Pharmacology, Toxicology and Environmental Health Commons^™

Exposure To Pm2.5 And Aging., Daniel Chris Gomes

Electronic Theses and Dissertations

Inhalation of fine airborne particulate matter (PM_2.5) is an environmental risk factor for numerous health disorders, including cardiovascular diseases (CVD). While several studies have shown that PM_2.5 exposure can induce oxidative stress, DNA damage, and inflammation, the underlying mechanisms that translate these effects into systemic pathology remain poorly understood. Some recent studies have shown that PM_2.5 exposure can lead to telomere shortening in leukocytes, but the generality of this outcome and contribution to endothelial dysfunction has not yet been fully explored. We hypothesized that PM_2.5inhalation accelerates cellular aging and senescence in both circulating peripheral …

Astrovascular Decoupling In Awake 5×Fad Mice Is Associated With Reduced Astrocytic Calcium, Ruei-Lung Lin, Sophiya L. Sims, Nicholas A. Wright, Léopoldine B. Galopin, Blaine Weiss, Susan D. Kraner, Jacquelyn E. Rhinehart, Ting-Hsuan Lu, Pradoldej Sompol, Christopher M. Norris, Olivier Thibault

Pharmacology and Nutritional Sciences Faculty Publications

INTRODUCTION

Evidence points to dysregulated Ca²⁺ in neurons and astrocytes in models of amyloidosis. While most of these data were obtained in vitro or in vivo under anesthesia, less work has investigated these variables in awake ambulating mice.

METHODS

Astrocytic Ca²⁺ fluctuations (GCaMP8f) were imaged concomitantly with vasoreactivity in S1 on a two-photon microscope during rest and ambulation. Single-cell resolution variables were extracted using continuous wavelet transform and traditional ΔF/F measures.

RESULTS

Along with increases in amyloid beta (Aβ) accumulation, we found significant reductions in measures of astrocyte functional connectivity, pairwise correlations, and network synchronicity in older 5×FAD …

Low Concentrations Of Hexavalent Chromium In Drinking Water Induce Alzheimer’S Disease Neuropathology: Using A Toxic Aging Coin Approach To Assess Hexavalent Chromium Neurotoxicity, Liam Buchanan, Samuel Vielee, Spencer Roof, Haiyan Lu, Jamie L Young, Idoia Meaza Isusi, Aggie Williams, Joseph Kouokam, Sandra Wise, Luping Guo, Jun Cai, John Wise, John P. Wise Jr.

The Cardinal Edge

Introduction: We are currently facing an aging crisis, as 20% of the U.S. population will be geriatric (65+) by 2030. This growing geriatric population will result in increasing prevalence of age-related diseases, coinciding with increasingly prevalent environmental pollution. Environmental pollution is a ubiquitous health threat that affects people at all ages and contributes to aging pathology. However, geriatric individuals are likely more susceptible to the negative health effects from environmental pollution. The distinct effects of environmental pollutants across age groups are currently understudied. We use a Toxic Aging Coin approach to investigate: 1) how age impacts toxicity (heads), …

Characterizing Gait In Young Male 5xfad Mice, Sophiya L. Sims, Kate E. Pauss, Sami L. Case, Ruei-Lung Lin, Leopoldine B. Galopin, Nicholas A. Wright, Olivier Thibault

Journal of Pharmacology & Nutritional Sciences

Gait control represents a non-cognitive domain that is affected negatively during late stages of Alzheimer’s Disease (AD) and AD Related Dementias (ADRDs). In some cases, early identification can be predictive of worsened cognitive function. Prompt detection could help define intervention windows, perhaps even years prior to formal diagnosis of dementia. In this study, the locomotor function of 3-month-old male 5xFAD mice was evaluated using several variables (speed, deviance from center, paw precision index, stride length, stride length deviation, and stride time) to characterize the change in ambulatory behavior prior to the onset of cognitive decline. The data presented here show …

Using A Toxic Aging Coin To Assess Hexavalent Chromium-Induced Neurotoxicity., Samuel Thomas Vielee

