-
Phytomedicine : International Journal... Jul 2023Drug-induced liver injury (DILI) is primarily caused by drugs or their metabolites. Acetaminophen (APAP) is an over-the-counter antipyretic analgesic that exhibits high...
BACKGROUND
Drug-induced liver injury (DILI) is primarily caused by drugs or their metabolites. Acetaminophen (APAP) is an over-the-counter antipyretic analgesic that exhibits high hepatotoxicity when used for long-term or in overdoses. Taraxasterol is a five-ring triterpenoid compound extracted from traditional Chinese medicinal herb Taraxacum officinale. Our previous studies have demonstrated that taraxasterol exerts protective effects on alcoholic and immune liver injuries. However, the effect of taraxasterol on DILI remains unclear.
HYPOTHESIS/PURPOSE
This study aimed to elucidate the effects and mechanisms of action of taraxasterol on APAP-induced liver injury using network pharmacology and in vitro and in vivo experiments.
METHODS
Online databases of drug and disease targets were used to screen the targets of taraxasterol and DILI, and a protein-protein interaction network (PPI) was constructed. Core target genes were identified using the tool of Analyze of Cytoscape, gene ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analyses were performed. Oxidation, inflammation and apoptosis were evaluated to determine the effect of taraxasterol on APAP-stimulated liver damage in AML12 cells and mice. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to explore the potential mechanisms of taraxasterol against DILI.
RESULTS
Twenty-four intersection targets for taraxasterol and DILI were identified. Among them, 9 core targets were identified. GO and KEGG analysis showed that core targets are closely related to oxidative stress, apoptosis, and inflammatory response. The in vitro findings showed that taraxasterol alleviated mitochondrial damage in AML12 cells treated with APAP. The in vivo results revealed that taraxasterol alleviated pathological changes in the livers of mice treated with APAP and inhibited the activity of serum transaminases. Taraxasterol increased the activity of antioxidants, inhibited the production of peroxides, and reduced inflammatory response and apoptosis in vitro and in vivo. Taraxasterol promoted Nrf2 and HO-1 expression, suppressed JNK phosphorylation, and decreased the Bax/Bcl-2 ratio and caspase-3 expression in AML12 cells and mice.
CONCLUSION
By integrating network pharmacology with in vitro and in vivo experiments, this study indicated that taraxasterol inhibits APAP-stimulated oxidative stress, inflammatory response and apoptosis in AML12 cells and mice by regulating the Nrf2/HO-1 pathway, JNK phosphorylation, and apoptosis-related protein expression. This study provides a new evidence for the use of taraxasterol as a hepatoprotective drug.
Topics: Animals; Mice; Acetaminophen; NF-E2-Related Factor 2; Chemical and Drug Induced Liver Injury, Chronic; Network Pharmacology; Liver; Triterpenes; Oxidative Stress; Chemical and Drug Induced Liver Injury
PubMed: 37209606
DOI: 10.1016/j.phymed.2023.154872 -
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue Nov 2023Acetaminophen (APAP) is the most common antipyretic, analgesic and anti-inflammatory drug, but its overdose often leads to acute liver injury, even acute liver failure,... (Review)
Review
Acetaminophen (APAP) is the most common antipyretic, analgesic and anti-inflammatory drug, but its overdose often leads to acute liver injury, even acute liver failure, and death in some severe cases. At present, there is still a lack of specific treatments. The c-Jun N-terminal kinase (JNK) signal pathway is one of the potential therapeutic targets identified in recent years in overdose APAP-induced acute liver injury. This article reviews the JNK signaling pathway of APAP in liver metabolism, the activation of JNK signaling pathway and the amplification of oxidative stress, other pathways or cellular processes related to JNK signaling pathway, and the possible challenges of drugs targeting JNK, so as to provide direction and feasibility analysis for further research and clinical application of JNK signaling pathway targets in APAP hepatotoxicity, and to provide reference for searching for other targets.
