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Impey ORE, Baker JD, Smyth RS, Potts SG. Death after psychiatric contraindications to urgent liver transplant for paracetamol overdose. World J Transplant 2025; 15:101865. [DOI: 10.5500/wjt.v15.i3.101865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 02/20/2025] [Accepted: 02/25/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND Paracetamol overdose (POD) is the most common cause of acute hepatic failure (AHF) in the United Kingdom. Without urgent orthotopic liver transplant (OLT), mortality is high. Psychiatric assessment for transplant is time-pressured and often undertaken by psychiatrists without transplant experience. Assessors may identify absolute psychiatric contraindications (APCIs) precluding transplant in otherwise medically suitable patients. It is unknown how often this occurs. The combination of high but unknown mortality, time pressure, and relative inexperience is likely to provoke anxiety in assessors. This study hypothesised that the proportion of POD patients assessed for OLT who die because psychiatric contraindications preclude transplant would be small but not negligible.
AIM To determine the proportion of patients with paracetamol-induced AHF, for whom psychiatric contraindications preclude transplantation, and the consequent mortality.
METHODS This is an 18-year single-centre retrospective cohort study based in a national liver transplant centre. 524 participants were identified from a departmental database and included if they had AHF from suspected POD and received a psychiatric assessment for OLT. For those who died before discharge, records were reviewed for medical and psychiatric contraindications to transplant, alongside age, sex, and primary psychiatric diagnosis. We calculated the proportion of patients assessed for whom APCIs precluded transplant, resulting in death.
RESULTS Among 524 patients undergoing psychiatric assessment for OLT, there were 102 in-episode deaths (19.5%). APCIs were identified in 46 patients who were otherwise medically suitable for transplant and went on to die. This statistic represents 8.8% of the number of persons evaluated and 45% of the number of deaths. Within this subgroup, 27 (59%) were female, with a mean age of 44.6 years (ranging from 19-72 years). The most common primary psychiatric diagnosis was alcohol dependence syndrome, which accounted for 67% (n = 31).
CONCLUSION 8.8% of medically suitable patients with AHF following POD died with APCIs to transplant. This indicates a need for ongoing assessor training and support, and (inter) national comparisons of practice.
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Affiliation(s)
- Olivia R E Impey
- Hammersmith and Fulham Mental Health Unit, West London NHS Trust, London W6 8LN United Kingdom
| | - Jennifer D Baker
- Department of Psychological Medicine, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, United Kingdom
| | - Roger S Smyth
- Department of Psychological Medicine, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, United Kingdom
| | - Stephen G Potts
- Department of Psychological Medicine, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, United Kingdom
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Hwang I, Kang CG, Lim SJ, Kim HJ, Kang R, Jeon SH, Lee SH, Kim JW, Kang JS. Human Placenta Hydrolysate Protects Against Acetaminophen-Induced Liver Injury in Mice. Biomedicines 2025; 13:1219. [PMID: 40427046 DOI: 10.3390/biomedicines13051219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2025] [Revised: 05/13/2025] [Accepted: 05/16/2025] [Indexed: 05/29/2025] Open
Abstract
Background/Objectives: Acetaminophen (APAP) is a widely used analgesic and antipyretic, but overdose can lead to APAP-induced liver injury (AILI), a major cause of acute liver failure. While N-acetylcysteine (NAC) is the current standard of care, its efficacy is significantly reduced when administered after the peak time of liver injury, highlighting the need for alternative therapeutic strategies. Human placenta hydrolysate (HPH) has shown potential as a therapeutic agent for various liver diseases due to its rich content of bioactive compounds. This study aimed to investigate the hepatoprotective effects of HPH in a mouse model of AILI. Methods: HPH was administered to mice for three days prior to APAP treatment. The effects of HPH on liver morphology, necrosis, liver enzymes, phase I/II detoxification enzymes, oxidative stress markers, and inflammatory cytokines were evaluated. Results: HPH pretreatment attenuated APAP-induced liver necrosis and congestion, reduced serum levels of liver enzymes. In addition, HPH showed a concentration-dependent attenuation of APAP-induced decrease in human hepatocyte viability. HPH modulated phase I/II enzyme expression by downregulating CYP2E1 and upregulating SULT1A1, UGT1A6, GSTP1, and TPMT. HPH also exhibited antioxidant effects by increasing SOD and GPx activities, reducing MDA levels, and restoring the GSH/GSSG ratio. Furthermore, HPH attenuated the APAP-induced increase in the inflammatory cytokines TNF-α and IL-6. These findings suggest that HPH protects against AILI through multiple mechanisms, including the modulation of phase I/II detoxification, activation of antioxidants, and inhibition of inflammation. Conclusions: HPH could be a potential therapeutic option for APAP overdose and related liver injuries.
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Affiliation(s)
- Inyoung Hwang
- Department of Clinical Pharmacology and Therapeutics, Hanyang University Seoul Hospital, Seoul 04736, Republic of Korea
| | - Chi-Gu Kang
- Department of Pharmacology, College of Medicine, Hanyang University, Seoul 04763, Republic of Korea
| | - So-Jung Lim
- Department of Pharmacology, College of Medicine, Hanyang University, Seoul 04763, Republic of Korea
| | - Hyun-Jin Kim
- Department of Pharmacology, College of Medicine, Hanyang University, Seoul 04763, Republic of Korea
| | - Ryun Kang
- Department of Medical and Digital Engineering, College of Engineering, Hanyang University, Seoul 04736, Republic of Korea
| | - So-Hyun Jeon
- Research and Development Center, Green Cross Wellbeing Corporation, Yongin 16950, Republic of Korea
| | - Sang-Hoon Lee
- Department of Family Medicine and Functional Medicine, Green Cross I-MED Gangnam Center, Seoul 06655, Republic of Korea
| | - Jae-Won Kim
- Research and Development Center, Green Cross Wellbeing Corporation, Yongin 16950, Republic of Korea
| | - Ju-Seop Kang
- Department of Pharmacology, College of Medicine, Hanyang University, Seoul 04763, Republic of Korea
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Zeng JM, Zhang J, Liu YP, Liu GC, Jiang XY, Yu JG. A novel electrochemical sensor based on mixed cubic and spherical Cu 2O composited with MWCNTs-COOH for sensitive determination of acetaminophen. Talanta 2025; 295:128341. [PMID: 40393242 DOI: 10.1016/j.talanta.2025.128341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 05/13/2025] [Accepted: 05/15/2025] [Indexed: 05/22/2025]
Abstract
The use of Cu2O for construction of efficient electrochemical sensors has become a hot research topic. The morphology and structure of Cu2O nanoparticles have an important influence on their catalytic performance. Mixed cubic and spherical Cu2O particles were prepared by a chemical reduction method, which were then composited with carboxylated multi-walled carbon nanotubes (MWCNTs-COOH) through a facile ultrasonic treatment. Cu2O/MWCNTs-COOH composite was modified onto glassy carbon electrode (GCE) to construct a novel sensor (Cu2O/MWCNTs-COOH/GCE) for highly sensitive detection of acetaminophen (APAP). Under the optimized experimental conditions, Cu2O/MWCNTs-COOH/GCE exhibits a wide linear range (1-200 μM), high sensitivity (1.022 μA/μM), low detection limit (LOD, 3σ/k, 0.25 μM), great anti-interference property, reproducibility, repeatability, and stability for APAP detection. The practical applicability of Cu2O/MWCNTs-COOH/GCE was verified by determining APAP in commercial tablets (recoveries: 96.0 %-104.7 %) and spiked human serum samples (recoveries: 94.0 %-104.0 %).
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Affiliation(s)
- Jin-Min Zeng
- College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan, 410083, China
| | - Jing Zhang
- College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan, 410083, China
| | - Yi-Ping Liu
- College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan, 410083, China; Hunan Provincial Institute of Cotton and Sericultural Research, Hunan Academy of Agricultural Sciences, Changsha, 410127, China
| | - Guo-Cong Liu
- School of Chemistry and Materials Engineering, Huizhou University, Huizhou, 516007, China
| | - Xin-Yu Jiang
- College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan, 410083, China
| | - Jin-Gang Yu
- College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan, 410083, China.
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4
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Goldin D, Salani DA, Valdes B. N-Acetylcysteine (NAC) for Trichotillomania and Excoriation Disorder: An Overview. J Psychosoc Nurs Ment Health Serv 2025:1-9. [PMID: 40359441 DOI: 10.3928/02793695-20250506-04] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/15/2025]
Abstract
Trichotillomania and excoriation/skin-picking disorder involve repetitive behaviors, such as hair pulling leading to hair loss or skin picking leading to skin lesions, that cause physical complications, significant mental distress, and functional impairment despite attempts to stop. Currently, no first-line pharmacological treatments are approved for these disorders, although glutamatergic agents, select antidepressants, and other medications have demonstrated some benefit. The therapeutic potential of N-acetylcysteine (NAC) is promising. NAC helps maintain glutamate homeostasis in the brain, thereby reducing compulsive and habitual behaviors. In addition, NAC is recognized as a low-risk, well-tolerated, and accessible dietary supplement with valuable therapeutic potential. Deficiencies in pharmacological protocols and lack of government controls place individuals at risk; therefore, health care providers are well positioned to provide reliable information and educate individuals to make informed decisions about their health. [Journal of Psychosocial Nursing and Mental Health Services, xx(x), xx-xx.].
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Ekaney ML, Pritt TA, Attal N, Murphy CM, McKillop IH. Acute Acetaminophen Hepatotoxicity And Platelet Dysfunction. J Med Toxicol 2025; 21:229-240. [PMID: 40014260 PMCID: PMC11933539 DOI: 10.1007/s13181-025-01065-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 02/10/2025] [Accepted: 02/12/2025] [Indexed: 02/28/2025] Open
Abstract
INTRODUCTION Acetaminophen (APAP) overdose remains a common cause of liver injury, primarily due to its toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). This study sought to investigate APAP-induced platelet aggregation in vitro, and the implication of CYP2E1 in the metabolism of APAP and hepatic cell toxicity. METHODS Co-cultures of platelets and hepatic cells that do not (HepG2) and do express CYP2E1 (HepG2E47) were exposed to APAP (0-20 mM), NAPQI (0-250 µM), APAP in the absence/presence of inhibitors of glutathione (50 μM buthionine sulphoximine (BSO)), or APAP in the absence/presence of inhibitors CYP2E1 (chlormethiazole (CMZ, 100 µM), or 4-methylpyrazole (4-MP, 5 mM)). Platelet aggregation, cell viability and reactive oxygen species (ROS) were analyzed. Changes in platelet aggregation was determined in platelets directly exposed to APAP/NAPQI. RESULTS Exposure to APAP decreased platelet aggregation under co-culture conditions but not in platelet-only cultures. Conversely, NAPQI exposure decreased platelet aggregation in both co-culture and platelet-only conditions. Both APAP and NAPQI reduced cell viability in HepG2 and HepG2E47 cells, with BSO enhancing APAP toxicity, while 4-MP mitigated it. Acetaminophen exposure led to ROS production in HepG2E47 cells, with no effect of CMZ and 4-MP. CONCLUSIONS Acetaminophen exposure impacts platelet aggregation in co-cultures of platelets and HepG2/HepG2E47 cells with increased ROS production in HepG2E47 cells and 4-MP preventing APAP-induced cytotoxicity in HepG2E47 cells. While APAP had no direct effect on platelets, NAPQI exposure acted to decrease platelet aggregation. These findings enhance our understanding of the mechanisms of APAP-induced hepatotoxicity and the potential role of APAP-induced hepatocellular toxicity in platelet aggregation.
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Affiliation(s)
- Michael L Ekaney
- Department of Surgery, Atrium Health - Carolinas Medical Center, 1000 Blythe Boulevard, Charlotte, NC, 28203, USA
| | - Trenton A Pritt
- Department of Surgery, Atrium Health - Carolinas Medical Center, 1000 Blythe Boulevard, Charlotte, NC, 28203, USA
| | - Neha Attal
- Department of Surgery, Atrium Health - Carolinas Medical Center, 1000 Blythe Boulevard, Charlotte, NC, 28203, USA
| | - Christine M Murphy
- Department of Emergency Medicine, Atrium Health - Carolinas Medical Center, Charlotte, NC, 28203, USA
| | - Iain H McKillop
- Department of Surgery, Atrium Health - Carolinas Medical Center, 1000 Blythe Boulevard, Charlotte, NC, 28203, USA.
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Shiau J, Engel P, Olsen M, Pais G, Chang J, Scheetz MH. Protamine protects against vancomycin-induced kidney injury. Antimicrob Agents Chemother 2025; 69:e0123624. [PMID: 39818985 PMCID: PMC11823679 DOI: 10.1128/aac.01236-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 12/17/2024] [Indexed: 01/19/2025] Open
Abstract
Vancomycin causes kidney injury by accumulating in the proximal tubule, likely mediated by megalin uptake. Protamine is a putative megalin inhibitor that shares binding sites with heparin and is approved for the treatment of heparin overdose. We employed a well-characterized Sprague-Dawley rat model to assess kidney injury and function in animals that received vancomycin, protamine alone, or vancomycin plus protamine over 5 days. Urinary KIM-1 was used as the primary measure for kidney injury, while plasma iohexol clearance was calculated to assess kidney function. Animals had samples drawn pre-treatment in order to serve as their own controls. Additionally, since protamine is not a known nephrotoxin, the protamine group also served as a control. Cellular inhibition studies were performed to assess the ability of protamine to inhibit organic anion transporter (OAT1 and OAT3) and organic cation transporter-2 (OCT2). Rats that received vancomycin alone had significantly increased urinary KIM-1 on day 2 (24.9 ng/24 h, 95% CI 1.87-48.0) compared to the protamine alone group. By day 4, animals that received protamine with their vancomycin had KIM-1 amounts that were elevated compared to protamine alone as a base comparison (KIM-1 29.0 ng/24 h, 95% CI 5.0-53.0). No statistically observed differences were identified for iohexol clearance changes between drug groups or when comparing clearance change from baseline (P > 0.05). No substantial inhibition of OAT1, OAT3, or OCT2 was observed with protamine. IC50 values for protamine were 0.1 mM for OAT1 and OAT3 and 0.043 mM for OCT2. Protamine, when added to vancomycin therapy, delays vancomycin-induced kidney injury as defined by urinary KIM-1 in the rat model by 1-3 days. Protamine putatively acts through the blockade of megalin and does not appear to have significant inhibition on OAT1, OAT3, or OCT2. Since protamine is an approved FDA medication, it has clinical potential as a therapeutic to reduce vancomycin-related kidney injury; however, greater utility may be found by pursuing compounds with fewer adverse event liabilities.