Electronic Theses and Dissertations

We are facing an aging crisis, with 20% of the U.S. population projected to be geriatric (65+) by 2030 and live another 40+ years. Age-related diseases accompany a growing geriatric population, emphasizing the need to understand their etiology. Environmental pollutants compound this crisis by: 1) geriatrics are more susceptible, exacerbating age-related diseases and comorbidities, and 2) they accelerate biological aging, inducing age-related diseases at younger ages. We address this crisis using a ‘toxic aging coin’ approach; heads examines how age impacts toxicity, tails examines how chemicals accelerate aging. This thesis applies the heads side for Cr(VI)-induced neurotoxicity across ages. We …

Neuroinflammatory And Metabolomic Temporal Dynamics From Inhaled Wildfire Smoke With Attenuation Via Pharmacological Intervention, David Scieszka

Biomedical Sciences ETDs

Wildfire smoke is a global issue affecting nearly all humans on the surface of this Earth. Smoke dispersion from wildfires can span continents and cross oceans with amazing ease. Furthermore, total acres of land burned per year in the United States has roughly doubled since 1980, meaning this issue will persist for an indeterminate amount of time. Exposure to wildfire smoke is hazardous and promotes aging-associated events in the cardiopulmonary systems. Yet long- and short-term effects on the brain remain relatively unknown. From these, it is critically important to understand the neurological impacts from wildfire smoke exposure; to compare these …

Age-Associated Increase Of Gamma Delta T Cells In Visceral Adipose Tissue And Mechanisms Of Their Accumulation, Sujata Mukherjee

Theses and Dissertations--Pharmacology and Nutritional Sciences

Chronic systemic inflammation, known as inflammaging is considered a hallmark of aging and associated diseases. While adipose tissue has long been considered only as a caloric reservoir regulating systemic energy homeostasis, research in the past couple of decades substantiate its endocrine function to secrete an array of inflammatory mediators and hormones, which have physiological effects on multiple organ systems, and contribute to inflammaging. Redistribution of adipose tissue from subcutaneous to visceral depots, changes in the immune profile and the chronic inflammatory state are among the major sources of adipose tissue dysfunction with aging.

This dissertation is focused on identifying and …

The Intersection Between Toxicology And Aging Research: A Toxic Aging Coin Perspective., John P. Wise Jr.

Faculty and Staff Scholarship

We are imminently faced with the challenges of an increasingly aging population and longer lifespans due to improved health care. Concomitantly, we are faced with ubiquitous environmental pollution linked with various health effects and age-related diseases which contribute to increased morbidity with age. Geriatric populations are rarely considered in the development of environmental regulations or in toxicology research. Today, life expectancy is often into one’s 80s or beyond, which means multiple decades living as a geriatric individual. Hence, adverse health effects and late-onset diseases might be due to environmental exposures as a geriatric, and we currently have no way of …

Developmental Ethanol Exposure Causes Central Nervous System Dysfunction And May Slow The Aging Process In A Drosophila Model Of Fetal Alcohol Spectrum Disorder, Khaoula Belhorma, Nahed Darwish, Elizabeth Benn-Hirsch, Annalisa Duenas, Hillary Gates, Navneet Sanghera, Jodie Wu, Rachael L. French

Faculty Research, Scholarly, and Creative Activity

Alcohol is a known teratogen, and developmental exposure to ethanol results in fetal alcohol spectrum disorder (FASD). Children born with FASD can exhibit a range of symptoms including low birth weight, microcephaly, and neurobehavioral problems. Treatment of patients with FASD is estimated to cost 4 billion dollars per year in the United States alone, and 2 million dollars per affected individual's lifetime. We have established Drosophila melanogaster as a model organism for the study of FASD. Here we report that mutations in Dementin (Dmtn), the Drosophila ortholog of the Alzheimer's disease-associated protein TMCC2, convey sensitivity to developmental ethanol exposure, …

Functions Of Atr Kinase In Terminally Differentiated Human Epidermal Keratinocyles And In Human Ex-Vivo Skin After Exposure To Ultraviolet B Radiation, Vivek Shashank Nag Gogusetti

