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Tamoxifen (TAM) is extensively used to manage estrogen receptor-positive breast cancer. Despite its effectiveness, its administration can negatively impact various organs, including the liver. This research focused on the effects of TAM on the pyroptotic pathway in the liver and evaluated the potential of cardamom extract (CRDE) to lessen hepatic damage of TAM in female rats. Rats received 45 mg/kg of TAM injections for 10 days, while the groups treated with CRDE received 12 ml/kg of CRDE for 20 days, commencing 10 days before TAM administration. TAM exposure resulted in apparent degenerations in hepatic tissue with inflammatory cell infiltration and loss of architectures. Serum levels of liver enzymes including alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase were elevated, along with hepatic oxidative stress, as shown by increased lipid peroxidation with lower levels of reduced glutathione. TAM caused inflammation in the liver tissue as indicated by higher levels of tumor necrosis factor-α and interleukin-6 as well as increased expression of CD68; a phagocytic Kupffer's cells marker. Additionally, the protein expression analysis revealed a high expression of pyroptotic markers including NLRP3-inflammasome, caspase-1, and gasdermin D. Conversely, CRDE treatment effectively neutralized the biochemical, histological, and protein expression alterations induced by TAM. In conclusion, CRDE demonstrated the potential to protect the liver from TAM-induced damage by regulating mechanisms involving oxidative damage, inflammation, and pyroptosis. [ABSTRACT FROM AUTHOR]

Introduction: Drug-induced liver injury (DILI) has been investigated at the patient level. Analysis of gene perturbation at the cellular level can help better characterize biological mechanisms of hepatotoxicity. Despite accumulating drug-induced transcriptome data such as LINCS, analyzing such transcriptome data upon drug treatment is a challenging task because the perturbation of expression is dose and time dependent. In addition, the mechanisms of drug toxicity are known only as literature information, not in a computable form. Methods: To address these challenges, we propose a Multi-Dimensional Transcriptomic Ruler (MDTR) that quantifies the degree of DILI at the transcriptome level. To translate transcriptome data to toxicity-related mechanisms, MDTR incorporates KEGG pathways as representatives of mechanisms, mapping transcriptome data to biological pathways and subsequently aggregating them for each of the five hepatotoxicity mechanisms. Given that a single mechanism involves multiple pathways, MDTR measures pathway-level perturbation by constructing a radial basis kernel-based toxicity space and measuring the Mahalanobis distance in the transcriptomic kernel space. Representing each mechanism as a dimension, MDTR is visualized in a radar chart, enabling an effective visual presentation of hepatotoxicity at transcriptomic level. Results and Discussion: In experiments with the LINCS dataset, we show that MDTR outperforms existing methods for measuring the distance of transcriptome data when describing for dose-dependent drug perturbations. In addition, MDTR shows interpretability at the level of DILI mechanisms in terms of the distance, i.e., in a metric space. Furthermore, we provided a user-friendly and freely accessible website (http://biohealth.snu.ac.kr/software/MDTR), enabling users to easily measure DILI in drug-induced transcriptome data. [ABSTRACT FROM AUTHOR]

Objective: Non-alcoholic steatohepatitis (NASH) is a progressive liver disease with lipid accumulation, inflammation, and liver fibrosis. Ponatinib, a third-generation tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia, was found to improve metabolic disorders in mice. However, the role of ponatinib in liver inflammation and fibrosis remains to be elucidated. Here we aimed to determine the effect of ponatinib in non-alcoholic steatohepatitis. Methods: We explored the function and mechanism of ponatinib using a mouse model of NASH induced by a methionine and choline deficient (MCD) diet and LO2 cells cultured in MCD mimic medium. Results: Here, we found that ponatinib reduced liver lipid deposition, fibrosis, and inflammation induced by MCD diet without affecting body weight and blood glucose. Meanwhile, we found that ponatinib attenuated steatohepatitis and inflammation in LO2 cells induced by MCD mimic medium. We further discovered that the expression levels of LC3II and lysosomal associated membrane protein 1 (LAMP1) were reduced and the expression level of p62 was upregulated in both mouse and cell models, suggesting that autophagy was inhibited, which was restored by ponatinib treatment. In addition, transcription factor EB (TFEB) is a major regulator of autophagy and lysosome biogenesis and the transcription and protein expression levels of TFEB were decreased in steatosis hepatocytes, which could be ameliorated by ponatinib treatment. Conclusion: These results revealed that the beneficial effects of ponatinib on NASH via TFEB-mediated autophagy. [ABSTRACT FROM AUTHOR]

