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Hossen MS, Akter A, Azmal M, Rayhan M, Islam KS, Islam MM, Ahmed S, Abdullah-Al-Shoeb M. Unveiling the molecular basis of paracetamol-induced hepatotoxicity: Interaction of N-acetyl- p-benzoquinone imine with mitochondrial succinate dehydrogenase. Biochem Biophys Rep 2024; 38:101727. [PMID: 38766381 PMCID: PMC11098724 DOI: 10.1016/j.bbrep.2024.101727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 03/13/2024] [Accepted: 04/30/2024] [Indexed: 05/22/2024] Open
Abstract
Background and aim N-acetyl-p-benzoquinoneimine (NAPQI), a toxic byproduct of paracetamol (Acetaminophen, APAP), can accumulate and cause liver damage by depleting glutathione and forming protein adducts in the mitochondria. These adducts disrupt the respiratory chain, increasing superoxide production and reducing ATP. The goal of this study was to provide computational proof that succinate dehydrogenase (SDH), a subunit of complex II in the mitochondrial respiratory chain, is a favorable binding partner for NAPQI in this regard. Method Molecular docking, molecular dynamics simulation, protein-protein interaction networks (PPI), and KEGG metabolic pathway analysis were employed to identify binding characteristics, interaction partners, and their associations with metabolic pathways. A lipid membrane was added to the experimental apparatus to mimic the natural cellular environment of SDH. This modification made it possible to develop a context for investigating the role and interactions of SDH within a cellular ecosystem that was more realistic and biologically relevant. Result The molecular binding affinity score for APAP and NAPQI with SDH was predicted -6.5 and -6.7 kcal/mol, respectively. Furthermore, RMSD, RMSF, and Rog from the molecular dynamics simulations study revealed that NAPQI has slightly higher stability and compactness compared to APAP at 100 ns timeframe with mitochondrial SDH. Conclusion This study serves to predict the mechanistic process of paracetamol toxicity by using different computational approaches. In addition, this study will provide information about the drug target against APAP hepatotoxicity.
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Affiliation(s)
- Md Sahadot Hossen
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh
| | - Adiba Akter
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh
| | - Mahir Azmal
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh
| | - Mostakim Rayhan
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh
| | - Kazi Saiful Islam
- Department of Biochemistry and Molecular Biology, Jahangirnagar University, Savar, Dhaka, Bangladesh
| | - Md Mahmodul Islam
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali 3814, Bangladesh
| | - Shamim Ahmed
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh
| | - Mohammad Abdullah-Al-Shoeb
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh
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2
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Hassan HM, Abdel-Halim NHM, El-Shenbaby I, Helmy MA, Hammad MO, Habotta OA, El Nashar EM, Alghamdi MA, Aldahhan RA, Al-Khater KM, Almohaywi B, Farrag EAE. Phytic acid attenuates acetaminophen-induced hepatotoxicity via modulating iron-mediated oxidative stress and SIRT-1 expression in mice. Front Pharmacol 2024; 15:1384834. [PMID: 38751780 PMCID: PMC11094543 DOI: 10.3389/fphar.2024.1384834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 04/04/2024] [Indexed: 05/18/2024] Open
Abstract
Introduction: Administration of high doses of acetaminophen (APAP) results in liver injury. Oxidative stress and iron overload play roles in the pathogenesis of APAP-induced hepatotoxicity. The present study assessed the potential hepatoprotective effects of phytic acid (PA), a natural antioxidant and iron chelator, on APAP-induced hepatotoxicity and the possible underlying mechanism through its effects on CYP2E1 gene expression, iron homeostasis, oxidative stress, and SIRT-1 expression levels. Methods: Twenty-four adult male albino mice were used in this study. Mice were divided into four groups (six mice in each group): control, APAP-treated, PA-treated and APAP + PA-treated groups. Liver function tests, serum and liver tissue iron load were evaluated in all the study groups. Hepatic tissue homogenates were used to detect oxidative stress markers, including malondialdehyde (MDA) and reduced glutathione (GSH). Histological hepatic evaluation and immunohistochemistry of SIRT-1 were performed. Quantitative real-time PCR was used for the assessment of CYP2E1 and SIRT-1 gene expressions. APAP-induced biochemical and structural hepatic changes were reported. Results: PA administration showed beneficial effects on APAP-induced hepatotoxicity through improvements in liver functions, decreased CYP2E1 gene expression, decreased serum and liver iron load, decreased MDA, increased GSH, increased SIRT-1 expression level and improvement in hepatic architecture. Conclusion: Conclusively, PA can be considered a potential compound that can attenuate acetaminophen-induced hepatotoxicity through its role as an iron chelator and antioxidant, as well as the up-regulation of SIRT-1 and down-regulation of CYP2E1.
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Affiliation(s)
- Hend M. Hassan
- Human Anatomy and Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
- Human Anatomy and Embryology Department, New Mansoura University, New Mansoura, Egypt
| | | | - Ibrahim El-Shenbaby
- Clinical Pharmacology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Manar A. Helmy
- Forensic Medicine and Toxicology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Maha O. Hammad
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ola A. Habotta
- Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Eman M. El Nashar
- Department of Anatomy, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Mansour A. Alghamdi
- Department of Anatomy, College of Medicine, King Khalid University, Abha, Saudi Arabia
- Genomics and Personalized Medicine Unit, The Center for Medical and Health Research, King Khalid University, Abha, Saudi Arabia
| | - Rashid A. Aldahhan
- Department of Anatomy, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Khulood M. Al-Khater
- Department of Anatomy, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Basmah Almohaywi
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Eman A. E. Farrag
- Clinical Pharmacology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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3
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Groeneveld DJ, Poole LG, Bouck EG, Schulte A, Wei Z, Williams KJ, Watson VE, Lisman T, Wolberg AS, Luyendyk JP. Robust coagulation activation and coagulopathy in mice with experimental acetaminophen-induced liver failure. J Thromb Haemost 2023; 21:2430-2440. [PMID: 37054919 PMCID: PMC10524846 DOI: 10.1016/j.jtha.2023.03.040] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 03/07/2023] [Accepted: 03/30/2023] [Indexed: 04/15/2023]
Abstract
BACKGROUND Patients with acetaminophen (APAP)-induced acute liver failure (ALF) display both hyper- and hypocoagulable changes not necessarily recapitulated by standard hepatotoxic doses of APAP used in mice (eg, 300 mg/kg). OBJECTIVES We sought to examine coagulation activation in vivo and plasma coagulation potential ex vivo in experimental settings of APAP-induced hepatotoxicity and repair (300-450 mg/kg) and APAP-induced ALF (600 mg/kg) in mice. RESULTS APAP-induced ALF was associated with increased plasma thrombin-antithrombin complexes, decreased plasma prothrombin, and a dramatic reduction in plasma fibrinogen compared with lower APAP doses. Hepatic fibrin(ogen) deposits increased independent of APAP dose, whereas plasma fibrin(ogen) degradation products markedly increased in mice with experimental ALF. Early pharmacologic anticoagulation (+2 hours after 600 mg/kg APAP) limited coagulation activation and reduced hepatic necrosis. The marked coagulation activation evident in mice with APAP-induced ALF was associated with a coagulopathy detectable ex vivo in plasma. Specifically, prolongation of the prothrombin time and inhibition of tissue factor-initiated clot formation were evident even after restoration of physiological fibrinogen concentrations. Plasma endogenous thrombin potential was similarly reduced at all APAP doses. Interestingly, in the presence of ample fibrinogen, ∼10 times more thrombin was required to clot plasma from mice with APAP-induced ALF compared with plasma from mice with simple hepatotoxicity. CONCLUSION The results indicate that robust pathologic coagulation cascade activation in vivo and suppressed coagulation ex vivo are evident in mice with APAP-induced ALF. This unique experimental setting may fill an unmet need as a model to uncover mechanistic aspects of the complex coagulopathy of ALF.
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Affiliation(s)
- Dafna J Groeneveld
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan, USA
| | - Lauren G Poole
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan, USA
| | - Emma G Bouck
- Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Anthony Schulte
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan, USA
| | - Zimu Wei
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan, USA
| | - Kurt J Williams
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan, USA
| | - Victoria E Watson
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan, USA
| | - Ton Lisman
- Section of Hepatobiliary Surgery and Liver Transplantation and Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Alisa S Wolberg
- Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina, Chapel Hill, North Carolina, USA
| | - James P Luyendyk
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan, USA; Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan, USA.
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4
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Kanth Kadiyala N, Mandal BK, Kumar Reddy LV, Barnes CHW, De Los Santos Valladares L, Maddinedi SB, Sen D. Biofabricated Palladium Nanoparticle-Decorated Reduced Graphene Oxide Nanocomposite Using the Punica granatum (Pomegranate) Peel Extract: Investigation of Potent In Vivo Hepatoprotective Activity against Acetaminophen-Induced Liver Injury in Wistar Albino Rats. ACS OMEGA 2023; 8:24524-24543. [PMID: 37457483 PMCID: PMC10339435 DOI: 10.1021/acsomega.3c02643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 06/15/2023] [Indexed: 07/18/2023]
Abstract
Acute acetaminophen (APAP) toxicity is a predominant clinical problem, which causes serious liver injury in both humans and experimental animals. This study presents the histological and biochemical factor and antioxidant enzyme level changes induced by an acute acetaminophen overdose in Wistar albino rat livers to elucidate the effective hepatoprotective potential of biofabricated palladium nanoparticle-decorated reduced graphene oxide nanocomposites (rGO/PdNPs-NC) compared to silymarin. After detailed characterization of the hepatoprotective potential of the synthesized rGO/PdNPs-NC, the rats were divided into eight groups (n = 6): control group (normal saline, 1 mL/kg b.w.), silymarin, Punica granatum (pomegranate) peel extract, PdNPs, reduced graphene oxide (rGO-PG), and reduced graphene oxide palladium nanocomposites (rGO/PdNPs-NC, low and high doses) for 7 successive days. The acetaminophen (APAP)-treated group was administered a single dose of acetaminophen (2 g/kg b.w.) on the 8th day. The histopathological results showed that the acetaminophen overdose group exhibited massive intrahepatic hemorrhagic necrosis around the centrilobular region with hepatocytes with vacuolization and swollen cytoplasm found in the liver architecture. This hepatopotential was further assessed by various biochemical parameters such as SGOT, SGPT, ALB, ALP, LDH, direct bilirubin, total bilirubin, and total protein. Also, the antioxidant parameters such as SOD, CAT, MDA, GSH, GRD, and GST were assayed. Rats of groups 7 and 8 showed a significant decrease in SGOT, SGPT, ALP, LDH, direct bilirubin, and total bilirubin (p < 0.001), while a significant increase in the final total protein and ALB as compared to group 2 rats (p < 0.001) was observed. The antioxidant parameters exhibited that rats of groups 7 and 8 showed a significant (p < 0.001) increase in the level of SOD, CAT, GSH, GRD, and GST without affecting the MDA as compared to group 2 rats. Also, the hepatoprotective potential of rGO/PdNPs-NC (low and high doses) was comparable to that of the standard reference drug silymarin. The present study reveals that the rGO/PdNPs-NC possesses significant hepatoprotective activity and acts as an effective and promising curative agent against acetaminophen-induced hepatotoxicity.
