High-Content Screening for the Detection of Drug-Induced Oxidative Stress in Liver Cells

Donato, M. Teresa; Tolosa, Laia

doi:10.3390/antiox10010106

Cited by 34 publications

(20 citation statements)

References 71 publications

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“…Similar findings have been illustrated in HepaRG cells treated with bavachinin, resulting in ROS generation and oxidative damage ( Wang S. et al, 2018 ). Additionally, excess ROS could induce lipid peroxidation ( Donato and Tolosa, 2021 ). Elsewhere, normal hepatocyte lipid metabolism has been shown as the balance between fatty acid synthesis (lipogenesis) and fat catabolism via β-oxidation (lipolysis) ( Wu et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Five Constituents Contributed to the Psoraleae Fructus-Induced Hepatotoxicity via Mitochondrial Dysfunction and Apoptosis

et al. 2021

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Backgrounds: Psoraleae Fructus (PF)-induced hepatotoxicity has been reported in clinical and animal experiments. However, the hepatotoxic constituents and mechanisms underlying PF-induced toxicity have remained unclear. Therefore, this study explored the potentially toxic PF components and revealed their relative mechanisms.Methods: The hepatotoxicity of PF water (PFW) and ethanol (PFE) extracts was compared using Kunming mice. The different compositions between PFW and PFE, which were considered toxic compositions, were identified using the UHPLC-Q-Exactive MS method. Then, L02 and HepG2 cell lines were used to evaluate the toxicity of these compositions. Cell viability and apoptosis were determined through the Cell Counting Kit-8 (CCK-8) assay and flow cytometry, respectively. An automatic biochemical analyzer detected the aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). Lastly, we used high-content screening (HCS) to determine the levels of reactive oxygen species (ROS), lipid, and mitochondrial membrane potential (MMP).Results: The ethanol extraction process aggravated the hepatotoxicity of PF, causing more severe injuries. The content of psoralen, isopsoralen, bavachin, psoralidin, bavachinin, neobavaisoflavone, and bakuchiol was higher in the PFE than PFW. Bavachin, psoralidin, bavachinin, neobavaisoflavone, and bakuchiol induced cell apoptosis and the AST, ALT, and ALP leakages. Furthermore, these five constituents increased intracellular lipid accumulation and ROS levels but decreased the MMP level.Conclusion: The ethanol extraction process could induce severe PF hepatotoxicity. Bavachin, psoralidin, bavachinin, neobavaisoflavone, and bakuchiol are the main hepatotoxic ingredients. This mechanism could be associated with oxidative stress and mitochondrial damage-mediated apoptosis. Taken together, this study provides a basis for the clinical application of PF that formulates and improves its herbal standards.

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Section: Discussionmentioning

confidence: 99%

Five Constituents Contributed to the Psoraleae Fructus-Induced Hepatotoxicity via Mitochondrial Dysfunction and Apoptosis

et al. 2021

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“…Several biochemical mechanisms are involved in the induction of fatty liver and liver damage caused by alcohol consumption, including an increase in intracellular reactive oxygen species (ROS) that affects mitochondrial damage and lipid peroxidation [33,34]. As a result, it is known that alcohol consumption damages cell membranes.…”

Section: Discussionmentioning

confidence: 99%

Enzyme-Treated Zizania latifolia Extract Protects against Alcohol-Induced Liver Injury by Regulating the NRF2 Pathway

Chang

Kim²,

Kim³

et al. 2021

Antioxidants

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Binge drinking patterns easily produce a state of oxidative stress that disturbs liver function. Eventually, this leads to alcoholic liver disease. A safe and effective therapy for alcoholic liver disease remains elusive. Enzyme-treated Z. latifolia extract (ETZL) was studied as a potential agent for treating alcohol-induced liver disease. In addition, its underlying mechanisms were elucidated. In the binge model, ETZL was pretreated with alcohol (5 g/kg) three times at 12-h intervals. Our results showed that ETZL pretreatment decreased the serum levels of ALT, AST, ALP, and TG. ETZL treatment appeared to prevent an increase in hepatic TG and MDA levels, and there was a decrease in total GSH following alcohol treatment. Histopathological examination showed that lipid droplets were significantly reduced in the ETZL group compared to the control group. ETZL also exhibited radical scavenging activity. It significantly reduced t-BHP-induced cytotoxicity and the production of reactive oxygen species (ROS) in HepG2 cells. ETZL also enhanced NRF2 nuclear translocation and increased expression of the downstream target genes HO-1, NQO1, and GCLC as an antioxidant defense. Finally, ETZL treatment significantly reduced cell death. Our study suggests that ETZL ameliorates binge ethanol-induced liver injury by upregulating the antioxidant defense mechanism.

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“…A life-threatening adverse drug reaction, drug-induced liver injury (DILI), is accompanied by oxidative stress, metaboliteinduced hepatotoxicity, and activated innate and adaptive immune responses (Donato and Tolosa, 2021). Of the affected patients, 9.4% die or require liver transplantation and 18.9% show persistent liver damage 6 months after DILI diagnosis (Fontana et al, 2014).…”

Section: Hepatotoxin Screening To Avoid Drug-induced Liver Injurymentioning

confidence: 99%

Human Three-Dimensional Hepatic Models: Cell Type Variety and Corresponding Applications

2021

Front. Bioeng. Biotechnol.

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Owing to retained hepatic phenotypes and functions, human three-dimensional (3D) hepatic models established with diverse hepatic cell types are thought to recoup the gaps in drug development and disease modeling limited by a conventional two-dimensional (2D) cell culture system and species-specific variability in drug metabolizing enzymes and transporters. Primary human hepatocytes, human hepatic cancer cell lines, and human stem cell–derived hepatocyte-like cells are three main hepatic cell types used in current models and exhibit divergent hepatic phenotypes. Primary human hepatocytes derived from healthy hepatic parenchyma resemble in vivo–like genetic and metabolic profiling. Human hepatic cancer cell lines are unlimitedly reproducible and tumorigenic. Stem cell–derived hepatocyte-like cells derived from patients are promising to retain the donor’s genetic background. It has been suggested in some studies that unique properties of cell types endue them with benefits in different research fields of in vitro 3D modeling paradigm. For instance, the primary human hepatocyte was thought to be the gold standard for hepatotoxicity study, and stem cell–derived hepatocyte-like cells have taken a main role in personalized medicine and regenerative medicine. However, the comprehensive review focuses on the hepatic cell type variety, and corresponding applications in 3D models are sparse. Therefore, this review summarizes the characteristics of different cell types and discusses opportunities of different cell types in drug development, liver disease modeling, and liver transplantation.

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High-Content Screening for the Detection of Drug-Induced Oxidative Stress in Liver Cells

Cited by 34 publications

References 71 publications

Five Constituents Contributed to the Psoraleae Fructus-Induced Hepatotoxicity via Mitochondrial Dysfunction and Apoptosis

Five Constituents Contributed to the Psoraleae Fructus-Induced Hepatotoxicity via Mitochondrial Dysfunction and Apoptosis

Enzyme-Treated Zizania latifolia Extract Protects against Alcohol-Induced Liver Injury by Regulating the NRF2 Pathway

Human Three-Dimensional Hepatic Models: Cell Type Variety and Corresponding Applications

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