Publications by authors named "Denise Fedele"

13 Publications

  • Page 1 of 1

Adenosine kinase: An epigenetic modulator in development and disease.

Neurochem Int 2021 Jul 5;147:105054. Epub 2021 May 5.

Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA; Department of Neurosurgery, New Jersey Medical School, Rutgers University, Newark, NJ 07102, USA; Brain Health Institute, Rutgers University, Piscataway, NJ 08854, USA. Electronic address:

Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5'-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). The two isoforms are developmentally regulated and are differentially expressed in distinct subcellular compartments with ADK-L localized in the nucleus and ADK-S localized in the cytoplasm. The nuclear localization of ADK-L and its biochemical link to the transmethylation pathway suggest a specific role for gene regulation via epigenetic mechanisms. Recent evidence reveals an adenosine receptor-independent role of ADK in determining the global methylation status of DNA and thereby contributing to epigenomic regulation. Here we summarize recent progress in understanding the biochemical interactions between adenosine metabolism by ADK-L and epigenetic modifications linked to transmethylation reactions. This review will provide a comprehensive overview of ADK-associated changes in DNA methylation in developmental, as well as in pathological conditions including brain injury, epilepsy, vascular diseases, cancer, and diabetes. Challenges in investigating the epigenetic role of ADK for therapeutic gains are briefly discussed.
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http://dx.doi.org/10.1016/j.neuint.2021.105054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178237PMC
July 2021

Adenosine Kinase Expression Determines DNA Methylation in Cancer Cell Lines.

ACS Pharmacol Transl Sci 2021 Apr 16;4(2):680-686. Epub 2021 Feb 16.

Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey 08854, United States.

DNA methylation has a major role in cancer, and its inhibitors are used therapeutically. DNA methylation depends on methyl group flux through the transmethylation pathway, which forms adenosine. We hypothesized that an adenosine kinase isoform with nuclear expression (ADK-L) determines global DNA methylation in cancer cells. We quantified ADK-L expression (Western Blot) and global DNA methylation as percent 5-methyldeoxycytidine (5mdC, LC-MS/MS) in three cancer lines (HeLa, HepG2, and U373). ADK-L expression and global DNA methylation correlated positively with the highest levels in HeLa cells compared to U373 and HepG2 cells. To determine whether ADK increases global DNA methylation and to validate its potential therapeutics, we treated HeLa cells with potent ADK inhibitors MRS4203 and MRS4380 (IC 88 and 140 nM, respectively). Both nucleosides, but not a structurally related poor ADK inhibitor, significantly reduced global DNA methylation in HeLa cells in a concentration-dependent manner. Thus, ADK-L is a potential target for the therapeutic manipulation of DNA methylation levels in cancer.
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http://dx.doi.org/10.1021/acsptsci.1c00008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033756PMC
April 2021

Suppression of phrenic nerve activity as a potential predictor of imminent sudden unexpected death in epilepsy (SUDEP).

Neuropharmacology 2021 02 16;184:108405. Epub 2020 Nov 16.

Department of Neurosurgery, Robert Wood Johnson and New Jersey Medical Schools, Rutgers University, Piscataway, NJ, 08854, USA; Brain Health Institute, Rutgers University, Piscataway, NJ, 08854, USA; Rutgers Neurosurgery H.O.P.E. Center, Department of Neurosurgery, Rutgers University, New Brunswick, NJ, 08901, USA. Electronic address:

Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death in patients with refractory epilepsy. Centrally-mediated respiratory dysfunction has been identified as one of the principal mechanisms responsible for SUDEP. Seizures generate a surge in adenosine release. Elevated adenosine levels suppress breathing. Insufficient metabolic clearance of a seizure-induced adenosine surge might be a precipitating factor in SUDEP. In order to deliver targeted therapies to prevent SUDEP, reliable biomarkers must be identified to enable prompt intervention. Because of the integral role of the phrenic nerve in breathing, we hypothesized that suppression of phrenic nerve activity could be utilized as predictive biomarker for imminent SUDEP. We used a rat model of kainic acid-induced seizures in combination with pharmacological suppression of metabolic adenosine clearance to trigger seizure-induced death in tracheostomized rats. Recordings of EEG, blood pressure, and phrenic nerve activity were made concomitant to the seizure. We found suppression of phrenic nerve burst frequency to 58.9% of baseline (p < 0.001, one-way ANOVA) which preceded seizure-induced death; importantly, irregularities of phrenic nerve activity were partly reversible by the adenosine receptor antagonist caffeine. Suppression of phrenic nerve activity may be a useful biomarker for imminent SUDEP. The ability to reliably detect the onset of SUDEP may be instrumental in the timely administration of potentially lifesaving interventions.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108405DOI Listing
February 2021

Role of Adenosine in Epilepsy and Seizures.

