Cellular and Molecular Physiology Commons^™

Gcn5l1-Mediated Lysine Acetylation Regulates Mitochondrial Dysfunction In The Aged Heart, Jackson Edmond Stewart

Graduate Theses, Dissertations, and Problem Reports (ETD)

For over a century, cardiovascular disease (CVD) has been and remains the leading cause of death globally. CVD risk and severity increase significantly with advanced age, and mitochondrial dysfunction has been implicated in the pathogenesis of aging. Furthermore, mitochondrial health is crucial for cardiac function, as one-third of total cardiomyocyte volume is occupied by mitochondria in order to meet the high energy demand of contractile and relaxational function. It is thus crucial that we understand the pathological mechanisms driving mitochondrial dysfunction in aging and how this contributes to age-associated cardiovascular disease. The current manuscript aims to fill this knowledge gap …

Circulating Biomarker Results From A Phase 2 Study Of Seralutinib In Pulmonary Arterial Hypertension, Robin Osterhout, Athénaïs Boucly, Raymond L. Benza, Richard N. Channick, Kelly M. Chin, Robert P. Frantz, Anna R. Hemnes, Luke S. Howard, Vallerie V. Mclaughlin, Olivier Sitbon, Jean-Luc Vachiéry, Rotham T. Zamanian, Richard Aranda, Matt Cravets, Zhaoqing Ding, Thao Duong-Verlé, David Mattola, Robert F. Roscigno, Ravikumar Sitapara, Lawrence S. Zisman, Jean-Marie Bruey, Hossein-Ardeschir Ghofrani

Department of Medicine Faculty Publications

[Introduction] To the Editor: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by obstructive pulmonary arterial remodeling (1). Seralutinib, an investigational inhaled tyrosine kinase inhibitor, potently and selectively targets kinases relevant to PAH pathobiology including platelet-derived growth factor receptors (PDGFR) α and β, colony stimulating factor 1 receptor (CSF1R), and mast/stem cell growth factor receptor kit (c-KIT) (2). In preclinical models, seralutinib improved cardiopulmonary hemodynamics, reversed pulmonary vascular pathology and decreased right ventricular hypertrophy (3). In TORREY, a phase 2, multicenter, double-blind, randomized, placebo-controlled trial in PAH, seralutinib significantly reduced pulmonary vascular resistance (PVR) after 24 weeks with good …

Geographic Variation In Proteomic Responses To Ocean Acidification In A Cold-Water Coral (Balanophyllia Elegans), Keana A. Richmond

Cal Poly Humboldt theses and projects

In the face of a rapidly changing climate, assessing organismal responses to future stressors in the context of current, natural exposure to stress could provide key insights to understanding marine ecosystem resilience. I used Balanophyllia elegans, a cold-water, solitary, azooxanthellate coral as a model to better understand how varying oceanographic conditions across its geographic range have shaped its ability to tolerate and potentially adapt to current and future ocean acidification conditions. I collected B. elegans individuals from four sites across 2,500km of their range and subjected them to two pH treatments to investigate site-specific protein expression in response to …

The Disruption Of Gastrointestinal Hormonal Control Of Digestion In Nile Tilapia By Omeprazole, Rema Abutaha

Theses and Dissertations (Comprehensive)

Stomach acidity is a critical feature of the digestive system, facilitating the breakdown of protein through the activation of the protease pepsin. Gastric acid is secreted by H⁺/K⁺ ATPase, the gastric proton pump. A previous study on Nile tilapia (Oreochromis niloticus) showed that inhibiting the production of stomach acid using the proton pump inhibitor omeprazole (omz), reduced growth that correlated with an acceleration of the rate of gastric emptying. This contrasts with omz exposure studies in mammals in which there is a delay in gastric emptying and no impact on growth. To understand the mechanism …

Prolonged Qt Interval In Hiv-1 Infected Humanized Mice Treated Chronically With Dolutegravir/Tenofovir Disoproxil Fumarate/Emtricitabine, Ali Namvaran, Julian V. Garcia, Mahendran Ramasamy, Kayla Nguyen, Farzaneh Tavakkoli Ghazani, Bryan T. Hackfort, Prasanta Dash, Reagan E. Fisher, Benson J. Edagwa, Santhi Gorantla, Keshoer R. Bidasee

