were associated with the other liver disease category or with K18 measurements. Eleven miRs were associated with 24 PCBs, most commonly congeners with anti-estrogenic activities. Most of the exposure-associated miRs were associated with at least one serum hepatocyte death, pro-inflammatory cytokine or insulin resistance bioarker, or with both. Within each biomarker category, associations were strongest for the liver-specific miR-122-5p. Pathways of liver toxicity that were identified included inflammation/hepatitis, hyperplasia/hyperproliferation, cirrhosis, and hepatocellular carcinoma. Tumor protein p53 and tumor necrosis factor α were well integrated within the top identified networks. DISCUSSION These results support the human hepatotoxicity of environmental PCB exposures while elucidating potential modes of PCB action. The MiR-derived liquid liver biopsy represents a promising new technique for environmental hepatology cohort studies. https://doi.org/10.1289/EHP9467.
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Affiliation(s)
- Matthew C. Cave
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Louisville, Louisville, Kentucky, USA
- Department of Pharmacology & Toxicology, School of Medicine, University of Louisville, Louisville, Kentucky, USA
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Hepatobiology and Toxicology Center, University of Louisville, Louisville, Kentucky, USA
- Superfund Research Center, University of Louisville, Louisville, Kentucky, USA
- Center for Integrative Environmental Health Sciences, University of Louisville, Louisville, Kentucky, USA
- Robley Rex Veterans Affairs Medical Center, Louisville, Kentucky, USA
- Liver Transplant Program at UofL Health–Jewish Hospital Trager Transplant Center, Louisville, Kentucky, USA
- University of Louisville Alcohol Research Center, Louisville, Kentucky, USA
| | - Christina M. Pinkston
- Hepatobiology and Toxicology Center, University of Louisville, Louisville, Kentucky, USA
- Department of Bioinformatics and Biostatistics, University of Louisville School of Public Health and Information Sciences, Louisville, Kentucky, USA
- Biostatistics and Bioinformatics Facility, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA
| | - Shesh N. Rai
- Hepatobiology and Toxicology Center, University of Louisville, Louisville, Kentucky, USA
- Superfund Research Center, University of Louisville, Louisville, Kentucky, USA
- Center for Integrative Environmental Health Sciences, University of Louisville, Louisville, Kentucky, USA
- University of Louisville Alcohol Research Center, Louisville, Kentucky, USA
- Department of Bioinformatics and Biostatistics, University of Louisville School of Public Health and Information Sciences, Louisville, Kentucky, USA
- Biostatistics and Bioinformatics Facility, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA
| | - Banrida Wahlang
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Louisville, Louisville, Kentucky, USA
- Superfund Research Center, University of Louisville, Louisville, Kentucky, USA
| | - Marian Pavuk
- Agency for Toxic Substances and Disease Registry, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Kimberly Z. Head
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Louisville, Louisville, Kentucky, USA
- Hepatobiology and Toxicology Center, University of Louisville, Louisville, Kentucky, USA
| | - Gleta K. Carswell
- United States Environmental Protection Agency, Research Triangle Park, North Carolina, USA
| | - Gail M. Nelson
- United States Environmental Protection Agency, Research Triangle Park, North Carolina, USA
| | - Carolyn M. Klinge
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Douglas A. Bell
- National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA
| | - Linda S. Birnbaum
- National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA
| | - Brian N. Chorley
- United States Environmental Protection Agency, Research Triangle Park, North Carolina, USA
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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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Xiao Y, Zhou Y, Zhou K, Cai W. Targeted Metabolomics Reveals Birth Screening Biomarkers for Biliary Atresia in Dried Blood Spots. J Proteome Res 2021; 21:721-726. [PMID: 34850627 DOI: 10.1021/acs.jproteome.1c00775] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Early diagnosis and timely surgical Kasai portoenterostomy greatly improve the survival of patients with biliary atresia (BA), a neonatal cholestatic disease, which has encouraged investigators to develop newborn screening for BA. In this study, we used ultraperformance liquid chromatography-triple quadrupole mass spectrometry-based targeted metabolomics profiling to identify potential BA biomarkers in dried blood spots (DBS) collected from BA patients (n = 21) and healthy controls (n = 100). A distinctive metabolic profile comprising eight significantly differentially expressed metabolites, taurohyocholic acid (THCA), glutamic acid, 2-hydroxyglutaric acid, ketoleucine, indoleacetic acid, alpha-ketoisovaleric acid, glycocholic acid, and taurocholic acid (TCA), clearly distinguished BA infants from control neonates. Three metabolites, THCA, 2-hydroxyglutaric acid, and indoleacetic acid, were selected using linear regression and receiver operating characteristic (ROC) curve analysis and model construction. The area under the ROC curve for this model to discriminate between BA and comparison infants was 0.938 (95% confidence interval, CI: 0.874-1.000). A cutoff value of -0.336 produced a sensitivity of 90.48% (95% CI: 69.62% - 98.83%) and specificity of 92% (95% CI: 84.84% - 96.48%). In conclusion, the results suggest that metabolic markers in DBS obtained from newborns have a great potential for BA screening.
