Pharmacology, Toxicology and Environmental Health Commons^™

Sensitizing Keap1 Loss Non-Small Cell Lung Cancer To Artesunate Anti-Cancer Activity, Keng Hee Peh

Theses and Dissertations--Pharmacy

Lung cancer is the global leading cause of cancer related death. Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancer diagnoses conferring a significant disease burden. However, certain mutations in tumor suppressors such as Kelch-like ECH-associated protein 1 (KEAP1) confers resistance to standard of care therapy in NSCLC. KEAP1 is known to regulate multiple cellular processes such as oxidative stress response and anti-apoptotic pathways. Furthermore, KEAP1 loss of function in NSCLC is associated with poorer clinical outcomes and there are no currently approved therapies for KEAP1 loss NSCLC and represents an unmet clinical need. Artesunate (Art) demonstrated anti-cancer …

Abl1/2 And Ddr1 Cooperate To Stabilize Braf/Craf To Drive Erk1/2 Reactivation And Promote Mek Inhibitor Resistance In Nras-Mutant Melanomas, Anastasia Lyon

Theses and Dissertations--Pharmacology and Nutritional Sciences

This study addresses the escalating incidence of NRAS-mutant melanomas, a type of skin cancer lacking FDA-approved targeted therapies. Despite ongoing research targeting the RAF/MEK/ERK pathway, existing drugs fail to enhance progression-free survival due to acquired resistance. This project identifies a novel role for ABL1/2 and DDR1 kinases in driving drug resistance and proliferation of NRAS-mutant melanoma cells. ABL1/2 and DDR1 cooperate to promote RAF homodimerization and protein stability in order to reactivate MEK/ERK signaling to drive MEK1/2 inhibitor (MEKi) resistance and promote survival of resistant cells. By targeting ABL1/2 and DDR1 with nilotinib, a FDA-approved anti-leukemic inhibitor, we …

Emerging Chromatin Regulators In Response To Heavy Metal Exposure, Wesley Saintilnord

Theses and Dissertations--Molecular and Cellular Biochemistry

Environmental exposure to heavy metals poses significant threats to human health as they are associated with various developmental and chronic pathologies such as reproductive defects and cancers. Despite their profound risks, a comprehensive understanding of their disease-causing mechanisms is lacking. Most studies point to reactive oxygen species-induced DNA damage; however, their mutagenic potential is relatively weak suggesting the involvement of alternative mechanisms. One important, yet underexplored mechanism, is their ability to rewire the epigenome via DNA methylation and histone variant incorporation, leading to aberrant gene regulatory networks.

This study investigates the epigenetic mechanisms targeted by two ubiquitous heavy metals with …

Enhancing Translation: A Need To Leverage Complex Preclinical Models Of Addictive Drugs To Accelerate Substance Use Treatment Options, Christa Corley, Ashley Craig, Safiyah M. Sadek, Julie A. Marusich, Samar N. Chehimi, Ashley M. White, Lexi J. Holdiness, Benjamin C. Reiner, Cassandra D. Gipson

Markey Cancer Center Faculty Publications

Preclinical models of addictive drugs have been developed for decades to model aspects of the clinical experience in substance use disorders (SUDs). These include passive exposure as well as volitional intake models across addictive drugs and have been utilized to also measure withdrawal symptomatology and potential neuro- behavioral mechanisms underlying relapse to drug seeking or taking. There are a number of Food and Drug Administration (FDA)-approved medications for SUDs, however, many demonstrate low clinical efficacy as well as potential sex differences, and we also note gaps in the continuum of care for certain aspects of clinical ex- periences in individuals …

Impacts Of Xylazine On Fentanyl Demand, Body Weight, And Acute Withdrawal In Rats: A Comparison To Lofexidine, Safiyah M. Sadek, Shailesh N. Khatri, Zachary A. Kipp, Kelly E. Dunn, Joshua S. Beckmann, William W. Stoops, Terry D. Hinds, Jr., Cassandra D. Gipson

