Digital Commons Network^™

Emerging Roles Of Xenobiotic Detoxification Enzymes In Metabolic Diseases, Michael C. Petriello, Jessie B. Hoffman, Andrew J. Morris, Bernhard Hennig

Superfund Research Center Faculty Publications

Mammalian systems have developed extensive molecular mechanisms to protect against the toxicity of many exogenous xenobiotic compounds. Interestingly, many detoxification enzymes, including cytochrome P450s and flavin-containing monooxygenases, and their associated transcriptional activators [e.g. the aryl hydrocarbon receptor (AhR)], have now been shown to have endogenous roles in normal physiology and the pathology of metabolic diseases. This mini-review will focus on two such instances: the role of flavin-containing monooxygenase 3 (FMO3) in the formation of the cardiometabolic disease biomarker trimethylamine-N-oxide (TMAO) and the role of AhR as a sensor of endogenous ligands such as those generated by the gut microbiota. Understanding …

Using A Respiratory Navigator Significantly Reduces Variability When Quantifying Left Ventricular Torsion With Cardiovascular Magnetic Resonance, Sean M. Hamlet, Christopher M. Haggerty, Jonathan D. Suever, Gregory J. Wehner, Kristin N. Andres, David K. Powell, Richard J. Charnigo, Brandon K. Fornwalt

Electrical and Computer Engineering Faculty Publications

Background: Left ventricular (LV) torsion is an important indicator of cardiac function that is limited by high inter-test variability (50% of the mean value). We hypothesized that this high inter-test variability is partly due to inconsistent breath-hold positions during serial image acquisitions, which could be significantly improved by using a respiratory navigator for cardiovascular magnetic resonance (CMR) based quantification of LV torsion.

Methods: We assessed respiratory-related variability in measured LV torsion with two distinct experimental protocols. First, 17 volunteers were recruited for CMR with cine displacement encoding with stimulated echoes (DENSE) in which a respiratory navigator was used to measure …

An Open-Sourced Statistical Application For Identifying Complex Toxicological Interactions Of Environmental Pollutants, Jordan T. Perkins, Michael C. Petriello, Li Xu, Arnold J. Stromberg, Bernhard Hennig

Superfund Research Center Faculty Publications

The rising number of chemicals that humans are exposed to on a daily basis, as well as advances in biomonitoring and detection technologies have highlighted the diversity of individual exposure profiles (complex body burdens). To address this, the toxicological sciences have begun to shift away from examining toxic agents or stressors individually to focusing on more complex models with multiple agents or stressors present. Literature on interactions between chemicals is fairly limited in comparison with dose-response studies on individual toxicants, which is largely due to experimental and statistical challenges. Experimental designs capable of identifying these complex interactions are often avoided …

Impact Of Nutrition On Pollutant Toxicity: An Update With New Insights Into Epigenetic Regulation, Jessie B. Hoffman, Michael C. Petriello, Bernhard Hennig

Superfund Research Center Faculty Publications

Exposure to environmental pollutants is a global health problem and is associated with the development of many chronic diseases, including cardiovascular disease, diabetes and metabolic syndrome. There is a growing body of evidence that nutrition can both positively and negatively modulate the toxic effects of pollutant exposure. Diets high in proinflammatory fats, such as linoleic acid, can exacerbate pollutant toxicity, whereas diets rich in bioactive and anti-inflammatory food components, including omega-3 fatty acids and polyphenols, can attenuate toxicant-associated inflammation. Previously, researchers have elucidated direct mechanisms of nutritional modulation, including alteration of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, …

Recent Advances On Iron Oxide Magnetic Nanoparticles As Sorbents Of Organic Pollutants In Water And Wastewater Treatment, Angela M. Gutierrez, Thomas D. Dziubla, J. Zach Hilt