J Caffeine Adenosine Res 2020 Jun 4;10(2):45-60. Epub 2020 Jun 4.

Deptartment of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA.

Adenosine is an endogenous anticonvulsant and neuroprotectant of the brain. Seizure activity produces large quantities of adenosine, and it is this seizure-induced adenosine surge that normally stops a seizure. However, within the context of epilepsy, adenosine plays a wide spectrum of different roles. It not only controls seizures (ictogenesis), but also plays a major role in processes that turn a normal brain into an epileptic brain (epileptogenesis). It is involved in the control of abnormal synaptic plasticity and neurodegeneration and plays a major role in the expression of comorbid symptoms and complications of epilepsy, such as sudden unexpected death in epilepsy (SUDEP). Given the important role of adenosine in epilepsy, therapeutic strategies are in development with the goal to utilize adenosine augmentation not only for the suppression of seizures but also for disease modification and epilepsy prevention, as well as strategies to block adenosine A receptor overfunction associated with neurodegeneration. This review provides a comprehensive overview of the role of adenosine in epilepsy.
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http://dx.doi.org/10.1089/caff.2019.0022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301316PMC
June 2020

Adenosine A1 receptors are crucial in keeping an epileptic focus localized.

Exp Neurol 2006 Jul 5;200(1):184-90. Epub 2006 Jun 5.

Institute of Pharmacology and Toxicology, University of Zurich, CH-8057 Zurich, Switzerland.

Adenosine is an endogenous neuromodulator with anticonvulsant and neuroprotective properties presumably mediated by activation of adenosine A1 receptors (A1Rs). To study the involvement of A1Rs in neuroprotection during epileptogenesis, we induced status epilepticus by a unilateral intrahippocampal kainic acid (KA) injection (1 nmol) in wild-type C57BL/6 and homozygous adenosine A1R knock out (A1R-KO) mice of the same genetic background. Whereas the KA injection caused non-convulsive status epilepticus in wild-type mice, in A1R-KO mice KA induced status epilepticus with severe convulsions and subsequent death of the animals within 5 days. 24 h after KA injection, brains from wild-type C57BL/6 mice were characterized by slight neuronal cell loss confined to the immediate location of the KA injection. In contrast, KA-injected A1R-KO mice displayed massive neuronal cell loss in the ipsilateral hippocampus, and, importantly, the contralateral hippocampus was also affected with significant cell loss in the hilus and in the CA1 region of the pyramidal cell layer. We conclude that activation of A1 receptors by ambient adenosine is crucial in keeping epileptic foci localized. These results open up a new dimension of the A1 receptor's role in controlling excitotoxic cell death and further demonstrate its importance in preventing the progression of status epilepticus to lethal consequences.
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http://dx.doi.org/10.1016/j.expneurol.2006.02.133DOI Listing
July 2006

The support of adenosine release from adenosine kinase deficient ES cells by silk substrates.

Biomaterials 2006 Sep 18;27(26):4599-607. Epub 2006 May 18.

Institute for Pharmaceutical Sciences, Drug Formulation and Delivery, ETH Zurich, CH 8093 Zurich, Switzerland.

Adenosine kinase deficient (Adk-/-) embryonic stem cells (ESCs) encapsulated in synthetic polymers have previously been shown to provide therapeutic adenosine release and transient seizure suppression in epileptic rats. Here we explored the utility of biopolymer-substrates to promote long-term adenosine release from Adk-/- ESCs. Three different substrates were studied: (1) type I collagen (Col-1), (2) silk-fibroin (SF), and (3) poly(L-ornithine) (PO) coated tissue culture plastic. Adk-/- or wild type (wt) ESC-derived glial precursor cells were seeded on the substrates and cultured either in proliferation medium containing growth factors or in differentiation medium devoid of growth factors. In proliferation medium cell proliferation was higher and metabolic activity lower on Col-1 and PO substrates as compared to SF. Cells from both genotypes readily differentiated into astrocytes after growth factor removal on all substrates. Adk-/- cells cultured on biopolymers released significantly more adenosine than their wt counterparts at all developmental stages. Adenosine release was similar on SF and PO substrates and the amounts released from Adk-/- cells (>20 ng/ml) were considered to be of therapeutic relevance. Taken together, these results suggest that silk matrices are particularly suitable biomaterials for ESC encapsulation and for the design of adenosine releasing bioincubators for the treatment of epilepsy.
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http://dx.doi.org/10.1016/j.biomaterials.2006.04.025DOI Listing
September 2006

Older adults--implications for private dental practitioners.