Markey Cancer Center Faculty Publications

The opioid use landscape has recently shifted to include xylazine, a veterinary anesthetic, as an adulterant in the fentanyl supply. The health impacts of xylazine as an emerging fentanyl adulterant has raised alarm regarding xylazine as a public health threat, warranting research on the impacts of xylazine on fentanyl’s behavioral effects. No prior studies have evaluated the effects of xylazine on fentanyl consumption at various unit doses, fentanyl demand, or withdrawal as compared to the Food and Drug Administration-approved opioid withdrawal medication, lofexidine (Lucemyra®). This is important because lofexidine and xylazine are both adrenergic α2a (A2aR) agonists, however, lofexidine is …

Oxycodone Withdrawal Is Associated With Increased Cocaine Self-Administration And Aberrant Accumbens Glutamate Plasticity In Rats, Shailesh N. Khatri, Hanaa Ulangkaya, Erin E. Maher, Safiyah M. Sadek, Mei Hong, Andrea M. Woodcox, William W. Stoops, Cassandra D. Gipson

Markey Cancer Center Faculty Publications

Individuals with opioid use disorder (OUD) frequently use other substances, including cocaine. Opioid with- drawal is associated with increased likelihood of cocaine use, which may represent an attempt to ameliorate opioid withdrawal effects. Clinically, 30% of co-using individuals take opioids and cocaine exclusively in a sequential manner. Preclinical studies evaluating mechanisms of drug use typically study drugs in isolation. However, polysubstance use is a highly prevalent clinical issue and thus, we established a novel preclinical model of sequential oxycodone and cocaine self-administration (SA) whereby rats acquired oxycodone and cocaine SA in an A-B-A-B design. Somatic signs of withdrawal were evaluated …

Perfluorooctanesulfonic Acid Exposure Leads To Downregulation Of 3-Hydroxy-3-Methylglutaryl-Coa Synthase 2 Expression And Upregulation Of Markers Associated With Intestinal Carcinogenesis In Mouse Intestinal Tissues, Josiane Weber Tessmann, Pan Deng, Jerika Durham, Chang Li, Moumita Banerjee, Qingding Wang, Ryan A. Goettl, Daheng He, Chi Wang, Eun Y. Lee, B. Mark Evers, Bernhard Hennig, Yekaterina Y. Zaytseva

Markey Cancer Center Faculty Publications

Perfluorooctanesulfonic acid (PFOS) is a widely recognized environment pollutant known for its high bio- accumulation potential and a long elimination half-life. Several studies have shown that PFOS can alter multiple biological pathways and negatively affect human health. Considering the direct exposure to the gastrointestinal (GI) tract to environmental pollutants, PFOS can potentially disrupt intestinal homeostasis. However, there is limited knowledge about the effect of PFOS exposure on normal intestinal tissues, and its contribution to GI- associated diseases remains to be determined. In this study, we examined the effect of PFOS exposure on the gene expression profile of intestinal tissues of …

Interactions Between Multiple Stressors, Nanomaterials And A Pathogen, In Caenorhabditis Elegans, Jarad Cochran

Theses and Dissertations--Plant and Soil Sciences

Metal and metal oxide nanoparticles (NP), which have received interest for use in agriculture, show in vitro and in vivo toxicity at relatively low concentrations. Silver nanoparticles (Ag NP) and zinc oxide nanoparticles (ZnO NP) cause adverse effects in model soil organisms under environmentally relevant conditions. In most toxicity assessments of nanomaterials, model organisms are exposed to a single stressor. Though single stressor experiments are essential to understanding the fate and effects of released NP, in nature, organisms are affected by multiple stressors, including pathogens, which might exacerbate or mitigate negative effects of NP exposure. There is limited research on …

Synthetic Contraceptive Hormones Occlude The Ability Of Nicotine To Reduce Ethanol Consumption In Ovary-Intact Female Rats, Erin E. Maher, Ashley M. White, Ashley Craig, Shailesh N. Khatri, Percell T. Kendrick Jr., Mary E. Matocha, Emma O. Bondy, Nikhil Pallem, Grace W. Breakfield, Madison Botkins, Olivia Sweatt, William C. Griffin, Brent A. Kaplan, Jessica Jane Weafer, Joshua S. Beckmann, Cassandra D. Gipson

