Medical Pharmacology Commons^™

Kinase Signaling In Liver Disease Via Clinical-Trial-On-A-Pamchip: A Distinctive Methodology For Drug Mechanisms And Personalized Medicine, Zachary A. Kipp, Evelyn A. Bates, Genesee J. Martinez, Wang-Hsin Lee, Sally N. Pauss, Terry D. Hinds, Jr.

Pharmacology and Nutritional Sciences Faculty Publications

The utilization of extensive datasets, such as those generated by DNA or RNA sequencing, has become a central focus in drug discovery and personalized medicine (PerMed). Nonetheless, these datasets are constrained by the absence of protein-functionality testing, which affects physiological responses. In this study, we employed PamGene PamStation technology to quantify protein function by kinase activity across more than 500 signaling pathways from patients with hepatocellular carcinoma (HCC). Using proteins derived from nine patients and five human HCC cell lines for drug discovery and the clinical trial-on-a-chip approach, we developed comprehensive PerMed scores from the PamStation data to differentiate individual …

A Ubiquitous Organophosphate Flame Retardant Disrupts Energy And Glucose Homeostasis In Mice, Krystal M. Sewell, Kelly Oriakhi, Sara Y. Ngo Tenlep, Megan L. Weaver, Mansura Shahad Bawa, Se-Hyung Park, Shubh Saraswat, Xiaohua D. Zhang, Robert N. Helsley, Samir Softic, Cetewayo S. Rashid

Pharmacology and Nutritional Sciences Faculty Publications

Organophosphate flame retardants (OPFRs) are used in many consumer products, and their presence in our environment raises concerns about potential health dangers. In humans, exposure to OPFRs, such as tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is associated with metabolic disorders such as obesity, hyperglycemia, and insulin resistance. Our current study seeks to determine how TDCPP exposure affects body composition, glucose homeostasis, and energy balance in a rodent model. C57Bl/6 J mice were divided into two weight-matched groups and fed purified low phytoestrogen diets containing either 0.1 % DMSO (control) or TDCPP 415 mg/kg resulting in an approximate exposure of 50 mg/kg/day. Both male …

Contribution Of Metabolism-Independent Glucose Sensing To Metabolic Homeostasis, Nadia Rashid, Kavaljit H. Chhabra

Pharmacology and Nutritional Sciences Faculty Publications

Glucose sensing and signaling are central to cellular metabolic machinery for the regulation of metabolic homeostasis. Glucose sensing has been almost always assumed to be coupled with glucose metabolism; however, recent findings have unraveled metabolism-independent sensing mechanisms. Here, we discuss whether glucose transporters (GLUTs) and sodium-glucose co-transporters (SGLTs) may also function as glucose sensors independent of their roles in transporting glucose. Moreover, we review the emerging roles of G protein-coupled receptors (GPCRs) in sensing glucose and, consequently, initiating its signaling pathways in a cell-specific manner. Altogether, this review offers insights into the newly identified glucose sensing mechanisms and highlights the …

Anatomical Atlas Of Kinase Responsiveness To Weight Gain: Adipose Depot Reprogramming In Diet-Induced Adiposity, Wang-Hsin Lee, Zachary A. Kipp, Sally N. Pauss, Genesee J. Martinez, Mei Xu, Terry D. Hinds, Jr.

Pharmacology and Nutritional Sciences Faculty Publications

Background/Objectives: Adipose tissue depots located at different anatomical sites exert differential functions in response to adiposity and glucose intolerance. These fat depots exhibit distinct metabolic signaling patterns that may influence pathological fat accumulation, thereby affecting the efficacy of anti-obesity interventions. Nonetheless, the mechanisms underpinning depot-specific signaling and pathway responsiveness remain insufficiently understood.

