Masters Research Project, An Oral History of Ethel Peterson

Masters Research Project: a transcribed Oral History of Ethel Peterson for Seminar in Researchhttps://scholars.fhsu.edu/ors/1224/thumbnail.jp

Olanzapine-induced liver injury : direct metabolic effects, exacerbation by high-fat diet, and protection with sulforaphane.

Olanzapine (OLZ) is an effective first-line treatment for schizophrenia and bipolar disorder. The benefits of OLZ are countermanded by side effects such as weight gain, glucose intolerance, dyslipidemia, and liver injury. These effects impact not only antipsychotic medication compliance, but also increase the health risks to patients. Most studies to date have focused on potential effects of OLZ on the central nervous system (e.g., hypothalamic regulation of satiety); however, peripheral changes in key metabolic organs such as the liver may also play a critical role. The obesity rates in the US are now at epidemic levels and obesity-induced liver disease (i.e., non-alcoholic fatty liver disease, or NAFLD) is on the rise. It is now understood that obesity is a significant risk factor for a myriad of drug-induced liver injuries. Given that the obesity incidence in the psychiatric population is even higher than in the US population as a whole, the effects of OLZ may exacerbate an underlying condition in these patients. The purpose of this work was to determine the mechanisms of OLZ-induced hepatic dysmetabolism, and to test the hypothesis that OLZ enhances obesity-induced hepatic injury. OLZ was administered in a mouse model for four weeks along with a high-fat diet (HFD) or low-fat control diet. OLZ alone increased body weight and caused mild glucose intolerance, without a commensurate increase in food consumption. OLZ alone also caused hepatic steatosis and injury. Interestingly, although OLZ increased hepatic triglyceride synthesis and storage, it did not increase the synthesis or abundance of hepatic free fatty acids. OLZ administration appeared to cause a pseudo-fasted state and dramatically depleted hepatic glycogen reserves. These effects of OLZ occurred in parallel to significant changes in hepatic metabolite profiles. The protein kinases AMPK and mTOR are generally differentially activated, and mediate opposing metabolic functions; however, OLZ administration simultaneously activated both AMPK and mTOR. When OLZ and HFD were combined, there was an even greater increase in weight gain and glucose intolerance. Liver damage from concurrent HFD and OLZ was worse than liver damage resulting from HFD or OLZ alone. Lastly, sulforaphane (SFN) was tested as a possible preventive against HFD- and OLZ-induced toxicity. Some mice receiving HFD and OLZ were also treated with SFN (90 mg/kg/d). SFN, a known inducer of the Nrf2 intrinsic antioxidant pathway, prevented weight gain and liver injury and rescued hepatic glycogen storage. Furthermore, SFN decreased the presence of 4-hydroxynonenal (4HNE) adducts in liver (\u3e20-fold), indicating that SFN treatment substantially limits oxidative stress in this model. In summary, these data show that OLZ dysregulates glucose and lipid metabolism and exacerbates hepatic changes caused by HFD exposure. The outcomes of OLZ administration on hepatic metabolism may reflect, in part, the contradictory inputs of simultaneous AMPK and mTOR activation. These data indicate that the metabolic changes caused by OLZ may sensitize the liver to injury caused by HFD and that underlying obesity/liver disease may aggravate OLZ-induced side effects. The activation of intrinsic antioxidant defenses with SFN can partially prevent these effects of OLZ and may represent a useful strategy to protect against liver injury

Sulforaphane prevents acetaminophen-induced hepatic injury in mice.

Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, is known to confer antioxidant protection in vivo. Rather than directly reacting with free radicals, however, SFN works by inducing Nrf2, a transcription factor that binds to the promoter regions of several known antioxidant genes and enhances detoxification. Because oxidative stress is a major contributor to acetaminophen (APAP)-induced hepatotoxicity, SFN may defend the liver against APAP overdose by activating the Nrf2 pathway and increasing endogenous antioxidant response. To test this hypothesis, mice were pre-treated with SFN for four days, injected with APAP on the fifth day, and sacrificed shortly thereafter. APAP overdose caused massive hepatic injury, as shown by increases in serum liver enzyme activity and lipid peroxidation. APAP overdose also manifested as decreases in total glutathione and glutathione reductase activity. SFN administration clearly prevented these manifestations of liver injury, however: increases in serum liver enzyme activity and lipid peroxidation were blunted, while total glutathione and glutathione reductase activity remained similar to those of control animals. SFN treatment did not affect the catalytic activity of acetaminophen-metabolizing enzyme CYP2E1, but did increase nuclear accumulation of Nrf2, suggesting that SFN acts primarily through the Nrf2 pathway. In summary, these data support the hypothesis that sulforaphane attenuates acute acetaminophen-induced liver injury. This decrease in injury results from the increased availability of glutathione to react with toxic metabolites of acetaminophen

Introduction: Axel Honneth’s “The Working Sovereign”

In his 2021 Walter Benjamin Lectures, Axel Honneth questioned the displacement of work from the center of contemporary political theories. This special issue collects an interview with Axel Honneth on central theses of his lectures and a number of commentaries that discuss issues like Honneth’s extended definition of work, his inclusion of long neglected care activities in the definition of work, the requirements for non-detrimental, meaningful work, Honneth’s criticism of contemporary trends in the division of labor, as well as his rejection of traditional critiques of working relations and conditions such as above all the critique of alienation. The special issue closes with a rejoinder by Axel Honneth

Introduction: Axel Honneth’s “The Working Sovereign”

In his 2021 Walter Benjamin Lectures, Axel Honneth questioned the displacement of work from the center of contemporary political theories. This special issue collects an interview with Axel Honneth on central theses of his lectures and a number of commentaries that discuss issues like Honneth’s extended definition of work, his inclusion of long neglected care activities in the definition of work, the requirements for non-detrimental, meaningful work, Honneth’s criticism of contemporary trends in the division of labor, as well as his rejection of traditional critiques of working relations and conditions such as above all the critique of alienation. The special issue closes with a rejoinder by Axel Honneth.Peer Reviewe

Global Education Through Children\u27s Literature

In this study I examined multicultural education and global education. Today, children live in a global society, thus it is necessary to provide them with meaningful learning experiences that familiarize the belief systems, values, and history of cultures and countries from around the world. A review of literature explores implications and effects that the curriculum had on students and its practical uses in everyday instruction. My focus of the study evolved to encompass the use of children’s literature as an instructional tool for global education. I discovered the crucial role that children’s literature plays in a student’s emotional, social and academic development. This genre of Children’s literature helps students make tangible sense of unfamiliar global concepts through stories and illustrations that generate classroom discussion, serve as a safe setting for the exploration of social and moral issues, and allow students to picture the world from the perspective of another