Journal Articles: Cellular & Integrative Physiology

The REPRIEVE Trial recently reported high rates of sudden cardiac death (SCD) middle-aged people living with HIV-1 infection (PWH) using the WHO/NIH-recommended two nucleoside reverse transcriptase inhibitors (NRTIs)/one integrase strand inhibitor (INSTI) regimen to manage HIV-1 viremia. To date, clinically relevant animal models to delineate underlying causes for this remain limited. Here, we assessed if HIV-1-infected NOD.Cg-Prkdc^scidIl2rg^tm1Wjl/SzJ humanized mice (Hu-mice) treated with the WHO/NIH-recommended antiretroviral regimen, dolutegravir (DTG, INSTI)/tenofovir disoproxil fumarate (TDF, NRTIs)/emtricitabine (FTC, NRTIs), can recapitulate abnormalities in the ECG and subclinical structural heart disease that serve as harbingers of SCD in middle-aged PWH. …

Attenuation Of Cardiac Dysfunction In The Collagen-Induced Arthritis Mouse Model Mediated By A Reactive Aldehyde Species Inhibitor, Wenxian Zhou, Hannah J. Johnson, Michael J. Duryee, Ali Namvaran, Aradhana Thapa, Cole Blasing, Amy J. Nelson, Engle E. Sharp, Carlos D. Hunter, Bryan T. Hackfort, Bryant England, Tate M. Johnson, Daniel R. Anderson, Adam Lazorchak, Robert G. Bennett, Jill A. Poole, Keshoer R. Bidasee, Geoffrey M. Thiele, Ted R. Mikuls

Journal Articles: Cellular & Integrative Physiology

Individuals with rheumatoid arthritis (RA) experience increased risk of heart failure. Malondialdehyde-acetaldehyde (MAA) adducts are overexpressed and co-localize with citrullinated (CIT) proteins in RA myocardium. This study investigated whether reactive aldehyde species (RASP) inhibitors prevent MAA formation in vitro and attenuate cardiac dysfunction in a collagen-induced arthritis (CIA) mouse model. Among eight RASP inhibitors screened, ADX-246 demonstrated the greatest inhibition of MAA formation in vitro. Mice with early CIA (week 5) exhibited elevated levels of myocardial MAA adducts, myocardial inflammation, and reduced ejection fraction, but normal cardiac collagen deposition and diastolic function vs. control. By weeks 10-12, mice with chronic …

Establishing Procedures For Primary Human Myoblast Cell Culture, Erica Duffy

Biomedical Engineering

Peripheral Artery Disease (PAD) affects an estimated 200 million people worldwide and is the leading cause of amputation in the United States. PAD is characterized by atherosclerotic narrowing of arteries, resulting in ischemia from reduced blood flow to distal tissues. Although surgical and percutaneous interventions can restore perfusion, fewer than 50% of patients experience sustained benefit, highlighting the need for alternative therapeutic strategies. One promising approach is promoting arteriogenesis, the growth and outward remodeling of pre-existing collateral vessels that improve blood flow around the occluded arteries. Arteriogenesis is regulated by regenerative, M2-polarized macrophages, making macrophage polarization a key therapeutic target. …

Exposure To Pm2.5 And Aging., Daniel Chris Gomes

Electronic Theses and Dissertations

Inhalation of fine airborne particulate matter (PM_2.5) is an environmental risk factor for numerous health disorders, including cardiovascular diseases (CVD). While several studies have shown that PM_2.5 exposure can induce oxidative stress, DNA damage, and inflammation, the underlying mechanisms that translate these effects into systemic pathology remain poorly understood. Some recent studies have shown that PM_2.5 exposure can lead to telomere shortening in leukocytes, but the generality of this outcome and contribution to endothelial dysfunction has not yet been fully explored. We hypothesized that PM_2.5inhalation accelerates cellular aging and senescence in both circulating peripheral …

Effects Of Temperature And Oxygen Stress On Two Populations Of Olympia Oysters (Ostrea Lurida) From Central California, Buyanzaya Buyanurt

Master's Theses

Olympia oysters (Ostrea lurida) are the only native oyster species to the North American West Coast. A once thriving species, O. lurida populations have dramatically declined over time due to factors such as overharvesting, habitat degradation, and the introduction of invasive predators. Although their populations are still present in estuaries along their habitat range, many of these same stressors persist today, preventing the re-establishment of dense oyster beds and hindering recovery of populations. Among these current day stressors, a major concern are the impacts of climate change, specifically warming water temperatures and the increased frequency of hypoxic events. …

Rebound Bursting Selectively Enables Fast Dynamics In Dopamine Midbrain Neurons Projecting To The Dorsolateral Striatum, Strahinja Stojanovic, Christopher J. Knowlton, Richard Egger-Mackrodt, Johanna Mankel, Josef Shin, Stephan Lammel, Carmen C. Canavier, Jochen Roeper

