Maria Eugenia Ariza

The Ohio State University | OSU · Department of Cancer Biology and Genetics

Myalgic Encephalomyelitis/ Chronic Fatigue syndrome (ME/CFS) is a complex, debilitating, long-term illness without a diagnostic biomarker. ME/CFS patients share overlapping symptoms with long COVID patients, an observation which has strengthened the infectious origin hypothesis of ME/CFS. However, the exact sequence of events leading to disease dev...

There is increasing evidence that put into question the classical dogma that the Epstein–Barr virus (EBV) exists in cells as either a lytic virus in which new progeny is produced or in a latent state in which no progeny is produced. Notably, a third state has now been described, known as the abortive-lytic phase, which is characterized by the expre...

First exposure to various human herpesviruses (HHVs) including HHV-6, HCMV and EBV does not cause a life-threatening disease. In fact, most individuals are frequently unaware of their first exposure to such pathogens. These herpesviruses acquire lifelong latency in the human body where they show minimal genomic activity required for their survival....

Rationale: The role of neutrophils and their extracellular vesicles (EVs) in the pathogenesis of pulmonary arterial hypertension is unclear. Objectives: Relate functional abnormalities in pulmonary arterial hypertension neutrophils and their EVs to mechanisms uncovered by proteomic and transcriptomic profiling. Methods: Production of elastase,...

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating multisystem illness of unknown etiology for which there is no cure and no diagnostic tests available. Despite increasing evidence implicating EBV and human herpesvirus-6A (HHV-6A) as potential causative infectious agents in a subset of ME/CFS patients, there are...

Members of the human Herpesviridae are found in high prevalence in the human virome. While these viruses are known to cause numerous disease pathologies in symptomatic individuals little is known concerning the role that these viruses may have in modulating the host immune system in asymptomatic “healthy” individuals especially during the aging pro...

Most free-living organisms encode for a deoxyuridine triphosphate nucleotidohydrolase (dUTPase; EC 3.6.1.23). dUTPases represent a family of metalloenzymes that catalyze the hydrolysis of dUTP to dUMP and pyrophosphate, preventing dUTP from being incorporated into DNA by DNA polymerases, maintaining a low dUTP/dTTP pool ratio and providing a necess...

Previously we reported heightened expression of human endogenous retroviral protein HERV-K deoxyuridine triphosphate nucleotidohydrolase (dUTPase) in circulating monocytes and pulmonary arterial (PA) adventitial macrophages of PA hypertension (PAH) patients. Furthermore, recombinant HERV-K dUTPase increased IL6 in PA endothelial cells (PAECs) and c...

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) is a chronic multisystem illness of unconfirmed etiology. There are currently no biomarkers and/or signatures available to assist in the diagnosis of the syndrome and while numerous mechanisms have been hypothesized to explain the pathology o...

Neutrophil elastase (NE) is implicated in pulmonary arterial hypertension (PAH) but the role of neutrophils in the pathogenesis of PAH is unclear. Here we show that neutrophils from PAH vs. control subjects produce and release increased NE associated with enhanced extracellular trap formation. PAH neutrophils are highly adherent and show decreased...

Purpose: Neuroinflammation is a common feature in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), affecting 85%-90% of all patients, yet the underlying mechanism or mechanisms responsible for the initiation and/or promotion of this process is largely unknown. Multiple reports, however, have suggested a role for Epstein-Barr virus (EBV...

The Epstein-Barr virus (EBV), which is a ubiquitous γ-herpesvirus, establishes a latent infection in more than 90% of the global adult population. EBV-associated malignancies have increased by 14.6% over the last 20 years, and account for approximately 1.5% of all cancers worldwide and 1.8% of all cancer deaths. However, the potential involvement/c...

Background: Immune dysregulation has been linked to occlusive vascular remodeling in pulmonary arterial hypertension (PAH) that is hereditary, idiopathic, or associated with other conditions. Circulating autoantibodies, lung perivascular lymphoid tissue, and elevated cytokines have been related to PAH pathogenesis but without a clear understanding...

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI) are debilitating diseases with overlapping symptomology and there are currently no validated tests for definitive diagnosis of either syndrome. While there is evidence supporting the premise that some herpesviruses may act as possible triggers of ME/CFS, the invo...

The human herpesviruses are ubiquitous viruses and have a prevalence of over 90% in the adult population. Following a primary infection they establish latency and can be reactivated over a person's lifetime. While it is well accepted that human herpesviruses are implicated in numerous diseases ranging from dermatological and autoimmune disease to c...

Most adult humans have been infected with Epstein-Barr virus (EBV), which is thought to contribute to the development of chronic fatigue syndrome. Stress is known to influence the immune system and can exacerbate the sickness response. Although a role for psychological stress in the sickness response, particularly in combination with EBV-encoded de...

We have previously shown that Epstein-Barr virus (EBV)-encoded dUTPase can modulate innate immune responses through the activation of TLR2 and NF-κB signaling. However, whether this novel immune function of the dUTPase is specific for EBV or a common property of the Herpesviridae family is not known. In this study, we demonstrate that the purified...

