Michael K. Pugsley, Siddhartha Bhatt, Christer Gottfridsson, Peter Hoffmann, Yevgeniya E. Koshman, Kevin Norton, Claire E. O’Brien, Jennifer Pierson, Eric I. Rossman, Alexandra Taraboletti, Tanja S. Zabka, C. Michael Foley

DOI: https://doi.org/10.1016/j.yrtph.2026.106098

Drug-induced hypertension or hypotension can have significant clinical consequences, yet BP regulation involves complex, multi-level mechanisms, making translational assessment of pressor effects more challenging than for endpoints such as cardiac repolarization (hERG/QT). Current nonclinical BP studies primarily use telemetry in conscious, freely moving non-rodents, enabling continuous high-fidelity hemodynamic monitoring. These models show reasonable concordance with human data, but some translational challenges exist.

The Health and Environmental Sciences Institute (HESI) Global Integrative Strategies Working Group (WG) was established to improve nonclinical cardiovascular (CV) safety assessment through more informative, translational preclinical models. After earlier success characterizing drug-induced effects on cardiac contractility, the WG focused on drug-associated blood pressure (BP) changes. Provided here is the importance of nonclinical models in predicting BP changes and associated challenges. A HESI Global multi-site study focused on addressing these gaps is also introduced. The study aimed to evaluate the reproducibility and translatability of the standard telemetered dog model using compounds with well-characterized mechanisms (midodrine, nifedipine, hydralazine, prazosin, milrinone). Early results show consistent hemodynamic profiles across laboratories, with final results published separately, showing utility of this model for BP liability assessment.

Regulatory Toxicology and Pharmacology

2026

Xiaowen Sun, Stephen D Dertinger, Azeddine Elhajouji, Daniel J Roberts, Jan van Benthem 5, Maik Schuler, Shambhu Roy, Alexandra Taraboletti, Connie L Chen

DOI: https://doi.org/10.1002/em.70023

The genotoxic potential of chemicals must be evaluated in regulatory safety assessment settings, including but not limited to, the development of new pharmaceuticals, industrial chemicals, food and cosmetic ingredients, and agrochemicals. Initial assessment of the chromosome-damaging potential of chemicals is often conducted in mammalian cells using the micronucleus (MN) assay, a method capable of detecting both aneugenicity and clastogenicity. When differentiation between these modes of action (MOAs) is necessary, microscopy-based analyses using fluorescent In Situ Hybridization (FISH) or CREST staining have traditionally been employed. More recently, semi-automated in vitro new approach methods (NAMs), which leverage technologies like flow cytometry and high-content imaging, have increasingly been used across sectors due to their higher throughput and faster turnaround times. A SWOT (strengths, weaknesses, opportunities, and threats) analysis was conducted to systematically evaluate the merits and limitations of widely used NAMs in industry, with a focus on the pharmaceutical sector. Data from cultured mammalian cells exposed to reference aneugens (colchicine, taxol, and AMG900) and DNA-reactive clastogens (mitomycin C and methyl methanesulfonate) across methodologies are presented to illustrate the process of distinguishing aneugens from clastogens for the different techniques described herein. Collectively, these analyses highlight the capabilities of NAMs to distinguish aneugens from clastogens. The newer, high information content, semi-automated approaches were considered preferable to traditional microscopy-based FISH and CREST techniques as they provide insight into molecular mechanisms of aneugenicity and help optimize the design of future in vivo genotoxicity studies to facilitate deriving points of departure which may contribute to margin of exposure estimates.

Environ Mol Mutagen

2025

Alexandra Taraboletti

DOI: https://doi.org/10.1021/acs.jchemed.3c00913

In response to the shifting modalities of laboratory-based education, particularly amidst the rise of virtual and at-home instruction, we introduce a novel hybrid laboratory module for undergraduate biochemistry and biology courses. Central to this innovative approach is the use of sourdough as a versatile and accessible model organism, enabling a blend of home and in-lab learning experiences. This sourdough-based module allows students to explore key biochemistry concepts and techniques both in a traditional laboratory setting and within their own home environments. Accompanied by a kit of disposable, economical equipment, the module is designed for flexibility and adaptability, catering to various instructional formats. The use of sourdough in this context serves as a powerful educational tool, facilitating hands-on learning and offering insights into microbial diversity and fermentation processes. By engaging with this module, students not only gain practical biochemistry experience but also develop a deeper understanding of the intricate relationship between microorganisms and their environments. The hybrid structure of this module reflects the evolving educational landscape, offering a sustainable and effective alternative to traditional lab setups. Our findings highlight the potential of sourdough as a model organism in biochemistry education, showcasing its effectiveness in fostering student engagement and comprehension in diverse learning contexts.