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Affiliation(s)
- Yongtao Xiao
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.,Shanghai Institute of Pediatric Research, Shanghai 200092, China.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
| | - Ying Zhou
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Kejun Zhou
- Human Metabolomics Institute, Inc., Shenzhen, Guangdong 518109, China
| | - Wei Cai
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.,Shanghai Institute of Pediatric Research, Shanghai 200092, China.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
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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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Berumen Sánchez G, Bunn KE, Pua HH, Rafat M. Extracellular vesicles: mediators of intercellular communication in tissue injury and disease. Cell Commun Signal 2021; 19:104. [PMID: 34656117 PMCID: PMC8520651 DOI: 10.1186/s12964-021-00787-y] [Citation(s) in RCA: 133] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 09/07/2021] [Indexed: 12/13/2022] Open
Abstract
Intercellular communication is a critical process that ensures cooperation between distinct cell types and maintains homeostasis. EVs, which were initially described as cellular debris and devoid of biological function, are now recognized as key components in cell-cell communication. EVs are known to carry multiple factors derived from their cell of origin, including cytokines and chemokines, active enzymes, metabolites, nucleic acids, and surface molecules, that can alter the behavior of recipient cells. Since the cargo of EVs reflects their parental cells, EVs from damaged and dysfunctional tissue environments offer an abundance of information toward elucidating the molecular mechanisms of various diseases and pathological conditions. In this review, we discuss the most recent findings regarding the role of EVs in the progression of cancer, metabolic disorders, and inflammatory lung diseases given the high prevalence of these conditions worldwide and the important role that intercellular communication between immune, parenchymal, and stromal cells plays in the development of these pathological states. We also consider the clinical applications of EVs, including the possibilities for their use as novel therapeutics. While intercellular communication through extracellular vesicles (EVs) is key for physiological processes and tissue homeostasis, injury and stress result in altered communication patterns in the tissue microenvironment. When left unchecked, EV-mediated interactions between stromal, immune, and parenchymal cells lead to the development of disease states Video Abstract.
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Affiliation(s)
- Greg Berumen Sánchez
- Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN USA
| | - Kaitlyn E. Bunn
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN USA
| | - Heather H. Pua
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN USA
| | - Marjan Rafat
- Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN USA
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN USA
- Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN USA
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Ramachandran A, Jaeschke H. Oxidant Stress and Acetaminophen Hepatotoxicity: Mechanism-Based Drug Development. Antioxid Redox Signal 2021; 35:718-733. [PMID: 34232786 PMCID: PMC8558076 DOI: 10.1089/ars.2021.0102] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Significance: Acetaminophen (APAP) is one of the quantitively most consumed drugs worldwide. Although safe at therapeutic doses, intentional or unintentional overdosing occurs frequently causing severe liver injury and even liver failure. In the United States, 50% of all acute liver failure cases are caused by APAP overdose. However, only one antidote with a limited therapeutic window, N-acetylcysteine, is clinically approved. Thus, more effective therapeutic interventions are urgently needed. Recent Advances: Although APAP hepatotoxicity has been extensively studied for almost 50 years, particular progress has been made recently in two areas. First, there is now a detailed understanding of involvement of oxidative and nitrosative stress in the pathophysiology, with identification of the reactive species involved, their initial generation in mitochondria, amplification through the c-Jun N-terminal kinase pathway, and the mechanisms of cell death. Second, it was demonstrated in human hepatocytes and through biomarkers in vivo that the mechanisms of liver injury in animals accurately reflect the human pathophysiology, which allows the translation of therapeutic targets identified in animals to patients. Critical Issues: For progress, solid understanding of the pathophysiology of APAP hepatotoxicity and of a drug's targets is needed to identify promising new therapeutic intervention strategies and drugs, which may be applied to humans. Future Directions: In addition to further refine the mechanistic understanding of APAP hepatotoxicity and identify additional drugs with complementary mechanisms of action to prevent cell death, more insight into the mechanisms of regeneration and developing of drugs, which promote recovery, remains a future challenge. Antioxid. Redox Signal. 35, 718-733.
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Affiliation(s)
- Anup Ramachandran
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
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