Superfund Research Center Faculty Publications

The constant growth in population worldwide over the past decades continues to put forward the need to provide access to safe, clean water to meet human needs. There is a need for cost-effective technologies for water and wastewater treatment that can meet the global demands and the rigorous water quality standards and at the same maximizing pollutant efficiency removal. Current remediation technologies have failed in keeping up with these factors without becoming cost-prohibitive. Most recently, nanotechnology has been sought as the best alternative to increase access to water supplies by remediating those already contaminated and offering ways to access unconventional …

Forage News [2017-03], Department Of Plant And Soil Sciences, University Of Kentucky

Forage News

• Alfalfa and Stored Forages Conference Award Winners
• Farmer Success with Novel Endophyte Fescue
• Making High Quality Baleage
• Don't Leave the Leaves
• Fertilizing Cool Season Pastures

Cytomegalovirus Serostatus, Inflammation, And Antibody Response To Influenza Vaccination In Older Adults: The Moderating Effect Of Beta Blockade, Rebecca G. Reed, Richard N. Greenberg, Suzanne C. Segerstrom

Psychology Faculty Publications

Cytomegalovirus (CMV) has been implicated as a factor in immunosenescence, including poor antibody response to vaccination and higher immune activation and inflammation. Some people may be more or less vulnerable to the negative effects of CMV. The present investigation tested the effects of beta-blocker use and chronological age on the associations between CMV and immunity in adults aged 60–91 (N=98; 69% CMV seropositive) who were administered the trivalent influenza vaccine for up to 5 years. Peak antibody response, corrected for baseline, and spring (persistent) antibody response, corrected for peak, were assessed, as well as beta-2 microglobulin (β2μ) and interleukin-6 (IL-6). …

Relb Expression Determines The Differential Effects Of Ascorbic Acid In Normal And Cancer Cells, Xiaowei Wei, Yong Xu, Fang Fang Xu, Luksana Chaiswing, David M. Schnell, Teresa Noel, Chi Wang, Jinfei Chen, Daret K. St. Clair, William H. St. Clair

Toxicology and Cancer Biology Faculty Publications

Cancer cells typically experience higher oxidative stress than normal cells, such that elevating pro-oxidant levels can trigger cancer cell death. Although pre-exposure to mild oxidative agents will sensitize cancer cells to radiation, this pre-exposure may also activate the adaptive stress defense system in normal cells. Ascorbic acid is a prototype redox modulator that when infused intravenously appears to kill cancers without injury to normal tissues; however, the mechanisms involved remain elusive. In this study, we show how ascorbic acid kills cancer cells and sensitizes prostate cancer to radiation therapy while also conferring protection upon normal prostate epithelial cells against radiation-induced …

Reduction Of Cocaine-Induced Locomotor Effects By Enriched Environment Is Associated With Cell-Specific Accumulation Of Δfosb In Striatal And Cortical Subregions, Audrey Lafragette, Michael T. Bardo, Virginie Lardeux, Marcello Solinas, Nathalie Thiriet

Psychology Faculty Publications

Background: Early exposure to enriched environments has been shown to decrease the locomotor effects induced by repeated injections of cocaine and modify basal and cocaine-induced total protein levels of the transcription factor ΔFosB in the whole striatum of mice. In this study, we aimed at characterizing whether the profile of ΔFosB accumulation induced by enriched environments and cocaine would be similar or different in terms of brain areas and cell type.

Methods: We used mice expressing the eGFP protein in D1 receptor positive (D1R(+)) neurons to determine whether ΔFosB induced by enriched environment or cocaine injections (5×15 mg/kg) would occur …

Faster Self-Paced Rate Of Drinking For Alcohol Mixed With Energy Drinks Versus Alcohol Alone, Cecile A. Marczinski, Mark T. Fillmore, Sarah F. Maloney, Amy L. Stamates