Psoriasis is a chronic, immune skin disease associated with significant morbidity. Development of psoriasis is influenced by numerous genes, one allele is HLA-CW*0602. Other genes and single nucleotide polymorphisms affect immunologic pathways and antimicrobial peptide synthesis. Dendritic cells initiate psoriasis by activating T-cells toward a Th1...

Most adult humans have been infected by Epstein-Barr virus (EBV), a putative cause of chronic fatigue syndrome, and carry latent EBV. The EBV-encoded dUTPase can induce sickness responses in mice and chronic stress exacerbates this response. Because individuals often adapt to chronic stress, we tested the hypothesis that acute restraint stress woul...

The role of viral infections in the pathogenesis of atherosclerosis remains controversial largely due to inconsistent detection of the virus in atherosclerotic lesions. However, viral infections elicit a pro-inflammatory cascade known to be atherogenic and to precipitate acute ischemic events. We have published in vitro data that provide the founda...

We have recently demonstrated that Epstein-Barr virus (EBV)-encoded deoxyuridine triphosphate nucleotidohydrolase (dUTPase) modulates innate immunity in human primary monocyte-derived macrophages through toll-like receptor (TLR) 2 leading to NF-κB activation and the production of pro-inflammatory cytokines. Our previous depletion studies indicated...

A defined diagnostic panel differentiated patients who had been diagnosed with chronic fatigue syndrome (CFS), based upon Fukuda/Carruthers criteria. This diagnostic panel identified an Epstein-Barr virus (EBV) subset of patients (6), excluding for the first time other similar "clinical" conditions such as cytomegalovirus (CMV), human herpesvirus 6...

Silver nanomaterials are the major components of healthcare products largely because of their antimicrobial effects. However, their unintended toxicity to biological organisms and its mechanism are not well understood. Using medaka fish embryo model, the toxic effects and corresponding mechanisms of silver nanocolloids (SNC, particle size 3.8 ± 1.0...

Previous genetic and functional studies have implicated the human endogenous retrovirus K (HERV-K) dUTPase located within the PSORS1 locus in the major histocompatibility complex region as a candidate psoriasis gene. Here, we describe a variant discovery and case-control association study of HERV-K dUTPase variants in 708 psoriasis cases and 349 he...

Psoriasis is a chronic inflammatory immune disease of the skin characterized by a complex interplay between multiple risk genes and their interactions with environmental factors. Recent haplotype analyses have suggested that deoxyuridine triphosphate nucleotidohydrolase (dUTPase) encoded by a human endogenous retrovirus K (HERV-K) may be a candidat...

Inflammation and lung remodeling are hallmarks of asbestos-induced fibrosis, but the molecular mechanisms that control these events are unclear. Using laser capture microdissection (LCM) of distal bronchioles in a murine asbestos inhalation model, we show that osteopontin (OPN) is up-regulated by bronchiolar epithelial cells after chrysotile asbest...

Bryostatin-1 (Bryo-1), a natural macrocyclic lactone, is clinically used as an anti-cancer agent. In this study, we demonstrate for the first time that Bryo-1 acts as a Toll-like receptor 4 (TLR4) ligand. Interestingly, activation of bone marrow-derived dendritic cells (in vitro with Bryo-1) led to a TLR4-dependent biphasic activation of nuclear fa...

The innate immune response plays a key role as the primary host defense against invading pathogens including viruses. We have previously shown that treatment of human monocyte-derived macrophages with EBV-encoded dUTPase induces the expression of proinflammatory cytokines through the activation of NF-kappaB. However, the receptor responsible for EB...

Fas receptor-Fas ligand interaction appears to be important in carcinogenesis, tumour outgrowth and metastasis. Emerging evidence suggests that CDK11 (cyclin-dependent kinase 11) plays a role in apoptosis and melanoma development. Here, we show that CDK11p110 protein kinase was cleaved after induction of apoptosis by Fas. The N-terminal portion of...

Uracil-DNA glycosylase (UNG) is the primary enzyme responsible for removing uracil residues from DNA. Increasing evidence suggests that UNG may be a potential target for the development of novel antiviral and/or anticancer agents. To determine whether the uracil-DNA glycosylase inhibitor protein (UGI) could be used to specifically target UNGs intra...

Nucleosides are currently used in the treatment of many infections caused by viruses and against various cancers. The principal historic limitations of the development of nucleoside drugs that either directly inhibit DNA or RNA polymerases or that inhibit RNA and DNA replication by virtue of their ability to act as alternative substrates for these...

We demonstrated that the uracil-DNA glycosylase inhibitor, when delivered to human melanoma cells using protein transduction technology, resulted in a dose and time dependent inhibition of uracil-DNA glycosylase (UNG) and this inhibited cell proliferation. These results suggest that a novel class of inhibitors specifically targeting UNG can be deve...

Uracil residues arise in DNA through the misincorporation of deoxyuridine triphosphate (dUTP) by DNA polymerizing enzymes (DNA polymerases and reverse transcriptases) and from the deamination of deoxycytidine residues in DNA. The detrimental effects of uracil residues in DNA are well established. However, recent studies have demonstrated, that the...

