Chemicals and Drugs Commons^™

The Myopia Epidemic: Integrating Genetic, Environmental, And Epigenetic Pathways To Define A Critical Window For Intervention, Pranavika Balaji

Undergraduate Research Posters

Myopia, or nearsightedness, has increased rapidly worldwide and is now a major public health concern caused by both genetic and environmental factors. Current understanding shows that too much near work, limited time spent outdoors, and prolonged screen use contribute to abnormal eye growth in individuals who may already have a genetic predisposition. At the molecular level, epigenetic changes and shifts in DNA activity, often influenced by environmental conditions, affect the signaling pathways that regulate eye development and may help explain why myopia is increasingly common among children. This paper synthesizes recent environmental, genetic, and epigenetic research to explain how these …

The Weight Of Stigma, Rebekah A. King, Michael S. Sinha

All Faculty Scholarship

Many health care providers, both implicitly and explicitly, perpetuate stigma in their treatment of patients classified as obese. While medical professionals understand that a one-size-fits-all approach to treatment is ineffective, patients classified as obese are frequently offered limited treatment options that fail to account for their unique needs. Access to a range of effective treatment options has historically been limited, but new GLP-1 receptor agonist medicines like Wegovy (semaglutide) and Zepbound (tirzepatide), have shown incredible promise in addressing the obesity crisis. Unfortunately, these transformative drugs are costly, in high demand, and not widely covered by insurance, rendering them inaccessible for …

A Unified Automated And Explainable Ai Framework For Drug Discovery, Clinical Diagnostics, And Public Health Data Prediction, Lord Coffie

College of Graduate Studies: Theses & Dissertations

This thesis investigates the development of automated, explainable artificial intelligence systems to improve automated scientific discovery, clinical diagnostic support, and public health decision-making. Three independent yet thematically aligned studies were conducted across cheminformatics, radiology, and population health. Study A introduces an automated and explainable machine learning pipeline for Quantitative Structure–Activity Relationship (QSAR) modeling using RDKit-derived molecular descriptors. The pipeline performs systematic preprocessing, consensus-based feature selection (mutual information, random forest importance, RFECV), and benchmarks six supervised models—Random Forest, XGBoost, Support Vector Machine, Balanced Random Forest, EasyEnsembleClassifier, and a blended meta-ensemble, achieving AUC = 0.90 and accuracy = 0.83, while ensuring interpretability …

Partial Post-Exposure Protection By Topical Inserts Containing Tenofovir Alafenamide Fumarate/Elvitegravir In A Macaque Model Of Rectal Simian Hiv (Shiv) Infection, Natalia Makarova, Tyana Singletary, M. Melissa Peet, Kristen Kelley, Ryan Johnson, Vivek Agrahari, Maria Mendoza, Yi Pan, Walid Heneine, Meredith R. Clark, J. Gerardo García Lerma, Gustavo F. Doncel, James W. Smith

CONRAD Publications

On-demand topical inserts for HIV prevention may be a good option for people who have a low frequency of sexual activity. We recently demonstrated in a preclinical macaque model that rectal application of inserts containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) conferred protection against SHIV infection (93% efficacy) when applied as pre-exposure prophylaxis 4 hours before SHIV exposure. Here, we show that the same inserts provide significant postexposure protection (82.9% efficacy) when applied 4 hours after SHIV exposure. Our findings further support the ongoing clinical development of TAF/EVG inserts for on-demand HIV prevention.

Investigation Of Genx Exposure To Pathways Associated With Colorectal Cancer Risk, Emily J. Ferguson

Theses and Dissertations--Toxicology and Cancer Biology

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants widely detected in drinking water and food sources, resulting in chronic human exposure. Among these compounds, hexafluoropropylene oxide dimer acid (HFPO-DA), commonly known as GenX, has been introduced as a short-chain replacement for legacy PFAS such as perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Although GenX is believed to be a safer alternative, emerging research suggests it can still affect human health.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related death in the United States, highlighting the need to better understand environmental …

Estetrol (E4) For The Treatment Of Moderate To Severe Vasomotor Symptoms In Postmenopausal Women - Efficacy And Safety Results From The Phase 3 E4comfort I Multicenter, Placebo-Controlled Study, Tommaso Simoncini, Céline Bouchard, Marie Cloes, Mélanie Taziaux, Santiago Palacios, Sebastião Freitas De Medeiros, Valeriu Vrabii, David F. Archer, Nick Panay

Department of Obstetrics & Gynecology Faculty Publications

Objective

To evaluate the efficacy and safety of estetrol in reducing moderate to severe vasomotor symptoms in postmenopausal women.