Psychology Faculty Publications

The consumption of alcohol mixed with energy drinks (AmED) has been associated with higher rates of binge drinking and impaired driving when compared with alcohol alone. However, it remains unclear why the risks of use of AmED are heightened compared with alcohol alone even when the doses of alcohol consumed are similar. Therefore, the purpose of this laboratory study was to investigate if the rate of self-paced beverage consumption was faster for a dose of AmED versus alcohol alone using a double-blind, within-subjects, placebo-controlled study design. Participants (n = 16) of equal gender who were social drinkers attended 4 separate …

Effect Of Cigarette Smoke Exposure And Mutant Kras Overexpression On Pancreatic Cell Proliferation, Howard P. Glauert, R. Scott Elliott, Sung Gu Han, Mark Athey, Eun Young Lee, C. Gary Gairola

Pharmacology and Nutritional Sciences Faculty Publications

Pancreatic cancer is the fourth leading cause of cancer‑associated mortality. The major risk factor for pancreatic cancer is cigarette smoking. Kras mutations are commonly observed in human pancreatic cancers. The present study examined the hypothesis that exposure to cigarette smoke and overexpression of a mutant Kras gene in the pancreas affects pancreatic cell proliferation in mice. Mice overexpressing the mutant Kras gene (KRas^G12D) in the pancreas as well as wild‑type mice were exposed to environmental tobacco smoke for 2 weeks. Overexpression of mutant Kras increased cell proliferation in pancreatic ductal, acinar and islet cells. Notably, cigarette smoke exposure …

Developmental Origins Of Cardiovascular Disease: Impact Of Early Life Stress In Humans And Rodents, Margaret O. Murphy, Dianne M. Cohn, Analia S. Loria

Pharmacology and Nutritional Sciences Faculty Publications

The Developmental Origins of Health and Disease (DOHaD) hypothesizes that environmental insults during childhood programs the individual to develop chronic disease in adulthood. Emerging epidemiological data strongly supports that early life stress (ELS) given by the exposure to adverse childhood experiences is regarded as an independent risk factor capable of predicting future risk of cardiovascular disease. Experimental animal models utilizing chronic behavioral stress during postnatal life, specifically maternal separation (MatSep) provides a suitable tool to elucidate molecular mechanisms by which ELS increases the risk to develop cardiovascular disease, including hypertension. The purpose of this review is to highlight current epidemiological …

Toxicity Evaluation Of Magnetic Hyperthermia Induced By Remote Actuation Of Magnetic Nanoparticles In 3d Micrometastasic Tumor Tissue Analogs For Triple Negative Breast Cancer, Nathanael A. Stocke, Pallavi Sethi, Amar Jyoti, Ryan Chan, Susanne M. Arnold, J. Zach Hilt, Meenakshi Upreti

Chemical and Materials Engineering Faculty Publications

Magnetic hyperthermia as a treatment modality is acquiring increased recognition for loco-regional therapy of primary and metastatic lung malignancies by pulmonary delivery of magnetic nanoparticles (MNP). The unique characteristic of magnetic nanoparticles to induce localized hyperthermia in the presence of an alternating magnetic field (AMF) allows for preferential killing of cells at the tumor site. In this study we demonstrate the effect of hyperthermia induced by low and high dose of MNP under the influence of an AMF using 3D tumor tissue analogs (TTA) representing the micrometastatic, perfusion independent stage of triple negative breast cancer (TNBC) that infiltrates the lungs. …

Neuroimaging Biomarkers Of Caloric Restriction On Brain Metabolic And Vascular Functions, Ai-Ling Lin, Ishita Parikh, Jared D. Hoffman, David Ma

Sanders-Brown Center on Aging Faculty Publications

Purpose of Review

Non-invasive neuroimaging methods have been developed as powerful tools for identifying in vivo brain functions for studies in humans and animals. Here, we review the imaging biomarkers that are being used to determine the changes within brain metabolic and vascular functions induced by caloric restriction (CR) and their potential usefulness for future studies with dietary interventions in humans.

