Medical Biochemistry Commons^™

Phytochemical And In-Vitro Cytotoxic Analyses Of Flavonoid Species Isolated From Chromolaena Leivensis, Luke A. Bryant

Electronic Theses and Dissertations

As a leading cause of death worldwide, cancer and its treatments remain a primary source of interest among researchers. Modern studies are looking into bioselective cytotoxicity to create new chemotherapies that do not have the same harsh side effects as those we use today. Natural product research has a promising future for the development of such treatments. Specifically, polar flavonoids may be the key to a bioselective treatment. Such flavonoid species are native to plants, often within flower petals or within the body. A natural antioxidant, they are designed not to harm healthy cells. This study focuses on the plant …

Exploration Of A Relationship Between The Activities Of Trail And 4’-Trifluoromethoxychalcone., Abigail C. Ernst

Undergraduate Theses

Cancer is the overgrowth of dysregulated or mutated cells that affects 1 in 3 Americans. Chalcones are natural products with many possible derivatives, such as 4’-trifluromethoxychalcone (4TF), developed in Dr. Krzysiak’s lab, which exhibit anticancer activity against cancer cell lines. Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) is a tumor surveillance cytokine that acts on two receptor types: death receptors and decoy receptors. One way cancer cells can become resistant to TRAIL is by upregulating decoy receptors and/or downregulating death receptors. In this study, MTS assays evaluated the potential relationship between TRAIL and 4TF that sensitizes A549 cells to TRAIL. The …

Relationships Between Clinical Symptom Scales And Eeg Biomarkers In Oud Patients, Jess Delange, Benjamin M. Latey, John Glinski, Braden Ashcraft, Jasmine Pannu, Cassidy Beatty, Lauren Knudson, Benjamin Chafetz, Bryan Fugal, Patrick Tanner Brain, N P. Griffin, Christopher Gowans, Amanda Brandaris, Amanda Page, Blake D. Harris, Sophia Delgado, Lorissa Thorpe, Kyle Bills, Andrew Payne

Annual Research Symposium

This poster examines the relationship between clinical symptom scales and electroencephalographic (EEG) biomarkers in patients with Opioid Use Disorder (OUD). Participants from inpatient substance use treatment facilities completed validated mental health and withdrawal assessments, including the COWS, PHQ-9, HAM-A, and ASRS followed by cognitive testing while undergoing 19-lead EEG recording.

Preliminary findings indicate that synthetic opioid use is associated with prolonged P300 response latency across brain regions, suggesting measurable neurophysiologic differences tied to substance type and addiction severity. The study explores how EEG metrics may complement subjective symptom reporting to provide more objective markers of addiction status, co-morbid psychiatric burden, …

Engineering Enac Constructs To Examine Pip2 And Ubiquitin Competition On Enac Regulation And Stability, Lacie Johnson

Chemistry & Biochemistry Undergraduate Honors Theses

The epithelial sodium channel (ENaC) plays a critical role in sodium homeostasis, fluid balance, and blood pressure regulation. ENaC activity is tightly controlled by post-translational mechanisms, including ubiquitination-mediated degradation and phosphatidylinositol 4,5-bisphosphate (PIP2) dependent channel activation. PIP2 is a phospholipid necessary to facilitate the maximal channel opening. Previous studies suggest that intracellular PIP2 binding sites are located in proximity to ubiquitination sites on ENaC subunits, raising the possibility of PIP2 binding to influence channel stability and function. This thesis aimed to engineer and validate molecular tools capable of examining the interplay between PIP2 binding and ubiquitination in ENaC regulation. A …

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 …

Influence And Excess: A Study Of Alcohol’S Governmental, Societal, Biochemical, And Enzymatic Impact In The U.S And Other Countries Around The World, Thomas W. Snider

Senior Honors Theses

The conduct of the thesis is to explore the intricacies of alcohol consumption. The thesis will outline the history of alcohol and the societal pressures and conduct of drinking with relation to the government. After the history of alcohol has been defined, the thesis will move into the chemistry portion, delineating the absorption, digestion, metabolism, and excretion of alcohol. This is the portion of the thesis that will contain the quantitative data and source material as much research has already been conducted regarding these components of alcohol consumption. The condition of the research is that the data will be collected …