Reactive oxygen species exacerbate nonalcoholic steatohepatitis (NASH) by oxidizing macromolecules; yet how they promote NASH remains poorly understood. Here, we show that peroxidase activity of global hepatic peroxiredoxin (PRDX) is significantly decreased in NASH, and palmitic acid (PA) binds to PRDX1 and inhibits its peroxidase activity. Using three genetic models, we demonstrate that hepatic PRDX1 protects against NASH in male mice. Mechanistically, PRDX1 suppresses STAT signaling and protects mitochondrial function by scavenging hydrogen peroxide, and mitigating the oxidation of protein tyrosine phosphatases and lipid peroxidation. We further identify rosmarinic acid (RA) as a potent agonist of PRDX1. As revealed by the complex crystal structure, RA binds to PRDX1 and stabilizes its peroxidatic cysteine. RA alleviates NASH through specifically activating PRDX1's peroxidase activity. Thus, beyond revealing the molecular mechanism underlying PA promoting oxidative stress and NASH, our study suggests that boosting PRDX1's peroxidase activity is a promising intervention for treating NASH. Oxidative stress is closely linked with nonalcoholic steatohepatitis (NASH). Here, the authors show that palmitic acid stimulates NASH by inhibiting PRDX1 to increase oxidative stress, while rosmarinic acid improves NASH by activating PRDX1 to reduce oxidative stress. [ABSTRACT FROM AUTHOR]

Perhexiline is an antianginal medication used in refractory disease. Despite being highly efficacious, it is seldom prescribed due to its risk of neurotoxicity and hepatotoxicity. These adverse effects are often linked to high plasma concentration in patients with impaired metabolism, identified through therapeutic drug monitoring. In this report, a man in his 70s developed hepatotoxicity, lower limb weakness, poor coordination and reduced mobility following 6 months of perhexiline use, leading to recurrent falls and multiple hospitalisations. Extensive testing ruled out other causes of the patient’s symptomatology. During his third hospital presentation, elevated serum perhexiline levels confirmed toxicity. Cessation of perhexiline led to a marked improvement in liver function, mobility and function, allowing for the patient to be discharged home. This case underscores the critical role of therapeutic drug monitoring and the need to consider adverse drug reactions in vulnerable older patients. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by lipid accumulation in the liver due to an excess in their supplies or an impairment in their management. While some patients remain stable for years, a proportion of them progress up to steatohepatitis (MASH). MASLD links with systemic pathways being associated with metabolic and non-metabolic diseases. Although liver lipid accumulation represents the first hit for MASLD, the pathophysiology of its development and progression to MASH remains not completely understood. Oxidative stress has received particular attention in recent years, as most of the oxidative process occurs in the liver, which is also the target of oxidative stress-induced damage. Growing evidence linked the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) to the increased liver production of reactive oxygen species up to liver damage and fibrosis. NOX acts both in hepatocytes and in non-parenchymal hepatic cells, contributing to hepatocyte lipotoxicity, impaired hepatic microcirculation, hepatic stellate, and mesenchymal stem cells activation and proliferation. This review aims to summarize the current knowledge on the involvement of oxidative stress in the MASLD–MASH transition, focusing on the role of NOX isoforms, and to suggest targeting NOX as a therapeutic approach in MASLD. [ABSTRACT FROM AUTHOR]

