Protein tyrosine phosphatase 1B modulates GSK3β/Nrf2 and IGFIR signaling pathways in acetaminophen-induced hepatotoxicity

Mobasher, Maysa A.; González-Rodriguez, Águeda; Santamaría, Beatriz; Ramos, Sonia; Martín, Maria Ángeles; Goya, Luis; Rada, Patricia; Letzig, Lynda; James, Laura P.; Cuadrado, Antonio; Martı́n-Pérez, Jorge; Simpson, Kenneth J.; Muntané, Jordi; Valverde, Ángela M.

doi:10.1038/cddis.2013.150

Cited by 79 publications

(76 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, 10 × 10 −3 m APAP exposure significantly decreased the cell viability after day 7. These results correlated well with results obtained from the literature and our previously published study 42. Remarkably, our data showed that the trend in cell viability at each day was consistent with the variation of albumin and GST‐α production rates at the same time points.…”

Section: Resultssupporting

confidence: 92%

Label‐Free and Regenerative Electrochemical Microfluidic Biosensors for Continual Monitoring of Cell Secretomes

et al. 2017

View full text Add to dashboard Cite

Development of an efficient sensing platform capable of continual monitoring of biomarkers is needed to assess the functionality of the in vitro organoids and to evaluate their biological responses toward pharmaceutical compounds or chemical species over extended periods of time. Here, a novel label‐free microfluidic electrochemical (EC) biosensor with a unique built‐in on‐chip regeneration capability for continual measurement of cell‐secreted soluble biomarkers from an organoid culture in a fully automated manner without attenuating the sensor sensitivity is reported. The microfluidic EC biosensors are integrated with a human liver‐on‐a‐chip platform for continual monitoring of the metabolic activity of the organoids by measuring the levels of secreted biomarkers for up to 7 d, where the metabolic activity of the organoids is altered by a systemically applied drug. The variations in the biomarker levels are successfully measured by the microfluidic regenerative EC biosensors and agree well with cellular viability and enzyme‐linked immunosorbent assay analyses, validating the accuracy of the unique sensing platform. It is believed that this versatile and robust microfluidic EC biosensor that is capable of automated and continual detection of soluble biomarkers will find widespread use for long‐term monitoring of human organoids during drug toxicity studies or efficacy assessments of in vitro platforms.

show abstract

Section: Resultssupporting

confidence: 92%

Label‐Free and Regenerative Electrochemical Microfluidic Biosensors for Continual Monitoring of Cell Secretomes

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Furthermore, there is growing evidence to suggest that the dysregulation of protein kinase phosphatases may influence APAP toxicity (Wancket et al, 2012). Protein tyrosine phosphatase 1B null mice are more resistant to APAP than wild-type mice and have reduced levels of phosphorylated JNK in response to APAP (Mobasher et al, 2013). Interestingly, previous reports have demonstrated that protein tyrosine phosphatase 1B S-glutathionylation results in enzyme inactivation (Barrett et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Altered ProteinS-Glutathionylation Identifies a Potential Mechanism of Resistance to Acetaminophen-Induced Hepatotoxicity