Markey Cancer Center Faculty Publications

Rates of tobacco and alcohol use in women are rising, and women are more vulnerable than men to escalating tobacco and alcohol use. Many women use hormonal birth control, with the oral contraceptive pill being the most prevalent. Oral contraceptives contain both a progestin (synthetic progesterone) and a synthetic estrogen (ethinyl estradiol; EE) and are contraindicated for women over 35 years who smoke. Despite this, no studies have examined how synthetic contraceptive hormones impact this pattern of polysubstance use in females. To address this critical gap in the field, we treated ovary-intact female rats with either sesame oil (vehicle), the …

Adipocyte-Derived Pxr Signaling Is Dispensable For Diet-Induced Obesity And Metabolic Disorders In Mices, Fang Wang, Jinwei Liu, Rebecca Hernandez, Se-Hyung Park, Ying-Jing Lai, Shuxia Wang, Bruce Blumberg, Changcheng Zhou

UK CARES Faculty Publications

Pregnane X receptor (PXR) is a xenobiotic receptor that can be activated by numerous chemicals including endogenous hormones, dietary steroids, pharmaceutical agents, and environmental chemicals. PXR has been established to function as a xenobiotic sensor to coordinately regulate xenobiotic metabolism by regulating the expression of many enzymes and transporters required for xenobiotic metabolism. Recent studies have implicated a potentially important role for PXR in obesity and metabolic disease beyond xenobiotic metabolism, but how PXR action in different tissues or cell types contributes to obesity and metabolic disorders remains elusive. To investigate the role of adipocyte PXR in obesity, we generated …

New Insights On The Differential Interaction Of Sulfiredoxin With Members Of The Peroxiredoxin Family Revealed By Protein-Protein Docking And Experimental Studies, Murli Mishra, Hong Jiang, Qiou Wei

Markey Cancer Center Faculty Publications

Sulfiredoxin (Srx) is the enzyme that restores the peroxidase activity of peroxiredoxins (Prxs) through catalyzing the reduction of hyperoxidized Prxs back to their active forms. This process involves protein-protein interaction in an enzyme-substrate binding manner. The integrity of the Srx-Prx axis contributes to the pathogenesis of various oxidative stress related human disorders including cancer, inflammation, cardiovascular and neurological diseases. The purpose of this study is to understand the structural and molecular biology of the Srx-Prx interaction, which may be of significance for prediction of target site for the novel drug-discovery. Homology modeling and protein-protein docking approaches were applied to examine …

Self-Reported Consumption Of Bottled Water V. Tap Water In Appalachian And Non-Appalachian Kentucky, Jason W. Marion

Journal of Appalachian Health

Introduction: Quantitative studies on drinking water perceptions in Appalachia are limited. High-profile water infrastructure failures in the U.S. and Eastern Kentucky, coupled with human-made and natural disasters in the Appalachian Region, have likely impacted opinions regarding tap water.

Purpose: To use existing unexplored data to describe baseline tap water v. bottled water consumption in Kentucky.

Methods: Telephone-based cross-sectional data were obtained from the 2013 Kentucky Health Issues Poll (KHIP) directed by the Foundation for a Healthy Kentucky. Among many items in KHIP, self-reported consumption of bottled water over tap water, reasons for bottled water use, and demographic data were obtained. …

Pcb126 Exposure During Pregnancy Alters Maternal And Fetal Gene Expression, Cetewayo S. Rashid, Joshua D. Preston, Sara Y. Ngo Tenlep, Marissa K. Cook, Eric M. Blalock, Changcheng Zhou, Hollie I. Swanson, Kevin J. Pearson