Topics: Animals; Mice; Acetaminophen; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; JNK Mitogen-Activated Protein Kinases; Liver; Mice, Inbred C57BL; Signal Transduction
PubMed: 37987136
DOI: 10.3760/cma.j.cn121430-20221205-01060 -
Stroke Apr 2024
Topics: Humans; Platelet Aggregation Inhibitors; Stroke; Aspirin; Stroke, Lacunar; Cerebral Small Vessel Diseases; Genome-Wide Association Study
PubMed: 38527142
DOI: 10.1161/STROKEAHA.124.046111 -
BMJ (Clinical Research Ed.) Nov 2023
Topics: Adult; Humans; Acetaminophen; Analgesics, Non-Narcotic
PubMed: 37973160
DOI: 10.1136/bmj-2022-070753 -
The New England Journal of Medicine Dec 2023
Topics: Humans; Aspirin; Drug Therapy, Combination; Ischemic Attack, Transient; Platelet Aggregation Inhibitors; Stroke
PubMed: 38157504
DOI: 10.1056/NEJMe2311961 -
Polish Archives of Internal Medicine Sep 2023Nonsteroidal anti‑inflammatory drug-exacerbated respiratory disease (N‑ERD) is a unique and often clinically severe disease affecting a subgroup of adults with... (Review)
Review
Nonsteroidal anti‑inflammatory drug-exacerbated respiratory disease (N‑ERD) is a unique and often clinically severe disease affecting a subgroup of adults with asthma, chronic rhinosinusitis with nasal polyposis, and respiratory reactions with exposure to all cyclooxygenase 1-inhibiting nonsteroidal anti‑inflammatory drugs. N‑ERD has a high disease burden and is estimated to affect 7% of adults with asthma and 30% of patients who have both asthma and nasal polyps. The disease is underdiagnosed and underrecognized by physicians on a routine basis, which leads to a delay in appropriate management. The goal of this review is to focus on the disease recognition, diagnosis, and different modes of up‑to‑date therapies, including medical management, surgical intervention, aspirin desensitization, and biologic therapy.
Topics: Adult; Humans; Aspirin; Anti-Inflammatory Agents, Non-Steroidal; Respiration Disorders; Nasal Polyps; Asthma; Chronic Disease
PubMed: 37548592
DOI: 10.20452/pamw.16544 -
Natural Product Research Mar 2024L., the sole species in the genus , which is a member of the subfamily Caesalpiniaceae in the family Leguminosae (Fabaceae), is extensively dispersed in many tropical... (Review)
Review
L., the sole species in the genus , which is a member of the subfamily Caesalpiniaceae in the family Leguminosae (Fabaceae), is extensively dispersed in many tropical and subtropical regions. This plant's Arabic name, Tamr Al-Hindi, is the basis for its English name, Tamarind. In traditional medicine, this genus has played a major role since the time of the ancient Egyptians. Folkloric medicine has traditionally used to treat a variety of conditions, including diabetes mellitus, fever, malaria, ulcers, diarrhoea, dysentery and wounds. The primary bioactive components of this species, which have a variety of biological functions, have been identified as flavonoids, phenolic contents, sterols, triterpenes, fatty acids, sugars and other substances. Genus has been shown to have anti-inflammatory, analgesic, anti-pyretic, antibacterial, hypolipidemic, anti-diabetic, hepatoprotective, anti-ulcerogenic and antioxidant properties. This article provides an overview of the identified chemicals from together with their stated biological activities.
PubMed: 38454320
DOI: 10.1080/14786419.2024.2323531 -
Toxicological Sciences : An Official... Oct 2023To minimize the occurrence of unexpected toxicities in early phase preclinical studies of new drugs, it is vital to understand fundamental similarities and differences...