The Non-Coding Rna Journal Club: Highlights On Recent Papers-14, El Cheima Mhamedi, Florent Hubé, Suresh K. Alahari, Francisco J. Enguita, Barbara Pardini, Mark W. Feinberg, Laura Poliseno, Beshoy Armanios, Jing Jin, Xiao-Bo Zhong, Nikolaos Sideris, Salih Bayraktar, Leandro Castellano, Gaetano Santulli, Stanislovas S. Jankauskas, Will S. Plewa, Simon J. Conn, Ling Yang, Patrick K. Shiu, Abhishek Kaushik, Alexander Serganov, Gentile, Giuseppe Viglietto, Nicola Amodio, Tijana Mitić, Andrea Caporali

School of Graduate Studies Faculty Publications

The field of non-coding RNA research is advancing at a breathtaking pace, continually uncovering new layers of regulatory complexity and functional diversity [...].

Proteomic Analysis Of Central Amygdala Systems Regulated By Mifepristone In The Context Of Alcohol Dependence, Stephanie S. Lee, Laura Monteagudo Romero, John W. Lammons, Jennifer M. Klein, Kimberly N. Edwards, Jessie J. Guidry, Scott Edwards

School of Graduate Studies Faculty Publications

Alcohol use disorder (AUD) is a psychiatric disorder characterized by escalated alcohol use and the emergence of negative affective symptoms. Studies have described a dysregulation of glucocorticoid receptor (GR) signaling in the context of AUD at the levels of the hypothalamic-pituitary-adrenal (HPA) axis and central amygdala (CeA). A functional increase in CeA GR activity occurs during alcohol withdrawal in alcohol-dependent animal models, and the GR antagonist mifepristone reduces alcohol-seeking and drinking behaviors in both rodents and humans. The aims of this study were to determine differential CeA protein expression in alcohol-dependent rats and examine the effects of mifepristone treatment in …

Synthesis, Pharmacokinetic Studies, And Metabolite Analysis Of Meridianin C In Rats Using A Validated Ultra High Performance Liquid Chromatography-Tandem Mass Spectrometry Method, Liangyu Xu, Zhaogen Wu, Karna Ramachandraiah, Guihun Jiang, Guozhe Zhang

School of Graduate Studies Faculty Publications

Introduction: Meridianin C (MC) is a marine-derived indole alkaloid that has demonstrated kinase inhibitory and anti-tumor activities. Despite its diverse biological properties, no previous reports have systematically evaluated the in vivo quantitative analysis of MC and its metabolites. Methods: In this study, MC was synthesized following a previously reported procedure with slight modifications. A sensitive, accurate, and reliable ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC–MS/MS) method was developed to simultaneously detect MC and its five major metabolites (MC-1-N-O-GluA, MC-1-N-O-SO3H, MC-2′-N-O-GluA, MC-2′-N-O-SO3H, and MC-O-GluA-didehydration) in rat plasma. Rats received a single oral dose of MC (100 mg/kg), and pharmacokinetic analysis was …

Novel Piperidone And Bispidine Derivatives: A New Approach In Cancer Therapy, Lereen Khaled Youssry

Theses and Dissertations

Cancer remains the second leading cause of death worldwide. As a result, scientists have been trying to find novel therapeutic approaches that target specific metabolic pathways selective to tumor cells. In this study, two novel piperidone and bispidine derivatives, organic molecules that target polyamine metabolism, were synthesized, and their potential cytotoxic, antioxidant and anti-inflammatory effects were investigated. Polyamines are naturally occurring metabolites that were reported to be in excess at cancer cells and were accounted for tumor proliferation, invasion and metastasis. Accordingly, the novel piperidone and bispidine derivatives were expected to disrupt tumor growth and progression via up-regulation of key …

The Impact Of An Iron-Rich Diet On Fatigue In Menstruating Women With Non-Anemic Iron Deficiency, Meagan Seraydar, Lauren Latimer, Sam Miragliatto

Department of Nutrition Student Projects

Fatigue without diagnosed anemia is prevalent in menstruating women, with iron deficiency being a potential contributor. While iron supplementation is a standard intervention, dietary sources of iron may offer a sustainable alternative. This study aims to assess the impact of an iron-rich diet on fatigue levels in menstruating women. A 12-week randomized controlled trial (RCT) will be conducted, assigning participants to either an iron-rich diet group or a control group following their usual diet without specific iron recommendations. Fatigue will be measured using the Fatigue Severity Scale (FSS) at baseline, six weeks, and twelve weeks, alongside iron status biomarkers, including …

Poor Birth Outcomes Related To Cannabis Use In Pregnancy, Reese Weissenfluh, Madison Hall, Branden Kadlubowski, Makayla Eversole, Elizabeth Clary, Layla Dials, Brenna Hissong, Brianna Lu, Joshua Honaker, Manoranjan D'Souza

Pharmacy and Wellness Review

Pregnancy, a period of dynamic physiological changes, necessitates careful consideration of external influences on maternal and fetal health. Despite increasing legalization and prevalence, the impact of cannabis use during gestation remains a topic of significant concern and investigation.