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Affiliation(s)
- Nalinee Kanth Kadiyala
- Trace
Elements Speciation Research Laboratory, Department of Chemistry,
School of Advanced Sciences, Vellore Institute
of Technology (VIT), Vellore 632014, India
| | - Badal Kumar Mandal
- Trace
Elements Speciation Research Laboratory, Department of Chemistry,
School of Advanced Sciences, Vellore Institute
of Technology (VIT), Vellore 632014, India
| | - L. Vinod Kumar Reddy
- Cellular
and Molecular Therapeutics Laboratory, Centre for Biomaterials, Cellular
and Molecular Theranostics, Vellore Institute
of Technology (VIT), Vellore 632014, India
| | - Crispin H. W. Barnes
- Cavendish
Laboratory, Department of Physics, University
of Cambridge, Cambridge CB3 0HE, United
Kingdom
| | - Luis De Los Santos Valladares
- Cavendish
Laboratory, Department of Physics, University
of Cambridge, Cambridge CB3 0HE, United
Kingdom
- Laboratorio
de Cerámicos y Nanomateriales, Facultad de Ciencias Físicas, Universidad Nacional Mayor de San Marcos, Ap. Postal 14-0149 Lima, Peru
| | - Sireesh Babu Maddinedi
- Trace
Elements Speciation Research Laboratory, Department of Chemistry,
School of Advanced Sciences, Vellore Institute
of Technology (VIT), Vellore 632014, India
| | - Dwaipayan Sen
- Cellular
and Molecular Therapeutics Laboratory, Centre for Biomaterials, Cellular
and Molecular Theranostics, Vellore Institute
of Technology (VIT), Vellore 632014, India
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5
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Porterfield JE, Sharma R, Jimenez AS, Sah N, McCracken S, Zhang L, An H, Lee S, Kannan S, Sharma A, Kannan RM. Galactosylated hydroxyl-polyamidoamine dendrimer targets hepatocytes and improves therapeutic outcomes in a severe model of acetaminophen poisoning-induced liver failure. Bioeng Transl Med 2023; 8:e10486. [PMID: 37206223 PMCID: PMC10189448 DOI: 10.1002/btm2.10486] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 10/28/2022] [Accepted: 12/22/2022] [Indexed: 07/30/2023] Open
Abstract
Toxicity to hepatocytes caused by various insults including drugs is a common cause of chronic liver failure requiring transplantation. Targeting therapeutics specifically to hepatocytes is often a challenge since they are relatively nonendocytosing unlike the highly phagocytic Kupffer cells in the liver. Approaches that enable targeted intracellular delivery of therapeutics to hepatocytes have significant promise in addressing liver disorders. We synthesized a galactose-conjugated hydroxyl polyamidoamine dendrimer (D4-Gal) that targets hepatocytes efficiently through the asialoglycoprotein receptors in healthy mice and in a mouse model of acetaminophen (APAP)-induced liver failure. D4-Gal localized specifically in hepatocytes and showed significantly better targeting when compared with the non-Gal functionalized hydroxyl dendrimer. The therapeutic potential of D4-Gal conjugated to N-acetyl cysteine (NAC) was tested in a mouse model of APAP-induced liver failure. A single intravenous dose of a conjugate of D4-Gal and NAC (Gal-d-NAC) improved survival in APAP mice, decreased cellular oxidative injury and areas of necrosis in the liver, even when administered at the delayed time point of 8 h after APAP exposure. Overdose of APAP is the most common cause of acute hepatic injury and liver transplant need in the United States, and is treated with large doses of NAC administered rapidly within 8 h of overdose leading to systemic side effects and poor tolerance. NAC is not effective when treatment is delayed. Our results suggest that D4-Gal is effective in targeting and delivering therapies to hepatocytes and Gal-D-NAC has the potential to salvage and treat liver injury with a broader therapeutic window.
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Affiliation(s)
- Joshua E. Porterfield
- Center for Nanomedicine, Department of OphthalmologyWilmer Eye Institute, Johns Hopkins University School of MedicineBaltimoreMarylandUSA
- Department of Chemical and Biomolecular EngineeringJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Rishi Sharma
- Center for Nanomedicine, Department of OphthalmologyWilmer Eye Institute, Johns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Ambar Scarlet Jimenez
- Center for Nanomedicine, Department of OphthalmologyWilmer Eye Institute, Johns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Nirnath Sah
- Department of Biomedical EngineeringJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Sean McCracken
- Center for Nanomedicine, Department of OphthalmologyWilmer Eye Institute, Johns Hopkins University School of MedicineBaltimoreMarylandUSA
- Department of Chemical and Biomolecular EngineeringJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Lucia Zhang
- Center for Nanomedicine, Department of OphthalmologyWilmer Eye Institute, Johns Hopkins University School of MedicineBaltimoreMarylandUSA
- Department of Biomedical EngineeringJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Hyoung‐Tae An
- Center for Nanomedicine, Department of OphthalmologyWilmer Eye Institute, Johns Hopkins University School of MedicineBaltimoreMarylandUSA
- Department of RadiologyJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Seulki Lee
- Center for Nanomedicine, Department of OphthalmologyWilmer Eye Institute, Johns Hopkins University School of MedicineBaltimoreMarylandUSA
- Department of RadiologyJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Sujatha Kannan
- Center for Nanomedicine, Department of OphthalmologyWilmer Eye Institute, Johns Hopkins University School of MedicineBaltimoreMarylandUSA
- Department of Anesthesiology and Critical Care MedicineJohns Hopkins University School of MedicineBaltimoreMarylandUSA
- Hugo W. Moser Research Institute at Kennedy Krieger, Inc.BaltimoreMarylandUSA
| | - Anjali Sharma
- Center for Nanomedicine, Department of OphthalmologyWilmer Eye Institute, Johns Hopkins University School of MedicineBaltimoreMarylandUSA
- Present address:
Department of ChemistryWashington State UniversityPullmanWashingtonUSA
| | - Rangaramanujam M. Kannan
- Center for Nanomedicine, Department of OphthalmologyWilmer Eye Institute, Johns Hopkins University School of MedicineBaltimoreMarylandUSA
- Department of Chemical and Biomolecular EngineeringJohns Hopkins UniversityBaltimoreMarylandUSA
- Hugo W. Moser Research Institute at Kennedy Krieger, Inc.BaltimoreMarylandUSA
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6
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Liao J, Lu Q, Li Z, Li J, Zhao Q, Li J. Acetaminophen-induced liver injury: Molecular mechanism and treatments from natural products. Front Pharmacol 2023; 14:1122632. [PMID: 37050900 PMCID: PMC10083499 DOI: 10.3389/fphar.2023.1122632] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 03/13/2023] [Indexed: 03/29/2023] Open
Abstract
Acetaminophen (APAP) is a widely used analgesic and antipyretic over-the-counter medicine worldwide. Hepatotoxicity caused by APAP overdose is one of the leading causes of acute liver failure (ALF) in the US and in some parts of Europe, limiting its clinical application. Excessive APAP metabolism depletes glutathione and increases N-acetyl-p-benzoquinoneimide (NAPQI) levels, leading to oxidative stress, DNA damage, and cell necrosis in the liver, which in turn leads to liver damage. Studies have shown that natural products such as polyphenols, terpenes, anthraquinones, and sulforaphane can activate the hepatocyte antioxidant defense system with Nrf2 as the core player, reduce oxidative stress damage, and protect the liver. As the key enzyme metabolizing APAP into NAPQI, cytochrome P450 enzymes are also considered to be intriguing target for the treatment of APAP-induced liver injury. Here, we systematically review the hepatoprotective activity and molecular mechanisms of the natural products that are found to counteract the hepatotoxicity caused by APAP, providing reference information for future preclinical and clinical trials of such natural products.
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Affiliation(s)
- Jiaqing Liao
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, China
- School of Pharmacy, Chengdu University, Chengdu, China
| | - Qiuxia Lu
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, China
- School of Food and Biological Engineering, Chengdu University, Chengdu, China
| | - Zhiqi Li
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, China
- School of Food and Biological Engineering, Chengdu University, Chengdu, China
| | - Jintao Li
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, China
- School of Pharmacy, Chengdu University, Chengdu, China
| | - Qi Zhao
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, China
- School of Food and Biological Engineering, Chengdu University, Chengdu, China
- *Correspondence: Qi Zhao, ; Jian Li,
| | - Jian Li
- Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, China
- School of Basic Medical Sciences, Chengdu University, Chengdu, China
- *Correspondence: Qi Zhao, ; Jian Li,
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7
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An Y, Luo Q, Han D, Guan L. Abietic acid inhibits acetaminophen-induced liver injury by alleviating inflammation and ferroptosis through regulating Nrf2/HO-1 axis. Int Immunopharmacol 2023; 118:110029. [PMID: 36963265 DOI: 10.1016/j.intimp.2023.110029] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/08/2023] [Accepted: 03/09/2023] [Indexed: 03/26/2023]
Abstract
Abietic acid has been known to exhibit anti-inflammatory activity. This study was designed to investigate the protective effects of abietic acid on acetaminophen (APAP)-induced liver injury. The data demonstrated that abietic acid significantly ameliorated APAP-induced liver pathological changes, TNF-α and IL-1β production. APAP could increase malondialdehyde (MDA) and Fe2+ levels, and decrease ATP and glutathione (GSH) levels, as well as glutathione peroxidase 4 (GPX4) and xCT expression. However, these changes induced by APAP were prevented by abietic acid, indicating abietic acid could inhibit APAP-induced ferroptosis. Furthermore, abietic acid inhibited APAP-induced NF-κB activation and increased the expression of Nrf2 and HO-1. Additionally, the inhibitory effects of abietic acid on APAP-induced liver injury were prevented in Nrf2-/- mice. In vitro, the inhibition of abietic acid on APAP-induced inflammation and ferroptosis were reversed when Nrf2 was knockdown. In summary, abietic acidexhibited a therapeutic effectagainst liver injury by attenuating inflammation and ferroptosis.
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Affiliation(s)
- Yuan An
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Qiang Luo
- Department of Ultrasound, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Donghai Han
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Lianyue Guan
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China.
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8
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Eze CT, Otitoloju AA, Eze OO, Ugochukwu TE, Onodugo C, Ali AM, Lyche JL, Karlsen OA, Goksøyr A. West African e-waste-soil assessed with a battery of cell-based bioassays. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 856:159068. [PMID: 36179844 DOI: 10.1016/j.scitotenv.2022.159068] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 09/17/2022] [Accepted: 09/23/2022] [Indexed: 06/16/2023]
Abstract
Soil samples randomly taken from major e-waste sites in West Africa (Nigeria, Benin and Ghana) were examined for an extensive range of organic contaminants. Cytotoxicity measurements and assessment of activation of xeno-sensing receptors from fish (Atlantic cod) were employed as a battery of in vitro biological assays to explore the quality and toxicity profile of West African e-waste soil. The concentrations of the measured contaminants of emerging concerns (CECs) and persistent organic pollutants (POPs) in the e-waste soil differs significantly from the reference soil with chemical profiles typically dominated by legacy polybrominated diphenyl ethers (PBDEs) (405.8 μgkg-1) and emerging organophosphate ester flame retardant tris (1-chloro-2-propyl) phosphate (TCPP) (404 μgkg-1), in addition to the short chain perfluorobutane sulfonate (PFBS) (275.3 μgkg-1) and perfluorobutanoate (PFBA) (16 μgkg-1). The study revealed that perfluorooctanoic acid (PFOA) occurred only in e-waste soil from Ghana and ranged from 2.6 to 5.0 μgkg-1. Overall, non-polar e-waste soil-derived extracts had a stronger effect on COS-7 cell viability than the polar extracts and elutriates. The highest receptor activation was observed with single polar and non-polar extracts from the Nigeria and Benin sites, indicating hotspots with Er-, PPARa- and Ahr-agonist activities. Thus, the results obtained with our battery of in vitro biological assays underscored these e-waste sites as remarkably polluted spots with complex toxicity profiles of great concern for human and environmental health.
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Affiliation(s)
- Chukwuebuka ThankGod Eze
- Department of Biochemistry, Federal University Oye-Ekiti, Ekiti State, Nigeria; Department of Zoology, University of Lagos, Akoka-Yaba, Lagos State, Nigeria; Department of Biological Sciences, University of Bergen, Bergen, Norway.
| | | | | | | | - Chinemelum Onodugo
- Department of Biochemistry, Federal University Oye-Ekiti, Ekiti State, Nigeria
| | - Aasim Musa Ali
- Section of Contaminants and Biohazards, Institute of Marine Research (IMR), P.O 1870 Nordnes, NO-5817 Bergen, Norway
| | - Jan Ludvig Lyche
- Department of Food Safety and Infection Biology, Norwegian University of Life Sciences, Oslo, Norway
| | - Odd André Karlsen
- Department of Biological Sciences, University of Bergen, Bergen, Norway
| | - Anders Goksøyr
- Department of Biological Sciences, University of Bergen, Bergen, Norway
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9
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The danger signal interferon-induced protein 35 (IFP35) mediates acetaminophen-induced liver injury. Biochem Biophys Res Commun 2022; 621:25-31. [DOI: 10.1016/j.bbrc.2022.06.086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 06/26/2022] [Indexed: 11/20/2022]
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10
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Inhibition of NAD kinase elevates the hepatic NAD+ pool and alleviates acetaminophen-induced acute liver injury in mice. Biochem Biophys Res Commun 2022; 612:70-76. [DOI: 10.1016/j.bbrc.2022.04.079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/14/2022] [Accepted: 04/18/2022] [Indexed: 11/22/2022]
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Wang M, Sun J, Yu T, Wang M, Jin L, Liang S, Luo W, Wang Y, Li G, Liang G. Diacerein protects liver against APAP-induced injury via targeting JNK and inhibiting JNK-mediated oxidative stress and apoptosis. Biomed Pharmacother 2022; 149:112917. [PMID: 36068777 DOI: 10.1016/j.biopha.2022.112917] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/28/2022] [Accepted: 03/30/2022] [Indexed: 11/02/2022] Open
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12
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Silva ARR, Gonçalves SF, Pavlaki MD, Morgado RG, Soares AMVM, Loureiro S. Mixture toxicity prediction of substances from different origin sources in Daphnia magna. CHEMOSPHERE 2022; 292:133432. [PMID: 34968511 DOI: 10.1016/j.chemosphere.2021.133432] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 12/22/2021] [Accepted: 12/23/2021] [Indexed: 05/27/2023]
Abstract
Due to several anthropogenic activities, water bodies have been heavily impacted by contaminants identified in aquatic ecosystems, including pharmaceuticals, personal care products, agricultural and industrial chemicals. Risk assessment based on chemical mixtures is still default in many monitoring studies, with decisions being based solely on a chemical-by-chemical basis. The present study aimed to improve risk assessment procedures in water bodies by focusing on mixtures of chemical substances of different origins. The goal was to analyze potential interactions occurring at different complexity levels (binary and quaternary mixtures) using standardised toxicity assays. Mixture toxicity effects were assessed using Daphnia magna as the model organism and the compounds sodium fluoride, boric acid, ammonium hydroxide and acetaminophen as general representatives of contaminants in the aquatic ecosystem. The results revealed interactions between the compounds, mainly showing antagonism but also dose level and dose ratio-dependent deviations. Overall antagonism was the dominant deviation pattern, particularly at low doses, though synergism was also detected at higher doses or specific ratios. Synergism at low doses was found for the binary mixture of ammonium hydroxide and acetaminophen, two common pollutants, which denotes an enhanced risk to aquatic ecosystems. Independent Action provided more accurate predictions for the quaternary mixture, whereas Concentration Addition overestimated the toxicity of the mixture. Regarding the environmental risk assessment of water bodies, the interaction between chemicals in a mixture should not be neglected. The complexity of the mixture interactions found in the present study highlights the importance of complementing chemical screenings of water bodies with mixture toxicity data, particularly when considering chemicals of multiple origins whose joint action remains unknown.