Recent Findings

CR causes an early shift in brain metabolism of glucose to ketone bodies and enhances ATP production, neuronal activity, and cerebral blood flow (CBF). With age, CR preserves mitochondrial activity, neurotransmission, CBF, and spatial memory. CR also …

Effectiveness Of A Home-Based Eccentric-Exercise Program On The Torque-Angle Relationship Of The Shoulder External Rotators: A Pilot Study, Timothy L. Uhl, Thomas Rice, Brianna M. Papotto, Timothy A. Butterfield

Physical Therapy Faculty Publications

Context: The role of the rotator cuff is to provide dynamic stability to the glenohumeral joint. Human and animal studies have identified sarcomerogenesis as an outcome of eccentric training indicated by more torque generation with the muscle in a lengthened position. Objective: The authors hypothesized that a home-based eccentric-exercise program could increase the shoulder external rotators’ eccentric strength at terminal internal rotation (IR). Design: Prospective case series. Setting: Clinical laboratory and home exercising. Participants: 10 healthy subjects (age 30 ± 10 y). Intervention: All participants performed 2 eccentric exercises targeting the posterior shoulder for 6 wk using a home-based intervention …

Reduced Skeletal Muscle Satellite Cell Number Alters Muscle Morphology After Chronic Stretch But Allows Limited Serial Sarcomere Addition, Matthew C. Kinney, Sudarshan Dayanidhi, Peter B. Dykstra, John J. Mccarthy, Charlotte A. Peterson, Richard L. Lieber

Physiology Faculty Publications

Introduction: Muscles add sarcomeres in response to stretch, presumably to maintain optimal sarcomere length. Clinical evidence from patients with cerebral palsy, who have both decreased serial sarcomere number and reduced satellite cells (SCs), suggests a hypothesis that SCs may be involved in sarcomere addition. Methods: A transgenic Pax7‐DTA mouse model underwent conditional SC depletion, and their soleii were then stretch‐immobilized to assess the capacity for sarcomere addition. Muscle architecture, morphology, and extracellular matrix (ECM) changes were also evaluated. Results: Mice in the SC‐reduced group achieved normal serial sarcomere addition in response to stretch. However, muscle fiber cross‐sectional …

Mice With Infectious Colitis Exhibit Linear Growth Failure And Subsequent Catch-Up Growth Related To Systemic Inflammation And Igf-1, Mark D. Deboer, Vidhya Vijayakumar, Meiqing Gong, John L. Fowlkes, Rachel M. Smith, Fernando Ruiz-Perez, James P. Nataro

Barnstable Brown Diabetes Center Faculty Publications

In developing communities, intestinal infection is associated with poor weight gain and linear-growth failure. Prior translational animal models have focused on weight gain investigations into key contributors to linear growth failure have been lacking. We hypothesized that murine intestinal infection with Citrobacter-rodentium would induce linear-growth failure associated with systemic inflammation and suppressed serum levels of insulin-like growth factor-1 (IGF-1). We evaluated 4 groups of mice infected or sham-infected on day-of-life 28: uninfected-controls, wild-type C.-rodentium-infected, partially-attenuated C. rodentium-infected (with deletion of 3 serine protease genes involved in colonization), and pair-fed (given the amount of daily food consumed by the …

Cattle In Kentucky, Dave Maples

Kentucky Journal of Equine, Agriculture, & Natural Resources Law Symposia

In this session, Dave Maples discussed the impact of cattle in Kentucky and why it is necessary to the Commonwealth.

Data Management And Metadata, Kathryn Lybarger

Research Data and Scholarly Communications Committee Workshops

Are you flooded with files? Drowning in data? Swimming in spreadsheets? Just add metadata! Doing research can generate a lot of data quickly, so quickly that it can easily get out of hand. Well-planned metadata can help you use, organize, search, share, and manage your data effectively! In this session, we'll review some standards and best practices for metadata, and then get some hands-on practice creating and using metadata for different types of data.

