Medicine and Health Sciences Commons^™

Developmental Origins Of Health And Disease: Current Knowledge And Potential Mechanisms, Daniel J. Hoffman, Rebecca M. Reynolds, Daniel B. Hardy

Physiology and Pharmacology Publications

Epidemiologic and clinical research has provided a large body of evidence supporting the developmental origins of health and disease (DOHaD), but there has been a relative dearth of mechanistic studies in humans due to the complexity of working with large, longitudinal cohorts. Nonetheless, animal models of undernutrition have provided substantial evidence for the potential epigenetic, metabolic, and endocrine mechanisms behind DOHaD. Furthermore, recent research has explored the interaction between the environment and the gastrointestinal system by investigating how the gut microbial ecology may impact the capacity for nutrient processing and absorption in a manner that may limit growth. This review …

Disruption Of Hippocampal Multisynaptic Networks By General Anesthetics., Min-Ching Kuo, L Stan Leung

Physiology and Pharmacology Publications

BACKGROUND: Previous studies showed that synaptic transmission is affected by general anesthetics, but an anesthetic dose response in freely moving animals has not been done. The hippocampus provides a neural network for the evaluation of isoflurane and pentobarbital on multisynaptic transmission that is relevant to memory function.

METHODS: Male Long-Evans rats were implanted with multichannel and single electrodes in the hippocampus. Spontaneous local field potentials and evoked field potentials were recorded in freely behaving rats before (baseline) and after various doses of isoflurane (0.25 to 1.5%) and sodium pentobarbital (10 mg/kg intraperitoneal).

RESULTS: Monosynaptic population excitatory postsynaptic potentials at the …

Maternal Nicotine Exposure Leads To Decreased Cardiac Protein Disulfide Isomerase And Impaired Mitochondrial Function In Male Rat Offspring., Nicole G Barra, Maria Lisyansky, Taylor A Vanduzer, Sandeep Raha, Alison C Holloway, Daniel B Hardy

Physiology and Pharmacology Publications

Smoking throughout pregnancy can lead to complications during gestation, parturition and neonatal development. Thus, nicotine replacement therapies are a popular alternative thought to be safer than cigarettes. However, recent studies in rodents suggest that fetal and neonatal nicotine exposure alone results in cardiac dysfunction and high blood pressure. While it is well known that perinatal nicotine exposure causes increased congenital abnormalities, the mechanisms underlying longer-term deficits in cardiac function are not completely understood. Recently, our laboratory demonstrated that nicotine impairs placental protein disulfide isomerase (PDI) triggering an increase in endoplasmic reticulum stress, leading us to hypothesize that this may also …

Increased Incidence Of Non-Alcoholic Fatty Liver Disease In Male Rat Offspring Exposed To Fluoxetine During Fetal And Neonatal Life Involves The Nlrp3 Inflammasome And Augmented De Novo Hepatic Lipogenesis., Nicole E De Long, Daniel B Hardy, Noelle Ma, Alison C Holloway

Physiology and Pharmacology Publications

Up to 10% of women take selective serotonin reuptake inhibitors (SSRI) during pregnancy. Children exposed to SSRIs in utero have an increased risk of being overweight suggesting that fetal exposure to SSRIs can cause permanent metabolic changes. We have previously shown in rats that fetal and neonatal exposure to the SSRI antidepressant fluoxetine results in metabolic perturbations including increased hepatic triglyceride content; a hallmark of non-alcoholic fatty liver disease (NAFLD). Therefore, the aim of this study was to identify the mechanism(s) underlying the fluoxetine-induced increase in intrahepatic triglyceride content. Female nulliparous Wistar rats were given vehicle or fluoxetine (10 mg/kg/day) …

Maternal Undernutrition And Long-Term Effects On Hepatic Function, Daniel B. Hardy

Physiology and Pharmacology Publications

Undernutrition in utero, regardless of the source, can impair proper liver development leading to long-term metabolic dysfunction. Understanding the molecular mechanisms underlying how nutritional deficits during perinatal life lead to permanent alterations in hepatic gene expression will provide better therapeutic strategies to alleviate the undernourished liver in postnatal life. This chapter addresses the different experimental models of undernutrition in utero, and highlights the direct and indirect mechanisms involved leading to metabolic diseases in the liver. These include hypoxia, oxidative stress, epigenetic alterations, and endoplasmic reticulum (ER) stress. In addition, promising perinatal nutritional and pharmaceutical interventions are highlighted which …