Markey Cancer Center Faculty Publications

Polychlorinated biphenyls (PCBs) are organic pollutants that can have lasting impacts on offspring health. Here, we sought to examine maternal and fetal gene expression differences of aryl hydrocarbon receptor (AHR)- regulated genes in a mouse model of prenatal PCB126 exposure. Female mice were bred and gavaged with 1 μmole/kg bodyweight PCB126 or vehicle control on embryonic days 0 and 14, and maternal and fetal tissues were collected on embryonic day 18.5. Total RNAs were isolated, and gene expression levels were analyzed in both maternal and fetal tissues using the NanoString nCounter system. Interestingly, we found that the expression levels of …

Lung And Colorectal Cancer Disparities In Appalachian Kentucky: Spatial Analysis On The Influence Of Education And Literacy, Nicole Robertson Mph, Todd Burus, Lauren Hudson, Pamela C. Hull, Lee Park, Nathan L. Vanderford

Markey Cancer Center Faculty Publications

Low educational attainment and high cancer incidence and mortality rates have long been a challenge in Appalachian Kentucky. Prior studies have reported disparities in cancer incidence and mortality between Appalachian and non-Appalachian populations, but the influence of education on this disparity has not been extensively studied. Herein, all cancers and two cancer sites with available screenings (colorectal and lung) were joined with education indicators (educational attainment and literacy) and one geographic indicator across all 120 Kentucky counties. This dataset was used to build choropleth maps and perform simple linear and spatial regression to assess statistical significance and to measure the …

Maternal Polychlorinated Biphenyl 126 (Pcb 126) Exposure Modulates Offspring Gut Microbiota Irrespective Of Diet And Exercise, Manisha Agarwal, Jessie Hoffman, Sara Y. Ngo Tenlep, Sara Santarossa, Kevin J. Pearson, Alexandra R. Sitarik, Andrea E. Cassidy-Bushrow, Michael C. Petriello

Markey Cancer Center Faculty Publications

The gut microbiota plays an important role throughout the lifespan in maintaining host health, and several factors can modulate microbiota composition including diet, exercise, and environmental exposures. Maternal microbiota is transferred to offspring during early life; thus, environmental exposures before gestation may also modulate offspring microbiota. Here we aimed to investigate the effects of maternal exposure to dioxin-like polychlorinated biphenyls (PCBs) on the microbiota of aged offspring and to determine if lifestyle factors, including maternal exercise or offspring high-fat feeding alter these associations. To test this, dams were exposed to PCB 126 (0.5 μmole/kg body weight) or vehicle oil by …

The Kappa Opioid Receptor Agonist 16-Bromo Salvinorin A Has Anti-Cocaine Effects Without Significant Effects On Locomotion, Food Reward, Learning And Memory, Or Anxiety And Depressive-Like Behaviors, Ross Van De Wetering, Amy Ewald, Susan Welsh, Lindsay Kornberger, Samuel E. Williamson, Bryan D. Mcelroy, Eduardo R. Butelman, Thomas E. Prisinzano, Bronwyn M. Kivell

Markey Cancer Center Faculty Publications

Kappa opioid receptor (KOR) agonists have preclinical antipsychostimulant effects; however, adverse side effects have limited their therapeutic development. In this preclinical study, conducted in Sprague Dawley rats, B6-SJL mice, and non-human primates (NHPs), we evaluated the G-protein-biased analogue of salvinorin A (SalA), 16-bromo salvinorin A (16-BrSalA), for its anticocaine effects, side effects, and activation of cellular signaling pathways. 16-BrSalA dose-dependently decreased the cocaine-primed reinstatement of drug-seeking behavior in a KOR-dependent manner. It also decreased cocaine-induced hyperactivity, but had no effect on responding for cocaine on a progressive ratio schedule. Compared to SalA, 16-BrSalA had an improved side effect profile, with …

Validation Of Monitoring Septic Thymus Involution In Mice Using Ultrasound., Jianyao Xue, Xiang-An Li