Recent studies have shed light on the consequences of in utero cannabis exposure, encompassing both fetal and maternal outcomes. Notably, several studies have identified associations between cannabis exposure during pregnancy and adverse fetal outcomes, including small-for-gestational-age birth, altered neurodevelopment, preterm birth, and increased risk of neonatal morbidity. Evidence to date underscores the urgent need for education, intervention, and regulatory oversight regarding cannabis …

Alpha-Synuclein Interaction With Gedunin, Tony Matundura Nyabayo

Graduate Theses/Dissertations

Parkinson’s disease (PD) and other Proteinopathies develop when α-synuclein misfolds and aggregates into toxic amyloids. While existing treatments for PD are primarily focused on managing its symptoms, a viable solution for slowing down the progress of Parkinson’s disease involves targeting the toxic α-synuclein amyloids. Gedunin, a natural inhibitor of heat shock protein 90, has been extensively used to treat malaria. Also, recent research investigations have shed light on its potential beyond malaria therapy, indicating that Gedunin may offer a possible solution for treating a variety of neurodegenerative diseases. Using plate-based assays, we examined how Gedunin influences α-synuclein fibrillation and its …

Automating The Amino Acid Identification In Elliptical Dichroism Spectrometer With Machine Learning, Ridhanya Sree Balamurugan, Yusuf Asad, Tommy Gao, Dharmakeerthi Nawarathna, Umamaheswara Rao Tida, Dali Sun

Electrical & Computer Engineering Faculty Publications

Amino acid identification is crucial across various scientific disciplines, including biochemistry, pharmaceutical research, and medical diagnostics. However, traditional methods such as mass spectrometry require extensive sample preparation and are time-consuming, complex and costly. Therefore, this study presents a pioneering Machine Learning (ML) approach for automatic amino acid identification by utilizing the unique absorption profiles from an Elliptical Dichroism (ED) spectrometer. Advanced data preprocessing techniques and ML algorithms to learn patterns from the absorption profiles that distinguish different amino acids were investigated to prove the feasibility of this approach. The results show that ML can potentially revolutionize the amino acid analysis …

The Effects Of Curcumin On Erα, P53, And P21 In The Mcf-7 Breast Cancer Cell Line, Samantha E. Pfiffner, Mia Morse, Erin Hallman, Kaylin Whittaker, Aisha Zanib, Sumi Dinda Ph.D.

Medical Student Research Symposium

Curcumin is a golden-yellow flavonoid compound derived from the turmeric plant root that has been used in Chinese and Indian medicine for centuries. Curcumin has been shown to have antioxidant and anti-inflammatory properties, and because of this, has been gaining traction in the field of cancer research. Breast cancer is the most commonly diagnosed cancer in women, and is the second leading cause of cancer death in women, next to lung cancer. Because of the prevalence and mortality of breast cancer, possible therapeutics must be investigated. Due to the beneficial properties of curcumin and pervasiveness of breast cancer, we have …

Regulation Of Tissue Factor Activity By Interaction With The First Pdz Domain Of Magi1, Mohammad A. Mohammad, Sophie Featherby, Camille Ettelaie

School of Medicine Faculty Publications

Background; Tissue factor (TF) activity is stringently regulated through processes termed encryption. Post-translational modification of TF and its interactions with various protein and lipid moieties allows for a multi-step de-encryption of TF and procoagulant activation. Membrane-associated guanylate kinase-with inverted configuration (MAGI) proteins are known to regulate the localisation and activity of a number of proteins including cell-surface receptors. Methods; The interaction of TF with MAGI1 protein was examined as a means of regulating TF activity. MDA-MB-231 cell line was used which express TF and MAGI1, and respond well to protease activated receptor (PAR)2 activation. Proximity ligation assay (PLA), co-immunoprecipitation and …

Exploring The Metabolic And Mitogenic Potential Of A Hyper-Stable Variant Of Fgf1, Emma Starr, Oshadi Edirisinghe, Thallapuranam Krishnaswamy Suresh Kumar