Methods: Kinase activity was characterized during the progression of adiposity across five adipose tissue depots in obese versus lean mice using the advanced PamGene kinome technology. Furthermore, kinase pathways in human preadipocytes and mouse 3T3-L1 preadipocytes were analyzed and compared with those in their differentiated, mature adipocytes. The …

A Hard Problem: Managing Constipation In The Geriatric Population, William G. Jones, Veeraen Jonnalagadda, Alexandra E. Thomson, Victoria Grumbles, Chase Cottle, Christian Robertson, Maulikkumar Patel

HCA Healthcare Journal of Medicine

Constipation is a common condition among geriatric patients with different presenting symptoms and potential serious complications. Additionally, the condition causes a significant burden on our healthcare system. Here, we summarized recommendations from several societies, including the American College of Gastroenterology, American Geriatrics Society, and American Academy of Family Physicians to provide guidance on managing constipation with geriatric patients. Our aim was to emphasize the importance of prevention of constipation in this population and methods to do so. We also give recommendations on how to manage constipation when it does develop and how to manage it across different healthcare settings. These …

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 …

Advancing Clinical Trial Readiness In White Matter Disease And Related Dementias: Key Steps For Future Research Progress, Pradoldej Sompol, Gregory A. Jicha, Jason D. Hinman, Adam M. Brickman, Steven M. Greenberg, Konstantinos Arfanakis, Marion S. Buckwalter, Irene Lorenzo Llorente, Jeff D. Williamson, Michael S. Wolf, Eric E. Smith, Aditi Gupta, Margaret E. Flanagan, Miguel A. Vazquez, Jeffrey M. Burns, S. Thomas Carmichael, Frank C. Barone

Pharmacology and Nutritional Sciences Faculty Publications

White matter disease, a broad-spectrum term that covers various types of white matter lesions and degeneration, is strongly related to age-related neurodegenerative disorders including Alzheimer’s disease (AD), and vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer’s related dementias (ADRD). There is no specific treatment for white matter disease. Therefore, basic research and clinical studies are essential for future outcomes. Since its formation in 2020, the Albert Research Institute for White Matter and Cognition (ARIWMC) mission has been to support white matter research by providing a forum for communication where basic and clinical scientists meet to discuss and debate …

A Unique Inflammaging Profile Generated By T Cells From People With Obesity Is Metformin Resistant, S. Santacruz‑Calvo, S. Saraswat, Gabriella Kalantar, E. Zukowski, H. Marszalkowski, Aida Javidan, F. Gholamrezaeinejad, L. P. Bharath, P. A. Kern, X. D. Zhang, Barbara S. Nikolajczyk

Pharmacology and Nutritional Sciences Faculty Publications

The alarmingly high prevalence of obesity in older adults coupled with the negative health effects of chronic inflammation in both obesity and aging highlight the importance of studies investigating the impacts of obesity on age-related inflammation. Since shifts in peripheral T-cell metabolism and function drive systemic inflammation in both obesity and aging, we hypothesize that obesity impacts the Th17-dominated inflammaging profile we identified in lean subjects and thus modifies the anti-inflammatory effects of geroprotective drugs like metformin. New cytokine profiling data showed that CD4+ T cells from older people with obesity generate a profile that specifically excludes Th17 cytokines. Metformin …

Bilirubin Hepatic And Intestinal Transport And Catabolism: Physiology, Pathophysiology, And Benefits, Zachary A. Kipp, Sally N. Pauss, Genesee J. Martinez, Terry D. Hinds, Jr., Wang-Hsin Lee

Pharmacology and Nutritional Sciences Faculty Publications

Bilirubin, a metabolite derived from heme degradation, has traditionally been regarded as a waste product and a marker of liver injury. However, increasing evidence suggests that bilirubin also functions as a hormone, and reduced levels are associated with metabolic dysfunction. Studies have shown a strong association between low circulating bilirubin levels and an increased risk of metabolic disorders and cardiovascular disease. To advance bilirubin-based treatment strategies, it is essential to elucidate the mechanisms underlying bilirubin transport and metabolism. Therefore, we provide an in-depth discussion of bilirubin production and its subsequent fates, with a particular focus on the transport between the …

Cd47: An Immunoregulatory Nexus In Liver And Gastrointestinal Disorders, Josephine Otuagomah, Alana Newcomb, Taesik Gwag, Shuxia Wang