Alcohol exposure during pregnancy disrupts fetal development and programs lifelong disease. We have shown, in rats, that alcohol exposure during the periconceptional period (PC:EtOH), causes placental dysfunction and cardiometabolic disease in offspring. The process of metabolising alcohol can cause oxidative stress and damage mitochondrial DNA (mtDNA). It is unknown whether alcohol metabolism in a rat model of PC:EtOH impacts oxidative stress markers and mitochondrial content in maternal and placental tissues. We aimed to determine whether PC:EtOH induced oxidative stress and reduced mtDNA in maternal liver and the placental labyrinth and junctional zone. Sprague-Dawley rats were given an ethanol liquid (12.5% v/v) or control (0%) diet for one oestrous cycle before mating to embryonic day (E) 4. Maternal livers were collected at E5 and E20. Placentas were collected at E20 and separated into the junctional zone and labyrinth zone. PC:EtOH reduced Cyp2e1 mRNA levels and mtDNA in the E5 liver with lower mtDNA persisting to E20, at which time mitochondrial proteins were also decreased. PC:EtOH also reduced mitochondrial content in the E20 junctional zone, although mitochondrial protein levels were unaffected. Superoxide dismutase activity was increased in the placental junctional zone and there was no evidence of oxidative stress. The present study demonstrates that alcohol exposure around conception, reduces mitochondrial content within the maternal liver and the junctional zone of the placenta towards the end of pregnancy. These prolonged deficits may have disrupted metabolic processes required for a healthy pregnancy. The study further supports avoiding alcohol when planning a pregnancy. KEY POINTS: Even when alcohol is consumed only around conception (PC:EtOH), it can have profound impacts on the developing baby. Here, we use our established rat model to investigate if PC:EtOH causes oxidative stress and reduces mitochondrial content in the maternal liver immediately after exposure on embryonic day (E) 5. We also investigate these parameters at the end of pregnancy (E20) in maternal liver and the placenta. PC:EtOH reduced mitochondrial DNA content in the maternal liver by 77% at E5 and by 40% at E20. At E20, expression of proteins that form the electron transport chain were also reduced. The placenta had a more subtle reduction in mitochondrial DNA content, but protein levels of mitochondrial complexes were unchanged. There was no evidence of oxidative stress in the maternal liver or placenta in response to PC:EtOH. The lack of oxidative stress in the placenta may be a result of compensatory increases in antioxidants., (© 2025 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Adverse outcome pathways (AOPs) describe toxicological processes from a dynamic perspective by linking a molecular initiating event to a specific adverse outcome via a series of key events and key event relationships. In the field of computational toxicology, AOPs can potentially facilitate the design and development of in silico prediction models for hazard identification. Various AOPs have been introduced for several types of hepatotoxicity, such as steatosis, cholestasis, fibrosis, and liver cancer. This chapter provides an overview of AOPs on hepatotoxicity, including their development, assessment, and applications in toxicology., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

During the past few decades and especially during and after the COVID-19 pandemic, the use of nutraceuticals has become increasingly popular in both humans and animals due to their easy access, cost-effectiveness, and tolerability with a wide margin of safety. While some nutraceuticals are safe, others have an inherent toxic potential. For a large number of nutraceuticals, no toxicity/safety data are available due to a lack of pharmacological/toxicological studies. The safety of some nutraceuticals can be compromised via contamination with toxic plants, metals, mycotoxins, pesticides, fertilizers, drugs of abuse, etc. Knowledge of pharmacokinetic/toxicokinetic studies and biomarkers of exposure, effect, and susceptibility appears to play a pivotal role in the safety and toxicity assessment of nutraceuticals. Interaction studies are essential to determine efficacy, safety, and toxicity when nutraceuticals and therapeutic drugs are used concomitantly or when polypharmacy is involved. This chapter describes various aspects of nutraceuticals, particularly their toxic potential, and the factors that influence their safety., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Type 2 diabetes (T2D) is a disease that occurs when cells do not respond normally to insulin, a condition called insulin resistance, which leads to high blood glucose levels. Although it can be treated pharmacologically, dietary habits beyond carbohydrate restriction can be highly relevant in the management of T2D. Emerging evidence supports the possibility that natural products (NPs) could contribute to managing blood glucose or counteract the undesirable effects of hyperglycemia and insulin resistance. This chapter summarizes the relevant preclinical evidence involving the flavonoid (-)-epicatechin (EC) in the optimization of glucose homeostasis, reducing insulin resistance and/or diabetes-associated disorders. Major effects of EC are observed on (i) intestinal functions, including digestive enzymes, glucose transporters, microbiota, and intestinal permeability, and (ii) redox homeostasis, including oxidative stress and inflammation. There is still a need for further clinical studies to confirm the in vitro and rodent data, allowing recommendations for EC, particularly in prediabetic and T2D patients. The collection of similar data and the lack of clinical evidence for EC is also applicable to other NPs., (© 2025. The Author(s), under exclusive license to Springer Nature Switzerland AG.)