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Pharmer's
Almanac

May 2020 Edition

Welcome to the May 2020 edition of the Pharmer's Almanac!

Welcome to the May 2020 edition of our Pharmer's Almanac Newsletter. A lot has happened since our last edition in December.

In this issue:

  • A close-up on great new studies led by trainees
  • New Departmental publications
  • Exciting biostats modules coming your way
  • Over 30 TV show recommendations from your fellow students and ways to stay active and inspired

We hope you enjoy the read!

Research Round-up

New evidence of brain mitochondrial dysfunction in bipolar disorder


Evidence is accumulating to support the role of mitochondrial dysfunction in bipolar disorder, but few studies have examined human brain tissue directly. Here, patients with bipolar disorder showed region-specific shifts in electron transport chain complex I subunit NDUFS7 protein expression, mitochondrial DNA content, and mitochondrial DNA oxidation in post-mortem brain tissue. Taken together, the results suggest a compensatory mechanism to maintain mitochondrial function and DNA integrity via the upregulation of mitochondrial biogenesis and stress response pathways in patients with bipolar disorder.

The work was published in npj Schizophrenia by David Bodenstein and colleagues from the Andreazza lab.

Higher peripheral lactate in adolescents with bipolar disorder


Evidence of mitochondrial dysfunction is growing in bipolar disorder, but it remains difficult to identify this in peripheral blood. In collaboration with the Centre for Youth Bipolar Disorder at Sunnybrook Health Sciences Centre, this study found higher lactate concentrations in the serum of adolescents with bipolar disorder compared to those without. Lactate levels also correlated with cell free mitochondrial DNA levels in blood. This is the first study to identify peripheral markers of mitochondrial dysfunction in youth bipolar disorder, offering new potential for clinical use as a biomarker for the disease.
 
The work was published in Journal of Psychiatric Research by Hyunjin Jeong, supervised by Dr. Ana Andreazza.

The genetic underpinnings of smoking behaviour


The largest genome-wide association meta-analysis to date involving objective biomarkers of nicotine metabolism and cigarette consumption measures has revealed novel insights into the genetic underpinnings of smoking-related traits. Nearly 40% of the variation in the nicotine metabolism biomarker was captured, with significant regions mapping to CYP2A6 (major nicotine metabolism gene), MAP3K10, ADCK4, and CYP2B6, among others, on chromosome 19, as well as TMPRSS11E on chromosome 4. Some loci were shared between the biomarkers, while others were unique. The study involved over 5,000 smokers recruited from North America, Finland, and Australia and was led by scientists at the University of Toronto/CAMH, the University of Helsinki, and the QIMR Berghofer Medical Research Institute in Australia.
 
The paper was recently published in Molecular Psychiatry, by Dr. Meghan Chenoweth from the Tyndale lab. Dr. Chenoweth is now a Scientist at CAMH.

Do neutrophils contribute to Alzheimer's disease?


Are neutrophils involved in the pathophysiology of Alzheimer’s disease, and how can we estimate their activation in living people? The study followed 109 people with mild Alzheimer’s disease, using an innovative statistical approach (confirmatory factor analysis) to triangulate neutrophil activity from 5 peripheral blood inflammatory markers measured together at baseline. Over 1 year, the neutrophil signature predicted a decline in executive function, a symptom consistent with neurovascular changes seen early in mild Alzheimer's disease. The study provides clinical evidence in support of recent animal work that peripheral neutrophils acting in small blood vessels may be early players contributing to neurodegeneration.
 
The paper was published in the Journal of Neuroinflamamtion by Kritleen Bawa, an undergraduate student in the Swardfager lab. Kritleen is now an MSc student in the Lanctôt Lab.

Human CYP2D6 is functional in brain and influences drug response


The human CYP2D6 enzyme metabolizes approximately 25% of all clinically used drugs, many of which are CNS-active. While CYP2D6 is known to be expressed and variable in human brain, it was previously unknown whether there is the correct biological milieu for CYP2D6 to be functional in the brain in vivo and whether its activity could alter drug and metabolite levels sufficiently to change drug response. As a translational step towards studying CYP2D6 in vivo in human brain, humanized transgenic mice that expressed human CYP2D6 were given pharmacological inhibitors centrally to selectively inhibit human CYP2D6 in the brain. Using this novel approach, we demonstrated for the first time that human CYP2D6 is active in the brain at levels sufficient to alter brain drug and metabolite levels in vivo and to change behavioural response to a peripherally administered drug.