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Affiliation(s)
- Ana Rita R Silva
- CESAM - Centre for Environmental and Marine Studies, Department of Biology, University of Aveiro, Portugal.
| | - Sandra F Gonçalves
- CESAM - Centre for Environmental and Marine Studies, Department of Biology, University of Aveiro, Portugal
| | - Maria D Pavlaki
- CESAM - Centre for Environmental and Marine Studies, Department of Biology, University of Aveiro, Portugal
| | - Rui G Morgado
- CESAM - Centre for Environmental and Marine Studies, Department of Biology, University of Aveiro, Portugal
| | - Amadeu M V M Soares
- CESAM - Centre for Environmental and Marine Studies, Department of Biology, University of Aveiro, Portugal
| | - Susana Loureiro
- CESAM - Centre for Environmental and Marine Studies, Department of Biology, University of Aveiro, Portugal
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13
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Qian H, Bai Q, Yang X, Akakpo JY, Ji L, Yang L, Rülicke T, Zatloukal K, Jaeschke H, Ni HM, Ding WX. Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice. Acta Pharm Sin B 2021; 11:3791-3805. [PMID: 35024307 PMCID: PMC8727897 DOI: 10.1016/j.apsb.2021.11.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 11/05/2021] [Accepted: 11/08/2021] [Indexed: 12/15/2022] Open
Abstract
Acetaminophen (APAP) overdose can induce liver injury and is the most frequent cause of acute liver failure in the United States. We investigated the role of p62/SQSTM1 (referred to as p62) in APAP-induced liver injury (AILI) in mice. We found that the hepatic protein levels of p62 dramatically increased at 24 h after APAP treatment, which was inversely correlated with the hepatic levels of APAP-adducts. APAP also activated mTOR at 24 h, which is associated with increased cell proliferation. In contrast, p62 knockout (KO) mice showed increased hepatic levels of APAP-adducts detected by a specific antibody using Western blot analysis but decreased mTOR activation and cell proliferation with aggravated liver injury at 24 h after APAP treatment. Surprisingly, p62 KO mice recovered from AILI whereas the wild-type mice still sustained liver injury at 48 h. We found increased number of infiltrated macrophages in p62 KO mice that were accompanied with decreased hepatic von Willebrand factor (VWF) and platelet aggregation, which are associated with increased cell proliferation and improved liver injury at 48 h after APAP treatment. Our data indicate that p62 inhibits the late injury phase of AILI by increasing autophagic selective removal of APAP-adducts and mitochondria but impairs the recovery phase of AILI likely by enhancing hepatic blood coagulation.
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Key Words
- 4EBP-1, translational initiation factor 4E binding protein-1
- AILI, APAP-induced liver injury
- ALT, alanine aminotransferase
- APAP, acetaminophen
- APAP-AD, APAP-adducts
- Autophagy
- CLEC-2, C-type lectin-like receptor
- CYP2E1, cytochrome P450 2E
- Coagulation
- DILI
- GCL, glutamate cysteine ligase
- GSH, glutathione
- H&E, hematoxylin and eosin
- Hepatotoxicity
- KC, Kupffer cells
- KEAP1, Kelch-like ECH-associated protein-1
- KIR, KEAP1-interacting region
- KO, knockout
- LC3, microtubule-associated light chain 3
- Liver regeneration
- Macrophage
- NAC, N-acetylcysteine
- NAPQI, N-acetyl-p-benzoquinone imine
- NF-κB, nuclear factor-κB
- NPCs, non-parenchymal cells
- NQO1, NADPH quinone dehydrogenase 1
- NRF2, nuclear factor erythroid 2-related factor 2
- Platelet
- S6, ribosomal protein S6 kinase
- TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling
- VWF, von Willebrand factor
- WT, wild type
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Affiliation(s)
- Hui Qian
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Qingyun Bai
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- School of Chemistry and Bioengineering, Yichun University, Yichun 336000, China
| | - Xiao Yang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jephte Y. Akakpo
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Lili Ji
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Li Yang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Thomas Rülicke
- Department of Biomedical Sciences, University of Veterinary Medicine Vienna Veterinärplatz, Vienna 1210, Austria
| | - Kurt Zatloukal
- The Institute of Pathology, Medical University of Graz, Graz A-8036, Austria
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Poudel S, Cabrera DP, Bhushan B, Manley MW, Gunewardena S, Jaeschke H, Apte U. Hepatocyte-Specific Deletion of Yes-Associated Protein Improves Recovery From Acetaminophen-Induced Acute Liver Injury. Toxicol Sci 2021; 184:276-285. [PMID: 34546377 PMCID: PMC8633918 DOI: 10.1093/toxsci/kfab115] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Overdose of acetaminophen (APAP) is the major cause of acute liver failure (ALF) in the Western world with very limited treatment options. Previous studies from our groups and others have shown that timely activation of liver regeneration is a critical determinant of transplant-free survival of APAP-induced ALF patients. Here, we report that hepatocyte-specific deletion of Yes-associated protein (Yap), the downstream mediator of the Hippo Kinase signaling pathway results in faster recovery from APAP-induced acute liver injury. Initial studies performed with male C57BL/6J mice showed a rapid activation of Yap and its target genes within first 24 h after APAP administration. Treatment of hepatocyte-specific Yap knockout (Yap-KO) mice with 300 mg/kg APAP resulted in equal initial liver injury but a significantly accelerated recovery in Yap-KO mice. The recovery was accompanied by significantly rapid hepatocyte proliferation supported by faster activation of Wnt/β-catenin pathway. Furthermore, Yap-KO mice had significantly earlier and higher pro-regenerative inflammatory response following APAP overdose. Global gene expression analysis indicated that Yap-KO mice had a robust activation of transcription factors involved in response to endoplasmic reticulum stress (XBP1) and maintaining hepatocyte differentiation (HNF4α). In conclusion, these data indicate that inhibition of Yap in hepatocytes results in rapid recovery from APAP overdose due to an earlier activation of liver regeneration.
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Affiliation(s)
- Samikshya Poudel
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Diego Paine Cabrera
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Bharat Bhushan
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Michael W Manley
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Sumedha Gunewardena
- Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Udayan Apte
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA
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15
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Yi Y, Zhang W, Tao L, Shao Q, Xu Q, Chen Y, Zhang H, Zhang J, Weng D. RIP1 kinase inactivation protects against acetaminophen-induced acute liver injury in mice. Free Radic Biol Med 2021; 174:57-65. [PMID: 34324981 DOI: 10.1016/j.freeradbiomed.2021.07.034] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 07/20/2021] [Accepted: 07/25/2021] [Indexed: 02/05/2023]
Abstract
Many studies have investigated the role of receptor-interacting protein 1 (RIP1) kinase in acetaminophen (APAP) overdose-induced acute liver injury. However, the results were not consistent and there still remain controversies. Importantly, in these previous studies, the usage of DMSO to dissolve the RIP1 kinase inhibitor Nec-1, resulted in misleading conclusion. Our study aimed to determine the role of RIP1 kinase in APAP-induced liver injury, via genetically or pharmaceutically inhibition of RIP1 kinase activity. Our results indicated that APAP-induced liver injury was significantly attenuated in RIP1 kinase-dead (Rip1K45A/K45A) mice compared to WT control. High dosage of APAP-induced mortality was also rescued by RIP1 kinase inactivation. In agreement, RIP1 kinase inhibitor, Nec-1 which was formulated with PEG400, could efficiently alleviate APAP-induced hepatotoxicity. For the underlying mechanism, our results suggested that RIP1 kinase inactivation did not influence the hepatic GSH depletion, but significantly reduced the hepatic cell death and inflammation induced by APAP treatment. Using bone marrow transplantation model, we also demonstrated that it was RIP1 kinase activity in tissue-resident hepatic cells other than hematopoietic-derived cells mainly responsible for APAP-induced liver injury. Our study confirmed the important role of RIP1 kinase activity in APAP-induced acute liver failure.
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Affiliation(s)
- Yuguo Yi
- Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China
| | - Weigao Zhang
- Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China
| | - Liang Tao
- Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China
| | - Qianchao Shao
- Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China
| | - Qian Xu
- Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China
| | - Yuxin Chen
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, 210008, China
| | - Haibing Zhang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 100864, China
| | - Jianfa Zhang
- Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China
| | - Dan Weng
- Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China.
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16
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Groeneveld DJ, Poole LG, Luyendyk JP. Targeting von Willebrand factor in liver diseases: A novel therapeutic strategy? J Thromb Haemost 2021; 19:1390-1408. [PMID: 33774926 PMCID: PMC8582603 DOI: 10.1111/jth.15312] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 03/08/2021] [Accepted: 03/22/2021] [Indexed: 12/11/2022]
Abstract
Acute and chronic liver disease are associated with substantial alterations in the hemostatic system. Evidence from both experimental and clinical studies suggests that anticoagulants slow the progression of liver disease. Efficacy of those anticoagulant drugs is, in part, attributed to a reduction of microthrombi formation within the liver. Although anticoagulant drugs show promising results, bleeding risk associated with these drugs is an obvious drawback, particularly in patients with a complex coagulopathy driven by decreased liver function. Identifying therapies that reduce intrahepatic thrombosis with minimal bleeding risk would significantly advance the field. Among the hemostatic alterations observed in patients are substantially increased levels of the platelet-adhesive protein von Willebrand factor (VWF). In contrast, levels of A Disintegrin and Metalloproteinase with Thrombospondin motifs, the enzyme that regulates VWF activity, are significantly reduced in patients with liver disease. Highly elevated VWF levels are proposed to accelerate intrahepatic thrombus formation and thus be a driver of disease progression. Strong clinical evidence suggesting a link between liver disease and changes in VWF is now being matched by emerging mechanistic data showing a detrimental role for VWF in the progression of liver disease. This review focuses on clinical and experimental evidence supporting a connection between VWF function and the progression of acute and chronic liver diseases. Furthermore, with the recent anticipated approval of several novel therapies targeting VWF, we discuss potential strategies and benefits of targeting VWF as an innovative therapy for patients with liver disease.
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Affiliation(s)
- Dafna J Groeneveld
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, USA
| | - Lauren G Poole
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, USA
| | - James P Luyendyk
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, USA
- Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, USA
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, USA
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17
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Dang XL, Yang LF, Shi L, Li LF, He P, Chen J, Zheng BJ, Yang P, Wen AD. Post-treatment with glycyrrhizin can attenuate hepatic mitochondrial damage induced by acetaminophen in mice. Exp Biol Med (Maywood) 2021; 246:1219-1227. [PMID: 33342284 PMCID: PMC8142107 DOI: 10.1177/1535370220977823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 11/03/2020] [Indexed: 11/16/2022] Open
Abstract
Overdose of acetaminophen (APAP) is responsible for the most cases of acute liver failure worldwide. Hepatic mitochondrial damage mediated by neuronal nitric oxide synthase- (nNOS) induced liver protein tyrosine nitration plays a critical role in the pathophysiology of APAP hepatotoxicity. It has been reported that pre-treatment or co-treatment with glycyrrhizin can protect against hepatotoxicity through prevention of hepatocellular apoptosis. However, the majority of APAP-induced acute liver failure cases are people intentionally taking the drug to commit suicide. Any preventive treatment is of little value in practice. In addition, the hepatocellular damage induced by APAP is considered to be oncotic necrosis rather than apoptosis. In the present study, our aim is to investigate if glycyrrhizin can be used therapeutically and the underlying mechanisms of APAP hepatotoxicity protection. Hepatic damage was induced by 300 mg/kg APAP in balb/c mice, followed with administration of 40, 80, or 160 mg/kg glycyrrhizin 90 min later. Mice were euthanized and harvested at 6 h post-APAP. Compared with model controls, glycyrrhizin post-treatment attenuated hepatic mitochondrial and hepatocellular damages, as indicated by decreased serum glutamate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase activities as well as ameliorated mitochondrial swollen, distortion, and hepatocellular necrosis. Notably, 80 mg/kg glycyrrhizin inhibited hepatic nNOS activity and its mRNA and protein expression levels by 16.9, 14.9, and 28.3%, respectively. These results were consistent with the decreased liver nitric oxide content and liver protein tyrosine nitration indicated by 3-nitrotyrosine staining. Moreover, glycyrrhizin did not affect the APAP metabolic activation, and the survival rate of ALF mice was increased by glycyrrhizin. The present study indicates that post-treatment with glycyrrhizin can dose-dependently attenuate hepatic mitochondrial damage and inhibit the up-regulation of hepatic nNOS induced by APAP. Glycyrrhizin shows promise as drug for the treatment of APAP hepatotoxicity.