Inquiry: The University of Arkansas Undergraduate Research Journal

Fibroblast growth factors (FGFs) are a family of 22 human cytokines involved in critical cellular processes, such as proliferation, differentiation, metabolism, angiogenesis, tumor metastasis, and wound healing. Among these, fibroblast growth factor 1 (FGF1) possesses a powerful mitogenic potential as it can nonspecifically bind to all four FGF receptors. However, the therapeutic applications of FGF1 are hindered by its inherent thermal and proteolytic instability, especially at physiological temperatures. This is believed to be attributed to the heparin-binding pocket at the C-terminus, which contains numerous positively charged residues that repel each other. To combat this instability, FGF1 binds to a negatively …

The Complex Protein Analysis Of Purified Extracellular Vesicles In The Study Of Colorectal Cancer, Renee Boone, Cecilia Osthoff

Science University Research Symposium (SURS)

Proteomics, the study of complex protein mixtures in which liquid chromatography-mass spectrometry (LC-MS) is used to analyze peptide sequences, is commonly utilized to study the double membrane, cell-derived vesicles known as exosomes. Exosomes are double membrane, cell-derived vesicles that contain cell components such as DNA, lipids, and proteins. They function to transport proteins and cellular materials between cells and are involved in the progression and metastasis of cancer. The impact of these extracellular vesicles on cancer spread can be analyzed using proteomics, through the purification of the proteins isolated from the vesicles. The purpose of our research is to analyze …

Design Of An Fgf-1-Fgf-2 Heterodimer Variant With Enhanced Stability And Cell Proliferation Activity, Nicholas Alan Pohlman

Chemistry & Biochemistry Undergraduate Honors Theses

The FGF-1 subfamily, composed of FGF-1 and FGF-2, assists in broad health-related processes such as cell proliferation and angiogenesis respectively.^1,2 The subfamily shows promising signs as a therapeutic, however, the inherent thermal instability leads to a low half-life in vivo.³ To assist in improving the stability, FGF-1 and FGF-2 were connected via a 12-residue glycine linker ultimately producing a heterodimer. This heterodimer was further examined to discover its novel properties. Inspiration for this project was drawn from previous research which performed five mutations on FGF-1 ultimately improving stability in the protein complex. In addition to these five …

Oral Dosages Of The Nsaid Aspirin Decreased The Growth Rate Of Species Found In The Human Gut Microbiome Including Akkermansia Muciniphila, Bacteroides Fragilis, Clostridium Sordellii, And Clostridium Difficile, Wyatt H. Greenbaum, Garrett J. Greenbaum, Anna Spiezio

PANDION: The Osprey Journal of Research and Ideas

Over past few decades, new insight has been revealed in the scientific community about the importance of the human gut microbiome relating to general health. It is known that imbalances in the species that reside in the human gut can cause organism-wide problems in humans. When prescribing or injecting oral medications, the thought of the downstream effects on the gut microbiome are not always considered. By exposing known healthy members of the gut; Akkermansia muciniphila, Bacteroides fragilis, Clostridium sordellii, and Clostridium difficile to the Aspirin, this study attempted to provide insight into the effects of the drug on bacterial growth. …

Development Of A Sensitive Microplate Assay For Characterizing Rna Methyltransferase Activity: Implications For Epitranscriptomics And Drug Development, Isaiah K. Mensah, Allison B. Norvil, Ming He, Emma Lendy, Nicole Hjortland, Hern Tan, Richard T. Pomerantz, Andrew Mesecar, Humaira Gowher

Department of Biochemistry and Molecular Biology Faculty Papers

RNA methylation is a ubiquitous post-transcriptional modification found in diverse RNA classes and is a critical regulator of gene expression. In this study, we used Zika virus RNA methyltransferase (MTase) to develop a highly sensitive microplate assay that uses a biotinylated RNA substrate and radiolabeled AdoMet coenzyme. The assay is fast, highly reproducible, exhibits linear progress-curve kinetics under multiple turnover conditions, has high sensitivity in competitive inhibition assays, and significantly lower background levels compared with the currently used method. Using our newly developed microplate assay, we observed no significant difference in the catalytic constants of the full-length nonstructural protein 5 …

Exogenous Exposure To Dihydroxyacetone Mimics High Fructose Induced Oxidative Stress And Mitochondrial Dysfunction, Raj Mehta