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Affiliation(s)
- Justin Shiau
- Department of Pharmacy Practice, College of Pharmacy, Midwestern University, Downers Grove, Illinois, USA
- Department of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois, USA
- College of Pharmacy, Pharmacometrics Center of Excellence, Midwestern University, Downers Grove, Illinois, USA
| | - Patti Engel
- Department of Pharmacy Practice, College of Pharmacy, Midwestern University, Downers Grove, Illinois, USA
- College of Pharmacy, Pharmacometrics Center of Excellence, Midwestern University, Downers Grove, Illinois, USA
| | - Mark Olsen
- College of Pharmacy, Pharmacometrics Center of Excellence, Midwestern University, Downers Grove, Illinois, USA
- Department of Pharmaceutical Sciences, College of Pharmacy, Midwestern University, Glendale, Arizona, USA
| | - Gwendolyn Pais
- Department of Pharmacy Practice, College of Pharmacy, Midwestern University, Downers Grove, Illinois, USA
- College of Pharmacy, Pharmacometrics Center of Excellence, Midwestern University, Downers Grove, Illinois, USA
| | - Jack Chang
- Department of Pharmacy Practice, College of Pharmacy, Midwestern University, Downers Grove, Illinois, USA
- Department of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois, USA
- College of Pharmacy, Pharmacometrics Center of Excellence, Midwestern University, Downers Grove, Illinois, USA
| | - Marc H. Scheetz
- Department of Pharmacy Practice, College of Pharmacy, Midwestern University, Downers Grove, Illinois, USA
- Department of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois, USA
- College of Pharmacy, Pharmacometrics Center of Excellence, Midwestern University, Downers Grove, Illinois, USA
- Department of Pharmacology, College of Graduate Studies, Midwestern University, Downers Grove, Illinois, USA
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Thomas MC, Edwards CJ, Dunlap A. Practice Patterns for N-acetylcysteine Dosing for Acetaminophen Toxicity in the United States. Innov Pharm 2025; 15:10.24926/iip.v15i4.6459. [PMID: 40401298 PMCID: PMC12090092 DOI: 10.24926/iip.v15i4.6459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2025] Open
Abstract
Background: Although the FDA approved acetaminophen toxicity dosing regimen for intravenous n-acetylcysteine (NAC) is a three-bag regimen, alternate regimens have been published which are generally simpler, and decrease errors and adverse effects. It is not clear how pervasive alternative regimens are used in hospitals in the US and reasons for a change from the FDA regimen. Objective: Characterize practice patterns for treating acetaminophen toxicity. Methods: A pilot-tested, electronic survey containing demographic and practice pattern questions for acetaminophen toxicity management was sent to residency program directors. The survey was open for 4 weeks with several reminder e-mails sent to non-responders. Descriptive statistics were used to summarize the data. Results: There were 119 responses (9.2% response rate). Responses were representative of all geographic areas in the US and were most commonly from community hospitals (67.2%) and those with 300 or more beds (72.2%). Nearly two-thirds used the FDA approved NAC regimen, whereas others used an alternate regimen. Reasons for making the change were for simplicity, to decrease errors or adverse events, or based on local poison center recommendations. More than one-third of respondents reported not using a maximum dosing weight. Conclusions: N-acetylcysteine is usually administered intravenously using the FDA approved regimen for acetaminophen toxicity. The weight for dosing was commonly capped at 100 kg, but some institutions did not use a maximum. Alternative intravenous regimens have been implemented at some institutions with the impetus for change being safety and simplicity.
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Affiliation(s)
- Michael C. Thomas
- Samford University McWhorter School of Pharmacy, Birmingham, Alabama
| | | | - Amanda Dunlap
- Samford University McWhorter School of Pharmacy, Birmingham, Alabama
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Yang Y, Chen Q, Liu Z, Huang T, Hong Y, Li N, Ai K, Huang Q. Novel reduced heteropolyacid nanoparticles for effective treatment of drug-induced liver injury by manipulating reactive oxygen and nitrogen species and inflammatory signals. J Colloid Interface Sci 2025; 678:174-187. [PMID: 39243718 DOI: 10.1016/j.jcis.2024.08.239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 08/07/2024] [Accepted: 08/29/2024] [Indexed: 09/09/2024]
Abstract
With the rapid advancements in biomedicine, the use of clinical drugs has surged sharply. However, potential hepatotoxicity limits drug exploitation and widespread usage, posing serious threats to patient health. Hepatotoxic drugs disrupt liver enzyme levels and cause refractory pathological damage, creating a challenge in the application of diverse first-line drugs. The activation and deterioration of reactive oxygen and nitrogen species (RONS) and inflammatory signals are key pathological mechanisms of drug-induced liver injury (DILI). Herein, a novel reduced heteropolyacid nanoparticle (RNP) has been developed, possessing high RONS-scavenging ability, strong anti-inflammatory activity, and excellent biosafety. These features enable it to swiftly restore the redox and immune balance of the liver. Intravenous administration of RNP effectively scavenged RONS storm, reversing liver oxidative stress and restoring normal mitochondrial membrane potential and function. Furthermore, by inhibiting c-Jun-N-terminal kinase phosphorylation, RNP facilitated the restoration of nuclear factor erythroid 2-related factor 2-mediated endogenous antioxidant signaling, ultimately rescuing the liver function and tissue morphology in acetaminophen-induced DILI mice. Crucially, the high biocompatible RNP exhibited superior efficacy in the DILI mouse model compared to the clinical antioxidant N-acetylcysteine. This targeted therapeutic approach, tailored to address the onset and progression of DILI, offers valuable new insights into controlling the condition and restoring liver structure and function.
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Affiliation(s)
- Yongqi Yang
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Qiaohui Chen
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Zerun Liu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Ting Huang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Ying Hong
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Niansheng Li
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
| | - Kelong Ai
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Qiong Huang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
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Ma Y, He R, Deng B, Luo M, Zhang W, Mao L, Hu W, Mao Y, Yang H, Huang P. Advanced 3D bioprinted liver models with human-induced hepatocytes for personalized toxicity screening. J Tissue Eng 2025; 16:20417314241313341. [PMID: 39839984 PMCID: PMC11748070 DOI: 10.1177/20417314241313341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 12/30/2024] [Indexed: 01/23/2025] Open
Abstract
The development of advanced in vitro models for assessing liver toxicity and drug responses is crucial for personalized medicine and preclinical drug development. 3D bioprinting technology provides opportunities to create human liver models that are suitable for conducting high-throughput screening for liver toxicity. In this study, we fabricated a humanized liver model using human-induced hepatocytes (hiHeps) derived from human fibroblasts via a rapid and efficient reprogramming process. These hiHeps were then employed in 3D bioprinted liver models with bioink materials that closely mimic the natural extracellular matrix. The constructed humanized 3D bioprinted livers (h3DPLs) exhibited mature hepatocyte functions, including albumin expression, glycogen storage, and uptake/release of indocyanine green and acetylated low-density lipoprotein. Notably, h3DPLs demonstrated increased sensitivity to hepatotoxic agents such as acetaminophen (APAP), making them a promising platform for studying drug-induced liver injury. Furthermore, our model accurately reflected the impact of rifampin, a cytochrome P450 inducer, on CYP2E1 levels and APAP hepatotoxicity. These results highlight the potential of hiHep-based h3DPLs as a cost-effective and high-performance alternative for personalized liver toxicity screening and preclinical drug testing, paving the way for improved drug development strategies and personalized therapeutic interventions.
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Affiliation(s)
- Yue Ma
- Engineering Research Center of Pulmonary and Critical Care Medicine Technology and Device (Ministry of Education), Tianjin Institutes of Health Science, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Runbang He
- Engineering Research Center of Pulmonary and Critical Care Medicine Technology and Device (Ministry of Education), Tianjin Institutes of Health Science, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Bo Deng
- Engineering Research Center of Pulmonary and Critical Care Medicine Technology and Device (Ministry of Education), Tianjin Institutes of Health Science, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Miaomiao Luo
- Engineering Research Center of Pulmonary and Critical Care Medicine Technology and Device (Ministry of Education), Tianjin Institutes of Health Science, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Wenjie Zhang
- Engineering Research Center of Pulmonary and Critical Care Medicine Technology and Device (Ministry of Education), Tianjin Institutes of Health Science, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Lina Mao
- Engineering Research Center of Pulmonary and Critical Care Medicine Technology and Device (Ministry of Education), Tianjin Institutes of Health Science, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Wenxiang Hu
- Department of Basic Research, Guangzhou National Laboratory, Guangdong, China
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Huayu Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Pengyu Huang
- Engineering Research Center of Pulmonary and Critical Care Medicine Technology and Device (Ministry of Education), Tianjin Institutes of Health Science, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
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Wang R, Chen Y, Han J, Ye H, Yang H, Li Q, He Y, Ma B, Zhang J, Ge Y, Wang Z, Sun B, Liu H, Cheng L, Wang Z, Lin G. Selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 as a rapid-acting therapy for advanced acute liver failure. Nat Commun 2024; 15:10690. [PMID: 39681560 PMCID: PMC11649909 DOI: 10.1038/s41467-024-55295-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 12/08/2024] [Indexed: 12/18/2024] Open
Abstract
Acute liver failure (ALF) is a hepatology emergency with rapid hepatic destruction, multiple organ failures, and high mortality. Despite decades of research, established ALF has minimal therapeutic options. Here, we report that the small bioactive compound SCM-198 increases the survival of male ALF mice to 100%, even administered 24 hours after ALF establishment. We identify adiponectin receptor 2 (AdipoR2) as a selective target of SCM-198, with the AdipoR2 R335 residue being critical for the binding and signaling of SCM-198-AdipoR2 and AdipoR2 Y274 residue serving as a molecular switch for Ca2+ influx. SCM-198-AdipoR2 binding causes Ca2+ influx and elevates the phosphorylation levels of CaMKII and NOS3 in the AdipoR2-CaM-CaMKII-NOS3 complex identified in this study, rapidly inducing nitric oxide production for liver protection in murine ALF. SCM-198 also protects human ESC-derived liver organoids from APAP/TAA injuries. Thus, selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 is a rapid-acting therapeutic strategy for advanced ALF.
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Affiliation(s)
- Rui Wang
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Youwei Chen
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
- School of Medicine, Tongji University, Shanghai, China
| | - Jiazhen Han
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Huikang Ye
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Huiran Yang
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Qianyan Li
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Yizhen He
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Boyu Ma
- Department of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, China
| | - Junjie Zhang
- Department of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, China
| | - Yanli Ge
- Department of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, China
| | - Zhe Wang
- Department of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, China
| | - Bo Sun
- Department of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, China
| | - Huahua Liu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Liming Cheng
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China.
- Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai, China.
| | - Zhirong Wang
- Department of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, China.
| | - Gufa Lin
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China.
- School of Medicine, Tongji University, Shanghai, China.
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11
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Philipp TM, Bottiglieri T, Clapper W, Liu K, Rodems S, Szabo C, Majtan T. Mechanism of action and impact of thiol homeostasis on efficacy of an enzyme replacement therapy for classical homocystinuria. Redox Biol 2024; 77:103383. [PMID: 39366068 PMCID: PMC11489331 DOI: 10.1016/j.redox.2024.103383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/01/2024] [Accepted: 10/01/2024] [Indexed: 10/06/2024] Open
Abstract
Homocystinuria (HCU) due to cystathionine beta-synthase (CBS) deficiency is characterized by elevated plasma and tissue homocysteine levels. There is no cure, but HCU is typically managed by methionine/protein restriction and vitamin B6 supplementation. Enzyme replacement therapy (ERT) based on human CBS has been developed and has shown significant efficacy correcting HCU phenotype in several mouse models by bringing plasma total homocysteine below the clinically relevant 100 μM threshold. As the reactive nature of homocysteine promotes disulfide formation and protein binding, and ERT is unable to normalize plasma total homocysteine levels, the mechanism of action of ERT in HCU remains to be further characterized. Here we showed that only a reduced homocysteine serves as a substrate for CBS and its availability restricts the homocysteine-degrading capacity of CBS. We also demonstrated that cells export homocysteine in its reduced form, which is efficiently metabolized by CBS in the culture medium. Availability of serine, a CBS co-substrate, was not a limiting factor in our cell-based model. Biological reductants, such as N-acetylcysteine, MESNA or cysteamine, increased the availability of the reduced homocysteine and thus promoted its subsequent CBS-based elimination. In a transgenic I278T mouse model of HCU, administration of biological reductants significantly increased the proportion of protein-unbound homocysteine in plasma, which improved the efficacy of the co-administered CBS-based ERT, as evidenced by significantly lower plasma total homocysteine levels. These results clarify the mechanism of action of CBS-based ERT and unveil novel pharmacological approaches to further increase its efficacy.
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Affiliation(s)
- Thilo Magnus Philipp
- Department of Pharmacology, University of Fribourg, Faculty of Science and Medicine, Fribourg, Switzerland
| | - Teodoro Bottiglieri
- Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX, 75204, USA
| | | | - Kai Liu
- Travere Therapeutics, Inc., San Diego, CA, 92130, USA
| | - Steve Rodems
- Travere Therapeutics, Inc., San Diego, CA, 92130, USA
| | - Csaba Szabo
- Department of Pharmacology, University of Fribourg, Faculty of Science and Medicine, Fribourg, Switzerland
| | - Tomas Majtan
- Department of Pharmacology, University of Fribourg, Faculty of Science and Medicine, Fribourg, Switzerland.
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12
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Xue L, Wang L, Xu Y, Shen Y, Shi Z, Li X, Feng H, Xie X, Xie L, Wang G, Liang Y. The regulation of GSH/GPX4-mediated lipid accumulation confirms that schisandra polysaccharides should be valued equally as lignans. JOURNAL OF ETHNOPHARMACOLOGY 2024; 333:118483. [PMID: 38914150 DOI: 10.1016/j.jep.2024.118483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 06/12/2024] [Accepted: 06/20/2024] [Indexed: 06/26/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Acetaminophen (APAP) induced liver injury (AILI) is a common cause of clinical hepatic damage and even acute liver failure. Our previous research has shown that Schisandra chinensis lignan extract (SLE) can exert a hepatoprotective effect by regulating lipid metabolism. Although polysaccharides from Schisandra chinensis (S. chinensis), like lignans, are important components of S. chinensis, their pharmacological activity and target effects on AILI have not yet been explored. AIM OF THE STUDY This study aims to quantitatively reveal the role of SCP in the pharmacological activity of S. chinensis, and further explore the pharmacological components, potential action targets and mechanisms of S. chinensis in treating AILI. MATERIALS AND METHODS The therapeutic effect of SCP on AILI was systematically determined via comparing the efficacy of SCP and SLE on in vitro and in vivo models. Network pharmacology, molecular docking and multi-omics techniques were then used to screen and verify the action targets of S. chinensis against AILI. RESULTS SCP intervention could significantly improve AILI, and the therapeutic effect was comparable to that of SLE. Notably, the combination of SCP and SLE did not produce mutual antagonistic effects. Subsequently, we found that both SCP and SLE could significantly reverse the down-regulation of GPX4 caused by the APAP modeling, and then further improving lipid metabolism abnormalities. CONCLUSIONS Hepatoprotective effects of SCP and SLE is most correlated with their regulation of GSH/GPX4-mediated lipid accumulation. This is the first exploration of the hepatoprotective effect and potential mechanism of SCP in treating AILI, which is crucial for fully utilizing S. chinensis and developing promising AILI therapeutic agents.