The presentation slides are available by clicking the Download button on the right.

Supporting materials for a workshop activity are listed as additional files below and …

Mechanisms Of Therapeutic Resistance In Prostate Cancer, Mary Nakazawa, Channing Paller, Natasha Kyprianou

Urology Faculty Publications

Prostate cancer is the second leading cause of cancer deaths in the USA. The challenge in managing castration-resistant prostate cancer (CRPC) stems not from the lack of therapeutic options but from the limited duration of clinical and survival benefit offered by treatments in this setting due to primary and acquired resistance. The remarkable molecular heterogeneity and tumor adaptability in advanced prostate cancer necessitate optimization of such treatment strategies. While the future of CRPC management will involve newer targeted therapies in deliberately biomarker-selected patients, interventions using current approaches may exhibit improved clinical benefit if employed in the context of optimal sequencing …

Dietary Risk Assessment Of V-Atpase A Dsrnas On Monarch Butterfly Larvae, Huipeng Pan, Xiaowei Yang, Keith Bidne, Richard L. Hellmich, Blair D. Siegfried, Xuguo Zhou

Entomology Faculty Publications

By suppressing the expression of genes with essential biological functions, in plantaRNAi can negatively affect the development and survival of target pests. As a part of a concerted effort to assess the risks of RNAi transgenic crops on non-target organisms, we developed an in vivo toxicity assay to examine the impacts of ingested dsRNAs incurred to the monarch butterfly, Danaus plexippus (L.), an iconic eco-indicator in North America. To create the worst case scenario, the full-length v-ATPase A cDNAs from the target pest, western corn rootworm, Diabrotica virgifera virgifera, and the non-target D. plexippus were respectively cloned. A …

Selecting Summer Annual Varieties Using Yield And Digestibility, Christopher D. Teutsch

Kentucky Alfalfa and Stored Forage Conference

Although cool-season grasses can provide ample and high quality forage for grazing livestock in the spring and fall, forage growth during the summer months is often restricted by high temperatures (Figure 1). In contrast warm-season annual grasses are most productive during the summer months and do not reach peak growth until temperatures approach 90 degrees Fahrenheit. Summer annual grasses such as forage sorghum (Sorghum bicolor (L.) Moench), sudangrass (Sorghum bicolor (L.) Moench), sorghum-sudangrass hybrids, and pearl millet (Pennisetum americanum (L.) Leeke) can provide high quality summer grazing for ruminant livestock in many regions of the United States.

The Economics Of Hay Quality, Madeline L. Dant, Kenneth H. Burdine, Brandon Sears

Kentucky Alfalfa and Stored Forage Conference

Hay quality is often discussed when one considers the viability of cash hay operations. A great deal is known about how production impacts quality and how quality impacts animal performance. This knowledge certainly has economic implications, but the economics of hay quality has primarily been evaluated from the animal performance perspective. Analyzing the economics of hay quality from the cash hay producer’s prospective becomes more difficult due to data limitations.

There are approximately 2.5 million acres of hay produced in Kentucky annually. The vast majority of this hay is grass type hay that is produced and fed on beef cattle …

Western Hay Production Vs. Eastern Hay Production, Tom Keene

Kentucky Alfalfa and Stored Forage Conference

Early in the history of mankind, man was nomadic and moved from location to location in order to gather and find sustenance for themselves as well as their livestock. At some point in time, man decided that rather than keep moving, they would establish a community in one location, usually near running water (or fresh water of some kind), and would begin to sustain themselves with production agricultural practices.