Pharmacology and Nutritional Sciences Faculty Publications

Cluster of differentiation 47 (CD47) is a widely expressed transmembrane protein that serves as a critical immunoregulatory checkpoint in both homeostatic and pathological conditions of the digestive system. It interacts with signal regulatory protein alpha to send a ‘do not eat me’ signal, thereby preventing phagocytosis and shaping immune responses. Beyond immunity, CD47 also influences cell death, growth and metabolism through interactions with integrins and thrombospondin-1. Recent studies implicate CD47 as a central nexus in the pathogenesis of diverse liver and gastrointestinal disorders, including metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, inflammatory bowel disease, liver ischaemia-reperfusion injury, drug-induced liver …

Gut Microbiome, Neuroinflammation, And Fetal Alcohol Spectrum Disorders: Insights From Rodent Models, Abdulrahman M. Busayli, Wenhua Xu, Ghaidaa A. Raffah, Gang Chen

Pharmacology and Nutritional Sciences Faculty Publications

Fetal alcohol spectrum disorder (FASD) is a significant public health issue that affects children. It results from ethanol exposure during pregnancy, leading to considerable physical, neurodevelopmental, behavioral, and cognitive deficits. The exact mechanism is not well understood. Recently, considerable attention has been focused on the influence of gut microbiome on brain development through the gut–brain axis. Changes in the gut microbiome resulting from ethanol exposure may contribute to the pathology of FASD, potentially involving neuroinflammation. This literature review summarizes the existing research and primary animal studies on the impact of early ethanol exposure on the gut microbiome, neuroinflammation, brain development, …

Calcineurin/Nfat Inhibitors Maintain Cognition In A Preclinical Prevention Study In An Aging Canine Model Of Alzheimer Disease, Lorena Sordo, Margo F. Ubele, Kathy Boaz, Jennifer L. Mefford, Erin Dehnart Jones, Katie L. Mccarty, Hollie Y. Van Rooyen, Jeffrey R. Smiley, Stasia A. Bembenek Bailey, Jessica A. Perpich, Beverly Meacham, David K. Powell, Frederick Bresch, Jacob W. Crump, Michael J. Phelan, Jessica A. Noche, Craig E. Stark, László G. Puskás, Christopher M. Norris, Elizabeth Head

Pharmacology and Nutritional Sciences Faculty Publications

Brain signaling of calcineurin (CN) and nuclear factor of activated T-cells (NFAT) transcription factor increases in Alzheimer disease (AD) and is associated with synaptic loss, neurodegeneration, neuroinflammation, amyloid-β (Aβ) production, and cognitive decline. CN/NFAT inhibitors ameliorate these neuropathologies in mouse models of AD. Further, chronic use of tacrolimus in transplant patients reduces risk of AD. Beagles naturally develop Aβ plaques and cognitive dysfunction. We evaluated the impact of FDA-approved CN inhibitor, tacrolimus, and experimental NFAT inhibitor, Q134R, on cognitive outcomes during a three-year prevention study in 37 middle-aged beagles. While beagles treated with CN/NFAT inhibitors showed differences in the pattern …

Curcumin Alleviates Inflammatory Effects Of Ketamine Anesthesia In Postnatal Rats, Soroush Afshar Ghahremani, Abbas Raisi, Sohrab Minaei Beirami, Houman Kahroba, Mahnaz Mardani, Omid Dezfoulian, Vahideh Tarhriz

School of Graduate Studies Faculty Publications

Curcumin has been employed in traditional medicine for over a millennium to treat various ailments, and its global use is now widespread. Chinese medicine relies heavily on curcumin as a primary element and uses it to cure infectious diseases, skin disorders, depression, and stress. It has cardioprotective, neuroprotective, and anti-diabetic properties, as well as pharmacological effects on disorders like type II diabetes, atherosclerosis, and human immunodeficiency virus replication. The anti-cancer activity of curcumin has been studied extensively with notable improvements in gastrointestinal, melanoma, urogenital, breast, and lung malignancies. We investigated the anti-inflammatory effects of curcumin on expression of tumor necrosis …

Adhesion G Protein-Coupled Receptor Latrophilin 1 (Adgrl1): A Novel Regulator Of Glucose And Energy Homeostasis., Kavaljit H Chhabra

Pharmacology and Nutritional Sciences Faculty Publications

No abstract provided.