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Affiliation(s)
- Lijuan Xue
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, PR China.
| | - Leyi Wang
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, PR China.
| | - Yexin Xu
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, PR China.
| | - Yun Shen
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, PR China.
| | - Zechang Shi
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, PR China.
| | - Xiaorun Li
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, PR China.
| | - Haoyang Feng
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, PR China.
| | - Xinrui Xie
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, PR China.
| | - Lin Xie
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, PR China.
| | - Guangji Wang
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, PR China.
| | - Yan Liang
- Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, PR China.
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13
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Hinz K, Niu M, Ni HM, Ding WX. Targeting Autophagy for Acetaminophen-Induced Liver Injury: An Update. LIVERS 2024; 4:377-387. [PMID: 39301093 PMCID: PMC11412313 DOI: 10.3390/livers4030027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/22/2024] Open
Abstract
Acetaminophen (APAP) overdose can induce hepatocyte necrosis and acute liver failure in experimental rodents and humans. APAP is mainly metabolized via hepatic cytochrome P450 enzymes to generate the highly reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), which forms acetaminophen protein adducts (APAP-adducts) and damages mitochondria, triggering necrosis. APAP-adducts and damaged mitochondria can be selectively removed by autophagy. Increasing evidence implies that the activation of autophagy may be beneficial for APAP-induced liver injury (AILI). In this minireview, we briefly summarize recent progress on autophagy, in particular, the pharmacological targeting of SQSTM1/p62 and TFEB in AILI.
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Affiliation(s)
- Kaitlyn Hinz
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Mengwei Niu
- 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
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
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14
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Prylutskyy Y, Nozdrenko D, Omelchuk O, Prylutska S, Motuziuk O, Soroсa V, Vareniuk I, Stetska V, Bogutska K, Ritter U, Piosik J. Effect of C 60 Fullerene on Muscle Injury-Induced Rhabdomyolysis and Associated Acute Renal Failure. Int J Nanomedicine 2024; 19:8043-8058. [PMID: 39130686 PMCID: PMC11316485 DOI: 10.2147/ijn.s468013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 07/19/2024] [Indexed: 08/13/2024] Open
Abstract
Introduction Rhabdomyolysis, as an acute stage of myopathy, causes kidney damage. It is known that this pathology is caused by the accumulation of muscle breakdown products and is associated with oxidative stress. Therefore, the present study evaluated the effect of intraperitoneal administration (dose 1 mg/kg) of water-soluble C60 fullerenes, as powerful antioxidants, on the development of rat kidney damage due to rhabdomyolysis caused by mechanical trauma of the muscle soleus of different severity (crush syndrome lasting 1 min under a pressure of 2.5, 3.5, and 4.5 kg/cm2, respectively). Methods Using tensometry, biochemical and histopathological analyses, the biomechanical parameters of muscle soleus contraction (contraction force and integrated muscle power), biochemical indicators of rat blood (concentrations of creatinine, creatine phosphokinase, urea and hydrogen peroxide, catalase and superoxide dismutase activity), glomerular filtration rate and fractional sodium excretion value, as well as pathohistological and morphometric features of muscle and kidney damages in rats on days 1, 3, 6 and 9 after the initiation of the injury were studied. Results Positive changes in biomechanical and biochemical parameters were found during the experiment by about 27-30 ± 2%, as well as a decrease in pathohistological and morphometric features of muscle and kidney damages in rats treated with water-soluble C60 fullerenes. Conclusion These findings indicate the potential application of water-soluble C60 fullerenes in the treatment of pathological conditions of the muscular system caused by rhabdomyolysis and the associated oxidative stress.
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Affiliation(s)
- Yuriy Prylutskyy
- ESC ”institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
| | - Dmytro Nozdrenko
- ESC ”institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
| | - Olexandr Omelchuk
- Faculty of Biology and Forestry, Lesya Ukrainka Volyn National University, Lutsk, Ukraine
| | - Svitlana Prylutska
- Faculty of Plant Protection, Biotechnology and Ecology, National University of Life and Environmental Science of Ukraine, Kyiv, Ukraine
| | - Olexandr Motuziuk
- ESC ”institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
- Faculty of Biology and Forestry, Lesya Ukrainka Volyn National University, Lutsk, Ukraine
| | - Vasil Soroсa
- ESC ”institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
| | - Igor Vareniuk
- ESC ”institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
| | - Viktoria Stetska
- ESC ”institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
| | - Kateryna Bogutska
- ESC ”institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
| | - Uwe Ritter
- Institute of Chemistry and Biotechnology, Technical University of Ilmenau, Ilmenau, Germany
| | - Jacek Piosik
- Intercollegiate Faculty of Biotechnology, University of Gdansk, Gdańsk, Poland
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15
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Kim SG, Jeon JH, Shin SH, Varias DC, Moon SH, Ryu BY. Inhibition of reactive oxygen species generation by N-Acetyl Cysteine can mitigate male germ cell toxicity induced by bisphenol analogs. Food Chem Toxicol 2024; 188:114652. [PMID: 38583502 DOI: 10.1016/j.fct.2024.114652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 03/25/2024] [Accepted: 04/04/2024] [Indexed: 04/09/2024]
Abstract
The estrogen-like effect of bisphenol A (BPA) disrupting the maintenance of functional male germ cells is associated with male sub-fertility. This study investigated toxicity of male germ cells induced by four bisphenol analogs: BPA, BPAF, BPF, and BPS. The investigation of bisphenol analogs' impact on male germ cells included assessing proliferation, apoptosis induction, and the capacity to generate reactive oxygen species (ROS) in GC-1 spermatogonia (spg) cells, specifically type B spermatogonia. Additionally, the therapeutic potential and protective effects of N-Acetyl Cysteine (NAC) and NF-κB inhibitor parthenolide was evaluated. In comparison to BPA, BPF and BPS, BPAF exhibited the most pronounced adverse effect in GC-1 spg cell proliferation. This effect was characterized by pronounced inhibition of phosphorylation of PI3K, AKT, and mTOR, along with increased release of cytochrome c and subsequent cleavages of caspase 3, caspase 7, and poly (ADP-ribose) polymerase. Both NAC and parthenolide were effective reducing cellular ROS induced by BPAF. However, only NAC demonstrated a substantial recovery in proliferation, accompanied by a significant reduction in cytochrome c release and cleaved PARP. These results suggest that NAC supplementation may play an effective therapeutic role in countering germ cell toxicity induced by environmental pollutants with robust oxidative stress-generating capacity.
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Affiliation(s)
- Seul Gi Kim
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea.
| | - Jeong Hoon Jeon
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea.
| | - Seung Hee Shin
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea.
| | - Daniel Chavez Varias
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea.
| | - Sung-Hwan Moon
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea.
| | - Buom-Yong Ryu
- Department of Animal Science and Technology, Chung-Ang University, Anseong-Si, Gyeonggi-Do, 17546, Republic of Korea.
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16
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Bresette CA, Ashworth KJ, Di Paola J, Ku DN. N-Acetyl Cysteine Prevents Arterial Thrombosis in a Dose-Dependent Manner In Vitro and in Mice. Arterioscler Thromb Vasc Biol 2024; 44:e39-e53. [PMID: 38126172 DOI: 10.1161/atvbaha.123.319044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 11/26/2023] [Indexed: 12/23/2023]
Abstract
BACKGROUND Platelet-rich thrombi occlude arteries causing fatal infarcts like heart attacks and strokes. Prevention of thrombi by current antiplatelet agents can cause major bleeding. Instead, we propose using N-acetyl cysteine (NAC) to act against the protein VWF (von Willebrand factor), and not platelets, to prevent arterial thrombi from forming. METHODS NAC was assessed for its ability to prevent arterial thrombosis by measuring platelet accumulation rate and occlusion time using a microfluidic model of arterial thrombosis with human blood. Acute clot formation, clot stability, and tail bleeding were measured in vivo with the murine modified Folts model. The effect of NAC in the murine model after 6 hours was also measured to determine any persistent effects of NAC after it has been cleared from the blood. RESULTS We demonstrate reduction of thrombi formation following treatment with NAC in vitro and in vivo. Human whole blood treated with 3 or 5 mmol/L NAC showed delayed thrombus formation 2.0× and 3.7× longer than control, respectively (P<0.001). Blood treated with 10 mmol/L NAC did not form an occlusive clot, and no macroscopic platelet aggregation was visible (P<0.001). In vivo, a 400-mg/kg dose of NAC prevented occlusive clots from forming in mice without significantly affecting tail bleeding times. A lower dose of NAC significantly reduced clot stability. Mice given multiple injections showed that NAC has a lasting and cumulative effect on clot stability, even after being cleared from the blood (P<0.001). CONCLUSIONS Both preclinical models demonstrate that NAC prevents thrombus formation in a dose-dependent manner without significantly affecting bleeding time. This work highlights a new pathway for preventing arterial thrombosis, different from antiplatelet agents, using an amino acid derivative as an antithrombotic therapeutic.
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Affiliation(s)
- Christopher A Bresette
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta (C.A.B., D.N.K.)
| | - Katrina J Ashworth
- Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine in St. Louis, MO (K.J.A., J.D.P.)
| | - Jorge Di Paola
- Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine in St. Louis, MO (K.J.A., J.D.P.)
| | - David N Ku
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta (C.A.B., D.N.K.)
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17
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Wu J, Maller B, Kaul R, Galabow A, Bryan A, Neuwelt A. High-Dose Acetaminophen as a Treatment for Cancer. LIVERS 2024; 4:84-91. [PMID: 40236464 PMCID: PMC11997869 DOI: 10.3390/livers4010007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/17/2025] Open
Abstract
The use of high-dose acetaminophen (AAP) with n-acetylcysteine (NAC) rescue was studied as an anti-cancer treatment in phase I trials with promising signals of anti-tumor efficacy. Correlative analysis suggested that AAP has a free-radical-independent mechanism of anti-tumor activity-in contrast to the well-established mechanism of AAP hepatotoxicity. Subsequent "reverse translational" studies in the pre-clinical setting have identified novel mechanisms of action of high-dose AAP, including modulation of JAK-STAT signaling in both the tumor cell and the tumor immune microenvironment. Importantly, these effects are free-radical-independent and not reversed by concurrent administration of the established AAP rescue agents fomepizole and NAC. By administering high-dose AAP concurrently with fomepizole and NAC, 100-fold higher AAP levels than those of standard dosing can be achieved in mice without detected toxicity and with substantial anti-tumor efficacy against commonly used mouse models of lung and breast cancer that are resistant to standard first-line anti-cancer therapies. With these recent advances, additional clinical trials of high-dose AAP with concurrent NAC and fomepizole-based rescue are warranted.
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Affiliation(s)
- Jeffrey Wu
- Department of Neurology, School of Medicine, Oregon Health and Sciences University, 3181 Sam Jackson Park Rd., Portland, OR 97239, USA
| | - Bradley Maller
- Department of Veterans Affairs, 1201 Broad Rock Blvd, Richmond, VA 23249, USA
- Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, 1201 E Marshall St., Richmond, VA 23298, USA
| | - Rujul Kaul
- Department of Veterans Affairs, 1201 Broad Rock Blvd, Richmond, VA 23249, USA
| | - Andrea Galabow
- Department of Veterans Affairs, 1201 Broad Rock Blvd, Richmond, VA 23249, USA
| | - Allyn Bryan
- Department of Veterans Affairs, 1201 Broad Rock Blvd, Richmond, VA 23249, USA
| | - Alexander Neuwelt
- Department of Veterans Affairs, 1201 Broad Rock Blvd, Richmond, VA 23249, USA
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18
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Bryan A, Pingali P, Faber A, Landry J, Akakpo JY, Jaeschke H, Li H, Lee WS, May L, Patel B, Neuwelt A. High-Dose Acetaminophen with Concurrent CYP2E1 Inhibition Has Profound Anticancer Activity without Liver Toxicity. J Pharmacol Exp Ther 2024; 388:209-217. [PMID: 37918853 PMCID: PMC10765416 DOI: 10.1124/jpet.123.001772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 09/25/2023] [Accepted: 10/13/2023] [Indexed: 11/04/2023] Open
Abstract
Acetaminophen (AAP) is metabolized by a variety of pathways such as sulfation, glucuronidation, and fatty acid amide hydrolase-mediated conversion to the active analgesic metabolite AM404. CYP2E1-mediated metabolism to the hepatotoxic reactive metabolite NAPQI (N-acetyl-p-benzoquinone imine) is a minor metabolic pathway that has not been linked to AAP therapeutic benefits yet clearly leads to AAP liver toxicity. N-acetylcysteine (NAC) (an antioxidant) and fomepizole (a CYP2E1 inhibitor) are clinically used for the treatment of AAP toxicity. Mice treated with AAP in combination with fomepizole (plus or minus NAC) were assessed for liver toxicity by histology and serum chemistry. The anticancer activity of AAP with NAC and fomepizole rescue was assessed in vitro and in vivo. Fomepizole with or without NAC completely prevented AAP-induced liver toxicity. In vivo, high-dose AAP with NAC/fomepizole rescue had profound antitumor activity against commonly used 4T1 breast tumor and lewis lung carcinoma lung tumor models, and no liver toxicity was detected. The antitumor efficacy was reduced in immune-compromised NOD-scid IL2Rgammanull mice, suggesting an immune-mediated mechanism of action. In conclusion, using fomepizole-based rescue, we were able to treat mice with 100-fold higher than standard dosing of AAP (650 mg/kg) without any detected liver toxicity and substantial antitumor activity. SIGNIFICANCE STATEMENT: High-dose acetaminophen can be given concurrently with CYP2E1 inhibition to allow for safe dose escalation to levels needed for anticancer activity without detected evidence of toxicity.