Effects Of Protein Deficiency On Perinatal And Postnatal Health Outcomes, Shelby L. Oke, Daniel B. Hardy

Physiology and Pharmacology Publications

There are a variety of environmental insults that can occur during pregnancy which cause low birth weight and poor fetal health outcomes. One such insult is maternal malnutrition, which can be further narrowed down to a low protein diet during gestation. Studies show that perinatal protein deficiencies can impair proper organ growth and development, leading to long-term metabolic dysfunction. Understanding the molecular mechanisms that underlie how this deficiency leads to adverse developmental outcomes is essential for establishing better therapeuticstrategies that may alleviate or prevent diseases in later life. This chapter reviews how perinatal protein restriction in humans and animals leads …

Perinatal Malnutrition And Epigenetic Regulation Of Long-Term Metabolism In The Liver And Adipose Tissue, Daniel B. Hardy

Physiology and Pharmacology Publications

Maternal malnutrition in perinatal life can have long-lasting adverse effects on glucose and lipid homeostasis in the offspring, culminating in dyslipidemia, insulin resistance and obesity. Understanding the molecular mechanisms underlying how these nutritional deficits during perinatal life lead to permanent changes in hepatic and adipose function will provide efficacious therapeutic strategies to mitigate these metabolic defects short- and long-term. This chapter addresses how epigenetic mechanisms mediate alterations in hepatic and adipose gene expression identified from clinical studies and different experimental models of maternal malnutrition. These include DNA methylation, post-translational histone modifications, and microRNAs.

Pharmaceutical Direct-To-Consumer Advertising: Analyses Of Policy Stakeholders And Supreme Court Of Canada Interveners, Tom T. Eldik

Electronic Thesis and Dissertation Repository

Background: Pharmaceutical direct-to-consumer advertising (DTCA) is a controversial form of advertising that markets prescription pharmaceuticals to patients and consumers. The positions, powers, interests and influence of pharmaceutical DTCA stakeholders shape Canadian DTCA policies; however, no focused analysis of pharmaceutical DTCA stakeholders has occurred.

Methods: This study involved a two-pronged stakeholder analysis: First was a broad analysis of pharmaceutical DTCA stakeholders using Canadian publicly available documents and websites. The second analyzed interveners on pharmaceutical litigation at the Supreme Court of Canada, and the comparisons to a leading tobacco advertising case, RJR-Macdonald v Canada (A.G) and a pharmaceutical DTCA case …

G Protein-Coupled Kiss1 Receptor Is Overexpressed In Triple Negative Breast Cancer And Promotes Drug Resistance., Alexandra Blake, Magdalena Dragan, Rommel G Tirona, Daniel B Hardy, Muriel Brackstone, Alan B Tuck, Andy V Babwah, Moshmi Bhattacharya

Physiology and Pharmacology Publications

Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptor α, progesterone receptor and human epidermal growth factor receptor 2 (HER2). TNBC patients lack targeted therapies, as they fail to respond to endocrine and anti-HER2 therapy. Prognosis for this aggressive cancer subtype is poor and survival is limited due to the development of resistance to available chemotherapies and resultant metastases. The mechanisms regulating tumor resistance are poorly understood. Here we demonstrate that the G protein-coupled kisspeptin receptor (KISS1R) promotes drug resistance in TNBC cells. KISS1R binds kisspeptins, peptide products of the KISS1 gene and in numerous cancers, this signaling pathway …

Resting State Functional Network Disruptions In A Kainic Acid Model Of Temporal Lobe Epilepsy., Ravnoor Singh Gill, Seyed M Mirsattari, L Stan Leung

Physiology and Pharmacology Publications

We studied the graph topological properties of brain networks derived from resting-state functional magnetic resonance imaging in a kainic acid induced model of temporal lobe epilepsy (TLE) in rats. Functional connectivity was determined by temporal correlation of the resting-state Blood Oxygen Level Dependent (BOLD) signals between two brain regions during 1.5% and 2% isoflurane, and analyzed as networks in epileptic and control rats. Graph theoretical analysis revealed a significant increase in functional connectivity between brain areas in epileptic than control rats, and the connected brain areas could be categorized as a limbic network and a default mode network (DMN). The …