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Affiliation(s)
- Xue-Liang Dang
- Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an 710032, China
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an 710038, China
| | - Long-Fei Yang
- Departments of Medical Laboratory and Research Center, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China
| | - Lei Shi
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an 710038, China
| | - Long-Fei Li
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an 710038, China
| | - Ping He
- Renji Hospital, Medical School of Shanghai Jiaotong University, Shanghai 200127, China
| | - Jie Chen
- Renji Hospital, Medical School of Shanghai Jiaotong University, Shanghai 200127, China
| | - Bei-Jie Zheng
- Renji Hospital, Medical School of Shanghai Jiaotong University, Shanghai 200127, China
| | - Peng Yang
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an 710038, China
| | - Ai-Dong Wen
- Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an 710032, China
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18
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Zhang J, Hu C, Li X, Liang L, Zhang M, Chen B, Liu X, Yang D. Protective Effect of Dihydrokaempferol on Acetaminophen-Induced Liver Injury by Activating the SIRT1 Pathway. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2021; 49:705-718. [PMID: 33657990 DOI: 10.1142/s0192415x21500324] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Acetaminophen (APAP) overdose is the leading cause of acute liver failure (ALF) in the Western world, with limited treatment opportunities. 3,5,7,4[Formula: see text]-Tetrahydroxyflavanone (Dihydrokaempferol, DHK, Aromadendrin) is a flavonoid isolated from Chinese herbs and displays high anti-oxidant and anti-inflammatory capacities. In this study, we investigated the protective effect by DHK against APAP-induced liver injury in vitro and in vivo and the potential mechanism of action. Cell viability assays were used to determine the effects of DHK against APAP-induced liver injury. The levels of reactive oxygen species (ROS), serum alanine/aspartate aminotransferases (ALT/AST), liver myeloperoxidase (MPO), and malondialdehyde (MDA) were measured and analyzed to evaluate the effects of DHK on APAP-induced liver injury. Western blotting, immunofluorescence staining, RT-PCR, and Transmission Electron Microscope were carried out to detect the signaling pathways affected by DHK. Here, we found that DHK owned a protective effect on APAP-induced liver injury with a dose-dependent manner. Meanwhile, Western blotting showed that DHK promoted SIRT1 expression and autophagy, activated the NRF2 pathway, and inhibited the translocation of nuclear p65 (NF-[Formula: see text]B) in the presence of APAP. Furthermore, SIRT1 inhibitor EX-527 aggravated APAP-induced hepatotoxicity when treating with DHK. Molecular docking results suggested potential interaction between DHK and SIRT1. Taken together, our study demonstrates that DHK protects against APAP-induced liver injury by activating the SIRT1 pathway, thereby promoting autophagy, reducing oxidative stress injury, and inhibiting inflammatory responses.
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Affiliation(s)
- Jiaqi Zhang
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P. R. China.,Shanghai TCM-Integrated Institute of Vascular Anomalies, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional, Chinese Medicine, Shanghai 200082, P. R. China
| | - Cheng Hu
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P. R. China
| | - Xiulong Li
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P. R. China
| | - Li Liang
- Department of Respiratory Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201999, P. R. China
| | - Mingcai Zhang
- Shuguang Hospital Affiliated to Shanghai University of Traditional, Chinese Medicine, Shanghai 201203, P. R. China
| | - Bo Chen
- Shuguang Hospital Affiliated to Shanghai University of Traditional, Chinese Medicine, Shanghai 201203, P. R. China
| | - Xinhua Liu
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P. R. China
| | - Dicheng Yang
- Department of Cardiovascular Surgery, Shanghai General Hospital Shanghai, Jiao Tong University School of Medicine, Shanghai 200080, P. R. China
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Almeida AACD, Ferreira JRDO, de Carvalho RBF, Rizzo MDS, Lopes LDS, Dittz D, Castro E Souza JMD, Ferreira PMP. Non-clinical toxicity of (+)-limonene epoxide and its physio-pharmacological properties on neurological disorders. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2020; 393:2301-2314. [PMID: 32653979 DOI: 10.1007/s00210-020-01943-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 07/06/2020] [Indexed: 12/13/2022]
Abstract
The compound (+)-limonene epoxide has antioxidant, anxiolytic, and antihelminthic properties. However, investigations to determine its long-term exposure were not performed. We investigated the systemic toxicological profile after chronic exposure as well as the antidepressant and antiepileptic potentialities of (+)-limonene epoxide on mice. Initially, we evaluated acute toxicity on Artemia salina nauplii and cytotoxicity on mice erythrocytes and peripheral blood mononuclear cells (PBMC). Aftterwards, mice were chronically treated for 120 days by gavage with (+)-limonene epoxide (25, 50, and 75 mg/kg/day) and this exposure was assessed by pathophysiological measurements. For antidepressant and anticonvulsivant analysis, we performed the forced swimming and tail suspension protocols and pentylenetetrazol- and picrotoxin-induced seizures, respectively. (+)-Limonene epoxide showed a LC50 value of 318.7 μg/mL on A. salina shrimps, caused lysis of red blood cells at higher concentrations only but did not show cytotoxicity on PMBC, which suggests pharmacological safety if plasma concentrations do not exceed 100 μg/mL. Macroscopic, hematological, clinical chemistry, and nutritional changes were not detected, though focal areas of hepatic necrosis, inflammatory infiltrate, and karyolysis have been detected at 75 mg/kg/day. The compound inhibited the developing of pentylenetetrazol- and picrotoxin-induced seizures, decreased deaths, and reduced immobility times, mainly at 75 mg/kg. So, it reversed reserpine effects, suggesting antidepressant effects should be linked to serotonergic and/or adrenergic transmission. It is feasible that (+)-limonene epoxide plays a benzodiazepine-like anticonvulsive action and may be also recommended as an antidote for poisonings caused by central depressants.
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Affiliation(s)
- Antonia Amanda Cardoso de Almeida
- Postgraduate Program in Pharmaceutical Sciences, Federal University of Piauí, Teresina, 64049-550, Brazil
- Department of Biophysics and Physiology, Laboratory of Experimental Cancerology, Federal University of Piauí, Universitária Avenue, Ininga, Teresina, Piauí, 64049-550, Brazil
| | | | | | | | - Luciano da Silva Lopes
- Postgraduate Program in Pharmaceutical Sciences, Federal University of Piauí, Teresina, 64049-550, Brazil
- Department of Biophysics and Physiology, Laboratory of Experimental Cancerology, Federal University of Piauí, Universitária Avenue, Ininga, Teresina, Piauí, 64049-550, Brazil
| | - Dalton Dittz
- Department of Biochemistry and Pharmacology, Federal University of Piauí, Teresina, 64049-550, Brazil
| | - João Marcelo de Castro E Souza
- Postgraduate Program in Pharmaceutical Sciences, Federal University of Piauí, Teresina, 64049-550, Brazil
- Department of Biochemistry and Pharmacology, Federal University of Piauí, Teresina, 64049-550, Brazil
| | - Paulo Michel Pinheiro Ferreira
- Postgraduate Program in Pharmaceutical Sciences, Federal University of Piauí, Teresina, 64049-550, Brazil.
- Department of Biophysics and Physiology, Laboratory of Experimental Cancerology, Federal University of Piauí, Universitária Avenue, Ininga, Teresina, Piauí, 64049-550, Brazil.
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20
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COVID-19-associated gastrointestinal and liver injury: clinical features and potential mechanisms. Signal Transduct Target Ther 2020; 5:256. [PMID: 33139693 PMCID: PMC7605138 DOI: 10.1038/s41392-020-00373-7] [Citation(s) in RCA: 141] [Impact Index Per Article: 28.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 10/08/2020] [Accepted: 10/15/2020] [Indexed: 02/07/2023] Open
Abstract
Coronavirus disease-2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection is spreading globally and poses a huge threat to human health. Besides common respiratory symptoms, some patients with COVID-19 experience gastrointestinal symptoms, such as diarrhea, nausea, vomiting, and loss of appetite. SARS-CoV-2 might infect the gastrointestinal tract through its viral receptor angiotensin-converting enzyme 2 (ACE2) and there is increasing evidence of a possible fecal–oral transmission route. In addition, there exist multiple abnormalities in liver enzymes. COVID-19-related liver injury may be due to drug-induced liver injury, systemic inflammatory reaction, and hypoxia–ischemia reperfusion injury. The direct toxic attack of SARS-CoV-2 on the liver is still questionable. This review highlights the manifestations and potential mechanisms of gastrointestinal and hepatic injuries in COVID-19 to raise awareness of digestive system injury in COVID-19.
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Alternatively activated macrophages promote resolution of necrosis following acute liver injury. J Hepatol 2020; 73:349-360. [PMID: 32169610 PMCID: PMC7378576 DOI: 10.1016/j.jhep.2020.02.031] [Citation(s) in RCA: 130] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 02/19/2020] [Accepted: 02/24/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIM Following acetaminophen (APAP) overdose, acute liver injury (ALI) can occur in patients that present too late for N-acetylcysteine treatment, potentially leading to acute liver failure, systemic inflammation, and death. Macrophages influence the progression and resolution of ALI due to their innate immunological function and paracrine activity. Syngeneic primary bone marrow-derived macrophages (BMDMs) were tested as a cell-based therapy in a mouse model of APAP-induced ALI (APAP-ALI). METHODS Several phenotypically distinct BMDM populations were delivered intravenously to APAP-ALI mice when hepatic necrosis was established, and then evaluated based on their effects on injury, inflammation, immunity, and regeneration. In vivo phagocytosis assays were used to interrogate the phenotype and function of alternatively activated BMDMs (AAMs) post-injection. Finally, primary human AAMs sourced from healthy volunteers were evaluated in immunocompetent APAP-ALI mice. RESULTS BMDMs rapidly localised to the liver and spleen within 4 h of administration. Injection of AAMs specifically reduced hepatocellular necrosis, HMGB1 translocation, and infiltrating neutrophils following APAP-ALI. AAM delivery also stimulated proliferation in hepatocytes and endothelium, and reduced levels of several circulating proinflammatory cytokines within 24 h. AAMs displayed a high phagocytic activity both in vitro and in injured liver tissue post-injection. Crosstalk with the host innate immune system was demonstrated by reduced infiltrating host Ly6Chi macrophages in AAM-treated mice. Importantly, therapeutic efficacy was partially recapitulated using clinical-grade primary human AAMs in immunocompetent APAP-ALI mice, underscoring the translational potential of these findings. CONCLUSION We identify that AAMs have value as a cell-based therapy in an experimental model of APAP-ALI. Human AAMs warrant further evaluation as a potential cell-based therapy for APAP overdose patients with established liver injury. LAY SUMMARY After an overdose of acetaminophen (paracetamol), some patients present to hospital too late for the current antidote (N-acetylcysteine) to be effective. We tested whether macrophages, an injury-responsive leukocyte that can scavenge dead/dying cells, could serve as a cell-based therapy in an experimental model of acetaminophen overdose. Injection of alternatively activated macrophages rapidly reduced liver injury and reduced several mediators of inflammation. Macrophages show promise to serve as a potential cell-based therapy for acute liver injury.
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Zhao L, Zhang J, Hu C, Wang T, Lu J, Wu C, Chen L, Jin M, Ji G, Cao Q, Jiang Y. Apigenin Prevents Acetaminophen-Induced Liver Injury by Activating the SIRT1 Pathway. Front Pharmacol 2020; 11:514. [PMID: 32425778 PMCID: PMC7212374 DOI: 10.3389/fphar.2020.00514] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 04/01/2020] [Indexed: 01/29/2023] Open
Abstract
Acetaminophen (APAP) overdose is the main cause of acute liver failure. Apigenin (API) is a natural dietary flavonol with high antioxidant capacity. Herein, we investigated protection by API against APAP-induced liver injury in mice, and explored the potential mechanism. Cell viability assays and mice were used to evaluate the effects of API against APAP-induced liver injury. Western blotting, immunofluorescence staining, RT-PCR, and Transmission Electron Microscope were carried out to determine the signalling pathways affected by API. Analysis of mouse serum levels of alanine/aspartate aminotransferase (ALT/AST), malondialdehyde (MDA), liver myeloperoxidase (MPO) activity, glutathione (GSH), and reactive oxygen species (ROS) revealed that API (80 mg/kg) owned protective effect on APAP-induced liver injury. Meanwhile, API ameliorated the decreased cell viability in L-02 cells incubated by APAP with a dose dependent. Furthermore, API promoted SIRT1 expression and deacetylated p53. Western blotting showed that API promoted APAP-induced autophagy, activated the NRF2 pathway, and inhibited the transcriptional activation of nuclear p65 in the presence of APAP. Furthermore, SIRT1 inhibitor EX-527 reduced protection by API against APAP-induced hepatotoxicity. Molecular docking results indicate potential interaction between API and SIRT1. API prevents APAP-induced liver injury by regulating the SIRT1-p53 axis, thereby promoting APAP-induced autophagy and ameliorating APAP-induced inflammatory responses and oxidative stress injury.