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Affiliation(s)
- Allyn Bryan
- Department of Veterans Affairs, Richmond, Virginia. (A.B., P.P., W.S.L., B.P., A.N.); Departments of Oral and Craniofacial Molecular Biology (A.F.) and Human and Molecular Genetics (J.L., L.M.), Virginia Commonwealth University, Richmond, Virginia; Department of Veterans Affairs, Charleston, South Carolina (H.L.); and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas, Lawrence, Kansas (J.Y.A., H.J.)
| | - Pavani Pingali
- Department of Veterans Affairs, Richmond, Virginia. (A.B., P.P., W.S.L., B.P., A.N.); Departments of Oral and Craniofacial Molecular Biology (A.F.) and Human and Molecular Genetics (J.L., L.M.), Virginia Commonwealth University, Richmond, Virginia; Department of Veterans Affairs, Charleston, South Carolina (H.L.); and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas, Lawrence, Kansas (J.Y.A., H.J.)
| | - Anthony Faber
- Department of Veterans Affairs, Richmond, Virginia. (A.B., P.P., W.S.L., B.P., A.N.); Departments of Oral and Craniofacial Molecular Biology (A.F.) and Human and Molecular Genetics (J.L., L.M.), Virginia Commonwealth University, Richmond, Virginia; Department of Veterans Affairs, Charleston, South Carolina (H.L.); and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas, Lawrence, Kansas (J.Y.A., H.J.)
| | - Joseph Landry
- Department of Veterans Affairs, Richmond, Virginia. (A.B., P.P., W.S.L., B.P., A.N.); Departments of Oral and Craniofacial Molecular Biology (A.F.) and Human and Molecular Genetics (J.L., L.M.), Virginia Commonwealth University, Richmond, Virginia; Department of Veterans Affairs, Charleston, South Carolina (H.L.); and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas, Lawrence, Kansas (J.Y.A., H.J.)
| | - Jephte Y Akakpo
- Department of Veterans Affairs, Richmond, Virginia. (A.B., P.P., W.S.L., B.P., A.N.); Departments of Oral and Craniofacial Molecular Biology (A.F.) and Human and Molecular Genetics (J.L., L.M.), Virginia Commonwealth University, Richmond, Virginia; Department of Veterans Affairs, Charleston, South Carolina (H.L.); and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas, Lawrence, Kansas (J.Y.A., H.J.)
| | - Hartmut Jaeschke
- Department of Veterans Affairs, Richmond, Virginia. (A.B., P.P., W.S.L., B.P., A.N.); Departments of Oral and Craniofacial Molecular Biology (A.F.) and Human and Molecular Genetics (J.L., L.M.), Virginia Commonwealth University, Richmond, Virginia; Department of Veterans Affairs, Charleston, South Carolina (H.L.); and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas, Lawrence, Kansas (J.Y.A., H.J.)
| | - Howard Li
- Department of Veterans Affairs, Richmond, Virginia. (A.B., P.P., W.S.L., B.P., A.N.); Departments of Oral and Craniofacial Molecular Biology (A.F.) and Human and Molecular Genetics (J.L., L.M.), Virginia Commonwealth University, Richmond, Virginia; Department of Veterans Affairs, Charleston, South Carolina (H.L.); and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas, Lawrence, Kansas (J.Y.A., H.J.)
| | - Won Sok Lee
- Department of Veterans Affairs, Richmond, Virginia. (A.B., P.P., W.S.L., B.P., A.N.); Departments of Oral and Craniofacial Molecular Biology (A.F.) and Human and Molecular Genetics (J.L., L.M.), Virginia Commonwealth University, Richmond, Virginia; Department of Veterans Affairs, Charleston, South Carolina (H.L.); and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas, Lawrence, Kansas (J.Y.A., H.J.)
| | - Lauren May
- Department of Veterans Affairs, Richmond, Virginia. (A.B., P.P., W.S.L., B.P., A.N.); Departments of Oral and Craniofacial Molecular Biology (A.F.) and Human and Molecular Genetics (J.L., L.M.), Virginia Commonwealth University, Richmond, Virginia; Department of Veterans Affairs, Charleston, South Carolina (H.L.); and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas, Lawrence, Kansas (J.Y.A., H.J.)
| | - Bhaumik Patel
- Department of Veterans Affairs, Richmond, Virginia. (A.B., P.P., W.S.L., B.P., A.N.); Departments of Oral and Craniofacial Molecular Biology (A.F.) and Human and Molecular Genetics (J.L., L.M.), Virginia Commonwealth University, Richmond, Virginia; Department of Veterans Affairs, Charleston, South Carolina (H.L.); and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas, Lawrence, Kansas (J.Y.A., H.J.)
| | - Alex Neuwelt
- Department of Veterans Affairs, Richmond, Virginia. (A.B., P.P., W.S.L., B.P., A.N.); Departments of Oral and Craniofacial Molecular Biology (A.F.) and Human and Molecular Genetics (J.L., L.M.), Virginia Commonwealth University, Richmond, Virginia; Department of Veterans Affairs, Charleston, South Carolina (H.L.); and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas, Lawrence, Kansas (J.Y.A., H.J.)
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19
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Tüylü Küçükkılınç T, Ercan A. Phenelzine protects against acetaminophen induced apoptosis in HepG2 cells. Drug Chem Toxicol 2024; 47:81-89. [PMID: 37246945 DOI: 10.1080/01480545.2023.2217696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 04/04/2023] [Accepted: 04/08/2023] [Indexed: 05/30/2023]
Abstract
Acetaminophen (APAP) overdosing is the most common cause of drug-induced liver failure. Despite extensive study, N-acetylcysteine is currently the only antidote utilized for treatment. The purpose of this study was to evaluate the effect and mechanisms of phenelzine, an FDA-approved antidepressant, on APAP-induced toxicity in HepG2 cells. The human liver hepatocellular cell line HepG2 was used to investigate APAP-induced cytotoxicity. The protective effects of phenelzine were determined by examining the cell viability, combination index calculation, Caspase 3/7 activation, Cytochrome c release, H2O2 levels, NO levels, GSH activity, PERK protein levels, and pathway enrichment analysis. Elevated H2O2 production and decreased glutathione (GSH) levels were indicators of APAP-induced oxidative stress. The combination index of 2.04 indicated that phenelzine had an antagonistic effect on APAP-induced toxicity. When compared to APAP alone, phenelzine treatment considerably reduced caspase 3/7 activation, cytochrome c release, and H2O2 generation. However, phenelzine had minimal effect on NO and GSH levels and did not alleviate ER stress. Pathway enrichment analysis revealed a potential connection between APAP toxicity and phenelzine metabolism. These findings suggested that phenelzine's protective effect against APAP-induced cytotoxicity could be attributed to the drug's capacity to reduce APAP-mediated apoptotic signaling.
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Affiliation(s)
| | - Ayşe Ercan
- Department of Biochemistry, Hacettepe University Faculty of Pharmacy, Ankara, Turkey
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20
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Anh NT, Tung LM, Vinh LK, Van Quy N, Van Hoang O, Dinh NX, Le AT. An on-site and portable electrochemical sensing platform based on spinel zinc ferrite nanoparticles for the quality control of paracetamol in pharmaceutical samples. NANOSCALE ADVANCES 2023; 6:256-267. [PMID: 38125592 PMCID: PMC10729869 DOI: 10.1039/d3na00749a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 11/15/2023] [Indexed: 12/23/2023]
Abstract
In this study, crystalline spinel zinc ferrite nanoparticles (ZnFe2O4 NPs) were successfully prepared and proposed as a high-performance electrode material for the construction of an electrochemical sensing platform for the detection of paracetamol (PCM). By modifying a screen-printed carbon electrode (SPE) with ZnFe2O4 NPs, the electrochemical characteristics of the ZnFe2O4/SPE and the electrochemical oxidation of PCM were investigated by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), chronoamperometry (CA), and differential pulse voltammetry (DPV) methods. The calculated electrochemical kinetic parameters from these techniques including electrochemically active surface area (ECSA), peak-to-peak separation (ΔEp), charge transfer resistance (Rct), standard heterogeneous electron-transfer rate constants (k0), electron transfer coefficient (α), catalytic rate constant (kcat), adsorption capacity (Γ), and diffusion coefficient (D) proved that the as-synthesized ZnFe2O4 NPs have rapid electron/mass transfer characteristics, intrinsic electrocatalytic activity, and facilitate the adsorption-diffusion of PCM molecules towards the modified electrode surface. As expected, the ZnFe2O4/SPE offered excellent analytical performance towards sensing of PCM with a detection limit of 0.29 μM, a wide linear range of 0.5-400 μM, and high electrochemical sensitivity of 1.1 μA μM-1 cm-2. Moreover, the proposed ZnFe2O4-based electrochemical nanosensor also exhibited good repeatability, high anti-interference ability, and practical feasibility toward PCM sensing in a pharmaceutical tablet. Based on these observations, the designed electrochemical platform not only provides a high-performance nanosensor for the rapid and highly efficient detection of PCM but also opens a new avenue for routine quality control analysis of pharmaceutical formulations.
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Affiliation(s)
- Nguyen Tuan Anh
- Phenikaa University Nano Institute (PHENA), PHENIKAA University Hanoi 12116 Vietnam
| | - Le Minh Tung
- Department of Physics, Tien Giang University My Tho City Tien Giang Province Vietnam
| | - Le Khanh Vinh
- National Institute of Applied Mechanics and Informatics, Vietnam Academy of Science and Technology (VAST) Ho Chi Minh 70000 Vietnam
| | - Nguyen Van Quy
- International Training Institute for Materials Science (ITIMS), Hanoi University of Science and Technology (HUST) 01 Dai Co Viet Road Hanoi 10000 Vietnam
| | - Ong Van Hoang
- Phenikaa University Nano Institute (PHENA), PHENIKAA University Hanoi 12116 Vietnam
- University of Transport Technology Trieu Khuc, Thanh Xuan District Hanoi Viet Nam
| | - Ngo Xuan Dinh
- Phenikaa University Nano Institute (PHENA), PHENIKAA University Hanoi 12116 Vietnam
| | - Anh-Tuan Le
- Phenikaa University Nano Institute (PHENA), PHENIKAA University Hanoi 12116 Vietnam
- Faculty of Materials Science and Engineering, PHENIKAA University Hanoi 12116 Vietnam
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21
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Sharma NR, Siriya P, Sandhu SPS, Pokhrel M, Ching D. Complex Diagnostic Dilemma of Viral Hepatitis vs. Drug-Induced Hepatitis: A Case Report. Cureus 2023; 15:e49191. [PMID: 38130546 PMCID: PMC10733608 DOI: 10.7759/cureus.49191] [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] [Accepted: 11/20/2023] [Indexed: 12/23/2023] Open
Abstract
This case report explores the intricate diagnostic challenges encountered in a 30-year-old male patient with abdominal pain, jaundice, and a history of acetaminophen use. Initially presenting as a potential case of drug-induced hepatitis due to acetaminophen overdose, the diagnosis took an unexpected turn when the patient tested positive for hepatitis B surface antigen. The case highlights the complexity of diagnosing acute hepatitis, considering multiple potential etiologies, including viral and drug-induced factors. Differential diagnoses for this case involve considering drug-induced hepatitis, autoimmune hepatitis, various viral hepatitis types, and the potential contribution of cocaine-induced hepatitis as individual possibilities or in combination. This case emphasizes the need for a comprehensive evaluation, the consideration of multiple potential causes, and the importance of ongoing monitoring and follow-up to ensure optimal patient care in cases of acute hepatitis.
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Affiliation(s)
- Nava R Sharma
- Internal Medicine, Maimonides Medical Center, New York, USA
| | - Pranay Siriya
- Internal Medicine, Maimonides Medical Center, New York, USA
| | | | - Madalasa Pokhrel
- Internal Medicine, Montefiore New Rochelle Hospital, New Rochelle, USA
| | - Diana Ching
- Gastroenterology, Maimonides Medical Center, New York, USA
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22
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Sasaki K, Kobayashi S, Iwagami Y, Yamada D, Tomimaru Y, Noda T, Takahashi H, Doki Y, Eguchi H. Rituximab administration one week before ABO-incompatible liver transplantation due to drug-induced acute liver failure with hepatic coma: a case report. Clin J Gastroenterol 2023; 16:709-714. [PMID: 37470968 DOI: 10.1007/s12328-023-01827-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 06/26/2023] [Indexed: 07/21/2023]
Abstract
In cases of acute liver failure (ALF) with hepatic coma, early liver transplantation, including ABO-incompatible (ABOi) living donor liver transplantation (LDLT), should be considered. The ABO antibody barrier can be reduced using plasma exchange (PE) and the anti-CD20 antibody rituximab. Plasma exchange is also performed for drug-induced ALF and is effective for desensitization. Rituximab treatment usually requires 14 days. There is presently no established desensitization protocol for ABOi-LDLT for ALF. Here, we report a case of drug-induced ALF with hepatic coma, which was treated with ABOi-LDLT using PE and rituximab 8 days prior to surgery. A 33-year-old female, with a history of headaches for which she was taking analgesics daily, developed drug-induced ALF with hepatic coma. Her ABOi sister desired to become a liver donor. We initiated desensitization using rituximab (500 mg) and mycophenolate mofetil (MMF, 2000 mg/day), followed by five sessions of PE. Eight days after rituximab administration, ABOi-LDLT with splenectomy was performed. Postoperatively, the patient received local infusion via portal vein for 14 days and immunosuppression with tacrolimus, methylprednisolone, and MMF. No episode of cellular or antibody-mediated rejection (AMR) was observed. The patient was discharged uneventfully 56 days after ABOi-LDLT with no problems up to 15 months after the transplant.
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Affiliation(s)
- Kazuki Sasaki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Yoshifumi Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yoshito Tomimaru
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takehiro Noda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hidenori Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
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Fukuda M, Hirayu N, Nabeta M, Takasu O. Acute Liver Failure After Administration of Acetaminophen at the Recommended Daily Dose in an Adult: A Case Report. Cureus 2023; 15:e45735. [PMID: 37872920 PMCID: PMC10590276 DOI: 10.7759/cureus.45735] [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] [Accepted: 09/21/2023] [Indexed: 10/25/2023] Open
Abstract
Acetaminophen may cause liver damage in a dose-dependent way: we experienced a case where an intravenous injection of 3 g/day of acetaminophen, which is less than the recommended maximum dose, was thought to have caused acute liver failure in a 73-year-old female. Four courses of postoperative adjuvant chemotherapy were given, without liver damage until the third course. After the administration of the fourth course, the patient experienced nausea and vomiting. She was admitted to the hospital with a diagnosis of enteritis a week later. At the time of admission, there was no liver impairment. For abdominal pain caused by enteritis, acetaminophen was administered intravenously over two days, totaling 4,000 mg. On the third day, acute liver failure developed, and N-acetylcysteine was administered. There was no improvement after the introduction of treatment; hence, 1,000 mg/day of steroid pulse therapy was administered. The patient's liver function started to improve, and she was discharged from the hospital two weeks later. This case suggests that the amount of acetaminophen used per unit of body weight may be unintentionally greater for adults with a small physique; thus, physicians should provide sufficient monitoring to discover side effects early and ensure there is appropriate use.