Honors Theses

Dihydroxyacetone (DHA) is a three-carbon sugar that is the active ingredient in sunless tanning products and a by-product of electronic cigarette (e-cigarette) combustion. Increased use of sunless tanning products and e-cigarettes has elevated exposures to DHA through inhalation and absorption. Studies have confirmed that DHA is rapidly absorbed into cells and can enter into metabolic pathways following phosphorylation to dihydroxyacetone phosphate (DHAP), a product of fructose metabolism. Recent reports have suggested metabolic imbalance and cellular stress results from DHA exposures. However, the impact of elevated exposure to DHA on human health is currently under-investigated. We propose that exogenous exposures to …

Targeting Mcl-1 By A Small Molecule Nsc260594 For Triple-Negative Breast Cancer Therapy, Shengli Dong, Margarite D. Matossian, Hassan Yousefi, Maninder Khosla, Bridgette M. Collins-Burow, Matthew E. Burow, Suresh K. Alahari

School of Graduate Studies Faculty Publications

Triple-negative breast cancers (TNBCs) are aggressive forms of breast cancer and tend to grow and spread more quickly than most other types of breast cancer. TNBCs can neither be targeted by hormonal therapies nor the antibody trastuzumab that targets the HER2 protein. There are urgent unmet medical needs to develop targeted drugs for TNBCs. We identified a small molecule NSC260594 from the NCI diversity set IV compound library. NSC260594 exhibited dramatic cytotoxicity in multiple TNBCs in a dose-and time-dependent manner. NSC260594 inhibited the Myeloid cell leukemia-1 (Mcl-1) expression through downregulation of Wnt signaling proteins. Consistent with this, NSC260594 treatment increased …

Targeting Cgas/Sting Signaling-Mediated Myeloid Immune Cell Dysfunction In Time, Vijay Kumar, Caitlin Bauer, John H. Stewart

School of Graduate Studies Faculty Publications

Myeloid immune cells (MICs) are potent innate immune cells serving as first responders to invading pathogens and internal changes to cellular homeostasis. Cancer is a stage of altered cellular homeostasis that can originate in response to different pathogens, chemical carcinogens, and internal genetic/epigenetic changes. MICs express several pattern recognition receptors (PRRs) on their membranes, cytosol, and organelles, recognizing systemic, tissue, and organ-specific altered homeostasis. cGAS/STING signaling is a cytosolic PRR system for identifying cytosolic double-stranded DNA (dsDNA) in a sequence-independent but size-dependent manner. The longer the cytosolic dsDNA size, the stronger the cGAS/STING signaling activation with increased type 1 interferon …

Photodynamic Therapy Agents: The Power Of Mjöllnir To Eradicate Cancer, Sidney M. Hopper

Honors College Theses

After its discovery back in the 1900s, photosensitizers became a critical study for potential treatments and cures for medical issues, including cancer. It was discovered that porphyrins appeared to target and accumulate in proliferating cells, and to reach the cells, a certain wavelength of light with maximum absorbance associated with the porphyrin was necessary to achieve cell death. Photodynamic therapy involves making use of porphyrins or metalloporphyrins as activators when exposed to such light. When activated, these compounds generate reactive oxygen species (ROS), such as HO- or O2-, which can react with nucleic acids found in DNA and RNA. In …

Fragment Based Drug Development Based On 6,7-Dimethoxyquinazoline As A Core Scaffold, Cody M. Orahoske

ETD Archive

The work entitled “Fragment Based Drug Design based on 6,7- Dimethoxyquinazoline core structure” presents a unique approach to drug discovery, specifically focusing on the pharmacophore 6,7-dimethoxyquinazoline. This study explores the structural diversity of 6,7-Dimethoxyquinazoline derivatives to identify other pharmacologically relevant targets, with evidence indicating that this core structure possesses intrinsic properties that make it suitable as a base structure of small molecule drugs. Furthermore, this pharmacophore has been observed in various approved therapeutics or drug candidates under investigation, highlighting its importance in drug discovery. My research showcases of 6,7-dimethoxyquinazoline core structure been derivatized to generate an anti-trypanosomiasis drug candidates and …

Nicotinamide Riboside And Beta-Hydroxybutyrate Activate Parallel Pathways For C. Elegans Lifespan Extension, Mckenzie Peters

