Gene Signatures Reduce the Stress of Preclinical Drug Hepatotoxicity Screening

Copple, Ian M.; Park, B. Kevin; Goldring, Christopher E.

doi:10.1002/hep.31736

Cited by 3 publications

(2 citation statements)

References 7 publications

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“…Sistare described 10 liver gene signatures that were indicative of various intracellular nuclear receptor activation and carcinogenic processes that were used for the stratification of internal drug candidates. Some of these have been recently published (Copple et al 2021 ). These gene signatures are used for the refinement of conventional initial rat tolerability studies, which is an important contribution to reduction and refinement.…”

Section: Workhop Presentationsmentioning

confidence: 99%

Applying genomics in regulatory toxicology: a report of the ECETOC workshop on omics threshold on non-adversity

Gant,

Auerbach,

Von Bergen

et al. 2023

Arch Toxicol

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In a joint effort involving scientists from academia, industry and regulatory agencies, ECETOC’s activities in Omics have led to conceptual proposals for: (1) A framework that assures data quality for reporting and inclusion of Omics data in regulatory assessments; and (2) an approach to robustly quantify these data, prior to interpretation for regulatory use. In continuation of these activities this workshop explored and identified areas of need to facilitate robust interpretation of such data in the context of deriving points of departure (POD) for risk assessment and determining an adverse change from normal variation. ECETOC was amongst the first to systematically explore the application of Omics methods, now incorporated into the group of methods known as New Approach Methodologies (NAMs), to regulatory toxicology. This support has been in the form of both projects (primarily with CEFIC/LRI) and workshops. Outputs have led to projects included in the workplan of the Extended Advisory Group on Molecular Screening and Toxicogenomics (EAGMST) group of the Organisation for Economic Co-operation and Development (OECD) and to the drafting of OECD Guidance Documents for Omics data reporting, with potentially more to follow on data transformation and interpretation. The current workshop was the last in a series of technical methods development workshops, with a sub-focus on the derivation of a POD from Omics data. Workshop presentations demonstrated that Omics data developed within robust frameworks for both scientific data generation and analysis can be used to derive a POD. The issue of noise in the data was discussed as an important consideration for identifying robust Omics changes and deriving a POD. Such variability or “noise” can comprise technical or biological variation within a dataset and should clearly be distinguished from homeostatic responses. Adverse outcome pathways (AOPs) were considered a useful framework on which to assemble Omics methods, and a number of case examples were presented in illustration of this point. What is apparent is that high dimension data will always be subject to varying processing pipelines and hence interpretation, depending on the context they are used in. Yet, they can provide valuable input for regulatory toxicology, with the pre-condition being robust methods for the collection and processing of data together with a comprehensive description how the data were interpreted, and conclusions reached.

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Section: Workhop Presentationsmentioning

confidence: 99%

Applying genomics in regulatory toxicology: a report of the ECETOC workshop on omics threshold on non-adversity

Gant,

Auerbach,

Von Bergen

et al. 2023

Arch Toxicol

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show abstract

“…As an important organ in the human body, the liver is involved in the metabolic transformation and detoxification of food and drugs, and is extremely vulnerable to damage from chemicals, alcohol, drugs, etc . However, some drugs and their metabolites can cause the accumulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) through multiple mechanisms, which can increase liver cell apoptosis and lead to the drug-induced liver injury (DILI). , The identification of the DILI process is crucial in clinical practice and is the single most important cause of both United States Food and Drug Administration (FDA) nonapproval and withdrawal from the market after approval. As the primary representative of RNS, excess ONOO – is derived from the drug-metabolite-induced mitochondrial toxicity caused by disruption of the electron transport chain .…”

mentioning

confidence: 99%

A New Ratiometric Design Strategy Based on Modulation of π-Conjugation Unit for Developing Fluorescent Probe and Imaging of Cellular Peroxynitrite

Wen

Yang

et al. 2022

Anal. Chem.

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Ratiometric fluorescent probes could effectively offset the changes of the autofluorescence and compartmental localization. FRET, ICT, etc. are the common strategies to design probes for biosensing, but these strategies have some deficiencies. Here, we proposed a new design strategy based on π-conjugation modulation, giving two different emission bands in the absence and presence of the target. The new fluorescence probe named Rhod-DCM-B was rationally designed and synthesized, which displayed a fluorescence emission peak at 670 nm because the electron cloud focuses on the conjugated DCM unit. With the addition of ONOO − , the fluorescence emission at 570 nm increased, accompanied by the decrease of fluorescence emission at 670 nm, showing a ratiometric signal change attributed to the opened spirane structure making the electron cloud concentrated on the xanthene core. The mechanism is well confirmed by MS and DFT calculations. Rhod-DCM-B exhibited outstanding sensitivity and excellent selectivity toward ONOO − . Moreover, Rhod-DCM-B was effectively employed to determine endogenous and exogenous ONOO − in living cells. As a marker for inflammation and drug-induced liver injury (DILI) process, ONOO − in vivo was successfully monitored by Rhod-DCM-B and presented a dramatic ratiometric response.

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Mechanism of Action of Dihydroquercetin in the Prevention and Therapy of Experimental Liver Injury

Wei,

Zhao,

Liu

et al. 2024

Molecules

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Liver disease is a global health problem that affects the well-being of tens of thousands of people. Dihydroquercetin (DHQ) is a flavonoid compound derived from various plants. Furthermore, DHQ has shown excellent activity in the prevention and treatment of liver injury, such as the inhibition of hepatocellular carcinoma cell proliferation after administration, the normalization of oxidative indices (like SOD, GSH) in this tissue, and the down-regulation of pro-inflammatory molecules (such as IL-6 and TNF-α). DHQ also exerts its therapeutic effects by affecting molecular pathways such as NF-κB and Nrf2. This paper discusses the latest research progress of DHQ in the treatment of various liver diseases (including viral liver injury, drug liver injury, alcoholic liver injury, non-alcoholic liver injury, fatty liver injury, and immune liver injury). It explores how to optimize the application of DHQ to improve its effectiveness in treating liver diseases, which is valuable for preparing potential therapeutic drugs for human liver diseases in conjunction with DHQ.

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Gene Signatures Reduce the Stress of Preclinical Drug Hepatotoxicity Screening

Cited by 3 publications

References 7 publications

Applying genomics in regulatory toxicology: a report of the ECETOC workshop on omics threshold on non-adversity

Applying genomics in regulatory toxicology: a report of the ECETOC workshop on omics threshold on non-adversity

A New Ratiometric Design Strategy Based on Modulation of π-Conjugation Unit for Developing Fluorescent Probe and Imaging of Cellular Peroxynitrite

Mechanism of Action of Dihydroquercetin in the Prevention and Therapy of Experimental Liver Injury

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