6-Hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline Demonstrates Anti-Inflammatory Properties and Reduces Oxidative Stress in Acetaminophen-Induced Liver Injury in Rats DOI Creative Commons
Е. Д. Крыльский,

Svetlana E. Kravtsova,

Т. Н. Попова

et al.

Current Issues in Molecular Biology, Journal Year: 2023, Volume and Issue: 45(10), P. 8321 - 8336

Published: Oct. 12, 2023

We examined the effects of 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline on markers liver injury, oxidative status, and extent inflammatory apoptotic processes in rats with acetaminophen-induced damage. The administration acetaminophen caused accumulation 8-hydroxy-2-deoxyguanosine 8-isoprostane serum, as well an increase biochemiluminescence indicators. Oxidative stress resulted activation pro-inflammatory cytokine NF-κB factor mRNA synthesis increased levels immunoglobulin G, along higher activities caspase-3, caspase-8, caspase-9. also development stress, leading to a decrease level reduced glutathione imbalance function antioxidant enzymes. This study discovered that by its activity, hence reducing mRNA, decreasing concentration G. These changes reduction activity caspase-8 caspase-9, which are involved ligand-induced mitochondrial pathways apoptosis inhibited effector caspase-3. In addition, promoted normalization system animals treated acetaminophen. As result, compound being tested alleviated inflammation led improved marker indices ameliorated histopathological alterations.

Language: Английский

Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury DOI Creative Commons
Hartmut Jaeschke, Anup Ramachandran

Annual Review of Pathology Mechanisms of Disease, Journal Year: 2024, Volume and Issue: 19(1), P. 453 - 478

Published: Jan. 24, 2024

Acetaminophen (APAP) overdose is the clinically most relevant drug hepatotoxicity in western countries, and, because of translational relevance animal models, APAP mechanistically studied drug. This review covers intracellular signaling events starting with metabolism and central role mitochondrial dysfunction involving oxidant stress peroxynitrite. Mitochondria-derived endonucleases trigger nuclear DNA fragmentation, point no return for cell death. In addition, adaptive mechanisms that limit death are discussed including autophagy, morphology changes, biogenesis. Extensive evidence supports oncotic necrosis as mode death; however, a partial overlap apoptosis, ferroptosis, pyroptosis basis controversial discussions. Furthermore, an update on sterile inflammation injury repair activation Kupffer cells, monocyte-derived macrophages, neutrophils provided. Understanding these led to discovery N-acetylcysteine recently fomepizole effective antidotes against toxicity.

Language: Английский

Citations

74
The multiple mechanisms and modes of cell death after acetaminophen overdose DOI Creative Commons
Hartmut Jaeschke, Anup Ramachandran

Published: April 7, 2025

Acetaminophen (APAP)-induced liver injury and acute failure is a significant clinical problem worldwide; in addition, APAP overdoses animals or cell culture are used as popular models to study drug-induced mechanisms test therapeutic interventions. Early assumptions that toxicity caused by single mechanism resulting defined mode of death hepatocytes had be questioned when over the years many different modes were reported. Although contradictory results conclusions reported can attributed lack understanding established mechanisms, methodological problems, misinterpretation data, it increasingly recognized some differences signaling even switch variations experimental conditions. In this review, examples will discussed how conditions (dose, solvent, etc.), system (species, strain, substrain vivo, type, vitro conditions), also adaptive responses off-target effects genetic manipulations chemical interventions, impact death. Given determine results, therefore critical importance keep mind translational aspect experiments, i.e., relevant human pathophysiology. Only full appreciation these issues lead reproducible clinically advance our all facets pathophysiology identify targets.

Language: Английский

Citations

1
Identification and validation of cuproptosis-related genes in acetaminophen-induced liver injury using bioinformatics analysis and machine learning DOI Creative Commons