Journal of Chemical Education

2024

Constantinos G. Broustas; Sanjay Mukherjee; Igor Shuryak; Alexandra Taraboletti; Jerry Angdisen; Pelagie Ake; Albert J. Fornace, Jr.; Sally A. Amundson

DOI: 10.1667/RADE-23-00052.1

High-dose-radiation exposure in a short period of time leads to radiation syndromes characterized by severe acute and delayed organ-specific injury accompanied by elevated organismal morbidity and mortality. Radiation biodosimetry based on gene expression analysis of peripheral blood is a valuable tool to detect exposure to radiation after a radiological/nuclear incident and obtain useful biological information that could predict tissue and organismal injury. The goal of this study was to elucidate how pre-existing inflammation in mice, induced by GADD45A ablation, can affect radiation biodosimetry. We exposed wild-type and GADD45A knockout male C57BL/6J mice to 7 Gy of X rays and 24 h later RNA was isolated from whole blood and subjected to whole genome microarray and gene ontology analyses. Dose reconstruction analysis using a gene signature trained on gene expression data from irradiated wild-type male mice showed accurate reconstruction of either a 0 Gy or 7 Gy dose with root mean square error of ± 1.05 Gy (R^2 = 1.00) in GADD45A knockout mice. Gene ontology analysis revealed that irradiation of both wild-type and GADD45A-null mice led to a significant overrepresentation of pathways associated with morbidity and mortality, as well as organismal cell death. However, based on their z-score, these pathways were predicted to be more significantly overrepresented in GADD45A-null mice, implying that GADD45A deletion may exacerbate the deleterious effects of radiation on blood cells.

Radiation Research

2023

Alexandra Anna Taraboletti, Alexus King, Yasheka Dixon, Oshane Orr, Chevell Parnell, Yashieka Watson, Bruce Nash, Chimdimnma Esimai, George Ude

doi: https://doi.org/10.1101/2023.03.31.535185

In this study, we investigated the microbial diversity and community composition of soil samples collected from various sites along the Potomac River within an urbanized region. Our findings revealed the presence of both typical marine soil bacteria and bacterial taxa indicative of urbanization and waste runoff. We observed significant variations in microbial community structure and diversity across different sampling sites, highlighting the influence of environmental factors on microbial abundance and diversity. Through taxon set analysis, we identified shared taxa strongly associated with agricultural pollution, organochlorine pesticide contamination, and bromochloromethane pollution. Additionally, the study revealed potential disparities in human impact, water retention, and tidal/current effects among the soil samples. These insights carry significant implications for understanding the consequences of urbanization on soil microbial communities along the Potomac River and can inform strategies for managing and preserving these ecosystems. Further research is warranted to elucidate the effects of soil health and microbial diversity in this region.

bioRxiv

2023

Monessha Jayabalan, Madeline E Caballero, Alyssa D Cordero, Brandyn M White, Kathryn C Asalone, Madison M Moore, Esohe G Irabor, Shari E Watkins, Kathryn B Walters-Conte, Alexandra Taraboletti, Matthew R Hartings, Brenda Y Chow, Bushra A Saeed, Kathryn A Bracht, John R Bracht

DOI: 10.1016/j.cell.2021.10.030

Diversity within science, technology, engineering, and mathematics (STEM) remains disturbingly low. Relative to larger, highly funded universities, smaller schools harbor more diverse student demographics and more limited resources. Here, we propose four strategies leveraging the unique advantages of smaller institutions to advance underrepresented scholars along STEM pathways.

