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

Jiang, Jian; Mathijs, Karen; Timmermans, L; Claessen, Sandra; Hecka, Audrey; Weusten, Jos; Peters, Ron; Delft, Joost H. van; Kleinjans, J. C. S.; Jennen, Danyel; Kok, Theo M. de

doi:10.1016/j.taap.2017.07.014

Cited by 17 publications

(13 citation statements)

References 40 publications

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“…Total RNA was converted into cRNA and labelled according to the One-Color Microarray-Based Gene Expression Analysis protocol version 6.6 (Agilent Technologies, The Netherlands) 65 as described previously 66 . In brief, 200 ng of total RNA was diluted in Spike Mix.…”

Section: Methodsmentioning

confidence: 99%

Transcriptome changes in undifferentiated Caco-2 cells exposed to food-grade titanium dioxide (E171): contribution of the nano- and micro- sized particles

Proquin

Jonkhout

Jetten

et al. 2019

Sci Rep

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The food additive titanium dioxide (TiO2), or E171, is a white food colorant. Recent studies showed after E171 ingestion a significantly increased number of colorectal tumours in a colorectal cancer mouse model as well as inflammatory responses and dysregulation of the immune system in the intestine of rats. In the mouse colon, E171 induced gene expression changes related to oxidative stress, impairment of the immune system, activation of signalling and cancer-related processes. E171 comprises nanoparticles (NPs) and microparticles (MPs). Previous in vitro studies showed that E171, NPs and MPs induced oxidative stress responses, DNA damage and micronuclei formation. This study aimed to investigate the relative contribution of the NPs and MPs to effects of E171 at the transcriptome level in undifferentiated Caco-2 cells by genome wide microarray analysis. The results showed that E171, NPs, and MPs induce gene expression changes related to signalling, inflammation, immune system, transport and cancer. At the pathway level, metabolism of proteins with the insulin processing pathway and haemostasis were specific to E171 exposure. The gene expression changes associated with the immune system and inflammation induced by E171, MPs, and NPs suggest the creation of a favourable environment for colon cancer development.

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Section: Methodsmentioning

confidence: 99%

Transcriptome changes in undifferentiated Caco-2 cells exposed to food-grade titanium dioxide (E171): contribution of the nano- and micro- sized particles

Proquin

Jonkhout

Jetten

et al. 2019

Sci Rep

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“…Applied transcriptomic and proteomic analyses to this cell model, Jiang et al (2015a) and Paemanee et al (2017) explained the mechanisms of mitochondrial dysfunction associated with APAP and nevirapine (NVP) administrations. Using a HepG2-based in vitro cytokine synergy model, an attempt has been made to investigate the relationship between inflammation and drug idiosyncrasy (Jiang et al 2017). Through comparing the differences of the transcriptomic and metabolomic profiles of HepG2 cells in response to idiosyncratic and nonidiosyncratic compounds, the study revealed the interaction between inflammatory cytokines and the idiosyncratic drugs and illustrated that the dynamic disequilibrium in ceramides/sphingolipids balance and its coupled ER stress-and JNK-mediated apoptosis could be the common mechanism underlying the inflammation-associated idiosyncratic drug hepatotoxicity (Jiang et al 2017).…”

Section: Hepatocellular Carcinoma Cell Linesmentioning

confidence: 99%

The application of omics-based human liver platforms for investigating the mechanism of drug-induced hepatotoxicity in vitro

et al. 2019

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Drug-induced liver injury (DILI) complicates safety assessment for new drugs and poses major threats to both patient health and drug development in the pharmaceutical industry. A number of human liver cell-based in vitro models combined with toxicogenomics methods have been developed as an alternative to animal testing for studying human DILI mechanisms. In this review, we discuss the in vitro human liver systems and their applications in omics-based drug-induced hepatotoxicity studies. We furthermore present bioinformatic approaches that are useful for analyzing toxicogenomic data generated from these models and discuss their current and potential contributions to the understanding of mechanisms of DILI. Human pluripotent stem cells, carrying donor-specific genetic information, hold great potential for advancing the study of individualspecific toxicological responses. When co-cultured with other liver-derived non-parenchymal cells in a microfluidic device, the resulting dynamic platform enables us to study immune-mediated drug hypersensitivity and accelerates personalized drug toxicology studies. A flexible microfluidic platform would also support the assembly of a more advanced organs-ona-chip device, further bridging gap between in vitro and in vivo conditions. The standard transcriptomic analysis of these cell systems can be complemented with causality-inferring approaches to improve the understanding of DILI mechanisms. These approaches involve statistical techniques capable of elucidating regulatory interactions in parts of these mechanisms. The use of more elaborated human liver models, in harmony with causality-inferring bioinformatic approaches will pave the way for establishing a powerful methodology to systematically assess DILI mechanisms across a wide range of conditions. Keywords Drug-induced hepatotoxicity • In vitro human liver model • Omics approaches • Bioinformatics • Graphical Gaussian networks • Bayesian networks

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“…Indeed, it has been shown that the presence of an inflammatory background is associated with increased susceptibility to iDILI[ 59 , 60 ]. Infection and inflammation act as the danger signal and further augment the immune response by cell death or cytokine release[ 61 ]. However, the specific mechanisms still need further study.…”

Section: Idilimentioning

confidence: 99%

Dissecting the molecular pathophysiology of drug-induced liver injury

Nelson

Moral

et al. 2018

WJG

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Drug-induced liver injury (DILI) has become a major topic in the field of Hepatology and Gastroenterology. DILI can be clinically divided into three phenotypes: hepatocytic, cholestatic and mixed. Although the clinical manifestations of DILI are variable and the pathogenesis complicated, recent insights using improved preclinical models, have allowed a better understanding of the mechanisms that trigger liver damage. In this review, we will discuss the pathophysiological mechanisms underlying DILI. The toxicity of the drug eventually induces hepatocellular damage through multiple molecular pathways, including direct hepatic toxicity and innate and adaptive immune responses. Drugs or their metabolites, such as the common analgesic, acetaminophen, can cause direct hepatic toxicity through accumulation of reactive oxygen species and mitochondrial dysfunction. The innate and adaptive immune responses play also a very important role in the occurrence of idiosyncratic DILI. Furthermore, we examine common forms of hepatocyte death and their association with the activation of specific signaling pathways.

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

Cited by 17 publications

References 40 publications

Transcriptome changes in undifferentiated Caco-2 cells exposed to food-grade titanium dioxide (E171): contribution of the nano- and micro- sized particles

Transcriptome changes in undifferentiated Caco-2 cells exposed to food-grade titanium dioxide (E171): contribution of the nano- and micro- sized particles

The application of omics-based human liver platforms for investigating the mechanism of drug-induced hepatotoxicity in vitro

Dissecting the molecular pathophysiology of drug-induced liver injury

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