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Affiliation(s)
- Licong Zhao
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Second Clinical College, China Medical University, Shenyang, China
| | - Jiaqi Zhang
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Cheng Hu
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tao Wang
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Juan Lu
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chenqu Wu
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Long Chen
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mingming Jin
- Shanghai University of Medicine & Health Sciences of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qin Cao
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuanye Jiang
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Bhushan B, Gunewardena S, Edwards G, Apte U. Comparison of liver regeneration after partial hepatectomy and acetaminophen-induced acute liver failure: A global picture based on transcriptome analysis. Food Chem Toxicol 2020; 139:111186. [PMID: 32045647 DOI: 10.1016/j.fct.2020.111186] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 02/05/2020] [Accepted: 02/06/2020] [Indexed: 12/19/2022]
Abstract
Liver regenerates following surgical removal and after drug-induced liver injury (DILI). However, most of the mechanisms of liver regeneration were identified using partial hepatectomy (PHX) model rather than using DILI models. We compared mechanisms of liver regeneration following PHX and after acetaminophen (APAP) overdose, a DILI model, using transcriptomic approach. Kinetics of hepatocyte proliferation and global gene expression profiles were studied in male C57BL/6J mice either subjected to PHX or following APAP overdose. Liver regeneration was much more synchronized after PHX as compared to APAP overdose. Transcriptomics analysis revealed activation of common upstream regulators in both models including growth factors HGF, EGF and VEGF; and cytokines IL6 and TNFα. However, magnitude of activation and temporality was significantly differed between the two models. HGF and VEGF showed similar activation between PHX and APAP but activation of EGF was significantly stronger in the APAP model. Activation of IL6 and TNFα transcriptional programs was delayed but remarkably higher in APAP. These dissimilarities could be attributed to inherent differences in the two models including significant injury and inflammation exclusively in the APAP model. This study highlights need to study mechanisms of liver regeneration after DILI separately from the mechanisms of regeneration PHX.
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Affiliation(s)
- Bharat Bhushan
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | | | - Genea Edwards
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Udayan Apte
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
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Nunes B. Ecotoxicological Effects of the Drug Paracetamol: A Critical Review of Past Ecotoxicity Assessments and Future Perspectives. THE HANDBOOK OF ENVIRONMENTAL CHEMISTRY 2020. [DOI: 10.1007/698_2020_546] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Groeneveld D, Cline-Fedewa H, Baker KS, Williams KJ, Roth RA, Mittermeier K, Lisman T, Palumbo JS, Luyendyk JP. Von Willebrand factor delays liver repair after acetaminophen-induced acute liver injury in mice. J Hepatol 2020; 72:146-155. [PMID: 31606553 PMCID: PMC6941657 DOI: 10.1016/j.jhep.2019.09.030] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 09/05/2019] [Accepted: 09/08/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIM Acetaminophen (APAP)-induced acute liver failure is associated with substantial alterations in the hemostatic system. In mice, platelets accumulate in the liver after APAP overdose and appear to promote liver injury. Interestingly, patients with acute liver injury have highly elevated levels of the platelet-adhesive protein von Willebrand factor (VWF), but a mechanistic connection between VWF and progression of liver injury has not been established. We tested the hypothesis that VWF contributes directly to experimental APAP-induced acute liver injury. METHODS Wild-type mice and VWF-deficient (Vwf-/-) mice were given a hepatotoxic dose of APAP (300 mg/kg, i.p.) or vehicle (saline). VWF plasma levels were measured by ELISA, and liver necrosis or hepatocyte proliferation was measured by immunohistochemistry. Platelet and VWF deposition were measured by immunofluorescence. RESULTS In wild-type mice, VWF plasma levels, high molecular weight (HMW) VWF multimers, and VWF activity decreased 24 h after APAP challenge. These changes coupled to robust hepatic VWF and platelet deposition, although VWF deficiency had minimal effect on peak hepatic platelet accumulation or liver injury. VWF plasma levels were elevated 48 h after APAP challenge, but with relative reductions in HMW multimers and VWF activity. Whereas hepatic platelet aggregates persisted in livers of APAP-challenged wild-type mice, platelets were nearly absent in Vwf-/- mice 48 h after APAP challenge. The absence of platelet aggregates was linked to dramatically accelerated repair of the injured liver. Complementing observations in Vwf-/- mice, blocking VWF or the platelet integrin αIIbβ3 during development of injury significantly reduced hepatic platelet aggregation and accelerated liver repair in APAP-challenged wild-type mice. CONCLUSION These studies are the first to suggest a mechanistic link between VWF, hepatic platelet accumulation, and liver repair. Targeting VWF might provide a novel therapeutic approach to improve repair of the APAP-injured liver. LAY SUMMARY Patients with acute liver injury due to acetaminophen overdose have highly elevated levels of the platelet-adhesive protein von Willebrand factor. It is not known whether von Willebrand factor plays a direct role in the progression of acute liver injury. We discovered that von Willebrand factor delays repair of the acetaminophen-injured liver in mice and that targeting von Willebrand factor, even in mice with established liver injury, accelerates liver repair.
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Affiliation(s)
- Dafna Groeneveld
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, USA
| | - Holly Cline-Fedewa
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, USA
| | - Kevin S Baker
- Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, USA; Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, USA
| | - Kurt J Williams
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, USA
| | - Robert A Roth
- Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, USA; Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, USA
| | - Karen Mittermeier
- Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Ton Lisman
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Joseph S Palumbo
- Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - James P Luyendyk
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, USA; Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, USA; Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, USA.
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26
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Presentations Related to Acute Paracetamol Intoxication in an Urban Emergency Department in Switzerland. Emerg Med Int 2019; 2019:3130843. [PMID: 31885923 PMCID: PMC6925749 DOI: 10.1155/2019/3130843] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 11/22/2019] [Indexed: 11/25/2022] Open
Abstract
Aim To investigate the characteristics of Emergency Department (ED) presentations due to acute paracetamol intoxication. Methods Retrospective observational study of patients presenting to the ED of Bern University Hospital between May 1, 2012, and October 31, 2018, due to a paracetamol overdose (defined as intake of >4 g/24 h). Cases were identified using the full-text search of the electronic patient database and were grouped into intentional (suicidal/parasuicidal) and unintentional intoxications (e.g., patient unaware of maximal daily dose). Results During the study period, 181 cases were included and 143 (79%) of those were intentional. Compared to the patients in the unintentional group, patients in the intentional group were more often female (85% vs 45%, p < 0.001) and younger (median age 23.0 vs 43.5 years, p < 0.001), more frequently suffered from psychiatric comorbidities (93%, (including 49% with borderline personality disorder) vs 24%, p < 0.001), and paracetamol was more often taken as a single dose (80% vs 13%, p < 0.001). Although the median daily ingested dose was lower in the unintentional than in the intentional group (8.2 g vs 12.9 g, p < 0.001), patients in the unintentional group presented later (29% vs 84% within 24 h of ingestion, p < 0.001), included more cases of acute liver failure (nine (24%) vs six (4%), p < 0.001), and were more often hospitalised (24% vs 52% treated as outpatients, p=0.002). There were no significant differences between the groups regarding drug-induced liver injury (seven cases (5%) in the intentional and one (3%) in the unintentional group) or fatalities (one in each group). Conclusions The majority of presentations due to paracetamol poisoning were intentional, most commonly in female patients with borderline personality disorder. Patients with unintentional paracetamol intoxication had worse outcomes with respect to acute liver failure and hospitalisation. Future preventive measures should raise awareness of paracetamol toxicity in the general population and encourage particular attention and frequent follow-ups when prescribing paracetamol for vulnerable groups.
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Aqueous Partition of Methanolic Extract of Dicranopteris linearis Leaves Protects against Liver Damage Induced by Paracetamol. Nutrients 2019; 11:nu11122945. [PMID: 31817058 PMCID: PMC6950669 DOI: 10.3390/nu11122945] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 10/09/2019] [Accepted: 10/11/2019] [Indexed: 01/24/2023] Open
Abstract
This study aimed to determine the antioxidant and hepatoprotective activities of semi-purified aqueous partition obtained from the methanol extract of Dicranopteris linearis (AQDL) leaves against paracetamol (PCM)-induced liver intoxication in rats. The test solutions, AQDL (50, 250, and 500 mg/kg), were administered orally to rats (n = 6) once daily for seven consecutive days followed by the hepatotoxicity induction using 3 g/kg PCM (p.o.). Blood was collected for serum biochemical parameters analysis while the liver was collected for histopathological examination and endogenous antioxidant enzymes analysis. AQDL was also subjected to antioxidant determination and phytochemical analysis. Results obtained show that AQDL possessed high total phenolic content (TPC) value and remarkable radical scavenging activities. AQDL also significantly (p < 0.05) reduced the liver weight/body weight (LW/BW) ratio or serum level of ALT, AST, and total bilirubin while significantly (p < 0.05) increase the level of superoxide dismutase (SOD) and catalase (CAT) without affecting the malondialdehyde (MDA) in the liver indicating its hepatoprotective effect. Phytoconstituents analyses showed only the presence of saponins and triterpenes, but lack of flavonoids. In conclusion, AQDL exerts hepatoprotective activity via its high antioxidant potential and ability to modulate the endogenous enzymatic antioxidant defense system possibly via the synergistic action of saponins and triterpenes.
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Schweighardt AE, Juba KM. A Systematic Review of the Evidence Behind Use of Reduced Doses of Acetaminophen in Chronic Liver Disease. J Pain Palliat Care Pharmacother 2019; 32:226-239. [DOI: 10.1080/15360288.2019.1611692] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Anne E. Schweighardt
- Anne E. Schweighardt, PharmD, and Katherine M. Juba, PharmD, are with the Department of Pharmacy Practice, Wegmans School of Pharmacy, St. John Fisher College, Rochester, New York, USA
| | - Katherine M. Juba
- Anne E. Schweighardt, PharmD, and Katherine M. Juba, PharmD, are with the Department of Pharmacy Practice, Wegmans School of Pharmacy, St. John Fisher College, Rochester, New York, USA
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29
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An Y, Wang P, Xu P, Tung HC, Xie Y, Kirisci L, Xu M, Ren S, Tian X, Ma X, Xie W. An Unexpected Role of Cholesterol Sulfotransferase and its Regulation in Sensitizing Mice to Acetaminophen-Induced Liver Injury. Mol Pharmacol 2019; 95:597-605. [PMID: 30944208 PMCID: PMC6491915 DOI: 10.1124/mol.118.114819] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 03/17/2019] [Indexed: 12/13/2022] Open
Abstract
Overdose of acetaminophen (APAP) is the leading cause of acute liver failure (ALF) in the United States. The sulfotransferase-mediated sulfation of APAP is widely believed to be a protective mechanism to attenuate the hepatotoxicity of APAP. The cholesterol sulfotransferase SULT2B1b is best known for its activity in catalyzing the sulfoconjugation of cholesterol to synthesize cholesterol sulfate. SULT2B1b can be transcriptionally and positively regulated by the hepatic nuclear factor 4α (HNF4α). In this study, we uncovered an unexpected role for SULT2B1b in APAP toxicity. Hepatic overexpression of SULT2B1b sensitized mice to APAP-induced liver injury, whereas ablation of the Sult2B1b gene in mice conferred resistance to the APAP hepatotoxicity. Consistent with the notion that Sult2B1b is a transcriptional target of HNF4α, overexpression of HNF4α sensitized mice or primary hepatocytes to APAP-induced hepatotoxicity in a Sult2B1b-dependent manner. We conclude that the HNF4α-SULT2B1b axis has a unique role in APAP-induced acute liver injury, and SULT2B1b induction might be a risk factor for APAP hepatotoxicity.
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Affiliation(s)
- Yunqi An
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
| | - Pengcheng Wang
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
| | - Pengfei Xu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
| | - Hung-Chun Tung
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
| | - Yang Xie
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
| | - Levent Kirisci
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
| | - Meishu Xu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
| | - Songrong Ren
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
| | - Xin Tian
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
| | - Xiaochao Ma
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
| | - Wen Xie
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, (Y.A., P.W., P.X., H-C.T., Y.X., L.K., M.X., S.R., X.T., X.M., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (X.T.)