Cell Press

2021

Stephanie M Bilinovich, Daniel L Morris, Jeremy W Prokop, Joel A Caporoso, Alexandra Taraboletti, Nilubol Duangjumpa, Matthew J Panzner, Leah P Shriver, Thomas C Leeper

https://doi.org/10.3390/biophysica1040027

Glutaredoxins (GRXs) are a class of enzymes used in the reduction of protein thiols and the removal of reactive oxygen species. The CPYC active site of GRX is a plausible metal binding site, but was previously theorized not to bind metals due to its cis-proline configuration. We have shown that not only do several transition metals bind to the CPYC active site of the Brucella melitensis GRX but also report a model of a dimeric GRX in the presence of silver. This metal complex has also been characterized using enzymology, mass spectrometry, size exclusion chromatography, and molecular modeling. Metalation of GRX unwinds the end of the helix displaying the CPYC active site to accommodate dimerization in a way that is similar to iron sulfur cluster binding in related homologs and may imply that metal binding is a more common occurrence in this class of oxidoreductases than previously appreciated.

Biophysica

2021

Lucille A. Ray, Gardenia Pacheco, Alexandra Taraboletti, Michael C. Konopka, Leah P. Shriver

doi: https://doi.org/10.1101/2020.12.18.423512

Cuprizone is a copper chelator that induces mitochondrial dysfunction in myelin-producing oligodendrocytes and hepatic cells. Inhibition of oxidative phosphorylation has been proposed as a potential mechanism, but the exact relationship between shape changes and metabolic alterations is not well-understood. Here we explore how mitochondrial shape influences oxidative phosphorylation rates by performing simultaneous imaging and respiration measurements within intact cells. We observed that MO3.13 cells exposed to cuprizone undergo an initial increase in respiration followed by mitochondrial dysfunction and genetic dysregulation within 8 hours. Oxygen consumption was measured within 30 minutes of treatment and found to be elevated. This increase was followed by swelling of mitochondria over the first 8 hours, but preceded cell death by 24 hours. A transcriptomic analysis of early changes in cellular gene expression identified alterations within the electron transport chain, stress response pathways, and mitochondrial dynamics compared to control cells. These results suggest that pathological mitochondrial swelling is associated with increased oxygen consumption rates leading to transcriptional changes in respiratory complexes and ultimately mitochondrial failure.

bioRxivs

2020

Alexandra Taraboletti, Maryam Goudarzi, Abuzar Kabir, Bo-Hyun Moon, Evagelia C. Laiakis, Jerome Lacombe, Pelagie Ake, Sueoka Shoishiro, David Brenner, Albert J. Fornace, and Frederic Zenhausern

DOI: 10.1021/acs.jproteome.9b00142

The modern application of mass spectrometry-based metabolomics to the field of radiation assessment and biodosimetry has allowed for the development of prompt biomarker screenings for radiation exposure. Our previous work on radiation assessment, in easily accessible biofluids (such as urine, blood, saliva), has revealed unique metabolic perturbations in response to radiation quality, dose, and dose rate. Nevertheless, the employment of swift injury assessment in the case of a radiological disaster still remains a challenge as current sample processing can be time consuming and cause sample degradation. To address these concerns, we report a metabolomics workflow using a mass spectrometry-compatible fabric phase sorptive extraction (FPSE) technique. FPSE employs a matrix coated with sol–gel poly(caprolactone-b-dimethylsiloxane-b-caprolactone) that binds both polar and nonpolar metabolites in whole blood, eliminating serum processing steps. We confirm that the FPSE preparation technique combined with liquid chromatography-mass spectrometry can distinguish radiation exposure markers such as taurine, carnitine, arachidonic acid, α-linolenic acid, and oleic acid found 24 h after 8 Gy irradiation. We also note the effect of different membrane fibers on both metabolite extraction efficiency and the temporal stabilization of metabolites in whole blood at room temperature. These findings suggest that the FPSE approach could work in future technology to triage irradiated individuals accurately, via biomarker screening, by providing a novel method to stabilize biofluids between collection and sample analysis.

J. Proteome Res.

2019

Dan Morris,  Anthony Zampino, Alexandra Taraboletti,  Leah P. Shriver,  Tom. C. Leeper and  Christopher J. Ziegler

Paper Link

Hen egg white lysozyme catalyzes the polymerization of 2-ethynylpyridine in water as the singular protein catalyst. Inhibition and NMR spectroscopy studies support the hypothesis that polymerization takes place in the active site cleft of the protein. This discovery marks the first time a metal-free hydrolase has been observed activating the formation for a conjugated polymer.

