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You searched for subject:(acetaminophen APAP ). Showing records 1 – 2 of 2 total matches.

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University of Southern California

1. Ybanez, Maria Cecilia D. Protein kinase C (PKC) participates in acetaminophen hepatotoxicity through JNK dependent and independent pathways.

Degree: MS, Biochemistry and Molecular Biology, 2013, University of Southern California

Our previous studies have shown that acetaminophen (APAP)-induced hepatocyte necrosis is mediated by JNK. In the present study we show that protein kinase C (PKC) plays an important role in APAP-induced liver injury through JNK-dependent and independent pathways. Treatment of primary mouse hepatocytes with two different broad-spectrum PKC inhibitors (Ro-31-8245, Go6983), protected against APAP hepatotoxicity without inhibiting JNK activation. Ro-31-8245 treatment to mice also resulted in upregulation of p-AMPK in the liver and protection against APAP-induced liver injury in vivo, despite sustained JNK activation. APAP treatment caused a decreased p-AMPK, which was prevented by broad-spectrum PKC inhibitors. AMPK inhibition by compound C or activation using AMPK activator oppositely modulated APAP hepatotoxicity. This suggests PKC-dependent downregulation of AMPK-regulated survival pathways is an important component of APAP hepatotoxicity. In contrast to broad-spectrum inhibitors, treatment of hepatocytes with a more specific classical PKC inhibitor (Go6976) that inhibits mainly PKC-α and PKC-βI protected against APAP by inhibiting JNK activation. Knockdown of PKC-α using antisense (ASO) in mice protected against APAP-induced liver injury by inhibiting JNK activation. APAP treatment resulted in PKC-α translocation to mitochondria, phosphorylation of mitochondrial proteins, and decline in mitochondria respiration in the liver. JNK 1 and 2 silencing using ASO in mice decreased APAP-induced PKC-α translocation to mitochondria, suggesting PKC-α and JNK act together through a feed forward mechanism to mediate APAP-induced liver injury. Conclusion: PKC-α and other PKC(s) regulate death (JNK) and survival (AMPK), to modulate APAP-induced liver injury. Advisors/Committee Members: Tokes, Zoltan A. (Committee Chair), Kalra, Vijay K. (Committee Member), Kaplowitz, Neil (Committee Member).

Subjects/Keywords: acetaminophen (APAP); AMPK; p70S6K; necrosis

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Ybanez, M. C. D. (2013). Protein kinase C (PKC) participates in acetaminophen hepatotoxicity through JNK dependent and independent pathways. (Masters Thesis). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/247992/rec/5294

Chicago Manual of Style (16th Edition):

Ybanez, Maria Cecilia D. “Protein kinase C (PKC) participates in acetaminophen hepatotoxicity through JNK dependent and independent pathways.” 2013. Masters Thesis, University of Southern California. Accessed June 19, 2019. http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/247992/rec/5294.

MLA Handbook (7th Edition):

Ybanez, Maria Cecilia D. “Protein kinase C (PKC) participates in acetaminophen hepatotoxicity through JNK dependent and independent pathways.” 2013. Web. 19 Jun 2019.

Vancouver:

Ybanez MCD. Protein kinase C (PKC) participates in acetaminophen hepatotoxicity through JNK dependent and independent pathways. [Internet] [Masters thesis]. University of Southern California; 2013. [cited 2019 Jun 19]. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/247992/rec/5294.

Council of Science Editors:

Ybanez MCD. Protein kinase C (PKC) participates in acetaminophen hepatotoxicity through JNK dependent and independent pathways. [Masters Thesis]. University of Southern California; 2013. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/247992/rec/5294


Loughborough University

2. Reddyhoff, Dennis. Mathematical modelling of acetaminophen induced hepatotoxicity.

Degree: PhD, 2016, Loughborough University

Acetaminophen, known as paracetamol in the UK and Tylenol in the United States, is a widespread and commonly used painkiller all over the world. Taken in large enough doses, however, it can cause fatal liver damage. In the U.S., 56000 people are admitted to hospital each year due to acetaminophen overdose and its related effects, at great cost to healthcare services. In this thesis we present a number of different models of acetaminophen metabolism and toxicity. Previously, models of acetaminophen toxicity have been complex and due to this complexity, do not lend themselves well to more advanced mathematical analysis such as the perturbation analysis presented later in this thesis. We begin with a simple model of acetaminophen metabolism, studying a single liver cell and performing numerical and sensitivity analysis to further understand the most important mechanisms and pathways of the model. Through this we identify key parameters that affect the total toxicity in our model. We then proceed to perform singular perturbation analysis, studying the behaviour of the model over different timescales, finding a number of key timescales for the depletion and subsequent recovery of various cofactors as well as critical dose above which we see toxicity occurring. Later in the thesis, this model is used to model metabolism in a spheroid cell culture, examining the difference spatial effects have on metabolism across a 3D cell culture. We then present a more complex model, examining the difference the addition of an adaptive response to acetaminophen overdose from the Nrf2 signalling pathway, has on our results. We aim to reproduce an unexplained result in the experimental data of our colleagues, and so analyse the steady states of our model when subjected to an infused dose, rather than a bolus one. We identify another critical dose which leads to GSH depletion in the infused dose case and find that Nrf2 adaptation decreases toxicity and model sensitivity. This model is then used as part of a whole-body PBPK model, exploring the effects that the distribution of the drug across the bloodstream and different organs has. We explore the affects of that a delay in up-regulation from the Nrf2 pathway has on the model, and find that with rescaled parameters we can qualitatively reproduce the results of our collaborators. Finally, we present the results of in vitro work that we have undertaken, the aim of which was to find new parameters for the model in human hepatocytes, rather than from rodent models, and find a new value for a parameter in our model from human cell lines.

Subjects/Keywords: 615.7; Mathematical modelling; Modelling; Toxicity; Acetaminophen; Paracetamol; Apap; Timescale; Nrf2; Spheroid; Ivive; Animal

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Reddyhoff, D. (2016). Mathematical modelling of acetaminophen induced hepatotoxicity. (Doctoral Dissertation). Loughborough University. Retrieved from https://dspace.lboro.ac.uk/2134/23008 ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.697687

Chicago Manual of Style (16th Edition):

Reddyhoff, Dennis. “Mathematical modelling of acetaminophen induced hepatotoxicity.” 2016. Doctoral Dissertation, Loughborough University. Accessed June 19, 2019. https://dspace.lboro.ac.uk/2134/23008 ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.697687.

MLA Handbook (7th Edition):

Reddyhoff, Dennis. “Mathematical modelling of acetaminophen induced hepatotoxicity.” 2016. Web. 19 Jun 2019.

Vancouver:

Reddyhoff D. Mathematical modelling of acetaminophen induced hepatotoxicity. [Internet] [Doctoral dissertation]. Loughborough University; 2016. [cited 2019 Jun 19]. Available from: https://dspace.lboro.ac.uk/2134/23008 ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.697687.

Council of Science Editors:

Reddyhoff D. Mathematical modelling of acetaminophen induced hepatotoxicity. [Doctoral Dissertation]. Loughborough University; 2016. Available from: https://dspace.lboro.ac.uk/2134/23008 ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.697687

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