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Pannala VR, Vinnakota KC, Rawls KD, Estes SK, O'Brien TP, Printz RL, Papin JA, Reifman J, Shiota M, Young JD, Wallqvist A. Mechanistic identification of biofluid metabolite changes as markers of acetaminophen-induced liver toxicity in rats. Toxicol Appl Pharmacol 2019; 372:19-32. [PMID: 30974156 DOI: 10.1016/j.taap.2019.04.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/22/2019] [Accepted: 04/05/2019] [Indexed: 12/12/2022]
Abstract
Acetaminophen (APAP) is the most commonly used analgesic and antipyretic drug in the world. Yet, it poses a major risk of liver injury when taken in excess of the therapeutic dose. Current clinical markers do not detect the early onset of liver injury associated with excess APAP-information that is vital to reverse injury progression through available therapeutic interventions. Hence, several studies have used transcriptomics, proteomics, and metabolomics technologies, both independently and in combination, in an attempt to discover potential early markers of liver injury. However, the casual relationship between these observations and their relation to the APAP mechanism of liver toxicity are not clearly understood. Here, we used Sprague-Dawley rats orally gavaged with a single dose of 2 g/kg of APAP to collect tissue samples from the liver and kidney for transcriptomic analysis and plasma and urine samples for metabolomic analysis. We developed and used a multi-tissue, metabolism-based modeling approach to integrate these data, characterize the effect of excess APAP levels on liver metabolism, and identify a panel of plasma and urine metabolites that are associated with APAP-induced liver toxicity. Our analyses, which indicated that pathways involved in nucleotide-, lipid-, and amino acid-related metabolism in the liver were most strongly affected within 10 h following APAP treatment, identified a list of potential metabolites in these pathways that could serve as plausible markers of APAP-induced liver injury. Our approach identifies toxicant-induced changes in endogenous metabolism, is applicable to other toxicants based on transcriptomic data, and provides a mechanistic framework for interpreting metabolite alterations.
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Affiliation(s)
- Venkat R Pannala
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA; Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, MD 21702, USA.
| | - Kalyan C Vinnakota
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA; Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, MD 21702, USA
| | - Kristopher D Rawls
- Department of Biomedical Engineering, University of Virginia, Box 800759, Health System, Charlottesville, Virginia 22908, USA
| | - Shanea K Estes
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Tracy P O'Brien
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Richard L Printz
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Jason A Papin
- Department of Biomedical Engineering, University of Virginia, Box 800759, Health System, Charlottesville, Virginia 22908, USA
| | - Jaques Reifman
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, MD 21702, USA
| | - Masakazu Shiota
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Jamey D Young
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemical and Biomolecular Engineering, Vanderbilt University School of Engineering, Nashville, TN 37232, USA.
| | - Anders Wallqvist
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, MD 21702, USA.
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Daniel D, Dionísio R, de Alkimin GD, Nunes B. Acute and chronic effects of paracetamol exposure on Daphnia magna: how oxidative effects may modulate responses at distinct levels of organization in a model species. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2019; 26:3320-3329. [PMID: 30506442 DOI: 10.1007/s11356-018-3788-y] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 11/16/2018] [Indexed: 06/09/2023]
Abstract
The modern usage of pharmaceutical drugs has led to a progressive increase in their presence and environment concentrations, particularly in the aquatic compartment which is the most common final dumping location for this specific class of chemicals. These substances, due to their chemical and biological properties, can exert mostly uncharacterized toxic effects to non-target aquatic species, given the diverse pathways they activate, and the large number of putative targets in the wild. Among drugs in the environment, paracetamol assumes a leading role, considering its widespread therapeutic use and consequently, environmental presence. The present study aimed to assess the acute and chronic effects of paracetamol, in ecologically relevant levels, in the freshwater cladoceran Daphnia magna, namely focusing on biochemical and reproductive parameters. Considering the pro-oxidant effects of paracetamol, already described for a large set of aquatic organisms, specific enzymes involved in the anti-oxidant and metabolic responses were quantified, namely catalase (CAT) and glutathione S-transferases (GSTs) activities. Cholinesterases (ChEs) activity was quantified to evaluate the capacity of paracetamol to induce neurotoxicity, an indirect outcome of oxidative effects by paracetamol, that may affect feeding behavior and reproductive outcomes of this crustacean. Paracetamol in the tested levels showed no effect on reproductive traits of D. magna. Results obtained for organisms acutely exposed included significant increases in the activities of both GSTs and CAT, demonstrating a short-term pro-oxidative effect by paracetamol. On the contrary, ChEs activity was significantly decreased in organisms exposed to this drug, showing a possible interference with neurotransmission. On the contrary, no noteworthy effects were reported for organisms chronically exposed to ecologically realistic concentrations, evidencing the transient nature of the obtained biological response. These results demonstrate the responsiveness of D. magna to paracetamol, especially for high levels of exposure that, despite not being environmentally relevant, are able to trigger significant antioxidant responses. No population effects were likely to be caused by realistic levels of paracetamol, and the absence of biochemical changes after chronic exposure suggests that this specific organism may not be deleteriously affected by low levels of paracetamol, under real scenarios of contamination.
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Affiliation(s)
- David Daniel
- Departamento de Biologia, Universidade de Aveiro, Campus de Santiago, 3810-193, Aveiro, Portugal
| | - Ricardo Dionísio
- Departamento de Biologia, Universidade de Aveiro, Campus de Santiago, 3810-193, Aveiro, Portugal
| | - Gilberto Dias de Alkimin
- Departamento de Biologia, Universidade de Aveiro, Campus de Santiago, 3810-193, Aveiro, Portugal
- Centro de Estudos do Ambiente e do Mar (CESAM), Universidade de Aveiro, Campus de Santiago, 3810-193, Aveiro, Portugal
| | - Bruno Nunes
- Departamento de Biologia, Universidade de Aveiro, Campus de Santiago, 3810-193, Aveiro, Portugal.
- Centro de Estudos do Ambiente e do Mar (CESAM), Universidade de Aveiro, Campus de Santiago, 3810-193, Aveiro, Portugal.
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Hepatoprotective Effect of Polysaccharides Isolated from Dendrobium officinale against Acetaminophen-Induced Liver Injury in Mice via Regulation of the Nrf2-Keap1 Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:6962439. [PMID: 30116489 PMCID: PMC6079321 DOI: 10.1155/2018/6962439] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 04/20/2018] [Accepted: 05/20/2018] [Indexed: 02/07/2023]
Abstract
The effect of polysaccharides isolated from Dendrobium officinale (DOP) on acetaminophen- (APAP-) induced hepatotoxicity and the underlying mechanisms involved are investigated. Male Institute of Cancer Research (ICR) mice were randomly assigned to six groups: (1) control, (2) vehicle (APAP, 230 mg/kg), (3) N-acetylcysteine (100 mg/kg), (4) 50 mg/kg DOP, (5) 100 mg/kg DOP, and (6) 200 mg/kg DOP. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the serum and glutathione (GSH), malondialdehyde (MDA), catalase (CAT), total antioxidant capacity (T-AOC), myeloperoxidase (MPO), and reactive oxygen species (ROS) levels in the liver were determined after the death of the mice. The histological examination of the liver was also performed. The effect of DOP on the Kelch-like ECH-associated protein 1- (Keap1-) nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway was evaluated using Western blot analysis and real-time polymerase chain reaction (PCR). The results showed that DOP treatment significantly alleviated the hepatic injury. The decrease in ALT and AST levels in the serum and ROS, MDA, and MPO contents in the liver, as well as the increases in GSH, CAT, and T-AOC in the liver, were observed after DOP treatment. DOP treatment significantly induced the dissociation of Nrf2 from the Nrf2-Keap1 complex and promoted the Nrf2 nuclear translocation. Subsequently, DOP-mediated Nrf2 activation triggered the transcription and expressions of the glutamate-cysteine ligase catalytic (GCLC) subunit, glutamate-cysteine ligase regulatory subunit (GCLM), heme oxygenase-1 (HO-1), and NAD(P)H dehydrogenase quinone 1 (NQO1) in APAP-treated mice. The present study revealed that DOP treatment exerted potentially hepatoprotective effects against APAP-induced liver injury. Further investigation about mechanisms indicated that DOP exerted the hepatoprotective effect by suppressing the oxidative stress and activating the Nrf2-Keap1 signaling pathway.
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Pant A, Kopec AK, Baker KS, Cline-Fedewa H, Lawrence DA, Luyendyk JP. Plasminogen Activator Inhibitor-1 Reduces Tissue-Type Plasminogen Activator-Dependent Fibrinolysis and Intrahepatic Hemorrhage in Experimental Acetaminophen Overdose. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:1204-1212. [PMID: 29454747 PMCID: PMC5911680 DOI: 10.1016/j.ajpath.2018.01.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 12/21/2017] [Accepted: 01/11/2018] [Indexed: 12/16/2022]
Abstract
Acetaminophen (APAP)-induced liver injury in mice is associated with activation of the coagulation cascade and deposition of fibrin in liver. Plasminogen activator inhibitor-1 (PAI-1) is an important physiological inhibitor of tissue-type plasminogen activator (tPA) and plays a critical role in fibrinolysis. PAI-1 expression is increased in both experimental APAP-induced liver injury and patients with acute liver failure. Prior studies have shown that PAI-1 prevents intrahepatic hemorrhage and mortality after APAP challenge, but the downstream mechanisms are not clear. We tested the hypothesis that PAI-1 limits liver-related morbidity after APAP challenge by reducing tPA-dependent fibrinolysis. Compared with APAP-challenged (300 mg/kg) wild-type mice, hepatic deposition of cross-linked fibrin was reduced, with intrahepatic congestion and hemorrhage increased in PAI-1-deficient mice 24 hours after APAP overdose. Administration of recombinant wild-type human PAI-1 reduced intrahepatic hemorrhage 24 hours after APAP challenge in PAI-1-/- mice, whereas a mutant PAI-1 lacking antiprotease function had no effect. Of interest, tPA deficiency alone did not affect APAP-induced liver damage. In contrast, fibrinolysis, intrahepatic congestion and hemorrhage, and mortality driven by PAI-1 deficiency were reduced in APAP-treated tPA-/-/PAI-1-/- double-knockout mice. The results identify PAI-1 as a critical regulator of intrahepatic fibrinolysis in experimental liver injury. Moreover, the results suggest that the balance between PAI-1 and tPA activity is an important determinant of liver pathology after APAP overdose.
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Affiliation(s)
- Asmita Pant
- Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan; Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan
| | - Anna K Kopec
- Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan; Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan
| | - Kevin S Baker
- Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan
| | - Holly Cline-Fedewa
- Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan
| | - Daniel A Lawrence
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - James P Luyendyk
- Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan; Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
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McGreal SR, Bhushan B, Walesky C, McGill MR, Lebofsky M, Kandel SE, Winefield RD, Jaeschke H, Zachara NE, Zhang Z, Tan EP, Slawson C, Apte U. Modulation of O-GlcNAc Levels in the Liver Impacts Acetaminophen-Induced Liver Injury by Affecting Protein Adduct Formation and Glutathione Synthesis. Toxicol Sci 2018; 162:599-610. [PMID: 29325178 PMCID: PMC6012490 DOI: 10.1093/toxsci/kfy002] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Overdose of acetaminophen (APAP) results in acute liver failure. We have investigated the role of a posttranslational modification of proteins called O-GlcNAcylation, where the O-GlcNAc transferase (OGT) adds and O-GlcNAcase (OGA) removes a single β-D-N-acetylglucosamine (O-GlcNAc) moiety, in the pathogenesis of APAP-induced liver injury. Hepatocyte-specific OGT knockout mice (OGT KO), which have reduced O-GlcNAcylation, and wild-type (WT) controls were treated with 300 mg/kg APAP and the development of injury was studied over a time course from 0 to 24 h. OGT KO mice developed significantly lower liver injury as compared with WT mice. Hepatic CYP2E1 activity and glutathione (GSH) depletion following APAP treatment were not different between WT and OGT KO mice. However, replenishment of GSH and induction of GSH biosynthesis genes were significantly faster in the OGT KO mice. Next, male C57BL/6 J mice were treated Thiamet-G (TMG), a specific inhibitor of OGA to induce O-GlcNAcylation, 1.5 h after APAP administration and the development of liver injury was studied over a time course of 0-24 h. TMG-treated mice exhibited significantly higher APAP-induced liver injury. Treatment with TMG did not affect hepatic CYP2E1 levels, GSH depletion, APAP-protein adducts, and APAP-induced mitochondrial damage. However, GSH replenishment and GSH biosynthesis genes were lower in TMG-treated mice after APAP overdose. Taken together, these data indicate that induction in cellular O-GlcNAcylation exacerbates APAP-induced liver injury via dysregulation of hepatic GSH replenishment response.