Browse all Theses and Dissertations

The functions of Ataxia telangiectasia and Rad-3 related protein (ATR) is very much important in a cell, as it is a DNA damage response protein, which plays an important role in cell division, DNA repair and apoptosis. This protein helps in proliferation in the actively DNA dividing normal cells and in cancer cells. The functions of ATR in a proliferating cell are well studied and known to involve regulation of replication fork and cell cycle progression after DNA damage. Whereas, in a non-replicating cell, the functions of ATR are not so well known. In the human body, most of the …

Impacts Of Embryonic Exposure To Cannabidiol Or ∆9-Tetrahydrocannabinol On Zebrafish (Danio Rerio) Frailty In F0 And F1 Generations, Anika Faruque

Honors Theses

Exposure to cannabinoids during critical development periods has increased with epileptic children being commonly prescribed CBD for seizures and pregnant women taking it recreationally. Many studies have been done on the possible benefits and drawbacks of cannabinoid exposure on the human brain, but not much is known about how it can affect the developing brain long-term. To see the potential adverse effects of cannabinoid exposure during critical stages of development and discover potential developmental origins of disease in consuming cannabinoids during embryogenesis, zebrafish embryos (6-96 hours post fertilization) were exposed to varying concentrations of CBD (0.02, 0.1, 0.5 µM), THC …

Is Rapamycin An Effective Anti-Aging Drug?, Basya Aboud

The Science Journal of the Lander College of Arts and Sciences

Scientific and pharmaceutical advancements have revolutionized medicine. Many once- debilitating or fatal diseases can now be managed with medication. However, the search for a cure for the inevitable aging diseased state remained futile until recently. Rapamycin has been studied for its possible longevity effects, providing promising results for the development of anti-aging therapies. This paper evaluates the benefits and risks of rapamycin use. While rapamycin cannot be supported as a safe anti-aging drug, rapamycin studies have elucidated parts of the aging pathway, providing a breakthrough for anti-aging research.

Epigenetic Regulation Of Drug Metabolizing Enzymes In Normal Aging, Mohamad M. Kronfol

Theses and Dissertations

Geriatric populations are at a higher risk for adverse drug reactions (ADRs). This may be partly due to changes in drug metabolism in old age, but the underlying mechanisms are poorly understood. Prior research in humans and mice has shown age-associated changes to the expression of several genes involved in drug metabolism. Furthermore, studies of human blood showed that epigenetic regulation of genes encoding drug metabolizing enzymes change with age. However, it is unknown if genes in the liver are similarly affected. Therefore, we hypothesize that genes encoding drug metabolizing enzymes may show differential epigenetic regulation in the liver with …

The Effects Of Aging On Skeletal Muscle Atp Production, Chaya Abboudi

The Science Journal of the Lander College of Arts and Sciences

The study of the aging process and its prevention is an incredibly popular field; the natural course of the human body is to age and theories abound on how to avoid it. Age affects every system and pathway of the body and alters many of the bodily functions. This paper, using articles from Touro’s library database examines the different areas in which aging negatively affects ATP production. The multifaceted process associated with the production of ATP in the human body was analyzed. Several features such as the mitochondria, physical activity, and hormones are linked to ATP production and the relationship …

Exploring The Role Of Insulin Receptor Signaling In Hippocampal Learning And Memory, Neuronal Calcium Dysregulation, And Glucose Metabolism, Hilaree N. Frazier

Theses and Dissertations--Pharmacology and Nutritional Sciences

In the late 90’s, emerging evidence revealed that the brain is insulin-sensitive, highlighted by broad expression of brain-specific insulin receptors and reports of circulating brain insulin. Contemporary literature robustly supports the role of insulin signaling in normal brain function and suggests that insulin-related processes diminish with aging, evidenced by decreased signaling markers, reduced insulin receptor density, and lower levels of insulin transport across the blood-brain barrier. In the context of pathological cognitive decline, clinical trials using intranasal insulin delivery have reported positive outcomes on memory and learning in patients with mild cognitive decline or early-stage Alzheimer’s disease. However, while the …