Polymer Chemistry

2017

Alexandra Taraboletti , Tia Walker, Robin Avila, He Huang, Joel Caporoso, Erendra Manandhar, Thomas C. Leeper, David A. Modarelli, Satish Medicetty, and Leah P. Shriver

DOI: 10.1021/acs.biochem.6b01072

Cuprizone intoxication is a common animal model used to test myelin regenerative therapies to treat diseases such as multiple sclerosis. Mice fed this copper chelator develop reversible, region-specific oligodendrocyte loss and demyelination. While the cellular changes influencing the demyelinating process have been explored in this model, there is no consensus on the biochemical mechanisms of toxicity in oligodendrocytes and if this damage arises from the chelation of copper in vivo. Here we have identified an oligodendroglial cell line that displays sensitivity to cuprizone toxicity and performed global metabolomic profiling to determine biochemical pathways altered by this treatment. We link these changes with alterations in brain metabolism in mice fed cuprizone for two and six weeks. We find that cuprizone induces widespread changes in one carbon and amino acid metabolism as well as alterations in small molecules important for energy generation. We used mass spectrometry to examine chemical interactions important for copper chelation and toxicity. Our results indicate that cuprizone induces global perturbations in cellular metabolism that may be independent of its copper chelating ability and potentially related to its interactions with pyridoxal 5’-phosphate, a co-factor essential for amino acid metabolism.

Biochemistry

2017

Lucas McDonald, Bin Liu, Alexandra Taraboletti, Kyle Whiddon, Leah P. Shriver, Michael Konopka, Qin Liub and Yi Pang

doi: 10.1039/c6tb02456d

Visualization of subcellular organelles in vivo is critical for basic biomedical research and clinical applications. Two new flavonoids with an amide substituent were synthesized and characterized. The flavonoids were nearly non-fluorescent in aqueous environment, but exhibited two emission peaks (one λem at 495–536 nm and the other at 570–587 nm) in organic solvents, which were assigned to the excited normal (N*) and tautomer (T*) emission. When the dyes were examined on oligodendrocyte cells, they were found to selectively accumulate in the endoplasmic reticulum (ER), a eukaryotic organelle involved in lipid and protein synthesis, giving fluorescence turn-on. The ER-selective flavonoids could be a valuable tool due to its low molecular mass (<500), large Stokes' shift, low toxicity, and biocompatibility.

J. Mater. Chem. B

2016n

Kerri L. Shelton, Michael A. DeBord, Patrick O. Wagers, Marie R. Southerland, Alexandra Taraboletti, Nikki K. Robishaw, Daniel P. Jackson, Radisa Tosanovic, William G. Kofron, Claire A. Tessier, Sailaja Paruchuri, Leah P. Shriver, Matthew J. Panzner, and Wiley J. Youngs

https://doi.org/10.1016/j.tet.2016.07.068

The syntheses and characterization of C4 and C5 substituted N,N′-bis(arylmethyl)imidazolium salts with hydrophilic or lipophilic substituents on the imidazole ring are reported. A structure-activity relationship study revealed that the lipophilicity of groups at the C4 and C5 positions plays a crucial role in modulating the efficacy against select non-small cell lung cancer cell lines tested. Compounds 11–17 were determined to be the most active against the panel of cell lines studied. Compounds 11 and 12 were examined by the National Cancer Institute's Developmental Therapeutic Program where they were tested against the NCI-60 human cancer cell line panel in a one-dose and five-dose assay. Compound 11 had high activity against the nine lung cancer lines tested while 12 had cytotoxic effects against 59 of the 60 cell lines. Compound 11 was also studied in a murine model to determine its in vivo toxicity.