J Calif Dent Assoc 2005 Sep;33(9):695-703

Dentsply International, USA.

Currently, 35 million people are over the age of 65 in the United States. This number is expected to double to 70 million by 2030 (Figure 1). In California, 3.7 million people are over the age of 65, and this number is expected to increase to 6.4 million in the next 20 years or within the practice lifetime of students presently enrolled in California's dental hygiene and dental schools. The oldest old, those over age 85, are the fastest-growing segment of the United States and California's population. California's aging population will reflect the diversity of the state in general. Table 1 lists California's 65-plus population by age and ethnic/racial categories. By 2030, one in five Americans and Californians will be 65 years or older. Women who reach age 65 can expect to live an additional 19 years of life, while men can expect to live an additional 16 years. The gap in life expectancy between men and women is narrowing due to improvements in medical care, preventive health services, and healthier lifestyles. Figures 2-4 show the improvements in life expectancy at birth, age 65, and age 75 for the U.S. population. In the United States, there are an estimated 1.8 million nursing home beds used by 80 percent of the residents over age 65. A report by the U.S. General Accounting Office estimated that 43 percent of all Americans over age 65 will reside in a nursing home at some time in their life. California currently has approximately 100,000 residents living in one of the 1503 nursing home facilities throughout the state. Nursing home care in California accounts for 5.6 billion dollars. In 1998, the U.S. General Accounting Office reported that one in three California nursing homes was cited for serious or potentially life-threatening care problems. With an aging imperative in California, this paper will discuss the implications of an aging society on maintaining oral health throughout one's life, and the ability of dental professionals to meet the oral health needs of this population.
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September 2005

Suppression of kindled seizures by paracrine adenosine release from stem cell-derived brain implants.

Epilepsia 2005 Aug;46(8):1162-9

Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.

Purpose: Stem cells and their derivatives have emerged as a promising tool for cell-based drug delivery because of (a) their unique ability to differentiate into various somatic cell types, (b) the virtually unlimited donor source for transplantation, and (c) the advantage of being amenable to a wide spectrum of genetic manipulations. Previously, adenosine-releasing embryonic stem (ES) cells have been generated by disruption of both alleles of adenosine kinase (Adk-/-). Lack of ADK did not compromise the cells' differentiation potential into embryoid bodies or glial precursor cells. The aim of the present study was to investigate the potential of differentiated Adk-/- ES cell progeny for seizure suppression by paracrine adenosine release.

Methods: To isolate paracrine effects of stem cell-derived implants from effects caused by network integration, ES cell-derived embryoid bodies and glial precursor cells were encapsulated into semipermeable polymer membranes and grafted into the lateral brain ventricles of kindled rats.

Results: While seizure activity in kindled rats with wild-type Adk+/+ implants remained unaltered, rats with adenosine-releasing Adk-/- ES cell-derived implants displayed transient protection from convulsive seizures and a profound reduction of afterdischarge activity in EEG recordings. Long-term seizure suppression was precluded by limited viability of the encapsulated cells.

Conclusions: We thereby provide a proof-of-principle that Adk-/- ES cell-derived brain implants can suppress seizure activity by a paracrine mode of action. Adk-deficient stem cells therefore represent a potential tool for the treatment of epileptic disorders.
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http://dx.doi.org/10.1111/j.1528-1167.2005.61804.xDOI Listing
August 2005

Astrogliosis in epilepsy leads to overexpression of adenosine kinase, resulting in seizure aggravation.

Brain 2005 Oct 1;128(Pt 10):2383-95. Epub 2005 Jun 1.

Institute of Pharmacology and Toxicology, University of Zurich, Switzerland.