Methods

Multicenter, randomized, parallel group (1:1:1), placebo-controlled, double-blind, phase 3 study in hysterectomized and non-hysterectomized participants aged 40-65 years. A total of 640 participants with seven or more moderate to severe hot flashes daily or 50 weekly received estetrol 15 mg, estetrol 20 mg, or placebo for 12 weeks. Co-primary endpoints were the change in frequency and severity of moderate to severe vasomotor symptoms from baseline to weeks 4 and 12. Comparisons versus placebo were made using a mixed-effects model for …

Cold-Sensitive Acral Hand Lesions, Avery H. Seward, Jocelyn H. Larocque

Department of Medicine Faculty Publications

[Case description] An otherwise healthy woman in her 60s presented with a 2-year history of a persistent, itchy, and tender rash on the dorsal hands. The rash fluctuated in severity with the seasons, worsening during the colder months. The patient denied joint pain and fatigue, or lesions elsewhere.

Examination revealed partially blanchable violaceous plaques on the dorsal hands with partial sparing of the proximal and distal interphalangeal joints (Fig 1). A few punctate, crusted erosions and purpuric macules were present on the dorsal and volar distal phalanges (Figs 2 and 3).

Antibody-Drug Conjugates Beyond Her2 In Non-Small Cell Lung Cancer (Nsclc): Mechanisms, Emerging Targets, And Future Directions, Ahmed Ismail, Akash Desai, George R. Simon, Yanis Boumber

Department of Medicine Faculty Publications

Antibody–drug conjugates (ADCs) are a rapidly evolving class of oncology therapeutics that enable precise delivery of potent cytotoxic agents to tumor cells while minimizing systemic toxicity. While HER2-targeted ADCs such as trastuzumab deruxtecan (T-DXd) in HER2-mutant, Datopotamab deruxtecan (Dato-Dxd) in EGFR-mutant, and telisotumumab vedotin (Teliso-V) in MET IHC 3+ expressing lung cancer have already established a clinical role in non-small cell lung cancer (NSCLC), multiple ADCs targeting alternative antigens, including additional TROP2 ADCs, HER3, MET, CEACAM5, B7-H3, Nectin-4, and others, are now in advanced clinical development. This review synthesizes the current evidence for non-HER2 ADCs in NSCLC, highlighting mechanisms of …

Effect Of Antipsychotic Medication Use And Type On Mortality And Cardiovascular Risks In Nursing Home Patients With Dementia, Hamid R. Okhravi, Fang Fang, Melissa P. Hunter, Brynn E. Sheehan

Glennan Center for Geriatrics and Gerontology Faculty Publications

Introduction

Antipsychotic medication (APM) use in nursing home (NH) patients with dementia is common but carries risks. This study assessed the association between APM use and mortality, stroke, and myocardial infarction (MI) compared to non-use, as well as differences between first- and second-generation APMs.

Methods

A serial cross-sectional study using Medicare data examined outcomes from 2012 to 2015 in a national sample of 328,138 US NH residents aged 50 and older with dementia. Multivariate logistic regressions were used to analyze risk.