To minimize the occurrence of unexpected toxicities in early phase preclinical studies of new drugs, it is vital to understand fundamental similarities and differences between preclinical species and humans. Species differences in sensitivity to acetaminophen (APAP) liver injury have been related to differences in the fraction of the drug that is bioactivated to the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI). We have used physiologically based pharmacokinetic modeling to identify oral doses of APAP (300 and 1000 mg/kg in mice and rats, respectively) yielding similar hepatic burdens of NAPQI to enable the comparison of temporal liver tissue responses under conditions of equivalent chemical insult. Despite pharmacokinetic and biochemical verification of the equivalent NAPQI insult, serum biomarker and tissue histopathology analyses revealed that mice still exhibited a greater degree of liver injury than rats. Transcriptomic and proteomic analyses highlighted the stronger activation of stress response pathways (including the Nrf2 oxidative stress response and autophagy) in the livers of rats, indicative of a more robust transcriptional adaptation to the equivalent insult. Components of these pathways were also found to be expressed at a higher basal level in the livers of rats compared with both mice and humans. Our findings exemplify a systems approach to understanding differential species sensitivity to hepatotoxicity. Multiomics analysis indicated that rats possess a greater basal and adaptive capacity for hepatic stress responses than mice and humans, with important implications for species selection and human translation in the safety testing of new drug candidates associated with reactive metabolite formation.
Topics: Rats; Mice; Humans; Animals; Acetaminophen; Proteomics; Species Specificity; Chemical and Drug Induced Liver Injury; Liver; Oxidative Stress; Systems Analysis
PubMed: 37647630
DOI: 10.1093/toxsci/kfad085 -
Urologie (Heidelberg, Germany) May 2024Pharmacological pain therapy in cancer patients is based on guideline recommendations, which, however, do not fully coincide in all aspects due to varying weighting of... (Review)
Review
Pharmacological pain therapy in cancer patients is based on guideline recommendations, which, however, do not fully coincide in all aspects due to varying weighting of evidence. The present article discusses current issues including the decreasing significance of the World Health Organization (WHO) analgesic ladder, with its distinction between step 2 and 3 being increasingly questioned. Risks of nonopioid analgesics such as paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs), particularly in older populations, are discussed. Paracetamol may potentially reduce the effectiveness of immunotherapies. Aspects of administering analgesics via a feeding tube are considered. Recommendations for the treatment of episodic pain, transitioning between different opioids, and some relevant interactions are also discussed.
Topics: Humans; Cancer Pain; Pain Management; Neoplasms; Analgesics; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Practice Guidelines as Topic; Acetaminophen
PubMed: 38597946
DOI: 10.1007/s00120-024-02347-x -
Environmental Science. Processes &... Dec 2023In the post-COVID-19 era, extensive quantities of antipyretic drugs are being haphazardly released from households into the environment, which may pose potential risks...
In the post-COVID-19 era, extensive quantities of antipyretic drugs are being haphazardly released from households into the environment, which may pose potential risks to ecological systems and human health. Identification of the mobility behaviors of these compounds in the subsurface environment is crucial to understand the environmental fate of these common contaminants. The mobility properties of three broad-spectrum antipyretic drugs, including ibuprofen (IBF), indometacin (IMC), and acetaminophen (APAP), in porous soil media, were investigated in this study. The results showed that the mobility of the three drugs (the background electrolyte was Na) through the soil column followed the order of APAP > IBF > IMC. The difference in the physicochemical characteristics of various antipyretic drugs (, the molecular structure and hydrophobicity) could explain this trend. Unlike Na, Ca ions tended to serve as bridging agents by linking the soil grains and antipyretic molecules, leading to the relatively weak mobility behaviors of antipyretic drugs. Furthermore, for a given antipyretic drug, the antipyretic mobility was promoted when the background solution pH values were raised from 5.0 to 9.0. The phenomenon stemmed from the improved electrostatic repulsion between the dissociated species of antipyretic molecules and soil grains, as well as the weakened hydrophobic interactions between antipyretic drugs and soil organic matter. Furthermore, a two-site non-equilibrium transport model was used to estimate the mobility of antipyretic drugs. The results obtained from this work provide vital information illustrating the transport and retention of various antipyretic drugs in aquifers.
Topics: Humans; Soil; Antipyretics; Acetaminophen; Molecular Structure; Porosity; Ibuprofen
PubMed: 37905737
DOI: 10.1039/d3em00358b