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Affiliation(s)
- Masafumi Fukuda
- Intensive Care Unit, Advanced Emergency and Critical Care Center, Kurume University Hospital, Kurume, JPN
| | - Nobuhisa Hirayu
- Intensive Care Unit, Advanced Emergency and Critical Care Center, Kurume University Hospital, Kurume, JPN
- Department of Emergency and Critical Care Medicine, Kurume University School of Medicine, Kurume, JPN
| | - Masakazu Nabeta
- Intensive Care Unit, Advanced Emergency and Critical Care Center, Kurume University Hospital, Kurume, JPN
- Department of Emergency and Critical Care Medicine, Kurume University School of Medicine, Kurume, JPN
| | - Osamu Takasu
- Intensive Care Unit, Advanced Emergency and Critical Care Center, Kurume University Hospital, Kurume, JPN
- Department of Emergency and Critical Care Medicine, Kurume University School of Medicine, Kurume, JPN
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24
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Lee DU, Choi D, Shaik MR, Schuster K, Schellhammer S, Ponder R, Lee KJ, Chou H, Ding S, Bahadur A, Fan G, Lominadze Z. The impact of race and gender on the outcomes of patients with acetaminophen-induced acute liver failure: propensity score-matched analysis of the NIS database. Eur J Gastroenterol Hepatol 2023; 35:1049-1060. [PMID: 37505978 PMCID: PMC10403278 DOI: 10.1097/meg.0000000000002613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/30/2023]
Abstract
BACKGROUND Acetaminophen overdose is one of the leading causes of acute liver failure in the USA. In this study, we investigated the impact of race and gender on the hospital outcomes of patients admitted with acetaminophen-induced acute liver failure. METHODS From the National Inpatient Sample between the years 2016 and 2019, patients with acetaminophen-induced acute liver failure were selected and stratified based on gender (Male and Female) and race (White, Black and Hispanic). The cases were propensity score-matched to controls (male and Whites) and were compared along the following endpoints: mortality, length of stay, hospitalization costs, and hepatic complications. RESULTS Among patients with acetaminophen-induced acute liver failure, females experienced higher rates of mortality (16.60% vs. 11.70%, P = 0.004) and clinical illness, including hypotension (11.80% vs. 7.15%, P = 0.002) and ventilator use (40.80% vs. 30.00%, P < 0.001). When stratified by race, Black patients had longer hospital stays (Black vs. White, 8.76 days vs. 7.46 days, P = 0.03). There were no significant differences in outcomes between Hispanic and White patients. No significant differences in mortality were shown between races. CONCLUSION We found that females had a higher rate of mortality and incidence of hepatic encephalopathy compared to males. When stratified by race, Blacks were shown to have longer hospital stay. Females and racial minorities were also affected by special healthcare needs after discharge compared to their male and White cohorts, respectively.
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Affiliation(s)
- David Uihwan Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, 22 S. Greene St, Baltimore, MD 21201, USA
| | - Dabin Choi
- Department of Medicine, University of Maryland School of Medicine, 22 S. Greene St, Baltimore, MD 21201, USA
| | - Mohammed Rifat Shaik
- Department of Medicine, University of Maryland Medical Center Midtown Campus. Baltimore, MD 21201. USA
| | - Kimmy Schuster
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA 02111, USA
| | - Sophie Schellhammer
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA 02111, USA
| | - Reid Ponder
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA 02111, USA
| | - Ki Jung Lee
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA 02111, USA
| | - Hannah Chou
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA 02111, USA
| | - Samuel Ding
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA 02111, USA
| | - Aneesh Bahadur
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA 02111, USA
| | - Gregory Fan
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA 02111, USA
| | - Zurabi Lominadze
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, 22 S. Greene St, Baltimore, MD 21201, USA
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25
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Alizadeh N, Yaryari A, Behnoush AH, Raoufinejad K, Behnoush B. Late N-acetylcysteine for successful recovery of acetaminophen-related acute liver failure: A case report. Clin Case Rep 2023; 11:e7946. [PMID: 37767143 PMCID: PMC10520410 DOI: 10.1002/ccr3.7946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 09/10/2023] [Accepted: 09/12/2023] [Indexed: 09/29/2023] Open
Abstract
Acetaminophen toxicity is one of the leading causes of liver failure. Although N-acetylcysteine (NAC) is generally successful in preventing acetaminophen hepatotoxicity when given in a timely manner, if not prescribed in the early golden time, the only practical way to save the patient might be liver transplantation. The case presented was a 20-year-old female with an acetaminophen overdose (30 g), for which more than 24 h had passed since the ingestion. Despite the critical clinical condition, loss of consciousness (Glasgow Coma Score of 4) of the patient, and passing the golden time of antidote administration, the decision was made by the healthcare team to administer NAC. After transferring the patient to the intensive care unit, the three-bag NAC regimen was initiated and appropriate monitoring was performed. After this, the regimen of 3 g q8h was continued for the patient. The patient's condition began to improve slowly on the second day and then she was extubated on the fourth day. Finally, she was discharged on the tenth day. Although the golden period of antidote administration had passed outwardly, there was no need for a liver transplant and the patient recovered successfully with late NAC administration. Hence, clinicians can benefit from the use of NAC even in the late phases of acetaminophen liver toxicity.
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Affiliation(s)
- Nafiseh Alizadeh
- Department of Pharmaceutical Care, Baharloo HospitalTehran University of Medical SciencesTehranIran
| | | | | | | | - Behnam Behnoush
- School of MedicineTehran University of Medical SciencesTehranIran
- Department of Forensic MedicineTehran University of Medical SciencesTehranIran
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26
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da Silva RHS, de Moura M, de Paula L, Arantes KC, da Silva M, de Amorim J, Miguel MP, Martins DB, de Melo e Silva D, Melo MM, Botelho AFM. Effects of coenzyme Q10 and N-acetylcysteine on experimental poisoning by paracetamol in Wistar rats. PLoS One 2023; 18:e0290268. [PMID: 37607187 PMCID: PMC10443853 DOI: 10.1371/journal.pone.0290268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 08/05/2023] [Indexed: 08/24/2023] Open
Abstract
Paracetamol (PAR) is a drug widely used in human and veterinary medicine as an analgesic and antipyretic, often involved in cases of intoxication. The most common clinical signs result from damage to red blood cells and hepatocytes, and this intoxication is considered a model for the induction of acute liver failure. In the present study, the hepatoprotective effects of coenzyme Q10 (CoQ10) and N-acetylcysteine (NAC) against experimental paracetamol (PAR) poisoning were analysed. Thirty-five adult Wistar rats (Rattus novergicus albinus) were randomly assigned to five groups, and thirty-one of these survived the treatments. Negative control group (CON-) received 1mL of 0.9% NaCl orally (PO). Other groups received 1.2g/kg of PAR (PO). Positive control group (CON+) received only PAR. NAC group received 800 mg/kg intraperitoneally (IP) of NAC 1h after the administration of PAR and at 12 h received 1mL of 0.9% NaCl, IP. The fourth group (CoQ10) received 1h and 12 h after intoxication, CoQ10 (10mg/kg IP). And the fifth group (NAC+CoQ10) received NAC (800mg/kg, IP) and CoQ10 (10mg/kg, IP). After 12 hours, the rats were euthanized and necropsied to collect liver and kidney tissues for histopathological evaluation and electronic microscopy. A single dose of PAR caused severe acute hepatitis. NAC couldn't reverse the liver and kidney damages. The group that received CoQ10 and NAC had moderate liver damage, while the group that received only CoQ10 had lower values of liver enzymes and mild liver and kidney damage. Animals that received treatment with CoQ10 or NAC+CoQ10 presented normal hepatocyte mitochondria and nuclei. Although CoQ10 couldn't reverse PAR organ damage, results indicate promising hepatoprotection in Wistar rats.
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Affiliation(s)
- Rayanne Henrique Santana da Silva
- Veterinary Toxicology Laboratory, Veterinary Hospital, Veterinary and Animal Science School, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Mariana de Moura
- Department of Genetics, Laboratory of Mutagenesis, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Larissa de Paula
- Pathology Sector, Instituto de Patologia Tropical e Saúde Pública, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Kelly Carolina Arantes
- Veterinary Toxicology Laboratory, Veterinary Hospital, Veterinary and Animal Science School, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Marina da Silva
- Veterinary Clinical Pathology Laboratory, Veterinary Hospital, Veterinary and Animal Science School, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Jaqueline de Amorim
- Veterinary Clinical Pathology Laboratory, Veterinary Hospital, Veterinary and Animal Science School, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Marina Pacheco Miguel
- Pathology Sector, Instituto de Patologia Tropical e Saúde Pública, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Danieli Brolo Martins
- Veterinary Clinical Pathology Laboratory, Veterinary Hospital, Veterinary and Animal Science School, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Daniela de Melo e Silva
- Department of Genetics, Laboratory of Mutagenesis, Federal University of Goiás, Goiânia, Goiás, Brazil
| | - Marília Martins Melo
- Veterinary Toxicology Laboratory, Veterinary Hospital, Veterinary and Animal Science School, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Ana Flávia Machado Botelho
- Veterinary Toxicology Laboratory, Veterinary Hospital, Veterinary and Animal Science School, Federal University of Goiás, Goiânia, Goiás, Brazil
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27
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Gao N, Pan J, Wang L, Cai Z, Chang G, Wu Y, He Y. Novel graphene electrochemical transistors incorporating zirconia inorganic molecular imprinted layer：Design, construction and application for highly sensitive and selective detection of acetaminophen. Anal Chim Acta 2023; 1269:341405. [PMID: 37290852 DOI: 10.1016/j.aca.2023.341405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/11/2023] [Accepted: 05/22/2023] [Indexed: 06/10/2023]
Abstract
Owing to their intrinsic amplifying effect together with chemical stability, graphene electrochemical transistor sensors (GECTs) are gaining momentum for sensing applications. However, the surface of GECTs for different detection substances must be modified with different recognition molecules, which was cumbersome and lack a universal method. Molecularly imprinted polymer (MIP) is a kind of polymer with specific recognition function for given molecules. Here, MIP and GECTs were combined to effectively solve the problem of weak selectivity of GECTs, and achieve the high sensitivity and selectivity of MIP-GECTs equipment in detecting acetaminophen (AP) in complex urine environment. A novel molecular imprinting sensor based on Au nanoparticles modified zirconia (ZrO2) inorganic molecular imprinting membrane on reduced graphene oxide (ZrO2-MIP-Au/rGO) was proposed. ZrO2-MIP-Au/rGO was synthesized by one-step electropolymerization using AP as template, ZrO2 precursor as the functional monomer. The -OH group on ZrO2 and the -OH/-CONH- group on AP were easily bonded by hydrogen bonding to form a MIP layer on the surface, which allows the sensor to have a large number of imprinted cavities for AP specific adsorption. As a proof of method, the GECTs based on ZrO2-MIP-Au/rGO functional gate electrode has the characteristics of wide linear range (0.1 nM-4 mM), low detection limit (0.1 nM) and high selectivity for AP detection. These achievements highlight the introduction of specific and selective MIP to GECTs with unique amplification function, which could effectively solve the problem of selectivity of GECTs in complex environments, suggesting the potential of MIP-GECTs in real-time diagnosis.
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Affiliation(s)
- Nan Gao
- Ministry-of-Education Key Laboratory for the Green Preparation and Application of Functional Materials, Hubei Key Laboratory of Polymer Materials, School of Materials Science and Engineering, Hubei University, No.368 Youyi Avenue, Wuchang, Wuhan, 430062, China
| | - Junzi Pan
- Ministry-of-Education Key Laboratory for the Green Preparation and Application of Functional Materials, Hubei Key Laboratory of Polymer Materials, School of Materials Science and Engineering, Hubei University, No.368 Youyi Avenue, Wuchang, Wuhan, 430062, China
| | - Lei Wang
- Ministry-of-Education Key Laboratory for the Green Preparation and Application of Functional Materials, Hubei Key Laboratory of Polymer Materials, School of Materials Science and Engineering, Hubei University, No.368 Youyi Avenue, Wuchang, Wuhan, 430062, China
| | - Zhiwei Cai
- Ministry-of-Education Key Laboratory for the Green Preparation and Application of Functional Materials, Hubei Key Laboratory of Polymer Materials, School of Materials Science and Engineering, Hubei University, No.368 Youyi Avenue, Wuchang, Wuhan, 430062, China
| | - Gang Chang
- Ministry-of-Education Key Laboratory for the Green Preparation and Application of Functional Materials, Hubei Key Laboratory of Polymer Materials, School of Materials Science and Engineering, Hubei University, No.368 Youyi Avenue, Wuchang, Wuhan, 430062, China.
| | - Yuxiang Wu
- School of Physical Education, Jianghan University, Wuhan, 430056, China.
| | - Yunbin He
- Ministry-of-Education Key Laboratory for the Green Preparation and Application of Functional Materials, Hubei Key Laboratory of Polymer Materials, School of Materials Science and Engineering, Hubei University, No.368 Youyi Avenue, Wuchang, Wuhan, 430062, China.
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Bhattacharya R, Saini S, Ghosh S, Roy P, Ali N, Parvez MK, Al-Dosari MS, Mishra AK, Singh LR. Organosulfurs, S-allyl cysteine and N-acetyl cysteine sequester di-carbonyls and reduces carbonyl stress in HT22 cells. Sci Rep 2023; 13:13071. [PMID: 37567958 PMCID: PMC10421908 DOI: 10.1038/s41598-023-40291-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 08/08/2023] [Indexed: 08/13/2023] Open
Abstract
Diabetes, characterized by high blood glucose level, is a progressive metabolic disease that leads to serious health complications. One of the major pathological consequences associated with diabetes is the accumulation of highly reactive carbonyl compounds called advanced glycation end products (AGEs). Most of the AGEs are dicarbonyls and have the potential to covalently modify proteins especially at the lysine residues in a non-enzymatic fashion (a process termed as glycation) resulting in the functional impairment and/or toxic gain in function. Therefore, non-toxic small molecules that can inhibit glycation are of interest for the therapeutic intervention of diabetes. In the present communication, we have investigated the effect of organosulfurs (S-allyl cysteine, SAC and N-acetyl cysteine, NAC) that are major principal components of Allium sativa against the glycation of different proteins. We discovered that both SAC and NAC are potent anti-glycating agents. We also found that both SAC and NAC reduce ROS level and inhibit apoptosis caused by protein glycation.