Undergraduate Honors Theses

Supplementation with nicotinamide riboside (NR), a form of vitamin B3 and a precursor of nicotinamide adenine dinucleotide (NAD⁺) extends lifespan in the nematode C. elegans and delays aging-related pathologies in mammals. During aging, levels of NAD⁺ decline causing metabolic dysfunction and oxidative damage. Studies in C. elegans found that when NR was administered during larval development it induced the mitochondrial unfolded protein response (UPR^mt), which is frequently associated with lifespan extension. Both calorie restriction (CR) and ketogenic diets (KD) have been shown to extend lifespan, in part through increasing NAD⁺ and through increasing levels …

An Investigation On The Effect Of Conserved Hinge Histidine On Influenza Hemagglutinin(Ha2) Protein Conformation Using Md Simulations, Nada Tolba

Chemistry & Biochemistry Undergraduate Honors Theses

Hemagglutinin is a protein on the surface of Human Influenza Viruses.¹ It is composed of two glycopolypeptide domains, the HA1 and HA2 domains. Previous studies have found that across different strains of Influenza viruses, HIS435 residues remain conserved.⁴ In studies where mutations occurred in hinge-site histadine residues, the Influenza virus was inactive.⁴ These investigations indicated a significant role of HIS435 (hinge-site histadines) in virulence. Four systems were created using Molecular dynamics (MD) simulations. Each system was composed of an Isolated HA2 trimer solvated in a 150 mM NaCl rectangular water box at 310 K under isobaric and …

Design And Synthesis Of Peripherally Selective Endocannabinoid Enzyme Inhibitors For Ocular Indications, Kezia Reji Thomas

Senior Honors Theses

Peripherally selective compounds have been found to stimulate endocannabinoid receptor activity, which has been observed to have positive physiological effects such as ocular wound healing and inflammation control. The activation of the cannabinoid 1 receptor via binding of the endogenous ligands, anandamide and 2-arachidonoylglycerol, has been indicated to elicit these effects. Both ligands are controlled by two hydrolase enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), which can be targeted for therapeutic inhibition. Sulfonamide derivatives of JZL195 containing carbamate functionalities in the southern region of the inhibitor compounds were produced using novel carbamate exchange reactions. Polar functionalities were …

Circulating Plasma Exosomal Proteins Of Either Shiv-Infected Rhesus Macaque Or Hiv-Infected Patient Indicates A Link To Neuropathogenesis, Partha K. Chandra, Stephen E. Braun, Sudipa Maity, Jorge A. Castorena-Gonzalez, Hogyoung Kim, Jeffrey G. Shaffer, Sinisa Cikic, Ibolya Rutkai, Jia Fan, Jessie J. Guidry, David K. Worthylake, Chenzhong Li, Asim B. Abdel-Mageed, David W. Busija

School of Medicine Faculty Publications

Despite the suppression of human immunodeficiency virus (HIV) replication by combined antiretroviral therapy (cART), 50–60% of HIV-infected patients suffer from HIV-associated neurocognitive disorders (HAND). Studies are uncovering the role of extracellular vesicles (EVs), especially exosomes, in the central nervous system (CNS) due to HIV infection. We investigated links among circulating plasma exosomal (crExo) proteins and neuropathogenesis in simian/human immunodeficiency virus (SHIV)-infected rhesus macaques (RM) and HIV-infected and cART treated patients (Patient-Exo). Isolated EVs from SHIV-infected (SHIV-Exo) and uninfected (CTL-Exo) RM were predominantly exosomes (particle size < 150 nm). Proteomic analysis quantified 5654 proteins, of which 236 proteins (~4%) were significantly, differentially expressed (DE) between SHIV-/CTL-Exo. Interestingly, different CNS cell specific markers were abundantly expressed in crExo. Proteins involved in latent viral reactivation, neuroinflammation, neuropathology-associated interactive as well as signaling molecules were expressed at significantly higher levels in SHIV-Exo than CTL-Exo. However, proteins involved in mitochondrial biogenesis, ATP production, autophagy, endocytosis, exocytosis, and cytoskeleton organization were significantly less expressed in SHIV-Exo than CTL-Exo. Interestingly, proteins involved in oxidative stress, mitochondrial biogenesis, ATP production, and autophagy were significantly downregulated in primary human brain microvascular endothelial cells exposed with HIV+/cART+ Patient-Exo. We showed that Patient-Exo significantly increased blood–brain barrier permeability, possibly due to loss of platelet endothelial cell adhesion molecule-1 protein and actin cytoskeleton structure. Our novel findings suggest that circulating exosomal proteins expressed CNS cell markers—possibly associated with viral reactivation and neuropathogenesis—that may elucidate the etiology of HAND.