Journal of Pharmacology & Nutritional Sciences

Sepsis is a dangerous condition commonly seen in the intensive care unit (ICU) of hospitals. It causes the thymus, a crucial immune organ, to shrink. This process is known as thymus involution. Although thymus involution is a natural process that occurs as we age, it is accelerated during sepsis. This process is associated with poor outcomes in septic patients, yet it had never been studied using ultrasonography in a septic mouse model. Researchers from the University of Kentucky have validated a non-invasive ultrasound imaging approach to monitor septic thymus involution in a cecum ligation and puncture (CLP) sepsis mouse model. …

The Last Of Us In Therapy: How Mind-Controlling Fungi And Gut Bacteria Affect Your Mental Health, Anastasia Lyon

Journal of Pharmacology & Nutritional Sciences

The "psilocybiome" represents the mutually beneficial relationship between ourselves, our bacteria, and psychedelic drugs. This short review briefly discusses the benefits and limitations surrounding the potential for psychedelic therapy to synergize with gut bacteria to help regulate and maintain proper balance in the immune system, diet, and stress levels. Psychedelic therapy is a novel treatment strategy that has the potential to improve patient mental health, and, by identifying the types of gut bacteria present in patients, it can aid in personalizing medicine by determining how well their "psilocybiome" may respond.

(Pro)Renin Receptor And Its Soluble Form In Metabolic Dysfunction: Friend Or Foe?, Gertrude Arthur

Journal of Pharmacology & Nutritional Sciences

(Pro)renin receptor is component of the renin angiotensin system which has been shown to be involved in several physiological and pathophysiological processes including blood pressure regulation and hypertension, water and electrolyte balance, kidney injury, obesity, and metabolic dysfunction. Enzymatic cleavage of prorenin receptor produces soluble prorenin receptor which can also activate the renin angiotensin system stimulate similar pathophysiological process like its full form receptor. This review explores findings on the role of prorenin receptor and soluble prorenin receptor in metabolic dysfunction and discusses the conflicting findings on soluble prorenin receptor in metabolic dysfunction.

Effect Of Lifestyle-Based Lipid Lowering Interventions On The Relationship Between Circulating Levels Of Per-And Polyfluoroalkyl Substances And Serum Cholesterol, Stephanie Morgan, M. Abdul Mottaleb, Maria P. Kraemer, Debra K. Moser, Jessica Worley, Andrew J. Morris, Michael C. Petriello

UK CARES Faculty Publications

Exposure to certain per-and polyfluoroalkyl substances (PFAS) has been shown to be positively associated with total and/or low-density lipoprotein cholesterol. Examining this association in lipid lowering interventions may provide additional evidence linking PFAS to cardiovascular risk. We examined the relationship of 6 PFAS with cholesterol in a 6-month lifestyle-based intervention. We quantitated PFAS in 350 individuals at baseline and post intervention and examined associations of PFAS with cholesterol before and after intervention. Food frequency questionnaires and GIS analyses were used to investigate PFAS hotspots and possible exposure routes. Cholesterol significantly decreased following intervention and in parallel, PFOS, PFOA, PFHxS, and …

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 …

Effects Of Elevated Extracellular Dopamine On Astrocytes In The Nucleus Accumbens, Mengfan Xia

Theses and Dissertations--Pharmacology and Nutritional Sciences

Nucleus accumbens is involved in processing of motivational and affective behaviors and plays a significant role in development and maintenance of substance use. Released from the ventral tegmental area into the nucleus accumbens, the mesolimbic dopamine controls incentive salience and facilitates learning of reinforcement and reward-related motor functions. Recent studies reveal that, in the context of cocaine exposure, dopamine transmission in the ventromedial striatum is pivotal to the regulation of initial drug use. Astrocytes, a major subpopulation of the brain glial cells, are an active component of the so-called tripartite synapse and communicate with neurons through the release of transmitters …

Beyond Mitosis, Plk1-Mediated Phosphorylation Re-Wires Cancer Metabolism And Promotes Cancer Progression, Qiongsi Zhang