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Affiliation(s)
- Reshmee Bhattacharya
- Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India
| | - Saakshi Saini
- Department of Biosciences and Bioengineering, IIT Roorkee, Roorkee, 247667, Uttarakhand, India
| | - Souvik Ghosh
- Department of Biosciences and Bioengineering, IIT Roorkee, Roorkee, 247667, Uttarakhand, India
| | - Partha Roy
- Department of Biosciences and Bioengineering, IIT Roorkee, Roorkee, 247667, Uttarakhand, India
| | - Nemat Ali
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Mohammad Khalid Parvez
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Mohammed S Al-Dosari
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Awdhesh Kumar Mishra
- Department of Biotechnology, Yeungnam University, Gyeongsan, Gyeongsanbuk-Do, Republic of Korea.
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Li X, Ni J, Chen L. Advances in the study of acetaminophen-induced liver injury. Front Pharmacol 2023; 14:1239395. [PMID: 37601069 PMCID: PMC10436315 DOI: 10.3389/fphar.2023.1239395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 07/28/2023] [Indexed: 08/22/2023] Open
Abstract
Acetaminophen (APAP) overdose is a significant cause of drug-induced liver injury and acute liver failure. The diagnosis, screening, and management of APAP-induced liver injury (AILI) is challenging because of the complex mechanisms involved. Starting from the current studies on the mechanisms of AILI, this review focuses on novel findings in the field of diagnosis, screening, and management of AILI. It highlights the current issues that need to be addressed. This review is supposed to summarize the recent research progress and make recommendations for future research.
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Affiliation(s)
- Xinghui Li
- West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Jiaqi Ni
- West China School of Pharmacy, Sichuan University, Chengdu, China
- Department of Pharmacy, Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
| | - Li Chen
- Department of Pharmacy, Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
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Haider MA, Gheit YS, Nagi T, Vallejo C, Suarez ZK, Hernandez OL, Gaisinskaya P, Markwart N. Severe Acetaminophen Toxicity From the Use of Oxycodone-Acetaminophen With Normal Liver Function Tests and a Completely Asymptomatic Course of Hospitalization. ACG Case Rep J 2023; 10:e01126. [PMID: 37601301 PMCID: PMC10435042 DOI: 10.14309/crj.0000000000001126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 07/17/2023] [Indexed: 08/22/2023] Open
Abstract
Acetaminophen (N-acetyl-p-aminophenol, APAP), after being metabolized to toxic N-acetyl-p-benzoquinone imine, can cause irreversible hepatic necrosis. The mainstay of treatment includes N-acetylcysteine and fomepizole or liver transplant in patients who further deteriorate. Currently, many overdoses unintentionally occur in the setting of ingesting combined products that contain APAP. We report a rare case of a 60-year-old woman who presented with altered mental status and APAP toxicity in the setting of oxycodone-APAP overdose. She had a toxic serum APAP level on arrival. During hospitalization, her APAP level remained at the toxic level on the Rumack-Matthew nomogram. However, her liver function tests remained within normal limits, and she remained completely asymptomatic. To our best knowledge, this is the second case report with asymptomatic APAP toxicity and normal liver function tests. We will explore the effect of concomitant oxycodone ingestion on possibly delaying APAP absorption and thus resulting in a more favorable prognosis without hepatotoxicity.
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Affiliation(s)
| | - Yousra S. Gheit
- Florida Atlantic University Hospital, Schmidt College of Medicine, Boca Raton, FL
| | - Talwinder Nagi
- Florida Atlantic University Hospital, Schmidt College of Medicine, Boca Raton, FL
| | - Charles Vallejo
- Florida Atlantic University Hospital, Schmidt College of Medicine, Boca Raton, FL
| | - Zoilo K. Suarez
- Florida Atlantic University Hospital, Schmidt College of Medicine, Boca Raton, FL
| | - Oscar L. Hernandez
- Florida Atlantic University Hospital, Schmidt College of Medicine, Boca Raton, FL
| | - Polina Gaisinskaya
- Florida Atlantic University Hospital, Schmidt College of Medicine, Boca Raton, FL
| | - Nathan Markwart
- Florida Atlantic University Hospital, Schmidt College of Medicine, Boca Raton, FL
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Rodimova S, Mozherov A, Elagin V, Karabut M, Shchechkin I, Kozlov D, Krylov D, Gavrina A, Bobrov N, Zagainov V, Zagaynova E, Kuznetsova D. Label-Free Imaging Techniques to Evaluate Metabolic Changes Caused by Toxic Liver Injury in PCLS. Int J Mol Sci 2023; 24:ijms24119195. [PMID: 37298155 DOI: 10.3390/ijms24119195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/16/2023] [Accepted: 05/17/2023] [Indexed: 06/12/2023] Open
Abstract
Abuse with hepatotoxic agents is a major cause of acute liver failure. The search for new criteria indicating the acute or chronic pathological processes is still a challenging issue that requires the selection of effective tools and research models. Multiphoton microscopy with second harmonic generation (SHG) and fluorescence lifetime imaging microscopy (FLIM) are modern label-free methods of optical biomedical imaging for assessing the metabolic state of hepatocytes, therefore reflecting the functional state of the liver tissue. The aim of this work was to identify characteristic changes in the metabolic state of hepatocytes in precision-cut liver slices (PCLSs) under toxic damage by some of the most common toxins: ethanol, carbon tetrachloride (CCl4) and acetaminophen (APAP), commonly known as paracetamol. We have determined characteristic optical criteria for toxic liver damage, and these turn out to be specific for each toxic agent, reflecting the underlying pathological mechanisms of toxicity. The results obtained are consistent with standard methods of molecular and morphological analysis. Thus, our approach, based on optical biomedical imaging, is effective for intravital monitoring of the state of liver tissue in the case of toxic damage or even in cases of acute liver injury.
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Affiliation(s)
- Svetlana Rodimova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
| | - Artem Mozherov
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
- Laboratory of Molecular Genetic Research of the Institute of Clinical Medicine, Lobachevsky Nizhny Novgorod National Research State University, 23 Gagarina Ave., 603022 Nizhny Novgorod, Russia
| | - Vadim Elagin
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
| | - Maria Karabut
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
| | - Ilya Shchechkin
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
- Laboratory of Molecular Genetic Research of the Institute of Clinical Medicine, Lobachevsky Nizhny Novgorod National Research State University, 23 Gagarina Ave., 603022 Nizhny Novgorod, Russia
| | - Dmitry Kozlov
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
- Laboratory of Molecular Genetic Research of the Institute of Clinical Medicine, Lobachevsky Nizhny Novgorod National Research State University, 23 Gagarina Ave., 603022 Nizhny Novgorod, Russia
| | - Dmitry Krylov
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
- Laboratory of Molecular Genetic Research of the Institute of Clinical Medicine, Lobachevsky Nizhny Novgorod National Research State University, 23 Gagarina Ave., 603022 Nizhny Novgorod, Russia
| | - Alena Gavrina
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
- Laboratory of Molecular Genetic Research of the Institute of Clinical Medicine, Lobachevsky Nizhny Novgorod National Research State University, 23 Gagarina Ave., 603022 Nizhny Novgorod, Russia
| | - Nikolai Bobrov
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
- The Volga District Medical Centre of Federal Medical and Biological Agency, 14 Ilinskaya St., 603000 Nizhny Novgorod, Russia
| | - Vladimir Zagainov
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
- Nizhny Novgorod Regional Clinical Oncologic Dispensary, Delovaya St., 11/1, 603126 Nizhny Novgorod, Russia
| | - Elena Zagaynova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
| | - Daria Kuznetsova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
- Laboratory of Molecular Genetic Research of the Institute of Clinical Medicine, Lobachevsky Nizhny Novgorod National Research State University, 23 Gagarina Ave., 603022 Nizhny Novgorod, Russia
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Guo X, Zhang C, Bai Y, Che Q, Cao H, Guo J, Su Z. Synthesis of Chitosan Oligosaccharide-Loaded Glycyrrhetinic Acid Functionalized Mesoporous Silica Nanoparticles and In Vitro Verification of the Treatment of APAP-Induced Liver Injury. Molecules 2023; 28:molecules28104147. [PMID: 37241887 DOI: 10.3390/molecules28104147] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 05/13/2023] [Accepted: 05/14/2023] [Indexed: 05/28/2023] Open
Abstract
OBJECTIVE the study was to find a suitable treatment for acute drug-induced liver injury. The use of nanocarriers can improve the therapeutic effect of natural drugs by targeting hepatocytes and higher loads. METHODS firstly, uniformly dispersed three-dimensional dendritic mesoporous silica nanospheres (MSNs) were synthesized. Glycyrrhetinic acid (GA) was covalently modified on MSN surfaces through amide bond and then loaded with COSM to form drug-loaded nanoparticles (COSM@MSN-NH2-GA). The constructed drug-loaded nano-delivery system was determined by characterization analysis. Finally, the effect of nano-drug particles on cell viability was evaluated and the cell uptake in vitro was observed. RESULTS GA was successfully modified to obtain the spherical nano-carrier MSN-NH2-GA (≤200 nm). The neutral surface charge improves its biocompatibility. MSN-NH2-GA has high drug loading (28.36% ± 1.00) because of its suitable specific surface area and pore volume. In vitro cell experiments showed that COSM@MSN-NH2-GA significantly enhanced the uptake of liver cells (LO2) and decreased the AST and ALT indexes. CONCLUSION this study demonstrated for the first time that formulation and delivery schemes using natural drug COSM and nanocarrier MSN have a protective effect on APAP-induced hepatocyte injury. This result provides a potential nano-delivery scheme for the targeted therapy of acute drug-induced liver injury.
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Affiliation(s)
- Xinghua Guo
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Chengcheng Zhang
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yan Bai
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Qishi Che
- Guangzhou Rainhome Pharm & Tech Co., Ltd., Science City, Guangzhou 510663, China
| | - Hua Cao
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China
| | - Jiao Guo
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Zhengquan Su
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China
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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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Elkhateeb N, Hyde S, Hogg SL, Allsop D, Shankar A, Deegan P, Tan CY. Paracetamol toxicity in classic homocystinuria: Effect of N-acetylcysteine on total homocysteine. JIMD Rep 2023; 64:238-245. [PMID: 37151359 PMCID: PMC10159864 DOI: 10.1002/jmd2.12363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 02/18/2023] [Accepted: 02/22/2023] [Indexed: 03/06/2023] Open
Abstract
Classical homocystinuria (HCU) is caused by cystathionine β-synthase deficiency leading to impaired homocysteine transsulfuration and accumulation of homocysteine and methionine. Patients present with a wide spectrum of manifestations including ocular, skeletal, neuropsychiatric, and vascular manifestations. We report a 48-year-old female with pyridoxine-unresponsive HCU treated with betaine, cyanocobalamin, and folate. Her diet was non-restricted due to intolerance of low-methionine diet. She was admitted to hospital following a fall, with multiple fractures and subsequently developed acute liver failure with encephalopathy. Shock, sepsis, and liver ischaemia/thrombosis were excluded. In the context of glutathione depletion expected in HCU, hepatic dysfunction was presumed to be due to iatrogenic paracetamol toxicity, despite paracetamol intake at conventional therapeutic dose, with role of hypermethioninemia as a contributing factor being uncertain. Betaine was discontinued on hospital admission. N-Acetylcysteine (NAC) infusion was initiated. Plasma total homocysteine (tHcy) was 3.4 μmol/L 9 days following initiation of NAC treatment with a markedly elevated plasma methionine of 1278 μmol/L. tHcy concentration returned to pre-admission baseline after NAC was discontinued. Recovery following this episode was slow with a prolonged cholestatic phase and gradual improvement in jaundice and coagulopathy. We recommend that paracetamol should be administered cautiously in HCU patients due to underlying glutathione depletion and risk of toxicity even at therapeutic doses. NAC is clearly effective in lowering tHcy in classical HCU in the short-term however further research is required to assess clinical efficacy and use as a potential therapy in classical HCU.
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Affiliation(s)
- Nour Elkhateeb
- Department of Metabolic MedicineCambridge University hospitals NHS Foundation TrustCambridgeUK
- Department of Clinical GeneticsCambridge University hospitals NHS Foundation TrustCambridgeUK
| | - Sarah Hyde
- Department of GastroenterologyNorfolk and Norwich University Hospital NHS TrustNorwichUK
| | - Sarah L. Hogg
- Biochemical Genetics UnitCambridge University Hospitals NHS Foundation TrustCambridgeUK
| | - Daniel Allsop
- Department of HistopathologyNorfolk and Norwich University Hospitals NHS TrustNorwichUK
| | - Arun Shankar
- Department of GastroenterologyNorfolk and Norwich University Hospital NHS TrustNorwichUK
| | - Patrick Deegan
- Department of Metabolic MedicineCambridge University hospitals NHS Foundation TrustCambridgeUK
| | - Chong Y. Tan
- Department of Metabolic MedicineCambridge University hospitals NHS Foundation TrustCambridgeUK
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Everton E, Del Rio-Moreno M, Villacorta-Martin C, Singh Bawa P, Lindstrom-Vautrin J, Muramatsu H, Rizvi F, Smith AR, Tam Y, Pardi N, Kineman R, Waxman DJ, Gouon-Evans V. Growth Hormone Accelerates Recovery From Acetaminophen-Induced Murine Liver Injury. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.17.537197. [PMID: 37131727 PMCID: PMC10153200 DOI: 10.1101/2023.04.17.537197] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Background and Aims Acetaminophen (APAP) overdose is the leading cause of acute liver failure, with one available treatment, N-acetyl cysteine (NAC). Yet, NAC effectiveness diminishes about ten hours after APAP overdose, urging for therapeutic alternatives. This study addresses this need by deciphering a mechanism of sexual dimorphism in APAP-induced liver injury, and leveraging it to accelerate liver recovery via growth hormone (GH) treatment. GH secretory patterns, pulsatile in males and near-continuous in females, determine the sex bias in many liver metabolic functions. Here, we aim to establish GH as a novel therapy to treat APAP hepatotoxicity. Approach and Results Our results demonstrate sex-dependent APAP toxicity, with females showing reduced liver cell death and faster recovery than males. Single-cell RNA sequencing analyses reveal that female hepatocytes have significantly greater levels of GH receptor expression and GH pathway activation compared to males. In harnessing this female-specific advantage, we demonstrate that a single injection of recombinant human GH protein accelerates liver recovery, promotes survival in males following sub-lethal dose of APAP, and is superior to standard-of-care NAC. Alternatively, slow-release delivery of human GH via the safe nonintegrative lipid nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP), a technology validated by widely used COVID-19 vaccines, rescues males from APAP-induced death that otherwise occurred in control mRNA-LNP-treated mice. Conclusions Our study demonstrates a sexually dimorphic liver repair advantage in females following APAP overdose, leveraged by establishing GH as an alternative treatment, delivered either as recombinant protein or mRNA-LNP, to potentially prevent liver failure and liver transplant in APAP-overdosed patients.