Neuroimaging Biomarkers Of Mtor Inhibition On Vascular And Metabolic Functions In Aging Brain And Alzheimer’S Disease, Jennifer Lee, Lucille M. Yanckello, David Ma, Jared D. Hoffman, Ishita Parikh, Scott Thalman, Bjoern Bauer, Anika M. S. Hartz, Fahmeed Hyder, Ai-Ling Lin

Pharmacology and Nutritional Sciences Faculty Publications

The mechanistic target of rapamycin (mTOR) is a nutrient sensor of eukaryotic cells. Inhibition of mechanistic mTOR signaling can increase life and health span in various species via interventions that include rapamycin and caloric restriction (CR). In the central nervous system, mTOR inhibition demonstrates neuroprotective patterns in aging and Alzheimer’s disease (AD) by preserving mitochondrial function and reducing amyloid beta retention. However, the effects of mTOR inhibition for in vivo brain physiology remain largely unknown. Here, we review recent findings of in vivo metabolic and vascular measures using non-invasive, multimodal neuroimaging methods in rodent models for brain aging and AD. …

Resveratrol And Pinostilbene Confer Neuroprotection Against Aging-Related Deficits Through An Erk1/2-Dependent Mechanism, Erika N. Allen, Sneha Potdar, Victor Tapias, Mayur Parmar, Cassia S. Mizuno, Agnes Rimando, Jane E. Cavanaugh

HPD Articles

Age-related declines in motor function may be due, in part, to an increase in oxidative stress in the aging brain leading to dopamine (DA) neuronal cell death. In this study, we examined the neuroprotective effects of natural antioxidants resveratrol and pinostilbene against age-related DAergic cell death and motor dysfunction using SH-SY5Y neuroblastoma cells and young, middle-aged, and old male C57BL/6 mice. Resveratrol and pinostilbene protected SH-SY5Y cells from a DA-induced decrease in cell viability. Dietary supplementation with resveratrol and pinostilbene inhibited the decline of motor function observed with age. While DA and its metabolites (DOPAC and HVA), dopamine transporter, and …

Fk506-Binding Protein 12.6/1b, A Negative Regulator Of [Ca2+], Rescues Memory And Restores Genomic Regulation In The Hippocampus Of Aging Rats, John C. Gant, Eric M. Blalock, Kuey-Chu Chen, Inga Kadish, Olivier Thibault, Nada M. Porter, Philip W. Landfield

Pharmacology and Nutritional Sciences Faculty Publications

Hippocampal overexpression of FK506-binding protein 12.6/1b (FKBP1b), a negative regulator of ryanodine receptor Ca²⁺ release, reverses aging-induced memory impairment and neuronal Ca²⁺ dysregulation. Here, we tested the hypothesis that FKBP1b also can protect downstream transcriptional networks from aging-induced dysregulation. We gave hippocampal microinjections of FKBP1b-expressing viral vector to male rats at either 13 months of age (long-term, LT) or 19 months of age (short-term, ST) and tested memory performance in the Morris water maze at 21 months of age. Aged rats treated ST or LT with FKBP1b substantially outperformed age-matched vector controls and performed similarly …

Dysregulation Of Daf-16/Foxo3a-Mediated Stress Responses Accelerates T Oxidative Dna Damage Induced Aging, Aditi U. Gurkar, Andria R. Robinson, Yuxiang Cui, Xuesen Li, Shailaja K. Allani, Amanda Webster, Mariya Muravia, Mohammad Fallahi, Herbert Weissbach, Paul D. Robbins, Yinsheng Wang, Eric E. Kelley, Claudette M. St. Croix, Laura J. Niedernhofer, Matthew S. Gill