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Affiliation(s)
- Steven R McGreal
- The Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Bharat Bhushan
- The Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Chad Walesky
- The Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Mitchell R McGill
- The Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Margitta Lebofsky
- The Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Sylvie E Kandel
- The Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Robert D Winefield
- The Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Hartmut Jaeschke
- The Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Natasha E Zachara
- Department of Biological Chemistry, The John Hopkins School of Medicine, Baltimore, Maryland 21205
| | - Zhen Zhang
- Department of Biochemistry and Molecular Biology, The University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Ee Phie Tan
- Department of Biochemistry and Molecular Biology, The University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Chad Slawson
- Department of Biochemistry and Molecular Biology, The University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Udayan Apte
- The Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
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Abstract
Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the US, and decades of intense study of its pathogenesis resulted in the development of the antidote N-acetylcysteine, which facilitates scavenging of the reactive metabolite and is the only treatment in clinical use. However, the narrow therapeutic window of this intervention necessitates a better understanding of the intricacies of APAP-induced liver injury for the development of additional therapeutic approaches that can benefit late-presenting patients. More recent investigations into APAP hepatotoxicity have established the critical role of mitochondrial dysfunction in mediating liver injury as well as clarified mechanisms of APAP-induced hepatocyte cell death. Thus, it is now established that mitochondrial oxidative and nitrosative stress is a key mechanistic feature involved in downstream signaling after APAP overdose. The identification of specific mediators of necrotic cell death further establishes the regulated nature of APAP-induced hepatocyte cell death. In addition, the discovery of the role of mitochondrial dynamics and autophagy in APAP-induced liver injury provides additional insight into the elaborate cell signaling mechanisms involved in the pathogenesis of this important clinical problem. In spite of these new insights into the mechanisms of liver injury, significant controversy still exists on the role of innate immunity in APAP-induced hepatotoxicity.
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Affiliation(s)
- Anup Ramachandran
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
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Shen Z, Wang Y, Su Z, Kou R, Xie K, Song F. Activation of p62-keap1-Nrf2 antioxidant pathway in the early stage of acetaminophen-induced acute liver injury in mice. Chem Biol Interact 2018; 282:22-28. [PMID: 29331651 DOI: 10.1016/j.cbi.2018.01.008] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 12/02/2017] [Accepted: 01/09/2018] [Indexed: 12/27/2022]
Abstract
Acetaminophen (APAP) overdose can cause severe liver failure even death. Nearly half of drug-induced liver injury is attributed to APAP in the US and many European countries. Oxidative stress has been validated as a critical event involved in APAP-induced liver failure. p62/SQSTM1, a selective autophagy adaptor protein, is reported to regulate Nrf2-ARE antioxidant pathway in response to oxidative stress. However, the exact role of p62-keap1-Nrf2 antioxidant pathway in APAP-induced hepatotoxicity remains unknown. In the present study, the dose-response and time-course model in C57/BL6 mice were established by intraperitoneal injection of APAP. The results of serum alanine/aspartate aminotransferases (ALT/AST) and histological examination demonstrated that APAP overdose resulted in the severe liver injury. In the meantime, the levels of p62, phospho-p62 and nuclear Nrf2 were significantly increased by APAP in mice liver, suggesting an activation of p62-keap1-Nrf2 pathway. In addition, the expression of GSTA1 mRNA was increased in a dose-dependent manner, while the mRNA levels of HO-1 and GCLC were decreased with the increase of APAP dose. Our further investigation found that expression of HO-1 and GCLC peaked at 3 h∼6 h, and then were decreased gradually. Taken together, these results indicated that p62-keap1-Nrf2 antioxidant pathway was primarily activated in the early stage of APAP hepatotoxicity, which might play a protective role in the process of APAP-induced acute liver injury.
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Affiliation(s)
- Zhenyu Shen
- Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, PR China
| | - Yu Wang
- Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, PR China
| | - Zhenhui Su
- Department of Pathology, Shandong Provincial Hospital, 324 Jingwu-Weiqi Road, Jinan, Shandong, 250021, PR China
| | - Ruirui Kou
- Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, PR China
| | - Keqin Xie
- Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, PR China
| | - Fuyong Song
- Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, PR China.
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Slack A, Hogan BJ, Wendon J. Acute Hepatic Failure. LIVER ANESTHESIOLOGY AND CRITICAL CARE MEDICINE 2018. [PMCID: PMC7121978 DOI: 10.1007/978-3-319-64298-7_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Kong SZ, Lin GS, Liu JJ, Su LY, Zeng L, Luo DD, Su ZR, Wang HF. Hepatoprotective Effect of Ultrafine Powder of Dendrobium officinale against Acetaminophen-Induced Liver Injury in Mice. FOOD SCIENCE AND TECHNOLOGY RESEARCH 2018. [DOI: 10.3136/fstr.24.339] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- Song-Zhi Kong
- Guangdong Ocean University, Faculty of Chemistry and Environmental Science
| | - Guo-Sheng Lin
- Guangzhou University of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine
- Guangzhou University of Chinese Medicine, Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine
| | - Jing-Jing Liu
- Guangzhou University of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine
- Guangzhou University of Chinese Medicine, Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine
| | - Ling-Ye Su
- Guangdong Provincial Key Laboratory of Silviculture, Protection and Utilization
- Guangdong Academy of Forestry
| | - Lei Zeng
- Guangdong Provincial Key Laboratory of Silviculture, Protection and Utilization
- Guangdong Academy of Forestry
| | - Dan-Dan Luo
- Guangzhou University of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine
- Guangdong Academy of Forestry
| | - Zi-Ren Su
- Guangzhou University of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine
- Guangzhou University of Chinese Medicine, Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine
| | - Hong-Feng Wang
- Guangdong Provincial Key Laboratory of Silviculture, Protection and Utilization
- Guangdong Academy of Forestry
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Wang X, Wu Q, Liu A, Anadón A, Rodríguez JL, Martínez-Larrañaga MR, Yuan Z, Martínez MA. Paracetamol: overdose-induced oxidative stress toxicity, metabolism, and protective effects of various compounds in vivo and in vitro. Drug Metab Rev 2017; 49:395-437. [PMID: 28766385 DOI: 10.1080/03602532.2017.1354014] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Paracetamol (APAP) is one of the most widely used and popular over-the-counter analgesic and antipyretic drugs in the world when used at therapeutic doses. APAP overdose can cause severe liver injury, liver necrosis and kidney damage in human beings and animals. Many studies indicate that oxidative stress is involved in the various toxicities associated with APAP, and various antioxidants were evaluated to investigate their protective roles against APAP-induced liver and kidney toxicities. To date, almost no review has addressed the APAP toxicity in relation to oxidative stress. This review updates the research conducted over the past decades into the production of reactive oxygen species (ROS), reactive nitrogen species (RNS), and oxidative stress as a result of APAP treatments, and ultimately their correlation with the toxicity and metabolism of APAP. The metabolism of APAP involves various CYP450 enzymes, through which oxidative stress might occur, and such metabolic factors are reviewed within. The therapeutics of a variety of compounds against APAP-induced organ damage based on their anti-oxidative effects is also discussed, in order to further understand the role of oxidative stress in APAP-induced toxicity. This review will throw new light on the critical roles of oxidative stress in APAP-induced toxicity, as well as on the contradictions and blind spots that still exist in the understanding of APAP toxicity, the cellular effects in terms of organ injury and cell signaling pathways, and finally strategies to help remedy such against oxidative damage.
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Affiliation(s)
- Xu Wang
- a Department of Toxicology and Pharmacology, Faculty of Veterinary Medicine , Universidad Complutense de Madrid , Madrid , Spain.,b National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues , Huazhong Agricultural University , Wuhan , Hubei , China
| | - Qinghua Wu
- c College of Life Science , Yangtze University , Jingzhou , China.,d Faculty of Informatics and Management , Center for Basic and Applied Research, University of Hradec Kralove , Hradec Kralove , Czech Republic
| | - Aimei Liu
- b National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues , Huazhong Agricultural University , Wuhan , Hubei , China
| | - Arturo Anadón
- a Department of Toxicology and Pharmacology, Faculty of Veterinary Medicine , Universidad Complutense de Madrid , Madrid , Spain
| | - José-Luis Rodríguez
- a Department of Toxicology and Pharmacology, Faculty of Veterinary Medicine , Universidad Complutense de Madrid , Madrid , Spain
| | - María-Rosa Martínez-Larrañaga
- a Department of Toxicology and Pharmacology, Faculty of Veterinary Medicine , Universidad Complutense de Madrid , Madrid , Spain
| | - Zonghui Yuan
- b National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues , Huazhong Agricultural University , Wuhan , Hubei , China.,e MAO Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products , Huazhong Agricultural University , Wuhan , Hubei , China.,f Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety , Wuhan , Hubei , China
| | - María-Aránzazu Martínez
- a Department of Toxicology and Pharmacology, Faculty of Veterinary Medicine , Universidad Complutense de Madrid , Madrid , Spain
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He GL, Feng L, Cai L, Zhou CJ, Cheng Y, Jiang ZS, Pan MX, Gao Y. Artificial liver support in pigs with acetaminophen-induced acute liver failure. World J Gastroenterol 2017; 23:3262-3268. [PMID: 28566885 PMCID: PMC5434431 DOI: 10.3748/wjg.v23.i18.3262] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 01/24/2017] [Accepted: 03/20/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To establish a reversible porcine model of acute liver failure (ALF) and treat it with an artificial liver system.
METHODS Sixteen pigs weighing 30-35 kg were chosen and administered with acetaminophen (APAP) to induce ALF. ALF pigs were then randomly assigned to either an experimental group (n = 11), in which a treatment procedure was performed, or a control group (n = 5). Treatment was started 20 h after APAP administration and continued for 8 h. Clinical manifestations of all animals, including liver and kidney functions, serum biochemical parameters and survival times were analyzed.
RESULTS Twenty hours after APAP administration, the levels of serum aspartate aminotransferase, total bilirubin, creatinine and ammonia were significantly increased, while albumin levels were decreased (P < 0.05). Prothrombin time was found to be extended with progression of ALF. After continuous treatment for 8 h (at 28 h), aspartate aminotransferase, total bilirubin, creatinine, and ammonia showed a decrease in comparison with the control group (P < 0.05). A cross-section of livers revealed signs of vacuolar degeneration, nuclear fragmentation and dissolution. Concerning survival, porcine models in the treatment group survived for longer times with artificial liver system treatment (P < 0.05).
CONCLUSION This model is reproducible and allows for quantitative evaluation of new liver systems, such as a bioartificial liver. The artificial liver system (ZHJ-3) is safe and effective for the APAP-induced porcine ALF model.
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Gao Y, Cao Z, Yang X, Abdelmegeed MA, Sun J, Chen S, Beger RD, Davis K, Salminen WF, Song BJ, Mendrick DL, Yu LR. Proteomic analysis of acetaminophen-induced hepatotoxicity and identification of heme oxygenase 1 as a potential plasma biomarker of liver injury. Proteomics Clin Appl 2016; 11. [PMID: 27634590 DOI: 10.1002/prca.201600123] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 09/02/2016] [Accepted: 09/13/2016] [Indexed: 02/06/2023]
Abstract
PURPOSE Overdose of acetaminophen (APAP) is a major cause of acute liver failure. This study was aimed to identify pathways related to hepatotoxicity and potential biomarkers of liver injury. EXPERIMENTAL DESIGN Rats were treated with low (100 mg/kg) and high (1250 mg/kg) doses of APAP, and liver tissues at 6 and 24 h post-treatment were analyzed using a proteomic approach of 16O/18O labeling and 2D-LC-MS/MS. RESULTS Molecular pathways evolved progressively from scattered and less significant perturbations to more focused and significant alterations in a dose- and time-dependent manner upon APAP treatment. Imbalanced expression of hemeoxygenase 1 (HMOX1) and biliverdin reductase A (BLVRA) was associated with hepatotoxicity. Protein abundance changes of a total of 31 proteins were uniquely correlated to liver damage, among which a dramatic increase of HMOX1 levels in plasma was observed. Liver injury-associated significant elevation of plasma HMOX1 was further validated in mice treated with APAP. CONCLUSIONS AND CLINICAL RELEVANCE This study unveiled molecular changes associated with APAP-induced liver toxicity at the pathway levels and identified HMOX1 as a potential plasma biomarker of liver injury.
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Affiliation(s)
- Yuan Gao
- Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA
| | - Zhijun Cao
- Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA
| | - Xi Yang
- Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA
| | - Mohamed A Abdelmegeed
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
| | - Jinchun Sun
- Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA
| | - Si Chen
- Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA
| | - Richard D Beger
- Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA
| | - Kelly Davis
- Toxicologic Pathology Associates, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA
| | - William F Salminen
- Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA
| | - Byoung-Joon Song
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
| | - Donna L Mendrick
- Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA
| | - Li-Rong Yu
- Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA
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Zhang T, Zhang Q, Guo J, Yuan H, Peng H, Cui L, Yin J, Zhang L, Zhao J, Li J, White A, Carmichael PL, Westmoreland C, Peng S. Non-cytotoxic concentrations of acetaminophen induced mitochondrial biogenesis and antioxidant response in HepG2 cells. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2016; 46:71-79. [PMID: 27438896 DOI: 10.1016/j.etap.2016.06.030] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 06/27/2016] [Accepted: 06/30/2016] [Indexed: 06/06/2023]
Abstract
Mitochondrial dysfunction has been implicated in acute, severe liver injury caused by overdose of acetaminophen (APAP). However, whether mitochondrial biogenesis is involved is unclear. Here we demonstrated that mitochondrial biogenesis, as indicated by the amounts of mitochondrial DNA and proteins, increased significantly in HepG2 cells exposed to low, non-cytotoxic concentrations of APAP. This heightened response was accompanied by upregulated expression of PGC-1α, NRF-1 and TFAM, which are key transcriptional regulators of mitochondrial biogenesis. Additionally, antioxidants including glutathione, MnSOD, HO-1, NQO1, and Nrf2 were also significantly upregulated. In contrast, for HepG2 cells exposed to high, cytotoxic concentration of APAP, mitochondrial biogenesis was inhibited and the expression of its regulatory proteins and antioxidants were concentration-dependently downregulated. In summary, our study indicated that mitochondrial biogenesis, along with antioxidant induction, may be an important cellular adaptive mechanism counteracting APAP-induced toxicity and overwhelming this cytoprotective capacity could result in liver injury.