School of Graduate Studies Faculty Publications

Dopamine (DA) midbrain neurons are involved in a wide array of key brain functions including movement control and reward-based learning. They are also critical for major brain disorders such as Parkinson's disease or schizophrenia. DA neurons projecting to distinct striatal territories are diverse with regard to their molecular makeup and cellular physiology, which are likely to contribute to the observed differences in temporal DA dynamics. Among these regions, the dorsolateral striatum (DLS) displays the fastest DA dynamics, which might control the moment-to-moment vigor and variability of voluntary movements. However, the underlying mechanisms for these DLS-specific fast DA fluctuations are unresolved. …

Female Cardioprotection In A Mouse Model Of Alcohol-Associated Cardiomyopathy, Joshua M. Edavettal, Meagan Donovan, Nicholas R. Harris, Xavier R. Chapa-Dubocq, Keishla M. Rodríguez-Graciani, Janos Paloczi, Liz Simon, Bysani Chandrasekar, Jason D. Gardner

School of Graduate Studies Faculty Publications

Chronic alcohol misuse is the leading cause of non-ischemic dilated cardiomyopathy, and the molecular mechanisms underlying the development of alcohol-associated cardiomyopathy (ACM), particularly regarding sex-specific susceptibility and mitochondrial contributions, are not fully known. In this study, we utilized a preclinical model of chronic + binge ethanol consumption to investigate sex differences in disease severity and mitochondrial function. Male and female C57BL/6J mice were fed ethanol or control liquid diets for 30 days, with 2 binge episodes on days 10 and 30. Cardiac morphology was assessed via echocardiography and cardiac function via left ventricular pressure-volume catheterization. Mitochondrial function was evaluated ex …

Alphasperm Data, Seth J. Parks, Timothy G. Jenkins

ScholarsArchive Data

Data from a prospective cohort study of sperm DNA methylation, semen analysis, and DNA fragmentation in fertile and infertile men before and after treatment with a male fertility antioxidant supplement.

A Novel Sialylation Pathway Mediated By Extracellular Vesicles In Aggressive Prostate Cancer, Camila A. Bach, Md Niamat Hossain, Ishan J. Chaudhari, Cecilia E. Verrillo, Nicole M. Naranjo, Isabella Amoroso, Anna Testa, Samuel Sey, W. Kevin Kelly, Susan L. Bellis, Aurelio Lorico, Ada G. Blidner, Gabriel A. Rabinovich, Lucia R. Languino

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Altered cell surface glycosylation is a hallmark of cancer; among aberrant glycan structures, hypersialylated proteins contribute to disease progression. The enzyme ST6 β-galactoside α2,6-sialyltransferase 1 (ST6GAL1) mediates α2,6-linked sialylation of N-glycosylated proteins and is upregulated in many cancers, including prostate cancer (PrCa). We propose that ST6GAL1 may be released by cancer cells in small extracellular vesicles (sEVs) in the PrCa tumor microenvironment to potentially modulate cell surface sialylation in recipient cells. We isolated sEVs from PrCa cells by density gradient separation and characterized them by nanoparticle tracking analysis using ZetaView and immunoblotting analysis. We identified ST6GAL1 in both its membrane-bound …

Enhancing Cataract Surgery Outcomes: Optimal Use Of Pre- And Post-Operative Eye Drops, Keith Skolnick M.D., Anu Valiaveedu

Mako: NSU Undergraduate Student Journal

Many preoperative and postoperative cataract patients struggle with comprehending the use of prescription medication as directed. Language barriers and low health literacy levels are major factors contributing to improper use of prescriptions. To increase patients comprehension, the Fort Lauderdale Eye Institute employed an educational intervention consisting of a live presentation and an instructional video. Results found that 44% of patients were hesitant to ask questions to clinical staff, 32% felt overwhelmed, and nearly 70% lacked confidence in using their prescribed eye drops. Following the intervention, 91% of patients reported increased confidence in their medications, and most indicated that the video …

Asymmetric Fgf Receptor Dimerization: Implications For Fgf23 Biology And Drug Discovery, Mohammed S. Razzaque, Moosa Mohammadi

School of Medicine Publications

Fibroblast growth factor 23 (FGF23) requires both αKlotho and heparan sulfate proteoglycans (HSPGs) as obligatory coreceptors to bind, dimerize, and activate its FGF receptors (FGFRs) in the kidney, thereby regulating mineral ion and vitamin D homeostasis. Cryogenic electron microscopy studies reveal that FGF23 signaling proceeds through an asymmetric 1:2:1:1 FGF23–FGFR–αKlotho–HS assembly. According to this structural model, αKlotho simultaneously anchors FGF23 and one FGFR chain, referred to as the primary receptor (FGFRP), to form a 1:1:1 FGF23-FGFRP-αKlotho triplex, which boosts FGF23-FGFRP interaction. Subsequently, the HS coreceptor aids the triplex in recruiting a second FGFR chain, or secondary receptor (FGFRS), leading to …