The paper was published recently in
Molecular Neurobiology by Cole Tolledo and Marlaina Stocco from the Tyndale Lab.





Differences in molecular mechanisms between cell lines and in vivo models: a cautionary tale


The function of microsomal cytochrome P450 enzymes depends on electron transfer from its partner protein, NADPH-cytochrome P450 oxidoreductase (POR).  Although the regulation of POR expression and function by adrenal steroids is poorly understood, we know that POR mRNA and protein levels are increased in rat liver by dexamethasone (DEX), a synthetic glucocorticoid that activates both the glucocorticoid receptor (GR) and the pregnane X receptor (PXR). Previous studies in vivo from Dr. David Riddick’s lab showed that POR regulation in rat liver is primarily PXR-mediated, although GR may contribute to POR mRNA induction. Now, his lab shows POR regulation by DEX in the H4IIE rat hepatoma cell line. Although an important role for POR mRNA stabilization by DEX seemed to be conserved between in vivo and in vitro cellular systems, the GR played a more important role in DEX-induced POR expression in H4IIE cells compared to the rat liver in vivo. The work raises important questions about the suitability of this hepatoma cell line as a model for mechanistic studies of POR induction.
 
The paper was published recently in the Canadian Journal of Physiology and Pharmacology by Drs. David Riddick and Anne Mullen Grey (PharmTox alumna).

The dopamine D3 receptor and nicotine craving


Preclinical studies show that the dopamine D3 receptor is involved in reinstating seeking drugs of abuse. This study investigated the relationship between the D3 receptor Ser9Gly variant and measures of both nicotine reinforcement and cue-elicited craving in 104 people who smoked at least 10 cigarettes per day. The results support the involvement of the D3 receptor in reacting to nicotine-related cues in humans.
 
The paper was recently published in Scientific Reports, by Chidera C. Chukwueke and others from the Le Foll lab.

The biomarker reproducibility crisis; detecting methodological artefacts


Biomarkers have the potential to improve our understanding of diseases, but biomarker studies frequently yield results that are inconsistent with one another. Technical factors, such as sample handling, processing, and storage affect the measurement of biological markers and may produce erroneous results. The initial aim of our study was to examine inflammatory cytokines in serum of patients with bipolar disorder compared to controls. Though we initially observed higher levels of inflammatory cytokines in patients with bipolar disorder, our subsequent investigations determined that the differences in cytokine concentrations were due to differences in sample transportation. This manuscript highlights the need for careful study design with consideration of all aspects of the sample collection and processing protocol that may influence the measurement of biological molecules.

The study was published by Alex Pan and colleagues from the Andreazza lab in the World Journal of Biological Psychiatry.

See other recent publications

If you would like your research featured here, please contact the Pharmer’s Almanac!

Biostats Modules

Biostats modules are on the way!


Are you having trouble deciding between a t-test vs. an ANOVA, or between a Pearson correlation vs. a linear regression? Do you find stats classes long and difficult to follow? We hear you, and we've created a basic biostatistics resource for PharmTox students to help. This series of quick interactive modules will help you describe your data and decide on the best biostats test for your hypothesis and design. The modules are designed to be self-guided so that you can easily find answers to your questions. Our PCL368 TA, Joey Wu, has also provided links to some of his R scripts to help you get started. Please contact us if you are interested in accessing these modules!

PharmTox Life Hacks 2020

In these complex times of ongoing change and uncertainty, we wanted to hear your tips and tricks for social distancing, together. So we put together a survey for our members to find out what you are finding inspirational, motivational and engaging these days. Thank you to all who participated!

Here is a summary of results!
 


What has helped you to keep active?

... and some of us are just relishing the inactivity!

 


What have you found inspiring?



Any TV Recommendations?



What has helped you stay engaged? Have you found anything that will help make your life better into the future?

 



Any Words of Wisdom?

We'd love to hear from you!

Have an event, story, award or publication you'd like to share? Let us know!
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