Aggravated Ulcerative Colitis Via Circnlgn-Mediated Suppression Of Nuclear Actin Polymerization., William W Du, Chi Zhou, Hui Yang, Shuoyang Wen, Yu Chen, Eric X Chen, Xiuwei H. Yang, Feiya Li, Kevin Y Du, Hui Yuan, Ting Ye, Javeria Qadir, Burton B Yang

Pharmacology and Nutritional Sciences Faculty Publications

Colitis is a chronic bowel disease characterized by damage to the lining of the large intestine, with its precise underlying causes remaining incompletely understood. In this study, we provide evidence that circular RNA circNlgn plays a pivotal role in promoting the development of colitis. Colitis patients produce significant higher levels of circNlgn. Transgenic mice expressing circNlgn exhibit heightened susceptibility to colitis development and progression, primarily attributed to the presence of the protein isoform Nlgn173 encoded by circNlgn. Nlgn173 undergoes translocation into cell nuclei, where it interacts with actin, impeding the binding of actin-related protein 2 and 3 (Arp2/3) complex to …

Adgrl1 Is A Glucose Receptor Involved In Mediating Energy And Glucose Homeostasis, Kavaljit H Chhabra, Siresha Bathina, Tumininu S Faniyan, Dennis J Samuel, Muhammad Ummear Raza, Leticia Maria De Souza Cordeiro, Gonzalo Viana Di Prisco, Brady K Atwood, Jorge Robles, Lauren Bainbridge, Autumn Davis

Pharmacology and Nutritional Sciences Faculty Publications

AIMS/HYPOTHESIS: The brain is a major consumer of glucose as an energy source and regulates systemic glucose as well as energy balance. Although glucose transporters such as GLUT2 and sodium-glucose cotransporter 2 (SGLT2) are known to regulate glucose homeostasis and metabolism, the identity of a receptor that binds glucose to activate glucose signalling pathways in the brain is unknown. In this study, we aimed to discover a glucose receptor in the mouse hypothalamus.

METHODS: Here we used a high molecular mass glucose-biotin polymer to enrich glucose-bound mouse hypothalamic neurons through cell-based affinity chromatography. We then subjected the enriched neurons to …

Dietary Analysis For Hashimoto’S Thyroiditis: An Integrative Review, Evan Thompson, Alison Hultquist

Master of Science in Nursing Final Projects

Abstract

Hashimoto’s Thyroiditis (HT) is the leading cause of primary hypothyroidism in the United States. In HT, there is an infiltration by lymphocytes which leads to the production of autoantibodies against the thyroid gland. Throughout this integrative review, the aim was to evaluate the effectiveness of micronutrient supplementation and dietary management as adjunct treatments in HT. The purpose was to assist primary care providers in the development of a more holistic plan of care. Literature published within the past seven years was gathered and reviewed from PubMed, CINAHL, and Cochrane Library. Findings indicate that many patients with HT may benefit …

Tris(1,3-Dichloro-2-Propyl) Phosphate Is A Metabolism-Disrupting Chemical In Male Mice, Sara Y. Ngo Tenlep, Megan L. Weaver, Jianzhong Chen, Olga A. Vsevolozhskaya, Andrew J. Morris, Cetewayo S. Rashid

Pharmacology and Nutritional Sciences Faculty Publications

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is an organophosphate flame retardant. The primary TDCPP metabolite, bis(1,3-dichloro-2-propyl) phosphate (BDCPP), is detectable in the urine of over 90 % of Americans. Epidemiological studies show sex-specific associations between urinary BDCPP levels and metabolic syndrome, which is an established risk factor for type 2 diabetes, heart disease, and stroke. We used a mouse model to determine whether TDCPP exposure disrupts glucose homeostasis. Six-week old male and female C57BL/6J mice were given ad libitum access to diets containing vehicle (0.1 % DMSO) and TDCPP resulting in the following treatment groups: 0 mg/kg/day, 0.02 mg/kg/day, 1 mg/kg/day, or 100 …