Zhenya Guo,

Jiaping Liu,

Guozhi Liang

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: June 27, 2024

Background Acetaminophen (APAP) is commonly used as an antipyretic analgesic. However, acetaminophen overdose may contribute to liver injury and even failure. Acetaminophen-induced (AILI) closely related mitochondrial oxidative stress dysfunction, which play critical roles in cuproptosis. Here, we explored the potential role of cuproptosis-related genes (CRGs) AILI. Methods The gene expression profiles were obtained from Gene Expression Omnibus database. differential CRGs was determined between AILI control samples. Protein protein interaction, correlation, functional enrichment analyses performed. Machine learning identify hub genes. Immune infiltration evaluated. mouse model established by intraperitoneal injection APAP solution. Quantitative real-time PCR western blotting validate model. copper content samples AML12 cells quantified using a colorimetric assay kit. Ammonium tetrathiomolybdate (ATTM), administered models order investigate effects chelator on Results analysis identified 7,809 differentially expressed genes, 4,245 downregulated 3,564 upregulated. Four optimal feature (OFGs; SDHB, PDHA1, NDUFB2, NDUFB6) through intersection two machine algorithms. Further nomogram, decision curve, calibration curve confirmed diagnostic predictive efficacy four OFGs. Enrichment indicated that OFGs involved multiple pathways, such IL-17 pathway chemokine signaling pathway, are progression. revealed macrophages more abundant than samples, whereas eosinophils endothelial less abundant. Subsequently, successfully established, histopathological hematoxylin–eosin staining along with function tests significant induction group. Consistent expectations, both mRNA levels exhibited substantial decrease. administration ATTAM effectively mitigates elevation induced cells. systemic ATTM did not significantly alleviate Conclusion This study first pathological process offered novel insights into its underlying pathogenesis.

Language: Английский

Citations

4
Mechanisms of Acetaminophen Hepatotoxicity: Cell Death Signaling Mechanisms in Hepatocytes DOI
Hartmut Jaeschke, Anup Ramachandran

Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
The Protective Effect of <i>Moringa oleifera</i> Leaves Extract on Paracetamol Hepatotoxicity in Male Rats DOI Open Access

Reham M. Al-Sultan,

Noorah Saleh Al‐Sowayan

Journal of Biomedical Science and Engineering, Journal Year: 2024, Volume and Issue: 17(03), P. 72 - 82

Published: Jan. 1, 2024

In recent years, there has been an increase in concern regarding the effects of paracetamol poisoning on liver tissues, particularly when consumed large amounts. Some studies have estimated that is involved 56% acute diseases, whereas 0.4% overdose cases result fatal-ity. this study, Moringa oleifera toxicity were explored. It demonstrated highly nu-tritious, contains bioactive molecules, and therapeutically beneficial. Many shown leaves possess a wide range biologi-cal properties, including antioxidant, tissue protection, analgesic, antihyperten-sive, immunomodulatory activities. This study highlights protective role handling possible hepatotoxicity male rats.

Language: Английский

Citations

2
Elaidic acid induced hepatocyte pyroptosis via autophagy-CTSB-NLRP3 pathway DOI
Jing Lu, Ziheng Chen,

Xiujuan Bu

et al.

Food and Chemical Toxicology, Journal Year: 2023, Volume and Issue: 181, P. 114060 - 114060

Published: Sept. 23, 2023

Language: Английский

Citations

4
6-Hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline Demonstrates Anti-Inflammatory Properties and Reduces Oxidative Stress in Acetaminophen-Induced Liver Injury in Rats DOI Creative Commons
Е. Д. Крыльский,

Svetlana E. Kravtsova,

Т. Н. Попова

et al.

Current Issues in Molecular Biology, Journal Year: 2023, Volume and Issue: 45(10), P. 8321 - 8336

Published: Oct. 12, 2023

We examined the effects of 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline on markers liver injury, oxidative status, and extent inflammatory apoptotic processes in rats with acetaminophen-induced damage. The administration acetaminophen caused accumulation 8-hydroxy-2-deoxyguanosine 8-isoprostane serum, as well an increase biochemiluminescence indicators. Oxidative stress resulted activation pro-inflammatory cytokine NF-κB factor mRNA synthesis increased levels immunoglobulin G, along higher activities caspase-3, caspase-8, caspase-9. also development stress, leading to a decrease level reduced glutathione imbalance function antioxidant enzymes. This study discovered that by its activity, hence reducing mRNA, decreasing concentration G. These changes reduction activity caspase-8 caspase-9, which are involved ligand-induced mitochondrial pathways apoptosis inhibited effector caspase-3. In addition, promoted normalization system animals treated acetaminophen. As result, compound being tested alleviated inflammation led improved marker indices ameliorated histopathological alterations.

Language: Английский

Citations

3