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Alaska YA, Alghadeer SM, Alrabiah AA, Harb A, Almadi B. Assessment of N-acetylcysteine use for acetaminophen overdose in the emergency department of a community teaching hospital: A pilot study. Saudi J Anaesth 2023; 17:168-173. [PMID: 37260659 PMCID: PMC10228870 DOI: 10.4103/sja.sja_707_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 10/08/2022] [Accepted: 10/11/2022] [Indexed: 03/11/2023] Open
Abstract
Introduction N-acetylcysteine (NAC) is the first-line treatment for acetaminophen (APAP) overdose. However, using NAC inappropriately is associated with an increased risk of adverse effects as well as a substantial increase in hospitalization and healthcare costs. This study aims to assess NAC utilization for acute APAP overdose in the emergency department of a community teaching hospital in Saudi Arabia. Methods A retrospective chart review in which the patients initiated on an NAC secondary to acute APAP overdose at KSUMC during the period of June 2015 till November 2018 were included and assessed based on developed validated evident-based protocol for administering NAC for acute APAP ingestion. Results A total of 29 patients received NAC treatment for acute APAP overdose; 15 of which were adults, and 14 were pediatrics. Appropriate prescribing of NAC was observed in 14 (48.28%) patients, whereas NAC was inappropriately indicated for 15 (51.72%) patients; 9 of them were adults and 6 patients were pediatric. APAP-Ingestion <150 mg/kg (<200 mg/kg in children) was the most common reason for inappropriate use (n = 7, 46.67%) followed by administering NAC <4 hours post-APAP ingestion (n = 4, 26.67%). Conclusion Improper NAC administration appears to be a significant issue among patients with APAP overdose. The utilization of a protocol for the management of APAP overdose will reduce the unnecessary usage of NAC.
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Affiliation(s)
- Yasser A. Alaska
- Department of Emergency Medicine - College of Medicine, King Saud University (KSU) and King Saud University Medical City (KSUMC), Riyadh, Saudi Arabia
| | - Sultan M. Alghadeer
- Department of Clinical Pharmacy-College of Pharmacy, King Saud University (KSU), Riyadh, Saudi Arabia
| | - Abdulaziz A. Alrabiah
- Department of Emergency Medicine - College of Medicine, King Saud University (KSU) and King Saud University Medical City (KSUMC), Riyadh, Saudi Arabia
| | - Abdulaziz Harb
- Department of Clinical Pharmacy-College of Pharmacy, King Saud University (KSU), Riyadh, Saudi Arabia
| | - Bana Almadi
- Department of Clinical Pharmacy-College of Pharmacy, King Saud University (KSU), Riyadh, Saudi Arabia
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Filip AB, Mullins ME. Fomepizole should be used more liberally in paracetamol overdose. Br J Clin Pharmacol 2023; 89:594-598. [PMID: 36471569 DOI: 10.1111/bcp.15594] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/26/2022] [Accepted: 10/31/2022] [Indexed: 12/12/2022] Open
Abstract
Growing clinical and basic science data support the use of fomepizole as an adjunct to N-acetylcysteine in paracetamol poisoning. This safe antidote may be helpful in severely poisoned patients.
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Affiliation(s)
- Ari B Filip
- Arkansas Poison and Drug Information Center, University of Arkansas for Medical Sciences College of Pharmacy, Little Rock, Arkansas, USA
| | - Michael E Mullins
- Department of Emergency Medicine, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
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Malnick SDH, Alin P, Somin M, Neuman MG. Fatty Liver Disease-Alcoholic and Non-Alcoholic: Similar but Different. Int J Mol Sci 2022; 23:16226. [PMID: 36555867 PMCID: PMC9783455 DOI: 10.3390/ijms232416226] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
In alcohol-induced liver disease (ALD) and in non-alcoholic fatty liver disease (NAFLD), there are abnormal accumulations of fat in the liver. This phenomenon may be related to excessive alcohol consumption, as well as the combination of alcohol consumption and medications. There is an evolution from simple steatosis to steatohepatitis, fibrosis and cirrhosis leading to hepatocellular carcinoma (HCC). Hepatic pathology is very similar regarding non-alcoholic fatty liver disease (NAFLD) and ALD. Initially, there is lipid accumulation in parenchyma and progression to lobular inflammation. The morphological changes in the liver mitochondria, perivenular and perisinusoidal fibrosis, and hepatocellular ballooning, apoptosis and necrosis and accumulation of fibrosis may lead to the development of cirrhosis and HCC. Medical history of ethanol consumption, laboratory markers of chronic ethanol intake, AST/ALT ratio on the one hand and features of the metabolic syndrome on the other hand, may help in estimating the contribution of alcohol intake and the metabolic syndrome, respectively, to liver steatosis.
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Affiliation(s)
- Stephen D. H. Malnick
- Department of Internal Medicine, Kaplan Medical Center, Affiliated to Hebrew University, Rehovot 76100, Israel
| | - Pavel Alin
- Department of Internal Medicine, Kaplan Medical Center, Affiliated to Hebrew University, Rehovot 76100, Israel
| | - Marina Somin
- Department of Internal Medicine, Kaplan Medical Center, Affiliated to Hebrew University, Rehovot 76100, Israel
| | - Manuela G. Neuman
- In Vitro Drug Safety and Biotechnology, Department of Pharmacology and Toxicology, Temerity Faculty of Medicine, University of Toronto, Toronto, ON M5G OA3, Canada
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Valerio V, Keceli G, Moschetta D, Porro B, Ciccarelli M, Massaiu I, Songia P, Maione AS, Alfieri V, Myasoedova VA, Zanobini M, Paolocci N, Poggio P. Enduring Reactive Oxygen Species Emission Causes Aberrant Protein S-Glutathionylation Transitioning Human Aortic Valve Cells from a Sclerotic to a Stenotic Phenotype. Antioxid Redox Signal 2022; 37:1051-1071. [PMID: 35459416 PMCID: PMC9689771 DOI: 10.1089/ars.2021.0133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 04/07/2022] [Accepted: 04/11/2022] [Indexed: 11/12/2022]
Abstract
Aims: During calcific aortic valve stenosis (CAVS) progression, oxidative stress and endothelial dysfunction mark the initial pathogenic steps with a parallel dysregulation of the antioxidant systems. Here, we tested whether oxidation-induced protein S-glutathionylation (P-SSG) accounts for a phenotypic switch in human aortic valvular tissue, eventually leading to calcium deposition. Next, we tested whether countering this reactive oxygen species (ROS) surge would prevent these perturbations. Results: We employed state-of-the-art technologies, such as electron paramagnetic resonance (EPR), liquid chromatography-tandem mass spectrometry, imaging flow-cytometry, and live-cell imaging on human excised aortic valves and primary valve endothelial cells (VECs). We observed that a net rise in EPR-detected ROS emission marked the transition from fibrotic to calcific in human CAVS specimens, coupled to a progressive increment in P-SSG deposition. In human VECs (hVECs), treatment with 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylthiocarbonylamino)phenylthiocarbamoylsulfanyl]propionic acid triggered highly oxidizing conditions prompting P-SSG accumulation, damaging mitochondria, and inducing endothelial nitric oxide synthase uncoupling. All the events conjured up in morphing these cells from their native endothelial phenotype into a damaged calcification-inducing one. As proof of principle, the use of the antioxidant N-acetyl-L-cysteine prevented these alterations. Innovation: Borne as a compensatory system to face excessive oxidative burden, with time, P-SSG contributes to the morphing of hVECs from their innate phenotype into a damaged one, paving the way to calcium deposition. Conclusion: Our data suggest that, in the human aortic valve, unremitted ROS emission along with a P-SSG build-up occurs and accounts, at least in part, for the morphological/functional changes leading to CAVS. Antioxid. Redox Signal. 37, 1051-1071.
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Affiliation(s)
- Vincenza Valerio
- Unità per lo Studio delle Patologie Aortiche, Valvolari e Coronariche, Centro Cardiologico Monzino IRCCS, Milan, Italy
- Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli Federico II, Napoli, Italy
| | - Gizem Keceli
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Donato Moschetta
- Unità per lo Studio delle Patologie Aortiche, Valvolari e Coronariche, Centro Cardiologico Monzino IRCCS, Milan, Italy
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - Benedetta Porro
- Unità per lo Studio delle Patologie Aortiche, Valvolari e Coronariche, Centro Cardiologico Monzino IRCCS, Milan, Italy
| | - Michele Ciccarelli
- Dipartimento di Medicina, Chirurgia e Odontoiatria, Università degli Studi di Salerno, Baronissi, Italy
| | - Ilaria Massaiu
- Unità per lo Studio delle Patologie Aortiche, Valvolari e Coronariche, Centro Cardiologico Monzino IRCCS, Milan, Italy
| | - Paola Songia
- Unità per lo Studio delle Patologie Aortiche, Valvolari e Coronariche, Centro Cardiologico Monzino IRCCS, Milan, Italy
| | - Angela S. Maione
- Unità per lo Studio delle Patologie Aortiche, Valvolari e Coronariche, Centro Cardiologico Monzino IRCCS, Milan, Italy
| | - Valentina Alfieri
- Unità per lo Studio delle Patologie Aortiche, Valvolari e Coronariche, Centro Cardiologico Monzino IRCCS, Milan, Italy
| | - Veronika A. Myasoedova
- Unità per lo Studio delle Patologie Aortiche, Valvolari e Coronariche, Centro Cardiologico Monzino IRCCS, Milan, Italy
| | - Marco Zanobini
- Unità per lo Studio delle Patologie Aortiche, Valvolari e Coronariche, Centro Cardiologico Monzino IRCCS, Milan, Italy
| | - Nazareno Paolocci
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Paolo Poggio
- Unità per lo Studio delle Patologie Aortiche, Valvolari e Coronariche, Centro Cardiologico Monzino IRCCS, Milan, Italy
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Hebert JF, Burfeind KG, Malinoski D, Hutchens MP. Molecular Mechanisms of Rhabdomyolysis-Induced Kidney Injury: From Bench to Bedside. Kidney Int Rep 2022; 8:17-29. [PMID: 36644345 PMCID: PMC9831947 DOI: 10.1016/j.ekir.2022.09.026] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/20/2022] [Accepted: 09/26/2022] [Indexed: 01/18/2023] Open
Abstract
Rhabdomyolysis-induced acute kidney injury (RIAKI) occurs following damage to the muscular sarcolemma sheath, resulting in the leakage of myoglobin and other metabolites that cause kidney damage. Currently, the sole recommended clinical treatment for RIAKI is aggressive fluid resuscitation, but other potential therapies, including pretreatments for those at risk for developing RIAKI, are under investigation. This review outlines the mechanisms and clinical significance of RIAKI, investigational treatments and their specific targets, and the status of ongoing research trials.
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Affiliation(s)
- Jessica F. Hebert
- Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, Oregon, USA,Correspondence: Jessica F. Hebert, Oregon Health and Science University, Department of Anesthesiology and Perioperative Medicine, Portland, Oregon, USA.
| | - Kevin G. Burfeind
- Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, Oregon, USA
| | - Darren Malinoski
- Department of Surgery, Oregon Health and Science University, Portland, Oregon, USA,Operative Care Division, Portland Veterans Administration Medical Center, Portland, Oregon, USA
| | - Michael P. Hutchens
- Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, Oregon, USA,Operative Care Division, Portland Veterans Administration Medical Center, Portland, Oregon, USA
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MRI Detection of Hepatic N-Acetylcysteine Uptake in Mice. Biomedicines 2022; 10:biomedicines10092138. [PMID: 36140239 PMCID: PMC9495914 DOI: 10.3390/biomedicines10092138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/15/2022] [Accepted: 08/23/2022] [Indexed: 11/17/2022] Open
Abstract
This proof-of-concept study looked at the feasibility of using a thiol–water proton exchange (i.e., CEST) MRI contrast to detect in vivo hepatic N-acetylcysteine (NAC) uptake. The feasibility of detecting NAC-induced glutathione (GSH) biosynthesis using CEST MRI was also investigated. The detectability of the GSH amide and NAC thiol CEST effect at B0 = 7 T was determined in phantom experiments and simulations. C57BL/6 mice were injected intravenously (IV) with 50 g L−1 NAC in PBS (pH 7) during MRI acquisition. The dynamic magnetisation transfer ratio (MTR) and partial Z-spectral data were generated from the acquisition of measurements of the upfield NAC thiol and downfield GSH amide CEST effects in the liver. The 1H-NMR spectroscopy on aqueous mouse liver extracts, post-NAC-injection, was performed to verify hepatic NAC uptake. The dynamic MTR and partial Z-spectral data revealed a significant attenuation of the mouse liver MR signal when a saturation pulse was applied at −2.7 ppm (i.e., NAC thiol proton resonance) after the IV injection of the NAC solution. The 1H-NMR data revealed the presence of hepatic NAC, which coincided strongly with the increased upfield MTR in the dynamic CEST data, providing strong evidence that hepatic NAC uptake was detected. However, this MTR enhancement was attributed to a combination of NAC thiol CEST and some other upfield MT-generating mechanism(s) to be identified in future studies. The detection of hepatic GSH via its amide CEST MRI contrast was inconclusive based on the current results.
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Licata A, Minissale MG, Stankevičiūtė S, Sanabria-Cabrera J, Lucena MI, Andrade RJ, Almasio PL. N-Acetylcysteine for Preventing Acetaminophen-Induced Liver Injury: A Comprehensive Review. Front Pharmacol 2022; 13:828565. [PMID: 36034775 PMCID: PMC9399785 DOI: 10.3389/fphar.2022.828565] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 06/03/2022] [Indexed: 12/28/2022] Open
Abstract
Aims: N-Acetylcysteine (NAC) is used as an antidote in acetaminophen (APAP) overdose to prevent and mitigate drug-induced liver injury (DILI). Our objective was to systematically review evidence of the use of NAC as a therapeutic option for APAP overdose and APAP-related DILI in order to define the optimal treatment schedule and timing to start treatment. Methods: Bibliographic databases (PubMed, Web of Science, Embase, and MEDLINE) were searched for retrospective and prospective cohort studies, case series, and clinical trials. The prespecified primary outcomes were DILI-related mortality, hepatotoxicity, and adverse events (AEs). Results: In total, 34 studies of NAC usage in APAP-related DILI cases with 19,580 patients were identified, of which 2,376 patients developed hepatotoxicities. The mortality rate across different studies ranged from 0 to 52%. Large variability of NAC regimens was found, i.e., intravenous (I.V.) (100-150 mg/kg) and oral (70-140 mg/kg), and length of treatment varied-12, 24, or 48 h for I.V. regimen and 72 h for oral administration. The timing of initiation of NAC treatment showed different results in terms of occurrence of hepatotoxicity and mortality; if started within 8 h and no more than 24 h from APAP overdose, either intravenously or orally, NAC administration was efficacious in terms of mortality. The most frequent AEs reported were anaphylactic reactions, followed by cutaneous AEs for the IV route and intestinal AEs for the oral one. Conclusion: NAC improves hepatotoxicity and reduces mortality. Timing of treatment, ranging from 8 to 24 h from APAP overdose, regardless of the regimen or route of administration, is important to prevent or minimize liver damage, particularly in children and in elderly and obese patients.