Ethanol Exposure Up-Regulates Pd-L1/Pd-1 Immune Checkpoint Pathway And Promotes Mammary Tumor Development, Wenhua Xu, Linqing Wu, Mei Xu, Jia Luo, Gang Chen

Pharmacology and Nutritional Sciences Faculty Publications

Alcohol consumption in women enhances breast cancer incidence and ethanol is the main causal factor. Compromised host immunity through immunosuppression facilitates the development of many types of cancer, including breast cancer. Immune cells in breast tissues, particularly tumor-infiltrating CD8 cytotoxic T cells, play a critical role in the host anti-tumor immunity against breast tumorigenesis. These cytotoxic T cells are the major immune cells to carry out anti-tumor immunity through their cytotoxic effector function, which can be regulated by immune checkpoint pathways. The PD-1/PD-L1 pathway (the interaction between programmed death-1, PD-1, and its ligand, programmed deathligand 1, PD-L1) is the best …

Targeting Squalene Epoxidase Interrupts Homologous Recombination Via The Er Stress Response And Promotes Radiotherapy Efficacy, Zhipeng Hong, Tao Liu, Lingfeng Wan, Pengyan Fa, Pankaj Kumar, Yanan Cao, Chandra Bhushan Prasad, Zhaojun Qiu, Joseph Liu, Hongbing Wang, Zaibo Li, Qi-En Wang, Peixuan Guo, Deliang Guo, Ayse S. Yilmaz, Lanchun Lu, Ioanna Papandreou, Naduparambil K. Jacob, Chunhong Yan, Qing-Bai She

Pharmacology and Nutritional Sciences Faculty Publications

Over 50% of all patients with cancer are treated with radiotherapy. However, radiotherapy is often insufficient as a monotherapy and requires a nontoxic radiosensitizer. Squalene epoxidase (SQLE) controls cholesterol biosynthesis by converting squalene to 2,3-oxidosqualene. Given that SQLE is frequently overexpressed in human cancer, this study investigated the importance of SQLE in breast cancer and non–small cell lung cancer (NSCLC), two cancers often treated with radiotherapy. SQLE-positive IHC staining was observed in 68% of breast cancer and 56% of NSCLC specimens versus 15% and 25% in normal breast and lung tissue, respectively. Importantly, SQLE expression was an independent predictor of …

Adipose-Specific Pparα Knockout Mice Have Increased Lipogenesis By Pask–Srebp1 Signaling And A Polarity Shift To Inflammatory Macrophages In White Adipose Tissue, Terry D. Hinds, Jr., Zachary A. Kipp, Mei Xu, Frederique B. Yiannikouris, Andrew J. Morris, Donald F. Stec, Walter Wahli, David E. Stec

Pharmacology and Nutritional Sciences Faculty Publications

The nuclear receptor PPARα is associated with reducing adiposity, especially in the liver, where it transactivates genes for β-oxidation. Contrarily, the function of PPARα in extrahepatic tissues is less known. Therefore, we established the first adipose-specific PPARα knockout (Ppara^FatKO) mice to determine the signaling position of PPARα in adipose tissue expansion that occurs during the development of obesity. To assess the function of PPARα in adiposity, female and male mice were placed on a high-fat diet (HFD) or normal chow for 30 weeks. Only the male Ppara^FatKO animals had significantly more adiposity in the inguinal white …

The Crosstalk Between Insulin Resistance, Systemic Inflammation, Redox Imbalance And The Thyroid In Subjects With Obesity, Nicoleta Răcătăianu, Nicoleta Valentina Leach, Sorana D. Bolboacă, Maria Loredana Soran, Mirela Flonta, Ana Valea, Andrada-Luciana Lazăr, Cristina Ghervan