Planting and harvesting soon took the place of packing up and moving every time the current resources had been depleted. Each year a new crop would be planted; livestock also became …

Why Is Intake Reduced When Cattle Are Fed Tall Fescue?, James L. Klotz

Kentucky Alfalfa and Stored Forage Conference

A major problem for the cattle producer that utilizes tall fescue forage is the unrealized or reduced gains in body weight in growing animals. This result has been reproduced across numerous studies evaluating cattle performance on tall fescue (Hoveland et al., 1983; Boling, 1985; Schmidt et al., 1986; Goetsch et al., 1987). Cattle have gained from 30 to 100% less consuming toxic endophyte-infected tall fescue compared to consumption of an endophyte-free tall fescue (Paterson et al., 1995). This effect of reduced gain is a consequence of a fungal endophyte present within the grass that produces toxins called ergot alkaloids. Fungal …

Understanding And Improving Fermentation In Alfalfa And Grass Baleage, Dennis Hancock

Kentucky Alfalfa and Stored Forage Conference

The ancient Egyptian and Carthaginians are believed to be the first conserve forage by ensiling it in the absence of oxygen. Though the technique has been refined in the 3500 years since, the basic fermentation process has not changed. Populations of naturally-occurring bacteria on the plant surface can consume some of the readily available carbohydrates and produce organic acids. These organic acids lower the pH of the forage material and prevent fungal deterioration of the product. Fermentation has been used for millennia as a natural method for preserving food. Similar bacterial fermentation occurs when one makes yogurt, sour cream, or …

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 …

Hendra Virus Fusion Protein Transmembrane Domain Contributes To Pre-Fusion Protein Stability, Stacy Webb, Tamas Nagy, Hunter Moseley, Michael G. Fried, Rebecca Ellis Dutch

Molecular and Cellular Biochemistry Faculty Publications

Enveloped viruses utilize fusion (F) proteins studding the surface of the virus to facilitate membrane fusion with a target cell membrane. Fusion of the viral envelope with a cellular membrane is required for release of viral genomic material, so the virus can ultimately reproduce and spread. To drive fusion, the F protein undergoes an irreversible conformational change, transitioning from a metastable pre-fusion conformation to a more thermodynamically stable post-fusion structure. Understanding the elements that control stability of the pre-fusion state and triggering to the post-fusion conformation is important for understanding F protein function. Mutations in F protein transmembrane (TM) domains …

Dub3 Inhibition Suppresses Breast Cancer Invasion And Metastasis By Promoting Snail1 Degradation, Yadi Wu, Yu Wang, Yiwei Lin, Yajuan Liu, Yifan Wang, Jianhang Jia, Puja Singh, Young-In Chi, Chi Wang, Chenfang Dong, Wei Li, Min Tao, Dana L. Napier, Qiuying Shi, Jiong Deng, B. Mark Evers, Binhua P. Zhou

Pharmacology and Nutritional Sciences Faculty Publications

Snail1, a key transcription factor of epithelial–mesenchymal transition (EMT), is subjected to ubiquitination and degradation, but the mechanism by which Snail1 is stabilized in tumours remains unclear. We identify Dub3 as a bona fide Snail1 deubiquitinase, which interacts with and stabilizes Snail1. Dub3 is overexpressed in breast cancer; knockdown of Dub3 resulted in Snail1 destabilization, suppressed EMT and decreased tumour cell migration, invasion, and metastasis. These effects are rescued by ectopic Snail1 expression. IL-6 also stabilizes Snail1 by inducing Dub3 expression, the specific inhibitor WP1130 binds to Dub3 and inhibits the Dub3-mediating Snail1 stabilization in vitroand in vivo. …

Compounds Including Cox Inhibitor Moiety And Enhanced Delivery Of Active Drugs Using Same, Audra Stinchcomb, Kyung Bo Kim, Ragotham Reddy Pinninti, Priyanka Ghosh, Kalpana S. Paudel

Pharmaceutical Sciences Faculty Patents

The presently-disclosed subject matter includes compounds including a cyclooxygenase enzyme inhibitor moiety and a moiety derived from a drug of interest. In some embodiments, the drug of interest is an opioid. In some embodiments, the compound includes a diclofenac moiety and a naltrexone or naltrexol moiety. The compounds allow for enhanced delivery rates across skin.