Results

APM use was associated with increased mortality in all years (odds ratio [OR] range: 2.39 to 1.23, all …

Combination Therapy With Hsp90 Inhibitors And Nanopulse Stimulation Synergistically Impedes Hepatocellular Carcinoma And Breast Cancer Growth In Mice, Christiana Dimitropoulou, Gagan Thangjam, Brittany P. Lassiter, Teresa Hooker, Ruben M. L. Colunga Biancatelli, John D. Catravas, Stephen J. Beebe

Bioelectrics Publications

Nanopulse Stimulation (NPS) represents a promising and innovative therapeutic approach to cancer. Heat shock protein 90 Inhibitors (HI), on the other hand, are currently under investigation in multi-drug chemotherapy trials for various types of malignancies. Here we present results of a combination therapy employing two HSP90 inhibitors (AUY-922 or 17-AAG) and NPS to ablate cancer growth. We firstly tested the inhibitors alone or in combination with NPS in vitro in N1S1 cells, and then into two models of orthotopic Hepatocellular Carcinoma (HCC) and 4T1-Luc breast cancer. NPS + HI reduced tumor growth more than the sum of HI and NPS …

Skeletal Muscle Myofiber Development In Non-Human Primate Offspring Deprived Of Estrogen In Utero, Phillip J. Gauronskas, Terrie J. Lynch, Eugene D. Albrecht, Gerald J. Pepe

Department of Biomedical and Translational Sciences Faculty Publications

Introduction: We previously showed that baboon offspring born to mothers deprived of estrogen during the second half of gestation exhibited insulin resistance prior to and after the onset of puberty. Moreover, the size of skeletal muscle myofibers and the number of microvessels important for delivery of insulin/glucose to myofibers were lower in near-term fetuses deprived of estrogen during pregnancy, and myofiber capillarization remained reduced in post-pubertal offspring deprived of estrogen in utero. However, it remains to be determined whether skeletal muscle size is restored to normal in animals deprived of estrogen in utero after the onset of puberty/gonadal estrogen production. …

Hu308, A Selective Cannabinoid Type-2 Receptor Agonist, Mitigates Sars-Cov-2 Spike Protein-Induced Acute Lung Injury In Mice, Janette Lockett, Gregory Nicholson, Nicholas Richards, Ryan Washington, Nagaraja Nagre

Department of Biomedical and Translational Sciences Faculty Publications

Introduction

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to pose major health challenges despite effective vaccination efforts. The sustained occurrence of breakthrough infections and emerging variants of the virus highlights the need for additional therapeutic strategies. Given the anti-inflammatory role of the cannabinoid type 2 receptor (CB2R), we examined the effect of CB2R activation in SARS-CoV-2 spike protein subunit 1 (S1SP)-induced acute lung injury (ALI).

Methods

ALI was induced in mice by intratracheal (i.t.) administration of S1SP, followed by treatment with the CB2R agonist HU308 (5 mg/kg, intraperitoneal: i.p.) 1 h …

P38 Mapk Is Involved In Epigenetic Regulation Of Fibrotic Genes In Replication Induced Senescence In Lung Fibroblasts, Shan Zhu, Jennifer Q. Zhou, Kan Wang, Ming-Lei Guo, Yan Sanders

Department of Biomedical and Translational Sciences Faculty Publications

Fibroblast activation is essential for tissue repair following injury; however, prolonged activation drives pathological fibrosis. Idiopathic pulmonary fibrosis (IPF), a progressive and age-associated lung disease, is characterized by aberrant fibroblast activation, with increasing evidence implicating senescent and near-senescent fibroblasts in its pathogenesis. However, the underlying mechanisms remain poorly defined. In this study, we investigated whether histone modification is involved in TGF-β1 treated lung fibroblasts and contributes to the fibrotic phenotype. Human IMR90 lung fibroblasts at low and high population doubling levels (LPDL and HPDL), as well as primary IPF fibroblasts, were used in this study. In response to TGF-β1, both …

Localization And Functional Exploration Of Leiomodin-2'S C-Terminal Binding Sites, Mason D. Summers, Madison Little, Robert P. Young, Brayan Osegueda, Alan Palma Guillen, Garry E. Smith Jr., John R. Cart, Vitold E. Galkin, Alla S. Kostyukova

Department of Biomedical and Translational Sciences Faculty Publications

Striated muscle contraction occurs through interactions between overlapping myosin-based thick and actin-based thin filaments within the sarcomere. For effective contraction to occur, the length of the thin filament must be maintained to ensure sufficient overlap with the thick filament. The proteins leiomodin and tropomodulin compete for binding at the pointed ends of thin filaments to regulate their length, using their homologous N-terminal actin and tropomyosin binding sites. Leiomodin also contains a region called the C-terminal extension, absent in tropomodulin. In this region, the cardiac isoform (leiomodin-2) contains additional actin-binding sites that enable it to bind along the sides of thin …