Tetrahedron

2016

He Huang, Alexandra Taraboletti, and Leah P. Shriver

DOI: 10.1016/j.redox.2015.04.011

Oxidative stress contributes to pathology associated with inflammatory brain disorders and therapies that upregulate antioxidant pathways may be neuroprotective in diseases such as multiple sclerosis. Dimethyl fumarate, a small molecule therapeutic for multiple sclerosis, activates cellular antioxidant signaling pathways and may promote myelin preservation. However, it is still unclear what mechanisms may underlie this neuroprotection and whether dimethyl fumarate affects oligodendrocyte responses to oxidative stress. Here, we examine metabolic alterations in oligodendrocytes treated with dimethyl fumarate by using a global metabolomic platform that employs both hydrophilic interaction liquid chromatography-mass spectrometry and shotgun lipidomics. Prolonged treatment of oligodendrocytes with dimethyl fumarate induces changes in citric acid cycle intermediates, glutathione, and lipids, indicating that this compound can directly impact oligodendrocyte metabolism. These metabolic alterations are also associated with protection from oxidant challenge. This study provides insight into the mechanisms by which dimethyl fumarate could preserve myelin integrity in patients with multiple sclerosis.

Redox Biology

2015

Y.J. Chen, S. Hill, H. Huang, A. Taraboletti, K. Cho, R. Gallo, M. Manchester, L.P. Shriver, and G.J. Patti

DOI: 10.1016/j.neuroscience.2014.08.011

Neuropathic pain is a chronic, refractory condition that arises after damage to the nervous system. We previously showed that an increased level of the endogenous metabolite N,N-dimethylsphingosine (DMS) in the central nervous system (CNS) is sufficient to induce neuropathic pain-like behavior in rats. However, several important questions remain. First, it has not yet been demonstrated that DMS is produced in humans and its value as a therapeutic target is therefore unknown. Second, the cell types within the CNS that produce DMS are currently unidentified. Here we provide evidence that DMS is present in human CNS tissue. We show that DMS levels increase in demyelinating lesions isolated from patients with multiple sclerosis, an autoimmune disease in which the majority of patients experience chronic pain. On the basis of these results, we hypothesized that oligodendrocytes may be a cellular source of DMS. We show that human oligodendrocytes produce DMS in culture and that the levels of DMS increase when oligodendrocytes are challenged with agents that damage white matter. These results suggest that damage to oligodendrocytes leads to increased DMS production which in turn drives inflammatory astrocyte responses involved in sensory neuron sensitization. Interruption of this pathway in patients may provide analgesia without the debilitating side effects that are commonly observed with other chronic pain therapies.

Neuroscience

2014

Richard G. Blair, Katerina Chagoya, Scott Biltek, Steven Jackson, Ashlyn Sinclair, Alexandra Taraboletti and  David T. Restrepo

https://doi.org/10.1039/C4FD00007B

Mechanochemical approaches to chemical synthesis offer the promise of improved yields, new reaction pathways, and greener syntheses. Scaling these syntheses is a crucial step toward realizing a commercially viable process. Although much work has been performed on laboratory-scale investigations little has been done to move these approaches toward industrially relevant scales. Moving reactions from shaker-type mills and planetary-type mills to scalable solutions can present a challenge. We have investigated scalability through discrete element models, thermal monitoring, and reactor design. We have found that impact forces and macroscopic mixing are important factors in implementing a truly scalable process. These observations have allowed us to scale reactions from a few grams to several hundred grams and we have successfully implemented scalable solutions for the mechanocatalytic conversion of cellulose to value-added compounds and the synthesis of edge-functionalized graphene.

Faraday Discussions

2014

Co-Author, Chapter 03- PFAS Toxicology for Water and Wastewater

Link: https://www.wef.org/publications/publications/books/pfas-in-the-water-and-wastewater-sectors-fundamentals-management-and-treatment/

This collection of essays provides a state of the field on PFAS from a variety of perspectives within the water sector. Contributors include experts in industrial wastewater, municipal water management, and public health, with each contributor highlighting a different facet of the impact of PFAS in water and wastewater and providing guidance on the responses necessary to limit the chemicals’ negative effects. The collection covers the current understanding of PFAS, the implications for human health, and the growing regulatory framework, as well as the various treatments available for water, wastewater, groundwater, biosolids, leachates, and soil/sediments. Our understanding of PFAS, its effects, and the necessary responses is still evolving—this collection is not intended to answer all outstanding questions, but rather to further this critical conversation within and around the water sector.

2023

Doctoral dissertation, University of Akron (2017)