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Affiliation(s)
- Anna Licata
- Medicina Interna ed Epatologia, Dipartimento di Promozione della Salute, Materno-infantile, di Medicina Interna e Specialistica di Eccellenza “G. D’Alessandro,” PROMISE, Università degli Studi di Palermo, Palermo, Italy
| | - Maria Giovanna Minissale
- Medicina Interna ed Epatologia, Dipartimento di Promozione della Salute, Materno-infantile, di Medicina Interna e Specialistica di Eccellenza “G. D’Alessandro,” PROMISE, Università degli Studi di Palermo, Palermo, Italy
| | - Simona Stankevičiūtė
- Medicina Interna ed Epatologia, Dipartimento di Promozione della Salute, Materno-infantile, di Medicina Interna e Specialistica di Eccellenza “G. D’Alessandro,” PROMISE, Università degli Studi di Palermo, Palermo, Italy
| | - Judith Sanabria-Cabrera
- UCICEC IBIMA, Plataforma SCReN (Spanish Clinical Research Network), Malaga, Spain
- Centro de Investigación Biomedica en Red de Enfermedades Hepáticas y Digestivas, CIBERehd, Madrid, Spain
| | - Maria Isabel Lucena
- UCICEC IBIMA, Plataforma SCReN (Spanish Clinical Research Network), Malaga, Spain
- Centro de Investigación Biomedica en Red de Enfermedades Hepáticas y Digestivas, CIBERehd, Madrid, Spain
- Servicio de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
| | - Raul J Andrade
- Servicio de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
| | - Piero Luigi Almasio
- Medicina Interna ed Epatologia, Dipartimento di Promozione della Salute, Materno-infantile, di Medicina Interna e Specialistica di Eccellenza “G. D’Alessandro,” PROMISE, Università degli Studi di Palermo, Palermo, Italy
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43
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Wang YP, Wang YD, Liu YP, Cao JX, Yang ML, Wang YF, Khan A, Zhao TR, Cheng GG. 6'- O-Caffeoylarbutin from Que Zui tea ameliorates acetaminophen-induced liver injury via enhancing antioxidant ability and regulating the PI3K signaling pathway. Food Funct 2022; 13:5299-5316. [PMID: 35441652 DOI: 10.1039/d2fo00507g] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Que Zui tea (QT), a traditional herbal tea in China, has a significant hepatoprotective effect. 6'-O-Caffeoylarbutin (CA) is the most abundant chemical compound in the QT. However, the hepatoprotective effect of CA has not been investigated. This study is aimed to evaluate the protective effect of CA on acetaminophen (APAP) induced hepatotoxicity in vivo and in vitro and its possible underlying mechanism. In APAP-induced HepG-2 cells, CA inhibited intracellular ROS accumulation and cell apoptosis, and improved the expression of antioxidants including SOD, CAT and GSH. In APAP-administrated mice, CA pretreatment remarkably ameliorated the histopathological damage and inflammatory response, and antioxidant enzyme activity in the serum and liver tissues. Moreover, the immunohistochemistry and immunofluorescence assay results revealed that the CA markedly reduced ROS production and apoptosis, and activated antioxidant transcription factor Nrf2 in the liver. Meanwhile, molecular docking results showed that the strong binding force of CA and PI3K was due to the higher number of hydrogen- and π-bonds with active site residues. Notably, CA pretreatment significantly regulated the expression of PI3K, Akt, Nrf2, NQO1, HO-1, Bcl-2, Bax, caspase-3, and caspase-9 proteins in APAP-treated liver tissues. These data demonstrated that CA had a protective effect against APAP-induced hepatotoxicity via regulating the PI3K/Akt and Nrf2 signaling pathway.
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Affiliation(s)
- Yong-Peng Wang
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China.
| | - Yu-Dan Wang
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China. .,National and Local Joint Engineering Research Center for Green Preparation Technology of Biobased Materials, Yunnan Minzu University, Kunming, 650500, China
| | - Ya-Ping Liu
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China.
| | - Jian-Xin Cao
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China.
| | - Mei-Lian Yang
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China.
| | - Yi-Fen Wang
- Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
| | - Afsar Khan
- Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, Pakistan
| | - Tian-Rui Zhao
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China.
| | - Gui-Guang Cheng
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China.
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44
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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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45
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Qin Y, Hang C, Huang L, Cheng H, Hu J, Li W, Wu J. An electrochemical biosensor of Sn@C derived from ZnSn(OH)6 for sensitive determination of acetaminophen. Microchem J 2022. [DOI: 10.1016/j.microc.2021.107128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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46
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Patel A, Perl A. Redox Control of Integrin-Mediated Hepatic Inflammation in Systemic Autoimmunity. Antioxid Redox Signal 2022; 36:367-388. [PMID: 34036799 PMCID: PMC8982133 DOI: 10.1089/ars.2021.0068] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/12/2021] [Accepted: 05/13/2021] [Indexed: 12/20/2022]
Abstract
Significance: Systemic autoimmunity affects 3%-5% of the population worldwide. Systemic lupus erythematosus (SLE) is a prototypical form of such condition, which affects 20-150 of 100,000 people globally. Liver dysfunction, defined by increased immune cell infiltration into the hepatic parenchyma, is an understudied manifestation that affects up to 20% of SLE patients. Autoimmunity in SLE involves proinflammatory lineage specification in the immune system that occurs with oxidative stress and profound changes in cellular metabolism. As the primary metabolic organ of the body, the liver is uniquely capable to encounter oxidative stress through first-pass derivatization and filtering of waste products. Recent Advances: The traffic of immune cells from their development through recirculation in the liver is guided by cell adhesion molecules (CAMs) and integrins, cell surface proteins that tightly anchor cells together. The surface expression of CAMs and integrins is regulated via endocytic traffic that is sensitive to oxidative stress. Reactive oxygen species (ROS) that elicit oxidative stress in the liver may originate from the mitochondria, the cytosol, or the cell membrane. Critical Issues: While hepatic ROS production is a source of vulnerability, it also modulates the development and function of the immune system. In turn, the liver employs antioxidant defense mechanisms to protect itself from damage that can be harnessed to serve as therapeutic mechanisms against autoimmunity, inflammation, and development of hepatocellular carcinoma. Future Directions: This review is aimed at delineating redox control of integrin signaling in the liver and checkpoints of regulatory impact that can be targeted for treatment of inflammation in systemic autoimmunity. Antioxid. Redox Signal. 36, 367-388.
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Affiliation(s)
- Akshay Patel
- Division of Rheumatology, Department of Medicine, College of Medicine, State University of New York Upstate Medical University, Syracuse, New York, USA
- Department of Microbiology and Immunology, College of Medicine, State University of New York Upstate Medical University, Syracuse, New York, USA
- Department of Biochemistry and Molecular Biology, College of Medicine, State University of New York Upstate Medical University, Syracuse, New York, USA
| | - Andras Perl
- Division of Rheumatology, Department of Medicine, College of Medicine, State University of New York Upstate Medical University, Syracuse, New York, USA
- Department of Microbiology and Immunology, College of Medicine, State University of New York Upstate Medical University, Syracuse, New York, USA
- Department of Biochemistry and Molecular Biology, College of Medicine, State University of New York Upstate Medical University, Syracuse, New York, USA
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Hussein RM, Kandeil MA, Mohammed NA, Khallaf RA. Evaluation of the hepatoprotective effect of curcumin-loaded solid lipid nanoparticles against paracetamol overdose toxicity : Role of inducible nitric oxide synthase. J Liposome Res 2022; 32:365-375. [PMID: 35132919 DOI: 10.1080/08982104.2022.2032737] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Curcumin (Cur) is a natural compound that exhibited therapeutic effects against various liver injuries however Cur showed poor water solubility and bioavailability. This study aimed to design Cur-loaded solid lipid nanoparticles (SLNs) and to evaluate the hepatoprotective and antioxidant effects in a model of acute hepatotoxicity induced by paracetamol (PCM) overdose compared to the raw Cur and N-acetylcysteine (NAC). SLNs were prepared by emulsion/solvent evaporation method and 32 factorial design was employed. Wistar rats were divided into Control, PCM, PCM + NAC, PCM + raw Cur, and PCM + Cur-SLNs groups and treated orally for 14 days before receiving a single PCM dose. The Cur-loaded SLNs showed high entrapment efficiency % ranging between 69.1 and 92.1%, particle size (PS) between 217 and 506 nm, and zeta potential values between -17.9 and -25.5 mV. The in vivo results revealed that the PCM group exhibited deterioration of liver functions, pathological lesions on the liver tissues, severe oxidative stress, and increases in both the serum and hepatic iNOS levels. Remarkably, the PCM + Cur-SLNs group showed significantly better liver functions and tissue integrity compared to the PCM group. Furthermore, higher reduced glutathione and catalase but lower malondialdehyde and iNOS levels were observed. In conclusion, Cur-loaded SLNs effectively prevented the liver damage induced by PCM overdose through alleviating the oxidative stress and inhibiting the serum and hepatic iNOS expression in an effect comparable to NAC and better than raw Cur.
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Affiliation(s)
- Rasha M Hussein
- Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Mutah University, Al-Karak, Jordan.,Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Mohamed A Kandeil
- Department of Biochemistry, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Norhan A Mohammed
- Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.,Department of Preventive Medicine, Al-Fayoum Health directorate, Al-Fayoum, Egypt
| | - Rasha A Khallaf
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni Suef, Egypt
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48
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Crosstalk between Oxidative Stress and Inflammatory Liver Injury in the Pathogenesis of Alcoholic Liver Disease. Int J Mol Sci 2022; 23:ijms23020774. [PMID: 35054960 PMCID: PMC8775426 DOI: 10.3390/ijms23020774] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/04/2022] [Accepted: 01/07/2022] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) is characterized by the injury, inflammation, and scarring in the liver owing to excessive alcohol consumption. Currently, ALD is a leading cause for liver transplantation. Therefore, extensive studies (in vitro, in experimental ALD models and in humans) are needed to elucidate pathological features and pathogenic mechanisms underlying ALD. Notably, oxidative changes in the liver have been recognized as a signature trait of ALD. Progression of ALD is linked to the generation of highly reactive free radicals by reactions involving ethanol and its metabolites. Furthermore, hepatic oxidative stress promotes tissue injury and, in turn, stimulates inflammatory responses in the liver, forming a pathological loop that promotes the progression of ALD. Accordingly, accumulating further knowledge on the relationship between oxidative stress and inflammation may help establish a viable therapeutic approach for treating ALD.
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49
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Matar AJ, Magliocca JF, Kitchens WH. Successful Liver Transplantation from a Deceased Donor After Ethylene Glycol Ingestion: A Case Report and Review of the Literature of Organ Donation from Poisoned Donors. Transplant Proc 2022; 54:128-134. [PMID: 34972567 DOI: 10.1016/j.transproceed.2021.11.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 11/01/2021] [Indexed: 11/27/2022]
Abstract
Despite the increase in deceased organ donation over the past ten years, the gap between patients awaiting transplant and available organs continues to widen. Deceased donors secondary to acute fatal poisonings represent less than 1% of all organ donors. Organs from poisoned donors have largely been discarded due to concerns of toxin transmission and poor organ function as well as the paucity of data that exists regarding this donor population. Here, we report a case of a 40-year-old male who underwent successful liver re-transplantation from a donor who died following ethylene glycol ingestion. To our knowledge this case report is the first to describe successful re-transplantation from an ethylene glycol-poisoned donor. We also provide a comprehensive review of the literature describing organ donation from poisoned donors.
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Affiliation(s)
- Abraham J Matar
- Department of Surgery, Emory University School of Medicine, Atlanta, Georgia
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50
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Jouzdani AF, Ganjirad Z, Firozian F, Soleimani-Asl S, Ranjbar A. Protective Effects of N-acetylcysteine Niosome Nanoparticles on Paraquatinduced Nephrotoxicity in Male Rats. Pharm Nanotechnol 2022; 10:137-145. [PMID: 35156589 DOI: 10.2174/2211738510666220214102034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 01/07/2022] [Accepted: 01/25/2022] [Indexed: 06/14/2023]
Abstract
INTRODUCTION Paraquat (PQ), as a bipyridyl compound, is widely used as an effective herbicide that produces reactive oxygen species (ROS), affecting the unsaturated lipids of cell membranes leading to cell mortality. N-acetylcysteine (NAC) is a medication that has a beneficial role in reducing the intoxication of kidneys caused by PQ. Niosomes are bilayer vesicles that enhance the bioavailability of drugs. This study aimed to compare the effects of NAC and niosome of NAC (NACNPs) on PQ-induced kidney toxicity concerning its antioxidant activity. METHODS In this experimental study, after formulating NACNP, 30 Wistar male rats weighing 180 to 250 gm were classified into five groups: the control group was treated with normal saline, while the other four groups received 35mg/kg/day of PQ via intraperitoneal route and, was treated with 25mg/kg/day NAC, 25mg/kg/day niosome and 25 mg/kg/day NACNP by gavage, Then, oxidative stress biomarkers such as total antioxidant capacity (TAC), catalase activity (CAT), lipid peroxidation (LPO), and total thiol group (TTG), plus blood urea nitrogen (BUN) and creatinine levels were evaluated in kidney tissue homogenate and examined histopathologically. RESULTS The results revealed that TTG increased significantly in NAC & NACNP groups than in the PQ group. Further, in the PQ group, LPO increased significantly compared with the control, NAC, and NACNP groups, while in the NAC and NACNP group, LPO diminished compared with the PQ group. There was no significant difference in TAC between groups. Blood urea nitrogen (BUN) and creatinine levels dropped in NACNP compared with the PQ group and the NAC. Histological studies also approved PQ-induced damage and the protective effect of NACNP. CONCLUSION The results indicated that NACNP could modulate oxidative stress status and kidney function against PQ toxicity.
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Affiliation(s)
- Ali Fathi Jouzdani
- Student Research Committee, Hamadan University of Medical Science, Hamadan, Iran
| | - Zahra Ganjirad
- Student Research Committee, Hamadan University of Medical Science, Hamadan, Iran
| | - Farzin Firozian
- Department of Pharmaceutics, Faculty of Pharmacy, Hamadan University of Medical Science, Hamadan, Iran
| | - Sara Soleimani-Asl
- Department of Anatomy, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Akram Ranjbar
- Department of Pharmacology and Toxicology, School of Pharmacy, Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
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