Apoptosis-associated speck-like protein containing a Caspase recruitment domain (ASC) belongs to a large family of proteins that contain a Pyrin, AIM, ASC, and death domain-like (PAAD) domain (also known as PYRIN, DAPIN, Pyk). Recent data have suggested that ASC functions as an adaptor protein linking various PAAD-family proteins to pathways involv...

PAAD domains are found in diverse proteins of unknown function and are structurally related to a superfamily of protein interaction modules that includes death domains, death effector domains, and Caspase activation and recruitment domains. Using bioinformatics strategies, cDNAs were identified that encode a novel protein of 110 kDa containing a PA...

Chromosomal aberrations in malignant melanoma cells have been reported using standard chromosome banding analysis and comparative genomic hybridization. To identify marker chromosomes and translocations that are difficult to characterize by standard banding analysis, 15 early passage malignant melanoma cell lines were examined using spectral karyot...

The Cdc2L locus encoding the PITSLRE protein kinases maps to chromosome band 1p36 and consists of two duplicated and tandemly linked genes. The purpose of the present study was to determine whether diminution of PITSLRE kinases leads to deregulation of apoptosis. The human melanoma cell lines A375 (Cdc2L wild-type alleles) and UACC 1227 (mutant Cdc...

The two genes encoding the PITSLRE protein kinase isoforms, CDC2L1 and CDC2L2, are localized to human chromosome band 1p36. The PITSLRE protein kinases are a part of the p34cdc2 supergene family. Several protein products of the CDC2L locus may be effector(s) in apoptotic signaling. The larger PITSLRE p110 isoforms appear to regulate some aspect of...

Lead and mercury are toxic metals that are widely distributed in the atmosphere, soil, and groundwater. It is estimated that 2-4 x 10(4) tons of these metals are released annually into the environment by natural and industrial processes. Therefore, human exposure to low relatively nontoxic concentrations of these metals is unavoidable. However, the...

In the last decade, there have been major advances in the fields of cell biology and molecular biology, which have provided insight into the biochemical mechanisms that control cell proliferation.We now have an understanding of the molecular processes that are required for duplication of a cell and how disruption of these processes can result in ce...

There is no doubt that exposure of humans to high concentrations of metal and metalloid compounds results in the development of specific diseases and in some cases death. Blackfoot disease, hard metal lung disease, itai-itai and Minamata disease are well characterized diseases that are associated with metal exposure. Acute or chronic exposure to me...

Metals and metalloids are elements present in every phase of the environment. Some of these elements are essential for life, while others have no known biological function (Table 1 and 2). The effects of metals, metalloids and compounds of these elements on health and behavior have been studied for hundreds of years. Large amounts of data have been...

Data obtained from epidemiological studies in humans and from experimental studies using animal models have demonstrated that some metal and metalloid compounds are carcinogenic. These studies stimulated investigations to determine the mechanism(s) by which metal and metalloid compounds are carcinogenic. As with any field of science, many mechanism...

The adverse effects of metals and metalloids on human health are well documented. Blackfoot disease (arsenic), hard-metal lung disease (cobalt and nickel), itai-itai disease (cadmium) and Minamata disease (methylmercury) are recognized clinical entities. There have been numerous studies performed, using different model systems, to determine the eff...

There is increasing evidence to support the concept that the cellular redox (reduction/oxidation) status regulates various cellular processes, including signal transduction, gene expression, cellular proliferation (cell cycle) and cell death (necrotic and apoptotic).The redox status of a cell reflects a delicate balance between two opposing factors...

It has been suggested that reactive oxygen intermediates (ROIs) may have a role in the genotoxic effects of lead (Pb2+) and mercury (Hg2+), but there have not been any definitive studies demonstrating a causal relationship between the induction of ROIs by these metals and mutagenesis. We previously demonstrated, using the transgenic Chinese hamster...

Ascorbic acid (AA) has both antioxidant and prooxidant activities. However, there have not been any studies to elucidate the molecular mechanisms that determine whether AA functions as an anti- or a prooxidant during oxidative stress. The results of this study, using the Chinese hamster ovary cell line AS52 as a model system, demonstrate that there...

Co-culture of AS52 cells with peripheral blood leukocytes (PBLs), obtained from SENCAR mice topically treated with either tetradecanoyl-phorbol-13-acetate (TPA) or 7,12-dimethylbenz[a]anthracene (DMBA)-TPA, resulted in a 7-160-fold increase in the mutation frequency of the gpt gene in AS52 cells when compared to that induced by PBLs isolated from m...

Little is known at the molecular level concerning the genotoxic effects following the acute exposure of eukaryotic cells to low concentrations of lead (II) or mercury (II). There have been conflicting reports concerning the mutagenic potential of these heavy metals, and there have not been any studies performed to determine the molecular mechanism(...

Acute exposure of KB and Chinese hamster ovary cells (AS52) to low concentrations of mercury (II) results in a dose dependent binding of mercury to DNA. This binding of mercury (II) to the DNA occurs at concentrations of mercury that have little if any effect on glutatione levels or on superoxide dismutase activity. Mutational studies with AS52 cel...