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Affiliation(s)
- Tingfen Zhang
- Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, The Academy of Military Medical Sciences, Beijing, PR China
| | - Qiang Zhang
- Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Jiabin Guo
- Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, The Academy of Military Medical Sciences, Beijing, PR China
| | - Haitao Yuan
- Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, The Academy of Military Medical Sciences, Beijing, PR China
| | - Hui Peng
- Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, The Academy of Military Medical Sciences, Beijing, PR China
| | - Lan Cui
- Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, The Academy of Military Medical Sciences, Beijing, PR China
| | - Jian Yin
- Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, The Academy of Military Medical Sciences, Beijing, PR China
| | - Li Zhang
- Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, The Academy of Military Medical Sciences, Beijing, PR China
| | - Jun Zhao
- Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, The Academy of Military Medical Sciences, Beijing, PR China
| | - Jin Li
- Unilever Safety and Environmental Assurance Center, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK
| | - Andrew White
- Unilever Safety and Environmental Assurance Center, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK
| | - Paul L Carmichael
- Unilever Safety and Environmental Assurance Center, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK
| | - Carl Westmoreland
- Unilever Safety and Environmental Assurance Center, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK
| | - Shuangqing Peng
- Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, The Academy of Military Medical Sciences, Beijing, PR China.
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43
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NCPDP recommendations for dose accumulation monitoring in the inpatient setting: Acetaminophen case model, version 1.0. Am J Health Syst Pharm 2016; 73:1144-65. [PMID: 27267535 PMCID: PMC6477888 DOI: 10.2146/ajhp160215] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
PURPOSE Best practices and guidance are provided for improved electronic detection and alerting of inadvertent supratherapeutic cumulative doses of acetaminophen and other medications with narrow therapeutic ranges in inpatient settings. SUMMARY Despite the use of medication safety technologies, overdosage and associated sentinel events continue to be serious problems in many inpatient settings. The tools needed to monitor and employ dose alerts, accumulators, and warning systems are available to reduce inadvertent overdose. Required are staff training and the implementation of processes that provide guidance and documentation of the drug reconciliation process from admittance to discharge for safe patient passage through the various transitions of care. Recommendations to achieve optimal patient safety outcomes include the adoption and integration of available technologies with full functionality configured to meet the institution's policies and processes, initial training and retraining of all staff who use these systems, continuing education of the patient care staff on the dosing safety requirements, and assigning a prominent role to the clinical pharmacist in the entire drug-use and reconciliation process. CONCLUSION The key factors contributing to inadvertent overdosage in inpatient settings include a lack of recognition of recommended maximum daily dosages; failure to optimally communicate medication information at transitions of care; failure to optimally implement medication safety technologies, particularly dose accumulator calculation features and associated alerts; and alert fatigue and override.
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44
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Abstract
Drug-induced liver injury (DILI) is among the most challenging acute or chronic liver conditions to be handled by physicians. Despite its low incidence in the general population, DILI is a frequent cause of acute liver failure. As such, the possibility of DILI should be considered in all patients who present with acute liver damage, independent of any known pre-existing liver disease. DILI can be classified as intrinsic/dose-dependent (e.g., acetaminophen toxicity) or idiosyncratic/dose-independent, with the latter form being relatively uncommon. Amoxicillin-clavulanate is the antimicrobial that is most frequently associated with idiosyncratic DILI. Large, ongoing, prospective studies in western countries have reported other drugs associated with DILI, including nonsteroidal anti-inflammatory drugs, statins, and herbal and dietary supplements. An important safety issue, DILI is one of the most frequently cited reasons for cessation of drug development during or after preclinical studies and for withdrawal of a drug from the market. This review summarizes the epidemiology, risk factors, commonly implicated drugs, clinical features, and diagnosis of DILI, with the aim of aiding physicians in the management of this debated problem. Old and new biomarkers for DILI and pharmacogenetic studies are also described.
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Affiliation(s)
- Anna Licata
- Sezione di Gastroenterologia & Epatologia, Dipartimento di Medicina Interna e Specialistica, DiBiMIS, Università di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy.
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45
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Beger RD, Bhattacharyya S, Yang X, Gill PS, Schnackenberg LK, Sun J, James LP. Translational biomarkers of acetaminophen-induced acute liver injury. Arch Toxicol 2015; 89:1497-522. [PMID: 25983262 PMCID: PMC4551536 DOI: 10.1007/s00204-015-1519-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 04/21/2015] [Indexed: 12/17/2022]
Abstract
Acetaminophen (APAP) is a commonly used analgesic drug that can cause liver injury, liver necrosis and liver failure. APAP-induced liver injury is associated with glutathione depletion, the formation of APAP protein adducts, the generation of reactive oxygen and nitrogen species and mitochondrial injury. The systems biology omics technologies (transcriptomics, proteomics and metabolomics) have been used to discover potential translational biomarkers of liver injury. The following review provides a summary of the systems biology discovery process, analytical validation of biomarkers and translation of omics biomarkers from the nonclinical to clinical setting in APAP-induced liver injury.
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Affiliation(s)
- Richard D Beger
- Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, USA,
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46
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Thiele K, Solano ME, Huber S, Flavell RA, Kessler T, Barikbin R, Jung R, Karimi K, Tiegs G, Arck PC. Prenatal acetaminophen affects maternal immune and endocrine adaptation to pregnancy, induces placental damage, and impairs fetal development in mice. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:2805-18. [PMID: 26254283 DOI: 10.1016/j.ajpath.2015.06.019] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Revised: 05/20/2015] [Accepted: 06/04/2015] [Indexed: 12/11/2022]
Abstract
Acetaminophen (APAP; ie, Paracetamol or Tylenol) is generally self-medicated to treat fever or pain and recommended to pregnant women by their physicians. Recent epidemiological studies reveal an association between prenatal APAP use and an increased risk for asthma. Our aim was to identify the effects of APAP in pregnancy using a mouse model. Allogeneically mated C57Bl/6J females were injected i.p. with 50 or 250 mg/kg APAP or phosphate-buffered saline on gestation day 12.5; nonpregnant females served as controls. Tissue samples were obtained 1 or 4 days after injection. APAP-induced liver toxicity was mirrored by significantly increased plasma alanine aminotransferase levels. In uterus-draining lymph nodes of pregnant dams, the frequencies of mature dendritic cells and regulatory T cells significantly increased on 250 mg/kg APAP. Plasma progesterone levels significantly decreased in dams injected with APAP, accompanied by a morphologically altered placenta. Although overall litter sizes and number of fetal loss remained unaltered, a reduced fetal weight and a lower frequency of hematopoietic stem cells in the fetal liver were observed on APAP treatment. Our data provide strong evidence that prenatal APAP interferes with maternal immune and endocrine adaptation to pregnancy, affects placental function, and impairs fetal maturation and immune development. The latter may have long-lasting consequences on children's immunity and account for the increased risk for asthma observed in humans.
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Affiliation(s)
- Kristin Thiele
- Department of Obstetrics and Fetal Medicine, Laboratory of Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - M Emilia Solano
- Department of Obstetrics and Fetal Medicine, Laboratory of Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Samuel Huber
- I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Richard A Flavell
- Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut
| | - Timo Kessler
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Roja Barikbin
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Roman Jung
- Center for Diagnostics, Department of Clinical Chemistry/Central Laboratories, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Khalil Karimi
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Gisa Tiegs
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Petra C Arck
- Department of Obstetrics and Fetal Medicine, Laboratory of Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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47
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Basta G, Turco SD, Navarra T, Lee WM, the Acute Liver Failure Study Group. Circulating levels of soluble receptor for advanced glycation end products and ligands of the receptor for advanced glycation end products in patients with acute liver failure. Liver Transpl 2015; 21:847-54. [PMID: 25825217 PMCID: PMC4933521 DOI: 10.1002/lt.24129] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Revised: 03/17/2015] [Accepted: 03/20/2015] [Indexed: 12/24/2022]
Abstract
Animal studies suggest that receptor for advanced glycation end products (RAGE)-dependent mechanisms contribute to acetaminophen-induced liver damage. We examined whether circulating levels of soluble receptor for advanced glycation end products (sRAGE) or RAGE ligands, including extracellular newly identified receptor for advanced glycation end products binding protein (EN-RAGE), high-mobility group box 1 (HMGB1), and Nε-(Carboxymethyl)lysine adducts (CML), could aid in prognostication after an acetaminophen overdose. Sixty well-characterized acetaminophen-related acute liver failure (ALF) patients (30 spontaneous survivors and 30 patients who underwent transplantation and/or died) who were enrolled in the National Institutes of Health-sponsored Acute Liver Failure Study Group, were matched by age, met standard criteria for encephalopathy, and had an international normalized ratio > 1.5 were retrospectively studied. HMGB1, EN-RAGE, CML, and sRAGE were detected by enzyme-linked immunosorbent assay methods in sera from ALF patients and 30 healthy controls. Levels of sRAGE, EN-RAGE, and HMGB1 (but not CML) were significantly greater (P < 0.001) in ALF patients versus normal controls. The levels of sRAGE, HMGB1, and EN-RAGE were significantly higher (P = 0.03, P < 0.01, and P = 0.03) in patients with a systemic inflammatory response syndrome (SIRS) score > 2 versus patients with a SIRS score ≤ 2. Nevertheless, only sRAGE levels were significantly higher in patients who underwent transplantation and/or died versus spontaneous survivors (P < 0.001), and they were positively associated with conventional markers of liver disease severity. Multivariate logistic regression identified an encephalopathy grade > 2 as an independent predictor of an adverse outcome on admission (odds ratio, 13; 95% confidence interval, 2.3-73; P < 0.001). The RAGE-ligand axis may interfere with liver regeneration and should be a promising objective for further research.
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Affiliation(s)
| | | | | | - William M Lee
- Division of Digestive and Liver Diseases, Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390
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Yang K, Woodhead JL, Shoda LK, Yang Y, Watkins PB, Brouwer KL, Howell BA, Siler SQ. Mechanistic Modeling of Drug‐Induced Liver Injury (DILI). METHODS AND PRINCIPLES IN MEDICINAL CHEMISTRY 2015:173-198. [DOI: 10.1002/9783527673643.ch09] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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49
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Zhang H, Gan J, Shu YZ, Humphreys WG. High-Resolution Mass Spectrometry-Based Background Subtraction for Identifying Protein Modifications in a Complex Biological System: Detection of Acetaminophen-Bound Microsomal Proteins Including Argininosuccinate Synthetase. Chem Res Toxicol 2015; 28:775-81. [DOI: 10.1021/tx500526s] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Affiliation(s)
- Haiying Zhang
- Biotransformation, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, United States
| | - Jinping Gan
- Biotransformation, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, United States
| | - Yue-Zhong Shu
- Biotransformation, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, United States
| | - W. Griffith Humphreys
- Biotransformation, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, United States
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50
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Drug-induced liver injury: an overview over the most critical compounds. Arch Toxicol 2015; 89:327-34. [PMID: 25618544 DOI: 10.1007/s00204-015-1456-2] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Accepted: 01/08/2015] [Indexed: 12/24/2022]
Abstract
There has been a substantial interest in drug-induced liver injury (DILI) recently. National Institutes of Health has sponsored a multicenter study in the USA for the last 10 years, which has collected valuable information in this context. Idiosyncratic DILI is like other adverse effects of drugs underestimated and underreported in most epidemiological studies. A recent prospective population-based study from Iceland found a crude incidence of approximately 19 cases per 100,000 and year. Antibiotic is the class of drugs most commonly implicated in patients with DILI. Amoxicillin-clavulanate continues to be the most commonly implicated agent occurring in approximately 1 out of 2,300 users. Drugs with the highest risk of DILI in the Icelandic study were azathioprine and infliximab. Although rare, statin-induced hepatotoxicity has been well documented. Liver injury associated with the use of herbal medicines and dietary supplements seems to be increasing. Information on the documented hepatotoxicity of drugs has recently been made easier by a website available in the public domain: LiverTox ( http://livertox.nlm.nih.gov ). Unfortunately, at the current time, pre-therapy risk assessment for DILI in the individual patient is difficult but previous well-documented hepatotoxicity is usually a contraindication for a subsequent treatment with the same drug.
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