Journal of Mind and Medical Sciences

We aimed at assessing the interaction between visceral adipose tissue (VAT), insulin resistance (IR), circulating levels of monocyte chemoattractant protein-1 (MCP-1) and malondialdehyde (MDA) and the thyroid parameters in obese subjects. Methods. Obese subjects without thyroid pathologies or diseases associated with systemic inflammation and OS were recruited. Insulinemia, visceral fat thickness, metabolic and thyroid parameters were assayed. Circulating levels of MCP-1 and MDA were used to quantify inflammation and OS. Results. A number of 160 obese subjects were included. The MCP-1 level increased with the degree of obesity and HOMA-IR. MCP 1 was positively associated with antithyroperoxidase antibody (TPOab) levels …

Precision Nutrition And Advanced Culinary Medicine, Sara B. Police

Pharmacology and Nutritional Sciences Textbook Gallery

This electronic textbook (eBook) accompanies NS801, Precision Nutrition and Advanced Culinary Medicine, a 1-credit, 8-week online medical elective course for the University of Kentucky College of Medicine Office of Medical Education. The eBook provides module-based background information including text, tables, and figures to support each module of the online course:

1. Introduction
2. Culinary Challenges Preparation
3. Emerging Concepts in Precision Nutrition
4. Cardiovascular Disease & Nutritional Considerations
5. Neurological and Mental Health Disorders & Nutritional Considerations
6. Cancer & Nutritional Considerations
7. Gastrointestinal (GI) Health, Microbiome & Nutritional Considerations
8. Renal Conditions & Nutritional Considerations

As an open access textbook supported by the University of Kentucky Libraries …

Vitamin D Levels Affect Survival In A Bcr-Abl Acute Lymphoblastic Leukemia Mouse Model But Do Not Cause Vitamin-Drug Interactions, Kavya Annu

Theses and Dissertations (ETD)

It is a well-established phenomenon that dietary components containing CYP3A inducers or inhibitors if co-administered with drugs that are CYP3A4 substrates lead to marked drug-drug interactions. Because vitamin D is known to regulate intestinal CYP3A expression and gut CYP3A expression plays an important role in pre-systemic metabolism of CYP3A drugs, we determined the impact of vitamin D (VD3) status on systemic exposure and efficacy of chemotherapeutic agents that are CYP3A substrates. We employed VD3 sufficient and deficient mice to perform pharmacokinetics (PK) and anti-leukemic efficacy studies.

First, using hCYP3A4 transgenic mouse model we evaluated the intestinal, hepatic and renal expression …

Hypercholesterolemia Accelerates Both The Initiation And Progression Of Angiotensin Ii-Induced Abdominal Aortic Aneurysms, Jing Liu, Hisashi Sawada, Deborah A. Howatt, Jessica J. Moorleghen, Olga A. Vsevolozhskaya, Alan Daugherty, Hong S. Lu

Pharmacology and Nutritional Sciences Faculty Publications

Objective: This study determined whether hypercholesterolemia would contribute to both the initiation and progression of angiotensin (Ang)II-induced abdominal aortic aneurysms (AAAs) in mice.

Methods and Results: To determine whether hypercholesterolemia accelerates the initiation of AAAs, male low-density lipoprotein (LDL) receptor -/- mice were either fed one week of Western diet prior to starting AngII infusion or initiated Western diet one week after starting AngII infusion. During the first week of AngII infusion, mice fed normal diet had less luminal expansion of the suprarenal aorta compared to those initiated Western diet after the first week of AngII infusion. The two groups …

The Pharmabiotic For Phenylketonuria: Development Of A Novel Therapeutic, Chloé Elizabeth Lebegue

Senior Theses

Phenylketonuria, now known as phenylalanine hydroxylase (PAH) deficiency, is a genetic disorder of metabolism affecting approximately one in every 15,000 infants born in the United States. Patients have nonfunctional PAH enzyme secondary to one or more genetic mutations. The enzyme deficit results in destructive supraphysiologic blood phenylalanine levels upon consumption of the essential dietary amino acid phenylalanine. Current standards of care mitigate signs and symptoms of the disorder, but do not approach a cure. The methods for creating a prototype pharmabiotic as an innovative treatment strategy for PAH deficiency are described herein.