Cervicovaginal Lavage Fluid Iron And Manganese Levels In Women With And Without Vaginitis, Barbara Kozma, David Ratonyi, Bence Kozma, Peter Takacs, Attila G. Sipos

Department of Obstetrics & Gynecology Faculty Publications

Transition metals such as iron and manganese are critical for cellular metabolism, redox balance, and immune function, and they also influence host–pathogen interactions. Vaginitis is characterized by mucosal inflammation that may alter local trace-element homeostasis. We hypothesize that inflammatory conditions such as vaginitis may be associated with altered cervicovaginal iron and manganese levels. We performed a prospective, single-center cohort study at the University of Debrecen (Hungary) between April 2023 and April 2024, enrolling 80 women ≥ 18 years with vulvovaginal complaints. Participants were assessed at baseline and at weeks 4, 8, and 12 with clinical evaluation and cervicovaginal lavage (CVL) …

Longitudinal Patterns Of Urinary Biomarkers Of Placental And Renal Function In Pregnancy And Associations With Early Pregnancy Exposure To Phthalates And Replacements, Erin E. Mcnell, Danielle R. Stevens, Barrett M. Welch, Suzanne Fenton, Antonia M. Calafat, Julianne Cook Botelho, Elena Sinkovskaya, Ann Przybylska, George Saade, Alfred Abuhamad, Kelly K. Ferguson

Department of Obstetrics & Gynecology Faculty Publications

Phthalates and replacements are endocrine-disrupting chemicals that may interfere with early pregnancy processes such as placentation and renal adaptation. Placental and renal biomarkers may help examine these toxicologic mechanisms. This study aims to characterize longitudinal changes in urinary protein biomarkers of placental angiogenesis (sFlt-1, PlGF, sEng) and renal function (KIM-1, NGAL, nephrin), and investigate associations with early pregnancy exposure to phthalates and replacements. Among 291 participants from the Human Placenta and Phthalates prospective cohort, urinary metabolites of eight phthalates and two replacements were quantified at up to 2 time points from 12 to 15 weeks gestation. Repeated measures were averaged …

Vaginal Pra1 Identifies Clinically Relevant Candida Albicans Vaginitis And Excludes Asymptomatic Colonization: An Exploratory Study, Elena Roselletti, Barbara Kozma, David Ratonyi, Alexandra Kunkli, Bence Kozma, Peter Takacs, Duncan Wilson

Department of Obstetrics & Gynecology Faculty Publications

Background

Accurate interpretation of Candida detection in women with vulvovaginal symptoms remains difficult, because organism recovery may reflect either clinically relevant infection or nonpathogenic colonization. We have recently demonstrated that the secreted fungal zinc-binding protein, Pra1 is responsible for driving the inflammatory immunopathology of VVC. We therefore reasoned that PRA1 expression by Candida albicans in the vagina may act as a diagnostic tool to discriminate between commensal colonisation and active disease.

Methods

We conducted a 12-week prospective, single-center exploratory biomarker analysis nested within a registered parent clinical trial. Nine women with vulvovaginal symptoms provided cervicovaginal lavage samples and clinical data …

Studies Towards Chemical Synthesis Of Homogeneous Prion Glycoprotein, Baotong Tian

Electronic Theses & Dissertations (2024 - present)

Prion diseases are fatal neurodegenerative disorders initiated by conformational misfolding of the prion protein (PrP), which generates pathogenic conformers that propagate via templated conversion and accumulate as aggregates. Glycosylation can modulate the PrP folding energy landscape, thereby biasing folding trajectories and the distribution of resulting conformational states. Bank vole PrP contains two N-linked glycosylation sites, and disentangling the contributions of site occupancy versus glycan structure requires homogeneous, site-defined glycoforms. In contrast, biosynthetic expression typically produces heterogeneous glycoform ensembles due to multistep Golgi processing, precluding independent control of glycan identity at each site. Here we report a chemical synthesis strategy of …

