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The role of corticosterone in nevirapine-induced idiosyncratic drug-induced liver injury

ABSTRACT: The role of corticosterone in nevirapine-induced idiosyncratic drug-induced liver injury

PROVIDER: PRJNA1073404 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27871226_1.fastq.gz	Fastqsanger.gz
	SRR27871226_2.fastq.gz	Fastqsanger.gz
	SRR27871227_1.fastq.gz	Fastqsanger.gz
	SRR27871227_2.fastq.gz	Fastqsanger.gz
	SRR27871228_1.fastq.gz	Fastqsanger.gz

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The role of corticosterone in nevirapine-induced idiosyncratic drug-induced liver injury

Project description:Nevirapine, an antiretroviral used in the treatment of HIV, is associated with idiosyncratic drug-induced liver injury (IDILI), a potentially life-threatening adverse drug reaction. Its usage has decreased due to this concern, but it is still widely used in lower-resource settings. In general, the mechanisms underlying idiosyncratic drug reactions (IDRs) are poorly understood, but evidence indicates that most are immune-mediated. There is very limited understanding of the early immune response following administration of drugs associated with IDRs, which likely occurs due to reactive metabolite formation. In this work, we aimed to characterize the links between covalent binding of nevirapine, the development of an early immune response, and the subsequent liver injury using a mouse model. We describe initial attempts to characterize an early immune response to nevirapine followed by the discovery that nevirapine induced the release of corticosterone. Corticosterone release was partially associated with the degree of drug covalent binding in the liver, but was also likely mediated by additional mechanisms at higher drug doses. Transcriptomic analysis confirmed metabolic activation, glucocorticoid signaling, and decreased immune activation; GDF-15 also warrants further investigation as part of the immune response to nevirapine. Finally, glucocorticoid blockade preceding the first dose of nevirapine attenuated nevirapine-induced liver injury at 3 weeks, suggesting that acute glucocorticoid signaling is harmful in the context of nevirapine-induced liver injury. This work demonstrates that nevirapine induces acute corticosterone release, which contributes to delayed-onset liver injury. It also has implications for screening drug candidates for IDILI risk and preventing nevirapine-induced IDILI.

2024-04-15 | GSE255038 | GEO

Drug-Induced Liver Injury (DILIN) GWAS

Project description:Drug-Induced Liver Injury (DILIN) GWAS

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NIDDK Drug-Induced Liver Injury Network (DILIN)

Project description:<p>The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has established the Drug-Induced Liver Injury Network (DILIN) to collect and analyze cases of severe liver injury caused by prescription drugs, over-the-counter drugs, and alternative medicines, such as herbal products and supplements.</p>

| phs000663 | dbGaP

Omics-based identification of the combined effects of idiosyncratic drugs and inflammatory cytokines on the development of drug-induced liver injury

Project description:To unravel the underlying mechanisms of inflammation-related idiosyncratic drug toxicity

2017-07-29 | GSE102006 | GEO

Small RNAs in anti-tuberculosis drug-induced liver injury

Project description:Small RNAs in anti-tuberculosis drug-induced liver injury

| PRJNA609915 | ENA

Small RNAs in anti-tuberculosis drug-induced liver injury

Project description:The antimicrobials isoniazid and pyrazinamide, used for the treatment of tuberculosis are known to cause drug-induced liver injury in humans. This limits the effectiveness of tuberculosis treatment, resulting in incomplete cure, relapse and the development of antimicrobial resistance. MicroRNAs are known to be good biomarkers of disease, with the microRNA miR-122 being diagnostic for liver injury. In this study zebrafish larvae were exposed to the anti-tuberculosis drugs isoniazid and pyrazinamide at concentrations which demonstrated liver injury by microscopy and histology. The aim of this study is to understand small RNA changes occurring in anti-tuberculosis drug-induced liver injury and to attempt to identify novel microRNA biomarkers of liver injury.

2023-12-25 | GSE146260 | GEO

Proteomic-based identification of APCS as candidate protein for diagnosis of patients exhibiting Anti-tubercular drug induced liver injury

Project description:In the present study, the proteomics approach identified potential protein signatures with high discriminative ability in TB patients with and without drug-induced liver injury which might play a crucial role in developing Anti-tubercular drug-induced liver injury.

2021-11-12 | MSV000088373 | MassIVE

Polygenic architecture informs potential vulnerability to drug-induced liver injury

Project description:Polygenic architecture informs potential vulnerability to drug-induced liver injury

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Proteomics analysis of monocyte-derived hepatocyte-like cells identifies integrin beta 3 as a specific biomarker for drug-induced liver injury by diclofenac

Project description:Idiosyncratic drug-induced liver injury (iDILI) is a major cause of acute liver failure resulting in liver transplantation or death. Prediction and diagnosis of iDILI remain a great challenge, as current models provide unsatisfying results in terms of sensitivity, specificity and prognostic value. The absence of appropriate tools for iDILI detection also impairs the development of reliable biomarkers. Here, we report on a new method for identification of drug-specific biomarkers. We combined the advantages of monocyte-derived hepatocyte-like (MH) cells, able to mimic individual characteristics, with those of a novel mass spectrometry (MS)-based proteomics technology to assess potential biomarkers for Diclofenac-induced DILI. We found over 2700 proteins differentially regulated in MH cells derived from individual patients. Herefrom, we identified integrin beta 3 (ITGB3) to be specifically upregulated in Diclofenac-treated MH cells from Diclofenac-DILI patients compared to control groups. Finally, we validated ITGB3 by flow cytometry analysis of whole blood and histological staining of liver biopsies derived from patients diagnosed with Diclofenac-DILI. In summary, our results show that biomarker candidates can be identified by proteomics analysis of MH cells. Application of this method to a broader range of drugs in the future will exploit its full potential for the development of drug-specific biomarkers.

2018-07-23 | PXD008918 | Pride

Establishment of a novel mouse model of troglitazone-induced liver injury and analysis of its hepatotoxic mechanism

Project description:Drug-induced liver injury (DILI) is a major problem in drug development and clinical drug therapy. Troglitazone (TGZ), a thiazolidinedione antidiabetic drug for the treatment of type II diabetes mellitus, was found to induce rare idiosyncratic severe liver injury in patients, which led to its withdrawal in 2000. In experimental animals in vivo, however, TGZ has never induced liver injury. In this study, administration of BALB/c female mice with TGZ alone significantly elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels 6 h after the treatment. Co-administration of L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of glutathione synthesis, unexpectedly restrained the TGZ-dependent increase of ALT and AST. Furthermore, the ratio of oxidative stress marker glutathione/disulfide glutathione was significantly decreased in TGZ-alone- and BSO plus TGZ-administered mice, and increased hepatic mRNA levels of inflammation- and oxidative stress-related factors in liver were observed. Subsequently, microarray studies were performed 6 h after administration and we discovered that the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was activated in TGZ-induced liver injury. Moreover, the activation of JAK/STAT pathway promoted phosphorylation of STAT3 in TGZ-alone- and BSO plus TGZ-administered mice. Consequently, upregulation of STAT3 activation increased mRNA levels of its downstream genes. In conclusion, the present study is the first time to establish a mouse model of TGZ-induced liver injury with BALB/c mouse for assessing DILI in drug development and the activation of JAK/STAT signaling pathway might be as an important role involved in hepatotoxic mechanisms of TGZ.

2021-07-14 | GSE117257 | GEO

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