Theses and Dissertations--Toxicology and Cancer Biology

Polo-like kinase 1 (PLK1) is a well- characterized regulator of cell division and is known to be highly expressed in certain types of tumors. It has been demonstrated the multifaceted roles of PLK1 in regulation of transcription, translation, epigenetics, DNA damage and cellular metabolism et al. Despite these findings, the precise mechanisms by which PLK1 regulates these processes beyond mitosis remain unclear. PLK1-mediated phosphorylation and misregulation of its substrates has been linked to tumorigenesis, cancer progression, drug resistance and worse prognosis. In this study, we investigated the non-canonical functions of PLK1 in cancer metabolism and drug resistance. We found that …

Nutritional & Colorectal Health, Tariq A. Alam, Brittany R. Rice, Sara B. Police

Journal of Pharmacology & Nutritional Sciences

Kentucky has the highest incidence and mortality rate of all site cancers, and Kentuckians residing in the Appalachian region often have worse outcomes, where cancer is a leading cause of death. Focusing on colorectal cancer (CRC) specifically, Kentucky ranks first nationwide for incidence (50 cases per 100,000 people) and fifth for mortality (about 17 deaths per 100,000 people). The Kentucky Colon Cancer Screening Program increased screening rates and reduced mortality since its launch. Yet, CRC remains a leading cause of death for Kentuckians. Risk factors for CRC include increasing age as well as a history of inflammatory bowel disease (IBD) …

Effectiveness Of A Long-Acting Cocaine Hydrolase In Metabolizing Cocaine And Its Physiologically Active Metabolites, Linyue Shang

Theses and Dissertations--Pharmacy

Cocaine is a widely abused, hepatotoxic drug without an FDA-approved pharmacotherapy specific for cocaine addiction or overdose. Cocaine-induced toxicity in animals and humans is due to its multiple physiological effects on the central nervous system, cardiovascular system, etc. The toxicity of cocaine is highly complex, as its metabolites also contribute to the toxicity. Notably, the combination of cocaine and alcohol is common among drug users and can produce additional metabolites. Some of the metabolites are more toxic than cocaine itself. Hence, to develop an ideal therapeutic candidate, the candidate should not only account for cocaine but should also detoxify other …

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 …

Chemical Immobilization Of Helicopter-Captured Elk (Cervus Canadensis) And Survival Of Elk Calves In Southeastern Kentucky, Kathleen E. Williams

Theses and Dissertations--Forestry and Natural Resources

Safe and effective chemical immobilization is critical to minimize stress and risk of injury when capturing free-ranging, wild ungulates. Many traditionally favored high potency opioids have been phased out or become unavailable because of increased regulations, leading to the development of two pre-mixed combination drugs, butorphanol-azaperone-medetomidine (BAM) and nalbuphine-medetomidine-azaperone (NalMed-A). Both drugs have been used to chemically immobilize ungulates, but their efficacy has not been documented in elk captured and transported via helicopter. During 2020 – 2022, we chemically immobilized helicopter-captured female elk (Cervus canadensis) with a single IM-injection of BAM (n = 41) or NalMed-A (n = …

Xylazine Suppresses Fentanyl Consumption During Self-Administration And Induces A Unique Sex-Specific Withdrawal Syndrome That Is Not Altered By Naloxone In Rats, Shailesh N. Khatri, Safiyah M. Sadek, Percell T. Kendrick, Emma O. Bondy, Mei Hong, Sally Pauss, Dan Luo, Thomas E. Prisinzano, Kelly E. Dunn, Julie A. Marusich, Joshua S. Beckmann, Terry D. Hinds Jr., Cassandra D. Gipson

Markey Cancer Center Faculty Publications

Prescription and illicit opioid use are a public health crisis, with the landscape shifting to fentanyl use. Since fentanyl is 100-fold more potent than morphine, its use is associated with a higher risk of fatal overdose that can be remediated through naloxone (Narcan) administration. However, recent reports indicate that xylazine, an anesthetic, is increasingly detected in accidental fentanyl overdose deaths. Anecdotal reports suggest that xylazine may prolong the fentanyl “high,” alter the onset of fentanyl withdrawal, and increase resistance to naloxone-induced reversal of overdose. To date, no preclinical studies have evaluated the impacts of xylazine on fentanyl self-administration (SA; 2.5 …

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 …