Photo And Spatial Control Of Rna Structures And Functions: Exploring Positional Effects And Photo-Responsiveness Of Azobenzene Modified Nucleotides, Jinxi Du

Electronic Theses & Dissertations (2024 - present)

RNA molecules perform many important biological functions by forming complex three-dimensional structures stabilized by base pairing, tertiary interactions, and metal ion coordination. Because RNA function depends strongly on its structure, methods that allow reversible control of RNA conformation and activity are important for understanding RNA behavior and for potential therapeutic applications. However, achieving reversible and site-specific control of RNA structure, especially at the single-nucleotide level, remains challenging. In this dissertation, I developed and applied azobenzene-modified nucleotides as a chemical tool to enable optical and spatial control of RNA structure and function.

The first part of this dissertation focuses on establishing …

Tezepelumab's Effects On Patient-Reported Symptoms In Severe Asthma, Overall And With History Of Comorbid Chronic Rhinosinusitis With Nasal Polyps (Crswnp), Njira L. Lugogo, Joseph K. Han, Anju T. Peters, Stella E. Lee, Monica Kraft, Mary Kay Margolis, Sonia F. Shenoy, Nicole Martin, Shradha Chandarana, Christopher S. Ambrose

Department of Otolaryngology (ENT) Faculty Publications

Background

Tezepelumab (an anti-thymic stromal lymphopoietin monoclonal antibody) treatment resulted in reduced exacerbations and improved sino-nasal symptoms and health-related quality of life in patients with severe uncontrolled asthma (SUA) and chronic rhinosinusitis with nasal polyps (CRSwNP) in the NAVIGATOR study.

Objective

To evaluate the effect of tezepelumab versus placebo on sleep disturbances, activity levels, and physical exertion tolerance in NAVIGATOR patients with SUA overall and in those with past medical history of comorbid CRSwNP.

Methods

Patients (12-80 years old) with SUA were randomized to receive tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. Patient responses to …

Glycomedicine: Unveiling The Paracentral Dogma, Wei Wang, Gordan Lauc

Research outputs 2022 to 2026

No abstract provided.

Intravenous Infusion Of Nicotinamide Adenine Dinucleotide (Nad+) Versus Nicotinamide Riboside (Nr): A Retrospective Tolerability Pilot Study In A Real-World Setting, Kirsten Reyna, Greer Heinzen, Nikita Patel, Marie Ritter, Alexandra Siojo, Henry Legere, Rachele Pojednic

Research outputs 2022 to 2026

Background: Nicotinamide adenine dinucleotide (NAD⁺) is a cofactor for NAD⁺-dependent enzymes that regulate DNA repair, cellular metabolism, and immune function. Supplementation with NAD⁺ and its precursors is commonly used to prevent age-related disease and extend healthspan. Commercial clinical and wellness settings increasingly provide intravenous (IV) NAD⁺ and nicotinamide riboside (NR) despite limited evaluation of safety and effectiveness. These considerations are important, as NAD⁺ and its precursors differ in reported side effects, cellular uptake, and metabolism. This study sought to compare commercially administered NAD⁺ IV and NR IV in humans by evaluating infusion …

Endothelin-1 In The Failing Fontan: Pathobiology, Precision Therapeutics, And Future Trial Design, Iman Maiza

Department of Pediatrics Faculty Publications

The Fontan circulation, devised as definitive palliation for single-ventricle congenital heart disease, imposes systemic venous hypertension, loss of pulmonary arterial pulsatility, and restricted preload reserve. These hemodynamic trade-offs progressively injure the pulmonary vasculature, liver, and lymphatic system, producing late morbidities including elevated pulmonary vascular resistance, Fontan-associated liver disease (FALD), protein-losing enteropathy, and arrhythmias. Endothelin-1 (ET-1), a potent vasoconstrictor and profibrotic mediator, plausibly unifies these complications. Mechanistic studies demonstrate ET-1 upregulation in failed Fontan lungs, activating PLC–Ca²⁺, RhoA/ROCK, and MAPK/ERK cascades to drive vasoconstriction and remodeling. In cirrhotic livers, ET-1 localizes to stellate cells, promoting contraction and fibrogenesis, mechanisms biologically relevant …