DNA molecular cloning techniques were utilized to engineer …

Saturated Fatty Acid Activates T Cell Inflammation Through A Nicotinamide Nucleotide Transhydrogenase (Nnt)-Dependent Mechanism, Grace Mccambridge, Madhur Agrawal, Alanna Keady, Philip A. Kern, Hatice Hasturk, Barbara S. Nikolajczyk, Leena P. Bharath

Pharmacology and Nutritional Sciences Faculty Publications

Circulating fatty acids (FAs) increase with obesity and can drive mitochondrial damage and inflammation. Nicotinamide nucleotide transhydrogenase (NNT) is a mitochondrial protein that positively regulates nicotinamide adenine dinucleotide phosphate (NADPH), a key mediator of energy transduction and redox homeostasis. The role that NNT-regulated bioenergetics play in the inflammatory response of immune cells in obesity is untested. Our objective was to determine how free fatty acids (FFAs) regulate inflammation through impacts on mitochondria and redox homeostasis of peripheral blood mononuclear cells (PBMCs). PBMCs from lean subjects were activated with a T cell-specific stimulus in the presence or absence of generally pro-inflammatory …

Dietary Polyunsaturated Fatty Acids Regulate Mammary Tumor Growth And Metastasis By Modulating Tissue Microenvironments, Saraswoti Khadge

Theses & Dissertations

Omega (ω)-6 and ω-3 polyunsaturated fatty acids (PUFAs) are essential fatty acids (FAs) and the precursors of pro- and anti-inflammatory mediators respectively. Epidemiological studies have shown a lower incidence of breast cancer (BC) in the countries where long-chain (LC)-ω-3FAs consumption is higher; however, the role of ω-3FAs in BC growth and metastasis is poorly understood. We used isocaloric, isolipidic ω-6 and ω-3 (contains LC-ω-3FAs) diets and a pair-fed model to evaluate the effects of dietary PUFAs in mammary tumor metastasis. Our studies have resulted in several novel observations including that dietary LC-ω-3FAs modulate mammary gland (MG) microenvironments in non-tumor bearing …

Isobavachalcone Sensitizes Cells To E2-Induced Paclitaxel Resistance By Down-Regulating Cd44 Expression In Er+ Breast Cancer Cells, Junfeng Shi, Yi Chen, Wenxing Chen, Cuiju Tang, Honghong Zhang, Yuetong Chen, Xiuwei H. Yang, Zhi Xu, Jingsun Wei, Jinfei Chen

Pharmacology and Nutritional Sciences Faculty Publications

Oestrogen receptor (ER) is expressed in approximately 60%‐70% of human breast cancer. Clinical trials and retrospective analyses have shown that ER‐positive (ER+) tumours are more tolerant to chemotherapeutic drug resistance than ER‐negative (ER−) tumours. In addition, isobavachalcone (IBC) is known as a kind of phytoestrogen with antitumour effect. However, the underlying mechanism of IBC in ER+ breast cancer needs to be elucidated further. Our in vitro experiments showed that IBC could attenuate 17β‐estradiol (E₂)‐induced paclitaxel resistance and that E₂ could stimulate CD44 expression in ER+ breast cancer cells but not in ER− cells. Meanwhile, E₂ could …

Myocyte [Na+]I Dysregulation In Heart Failure And Diabetic Cardiomyopathy, Sanda Despa

Pharmacology and Nutritional Sciences Faculty Publications

By controlling the function of various sarcolemmal and mitochondrial ion transporters, intracellular Na⁺ concentration ([Na⁺]_i) regulates Ca²⁺ cycling, electrical activity, the matching of energy supply and demand, and oxidative stress in cardiac myocytes. Thus, maintenance of myocyte Na⁺ homeostasis is vital for preserving the electrical and contractile activity of the heart. [Na⁺]_i is set by the balance between the passive Na⁺ entry through numerous pathways and the pumping of Na⁺ out of the cell by the Na⁺/K⁺-ATPase. This equilibrium is perturbed in heart failure, …