Metabolic Regulation Of Cardiac Fibroblast Phenotype And Function., Collin Kleis Wells

Electronic Theses and Dissertations

Cardiac fibroblasts are central effectors of cardiac repair after myocardial infarction (MI). In response to signaling cues, they differentiate to a range of phenotypes with robust capacities to synthesize and secrete extracellular matrix (ECM) and signaling molecules. Although activated fibroblast phenotypes are associated with pronounced changes in metabolism, it remains unclear how the metabolic network upholds the effector functions of fibroblasts in the post-infarcted heart. Here, we identified that critical enzymes in the phosphoenolpyruvate (PEP) cycle, i.e. pyruvate kinase muscle-2 (PKM2) and phosphoenolpyruvate carboxykinase-2 (PCK2), are elevated in the heart after MI and examined their role in regulating post-MI remodeling …

Advanced Interactions Of Directed Energy With Retinal Pigment Epithelial Cells And Their Photochemical And Photothermal Responses, Jin B. Ha

Theses & Dissertations

Excess optical radiation can injure the retina through either rapid heat deposition (photothermal damage) or cumulative photo‑oxidative stress (photochemical damage), yet current laser‑safety limits treat these mechanisms as independent. To test that assumption, this dissertation integrated systematic wavelength, duration and temperature‑controlled laser exposures with live/dead fluorescence imaging in a melanin‑loaded hTERT‑RPE1 monolayer model. First, concurrent 447 nm (blue) and 2 µm (infra‑red) beams delivered for 200 s demonstrated a strong thermal–photochemical synergy: each beam alone was sub‑threshold (≤25 % lethality) but together produced 100 % RPE death without exceeding 50 °C, proving that modest heating markedly lowers the photon dose …

Identification Of Serum Exosome Proteins In Systemic Sclerosis With Interstitial Lung Disease By Aptamer Proteomics, Sonsoles Piera-Velazquez, Simon T. Dillon, Xuesong Gu, Towia A. Libermann, Sergio A. Jimenez

Jefferson Institute of Molecular Medicine Papers and Presentations

OBJECTIVE: A major unmet need for Systemic Sclerosis (SSc) clinical management is the absence of well validated biomarkers for early diagnosis of SSc-associated interstitial lung disease (SSc-ILD). The objective of this study was to identify proteins contained within serum exosomes that may serve as potential biomarkers to differentiate patients with Diffuse SSc without SSc-ILD from patients with Diffuse SSc with SSc-ILD employing aptamer-based proteomics.

METHODS: Serum exosomes were isolated from two cohorts of patients. The first cohort included 15 patients with Diffuse SSc without SSc-ILD and 14 patients with Diffuse SSc with SSc-ILD and the second cohort included 12 patients …

The Loss Of Opa1 Accelerates Intervertebral Disc Degeneration And Osteoarthritis In Aged Mice, Vedavathi Madhu, Miriam Hernandaz-Meadows, Ashley Coleman, Kimheak Sao, Kameron Inguito, Owen Haslam, Paige Boneski, Hiromi Sesaki, Ruteja Barve, John Collins, Makarand Risbud

Department of Orthopaedic Surgery Faculty Papers

Recent studies have highlighted the importance of mitochondria in NP cells and articular chondrocyte health. Since the understanding of mechanisms governing mitochondrial dynamics in these tissues is lacking, we investigated the role of OPA1, a mitochondrial fusion protein, in their homeostasis. OPA1 knockdown in NP cells altered mitochondrial size and cristae shape and increased the oxygen consumption rate. OPA1 governed the morphology of multiple organelles, including peroxisomes, early endosomes and cis-Golgi and loss resulted in the dysregulation of autophagy. Metabolic profiling and

Breaking The Rules: Post-Translational Modifications And Proteome Dynamics During Anoxia, Chelsea Jordan Hughes

Dissertations and Theses

Most organisms are ill-equipped to survive anoxia, but some organisms have developed molecular strategies to mitigate the cellular stressors associated with a lack of oxygen. While it is established that anoxic survival is contingent on metabolic suppression, it is unclear what mechanisms support this change in gene expression. Gene expression is regulated by a variety of mechanisms within the cell, including alteration of chromatin structure through histone modifications and protein modifications which contribute to the ever-changing proteomic landscape of the cell. Protein modifications such as ubiquitylation can lead to the degradation of proteins, while modifications to transcription factors can change …