Bortezomib And Vorinostat In Combination With Mitoxantrone, Dexamethasone, And Pegasparaginase During Induction And Reinduction For Infants With Acute Lymphoblastic Leukaemia: A Multicentre Single-Arm Phase 1/2 Study, Tanja A. Gruber, Sima Jeha, Rebecca J. Deyell, Victor Lewis, Bill H. Chang, Eric J. Lowe, Jamie Frediani, Catherine Vezina, Bruno Michon, Michael Richards, Erin H. Breese, Thai-Hoa Tran, Norman Lacayo, Christine Bolen, Sunil Desai, Jennifer L. Pauley, Minxuan Huang, Emily Ashcraft, Cheng Cheng, Kirk R. Schultz, Linda Stork, Krysta Schlis, Van T. Huynh, Nathan Gossai, Yoav H. Messinger, Henrique Bittencourt, Terzah M. Horton, Uma Athale, Duncan Stearns, Deborah Schiff, Paul S. Gaynon

Department of Pediatrics Faculty Publications

Background: Acute lymphoblastic leukaemia in infants remains a therapeutic challenge. In preclinical studies we previously identified bortezomib and vorinostat as active agents against KMT2A rearranged (KMT2Ar) leukaemia. The aim of this study was to determine the tolerability of incorporating bortezomib and vorinostat into an acute lymphoblastic leukaemia-chemotherapy backbone for newly diagnosed infants with acute lymphoblastic leukaemia both with and without KMT2Ar.

Methods: In this single-arm phase 1/2 study conducted at 18 hospitals in the USA and Canada, we enrolled patients aged 1 year or younger at the time of diagnosis with newly diagnosed acute lymphoblastic leukaemia or undifferentiated leukaemia (with …

Inflammatory Co-Regulation Of Voltage-Gated Sodium Channels And Na,K-Atpase In Metastatic Breast Cancer, Steven D. Scahill, Kelly Jean Sherman, Dennis Paul

School of Graduate Studies Faculty Publications

Sodium regulation is a potentially major driver of cancer metastasis. Voltage-gated sodium channels (VGSCs) and Na,K-ATPase are sodium transporters that are upregulated in many advanced carcinomas and are implicated as metastatic drivers. However, little is known about what drives this overexpression, how these proteins influence metastatic behavior, or whether these complementary sodium transporters are co-regulated in cancer. Using sodium transporter regulation in healthy neurons as a model, the present study demonstrated that the inflammatory mediator tumor necrosis factor alpha (TNFα) affects the expression of VGSCs and Na,K-ATPase in an in vitro model of metastatic breast cancer. Acute TNFα challenge increased …

The Evolving Therapeutic Landscape Of Nanoscale Cancer Drug Delivery Systems: Future Perspectives, Nafeesa Qudsia Hanif, Bushra Arshad, Anila Fariq, Syed Imam Hussain Abidi, Sohail Ameer Marwat, Aneela Fatima

Journal of Bioresource Management

Cancer is one of the main causes of deaths in the world. Conventional cancer therapeutic approaches such as chemo- and radiotherapy have burdened the cancer patients with arduous physical and psychological challenges. Moreover, in case of onset of this disease, huge amount is required against the medications (chemotherapy and radiotherapy). It is estimated that annually, the increasing cancer disease incidence rate is alarming. In developed countries, the health support is given by the nation. Therefore, the health managements in the developed nations are over-burdened due to heavy expanses against expansive cancer therapy treatments. Interestingly, tumor treatments have undergone a comprehensive …

Isg15 Dysregulates Endoplasmic Reticulum-Mitochondrial Contacts And Calcium Homeostasis In Ataxia Telangiectasia, Oygul Mirzalieva, Ryan E. Reed, Arthur L. Haas, Meredith A. Juncker, Patrick Logarbo, Jennifer M. Klein, David Worthylake, Shyamal D. Desai