Faculty & Staff Scholarship

DNA damage is presumed to be one type of stochastic macromolecular damage that contributes to aging, yet little is known about the precise mechanism by which DNA damage drives aging. Here, we attempt to address this gap in knowledge using DNA repair-deficient C. elegans and mice. ERCC1-XPF is a nuclear endonuclease required for genomic stability and loss of ERCC1 in humans and mice accelerates the incidence of age-related pathologies. Like mice, ercc-1 worms are UV sensitive, shorter lived, display premature functional decline and they accumulate spontaneous oxidative DNA lesions (cyclopurines) more rapidly than wild-type worms. We found that ercc-1 worms …

Age-Related Host Factors Regulate Lung Cancer Progression., John Caleb Greenwell

Electronic Theses and Dissertations

Cancer is largely a disease of the elderly. In the United States alone, 87% of all cancers in 2017 will be diagnosed in individuals aged 50 years or older. Among them, lung cancer is the deadliest, accounting for 1 in 4 cancer deaths. The 5-year survival rate is below 20%, a number which has not changed substantially over the past several decades. This underscores a desperate need for new strategies in prevention, early detection and treatment of this deadly disease. While tobacco use is unquestionably the number one risk factor for the development of lung cancer, the majority of diagnoses …

Novel Calcium-Related Targets Of Insulin In Hippocampal Neurons, Shaniya Maimaiti, Hilaree N. Frazier, Katie L. Anderson, Adam O. Ghoweri, Lawrence D. Brewer, Nada M. Porter, Olivier Thibault

Pharmacology and Nutritional Sciences Faculty Publications

Both insulin signaling disruption and Ca²⁺ dysregulation are closely related to memory loss during aging and increase the vulnerability to Alzheimer's disease (AD). In hippocampal neurons, aging-related changes in calcium regulatory pathways have been shown to lead to higher intracellular calcium levels and an increase in the Ca²⁺-dependent afterhyperpolarization (AHP), which is associated with cognitive decline. Recent studies suggest that insulin reduces the Ca²⁺-dependent AHP. Given the sensitivity of neurons to insulin and evidence that brain insulin signaling is reduced with age, insulin-mediated alterations in calcium homeostasis may underlie the beneficial actions of insulin in …

Calcium's Role As Nuanced Modulator Of Cellular Physiology In The Brain, Hilaree N. Frazier, Shaniya Maimaiti, Katie L. Anderson, Lawrence D. Brewer, John C. Gant, Nada M. Porter, Olivier Thibault

Pharmacology and Nutritional Sciences Faculty Publications

Neuroscientists studying normal brain aging, spinal cord injury, Alzheimer’s disease (AD) and other neurodegenerative diseases have focused considerable effort on carefully characterizing intracellular perturbations in calcium dynamics or levels. At the cellular level, calcium is known for controlling life and death and orchestrating most events in between. For many years, intracellular calcium has been recognized as an essential ion associated with nearly all cellular functions from cell growth to degeneration. Often the emphasis is on the negative impact of calcium dysregulation and the typical worse-case-scenario leading inevitably to cell death. However, even high amplitude calcium transients, when executed acutely can …

Development Of Activity In The Mouse Visual Cortex., Jing Shen, Matthew T Colonnese

Pharmacology and Physiology Faculty Publications

No abstract provided.

Optimizing Pharmacological Lifespan Extension: Testing Chemical Compounds For Additive Effects On Longevity, Elizabeth Chao

Dissertations, Masters Theses, Capstones, and Culminating Projects

No abstract available

Role Of Erk1, 2, And 5 In Dopamine Neuron Survival During Aging, Mayur S. Parmar, Juliann D. Jaumotte, Stephanie L. Wyrostek, Michael J. Zigmond, Jane E. Cavanaugh

HPD Articles

Extracellular signal-regulated kinases (ERKs) 1, 2, and 5 have been shown to play distinct roles in proliferation, differentiation, and neuronal viability. In this study, we examined ERK1, 2, and 5 expression and activation in the substantia nigra (SN), striatum (STR), and ventral tegmental area (VTA) during aging. An age-related decrease in phosphorylated ERK5 was observed in the SN and STR, whereas an increase in total ERK1 was observed in all 3 regions. In primary cultures of the SN and VTA, inhibition of ERK5 but not ERK1 and 2 decreased dopamine neuronal viability significantly. These data suggest that ERK5 is essential …