McGarry

Chakravarty

Wolf

et al. 2015

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Acetaminophen (APAP) is the most commonly used over-thecounter analgesic. However, hepatotoxicity induced by APAP is a major clinical issue, and the factors that define sensitivity to APAP remain unclear. We have previously demonstrated that mice nulled for glutathione S-transferase Pi (GSTP) are resistant to APAP-induced hepatotoxicity. This study aims to exploit this difference to delineate pathways of importance in APAP toxicity. We used mice nulled for GSTP and heme oxygenase-1 oxidative stress reporter mice, together with a novel nanoflow liquid chromatography-tandem mass spectrometry methodology to investigate the role of oxidative stress, cell signaling, and protein S-glutathionylation in APAP hepatotoxicity. We provide evidence that the sensitivity difference between wild-type and Gstp1/2 2/2 mice is unrelated to the ability of APAP to induce oxidative stress, despite observing significant increases in c-Jun N-terminal kinase and extracellular signal-regulated kinase phosphorylation in wildtype mice. The major difference in response to APAP was in the levels of protein S-glutathionylation: Gstp1/2 2/2 mice exhibited a significant increase in the number of S-glutathionylated proteins compared with wild-type animals. Remarkably, these S-glutathionylated proteins are involved in oxidative phosphorylation, respiratory complexes, drug metabolism, and mitochondrial apoptosis. Furthermore, we found that S-glutathionylation of the rate-limiting glutathione-synthesizing enzyme, glutamate cysteine ligase, was markedly increased in Gstp1/2 2/2 mice in response to APAP. The data demonstrate that S-glutathionylation provides an adaptive response to APAP and, as a consequence, suggest that this is an important determinant in APAP hepatotoxicity. This work identifies potential novel avenues associated with cell survival for the treatment of chemical-induced hepatotoxicity.

show abstract

“…CK2 interacts with two phosphorylated forms of Nrf2, specifically Nrf2-118 and Nrf2-98, the latter of which has transcription activity, which makes it easier for it to degrade (Pi et al 2007). Additionally, glycogen synthesis kinase 3 (GSK3; Chowdhry et al 2013, Mobasher et al 2013) and RNA-dependent protein kinase endoplasmic reticulum enzyme also phosphorylate Nrf2 (Zhang et al 2014b).…”

Section: Regulation Of the Nrf2-are Pathwaymentioning

confidence: 99%

The role of Nrf2 in oxidative stress-induced endothelial injuries

Chen¹,

Lu²,

Chen³

et al. 2015

Journal of Endocrinology

321

244

View full text Add to dashboard Cite

Endothelial dysfunction is an important risk factor for cardiovascular disease, and it represents the initial step in the pathogenesis of atherosclerosis. Failure to protect against oxidative stress-induced cellular damage accounts for endothelial dysfunction in the majority of pathophysiological conditions. Numerous antioxidant pathways are involved in cellular redox homeostasis, among which the nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway is perhaps the most prominent. Nrf2, a transcription factor with a high sensitivity to oxidative stress, binds to AREs in the nucleus and promotes the transcription of a wide variety of antioxidant genes. Nrf2 is located in the cytoskeleton, adjacent to Keap1. Keap1 acts as an adapter for cullin 3/ring-box 1-mediated ubiquitination and degradation of Nrf2, which decreases the activity of Nrf2 under physiological conditions. Oxidative stress causes Nrf2 to dissociate from Keap1 and to subsequently translocate into the nucleus, which results in its binding to ARE and the transcription of downstream target genes. Experimental evidence has established that Nrf2-driven free radical detoxification pathways are important endogenous homeostatic mechanisms that are associated with vasoprotection in the setting of aging, atherosclerosis, hypertension, ischemia, and cardiovascular diseases. The aim of the present review is to briefly summarize the mechanisms that regulate the Nrf2/Keap1-ARE signaling pathway and the latest advances in understanding how Nrf2 protects against oxidative stress-induced endothelial injuries. Further studies regarding the precise mechanisms by which Nrf2-regulated endothelial protection occurs are necessary for determining whether Nrf2 can serve as a therapeutic target in the treatment of cardiovascular diseases.

show abstract

Protein tyrosine phosphatase 1B modulates GSK3β/Nrf2 and IGFIR signaling pathways in acetaminophen-induced hepatotoxicity

Cited by 79 publications

References 48 publications

Label‐Free and Regenerative Electrochemical Microfluidic Biosensors for Continual Monitoring of Cell Secretomes

Label‐Free and Regenerative Electrochemical Microfluidic Biosensors for Continual Monitoring of Cell Secretomes

Altered ProteinS-Glutathionylation Identifies a Potential Mechanism of Resistance to Acetaminophen-Induced Hepatotoxicity

The role of Nrf2 in oxidative stress-induced endothelial injuries

Contact Info

Product

Resources

About