School of Graduate Studies Faculty Publications

Dysregulation of endoplasmic reticulum and mitochondrial (ER:Mit) contacts and mitochondrial calcium (mitCa2+) homeostasis are found in several neurodegenerative disorders, including Ataxia Telangiectasia (A-T). However, the cellular basis of these defects remains unclear. Previously, we demonstrated that the aberrantly elevated Interferon-Stimulated Gene 15 (ISG15) pathway inhibits protein polyubiquitylation, its dependent protein turnover, and mitophagy pathways in A-T. Literature indicates that silencing of mitochondrial ubiquitin ligase 1 (MUL1) stabilizes mitofusin2 (MFN2) and attenuates mitCa2+ uptake from ER to Mit (mitCa2+influx) in primary neurons. We have replicated these findings in apparently healthy fibroblasts. We hypothesized that elevated ISG15 may inhibit ubiquitin-dependent MUL1-mediated degradation …

Microglial Expression Of Serotonin Receptors Reveals Parallel Regulation Of 5-Ht2b And Bdnf In The Rat Hippocampus, Andrei Turkin, Maria Sidorova, Ekaterina Kurilova, Natalia Alenina, Oksana Tuchina, Friederike Klempin

School of Graduate Studies Faculty Publications

Growing evidence suggests that psychiatric disorders are characterized by a prolonged inflammatory state, which may influence the efficacy of compounds targeting serotonin. Serotonin is a key signaling molecule in neuroplasticity of the adult hippocampus and involved in antidepressant action. Recent in vitro studies indicate the neurotransmitter may also facilitate the response to inflammation and potentially modulate microglial function towards neuroprotection. Using Tph2−/− rats depleted of brain serotonin, we examined microglial expression of various serotonin receptors (5-HTRs) in vivo in both the hippocampus and prefrontal cortex and assessed mRNA levels of cytokines and brain-derived neurotrophic factor (BDNF). We observed age-dependent and …

Hepatocyte-Specific Lrp1 Silencing Exacerbates Brain Amyloidosis Without Compensatory Ldl Receptor Family Involvement, Brian Carson, Josephine Chu, Devaraj V. Chandrashekar, Jerome Garcia, Rachita K. Sumbria, Derick Han

Pharmacy Faculty Articles and Research

Background

LDL receptor related protein 1 (LRP1) is a major hepatic receptor involved in lipoprotein metabolism, protease degradation, transmembrane receptor modulation, and clearance of excess protein, such as Aβ. Decreased expression of LRP1 due to liver injury can impair receptor-mediated clearance, increasing Aβ availability in the periphery. We investigated the effects of hepato-specific silencing of LRP1 on Aβ deposition in the brain. Additionally, other LDL family members (LRP5, LRP6, and LDLR) that may participate in Aβ clearance were monitored in the liver to ensure non-compensatory effects of LRP1 silencing.

Method

4-month-old male double transgenic (APP/PS1) AD mice were injected with …

The Mitochondria Is The Source Of Hepatic Amyloid Precursor Protein And Peripheral Amyloid Beta: Implications Of Alcohol-Induced Liver Steatosis In Alzheimer's Disease, Josephine Chu, Ross A. Steinberg, Brian Carson, Devaraj Venkatapura Chandrashekar, Rachita K. Sumbria, Derick Han

Pharmacy Faculty Articles and Research

Background

Alcohol-induced liver injury occurs in the pericentral region of the liver and can induce mitochondrial remodeling and exacerbate Alzheimer's Disease (AD) progression. Subpopulations of mitochondria: general mitochondria (GM), peridroplet mitochondria (PDM) and endoplasmic reticulum(ER)-bound mitochondria (ERM) maintain cellular homeostasis via energy synthesis, lipid homeostasis, and regulation of intracellular calcium. Hepatic amyloid precursor protein (APP) is a source of peripheral amyloid beta (aB) and affects AD pathology in the brain. Understanding the localization and expression of hepatic APP in mitochondrial subpopulations are critical to understanding aB metabolism and may play a role in identifying a potential mechanism for metabolic dysfunction. …