Aged Rats Are Hypo-Responsive To Acute Restraint: Implications For Psychosocial Stress In Aging, Heather M. Buechel, Jelena Popovic, Kendra Staggs, Katie L. Anderson, Olivier Thibault, Eric M. Blalock

Pharmacology and Nutritional Sciences Faculty Publications

Cognitive processes associated with prefrontal cortex and hippocampus decline with age and are vulnerable to disruption by stress. The stress/stress hormone/allostatic load hypotheses of brain aging posit that brain aging, at least in part, is the manifestation of life-long stress exposure. In addition, as humans age, there is a profound increase in the incidence of new onset stressors, many of which are psychosocial (e.g., loss of job, death of spouse, social isolation), and aged humans are well-understood to be more vulnerable to the negative consequences of such new-onset chronic psychosocial stress events. However, the mechanistic underpinnings of this age-related shift …

Hippocampal Ca1 Transcriptional Profile Of Sleep Deprivation: Relation To Aging And Stress, Nada M. Porter, Julia H. Bohannon, Meredith Curran-Rauhut, Heather M. Buechel, Amy L.S. Dowling, Lawrence D. Brewer, Jelena Popovic, Veronique Thibault, Susan D. Kraner, Kuey-Chu Chen, Eric M. Blalock

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Many aging changes seem similar to those elicited by sleep-deprivation and psychosocial stress. Further, sleep architecture changes with age suggest an age-related loss of sleep. Here, we hypothesized that sleep deprivation in young subjects would elicit both stress and aging-like transcriptional responses.

METHODOLOGY/PRINCIPAL FINDINGS: F344 rats were divided into control and sleep deprivation groups. Body weight, adrenal weight, corticosterone level and hippocampal CA1 transcriptional profiles were measured. A second group of animals was exposed to novel environment stress (NES), and their hippocampal transcriptional profiles measured. A third cohort exposed to control or SD was used to validate transcriptional results …

Aging And Down Syndrome, Elizabeth Head, Wayne Silverman, David Patterson, Ira T. Lott

Pharmacology and Nutritional Sciences Faculty Publications

No abstract provided.

Reversal Of Glial And Neurovascular Markers Of Unhealthy Brain Aging By Exercise In Middle-Aged Female Mice, Caitlin S. Latimer, James L. Searcy, Michael T. Bridges, Lawrence D. Brewer, Jelena Popović, Eric M. Blalock, Philip W. Landfield, Olivier Thibault, Nada M. Porter

Pharmacology and Nutritional Sciences Faculty Publications

Healthy brain aging and cognitive function are promoted by exercise. The benefits of exercise are attributed to several mechanisms, many which highlight its neuroprotective role via actions that enhance neurogenesis, neuronal morphology and/or neurotrophin release. However, the brain is also composed of glial and vascular elements, and comparatively less is known regarding the effects of exercise on these components in the aging brain. Here, we show that aerobic exercise at mid-age decreased markers of unhealthy brain aging including astrocyte hypertrophy, a hallmark of brain aging. Middle-aged female mice were assigned to a sedentary group or provided a running wheel for …

Deep Sleep And Parietal Cortex Gene Expression Changes Are Related To Cognitive Deficits With Age, Heather M. Buechel, Jelena Popovic, James L. Searcy, Nada M. Porter, Olivier Thibault, Eric M. Blalock

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Age-related cognitive deficits negatively affect quality of life and can presage serious neurodegenerative disorders. Despite sleep disruption's well-recognized negative influence on cognition, and its prevalence with age, surprisingly few studies have tested sleep's relationship to cognitive aging.

METHODOLOGY: We measured sleep stages in young adult and aged F344 rats during inactive (enhanced sleep) and active (enhanced wake) periods. Animals were behaviorally characterized on the Morris water maze and gene expression profiles of their parietal cortices were taken.

PRINCIPAL FINDINGS: Water maze performance was impaired, and inactive period deep sleep was decreased with age. However, increased deep sleep during the …