Adenosine kinase (ADK) is considered to be the key regulator of the brain's endogenous anticonvulsant, adenosine. In adult brain, ADK is primarily expressed in a subpopulation of astrocytes and striking upregulation of ADK in these cells has been associated with astrogliosis after kainic acid-induced status epilepticus (KASE) in the kainic acid mouse model of temporal lobe epilepsy. To investigate the causal relationship between KASE-induced astrogliosis, upregulation of ADK and seizure activity, we have developed a novel mouse model [the Adktm1(-/-)-Tg(UbiAdk) mouse] lacking the endogenous astrocytic enzyme due to a targeted disruption of the endogenous gene, but containing an Adk transgene under the control of a human ubiquitin promoter. Mutant Adktm1(-/-)-Tg(UbiAdk) mice were characterized by increased brain ADK activity and constitutive overexpression of transgenic ADK throughout the brain, with particularly high levels in hippocampal pyramidal neurons. This ADK overexpression was associated with increased baseline levels of locomotion. Most importantly, two-thirds of the mutant mice analysed exhibited spontaneous seizure activity in the hippocampus and cortex. This was the direct consequence of transgene expression, since this seizure activity could be prevented by systemic application of the ADK inhibitor 5-iodotubercidin. Intrahippocampal injection of kainate in the mutant mice resulted in astrogliosis to the same extent as that observed in wild-type mice despite the absence of endogenous astrocytic ADK. Therefore, KASE-induced upregulation of endogenous ADK in wild-type mice is a consequence of astrogliosis. However, seizures in kainic acid-injected mutants displayed increased intra-ictal spike frequency compared with wild-type mice, indicating that, once epilepsy is established, increased levels of ADK aggravate seizure severity. We therefore conclude that therapeutic strategies that augment the adenosine system after astrogliosis-induced upregulation of ADK constitute a neurochemical rationale for the prevention of seizures in epilepsy.
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http://dx.doi.org/10.1093/brain/awh555DOI Listing
October 2005

Gene dose-dependent alterations in extraneuronal serotonin but not dopamine in mice with reduced serotonin transporter expression.

J Neurosci Methods 2004 Dec;140(1-2):169-81

Department of Chemistry, The Pennsylvania State University, 104 Chemistry Building, University Park, PA 16802-6300, USA.

Serotonin (5-HT) plays an integral regulatory role in mood, anxiety, cognition, appetite and aggressive behavior. Many therapeutic and illicit drugs that modulate these functions act at the serotonin transporter (SERT), thus a mouse model with reduced transporter expression was created to further investigate the effects of differential serotonin reuptake. In the present study, in vivo microdialysis was used to determine homeostatic alterations in extracellular 5-HT levels in unanesthetized SERT knockout mice. SERT(-/-) mice had significantly higher levels of basal dialysate 5-HT than SERT(+/+) mice in striatum and frontal cortex. In addition, although gene-specific increases in 5-HT were evident, neuroadaptive alterations in dialysate dopamine levels were not detected in striatum. Zero net flux microdialysis was utilized to further investigate alterations in extracellular 5-HT. Using this method, a gene dose-dependent increase in extraneuronal 5-HT was observed in striatum (2.8 +/- 1, 9.4 +/- 1 and 18 +/- 3 nM) and frontal cortex (1.4 +/- 0.4, 3.5 +/- 0.9 and 14 +/- 1 nM) in SERT(+/+), SERT(+/-) and SERT(-/-) mice, respectively. Potassium stimulation revealed greater depolarization-induced increases in striatal 5-HT but not dopamine in SERT(-/-) mice. Furthermore, dialysate 5-hydroxyindoleacetic acid (5-HIAA) levels were reduced in striatum in a gene dose-dependent manner, while DOPAC was unchanged in SERT knockout mice. Finally, determination of monoamine oxidase (MAO) activity revealed no significant differences in KM or Vmax of type-A or type-B isozymes indicating that alterations in SERT expression do not cause adaptive changes in the activities of these key catabolic enzymes. Overall, these results demonstrate that constitutive reductions in SERT are associated with increases in 5-HT in the extracellular signaling space in the absence of changes in dopamine neurochemistry. Furthermore, use of zero net flux microdialysis appears warranted in investigations of serotonergic synaptic function where modest changes in extracellular 5-HT are thought to occur in response to altered uptake.
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http://dx.doi.org/10.1016/j.jneumeth.2004.05.017DOI Listing
December 2004

Engineering embryonic stem cell derived glia for adenosine delivery.

Neurosci Lett 2004 Nov;370(2-3):160-5

Institute of Pharmacology and Toxicology, University of Zürich, CH-8057 Zürich, Switzerland.

Based on the anticonvulsant and neuroprotective properties of adenosine, and based on the long-term survival potential of stem cell derived brain implants, adenosine releasing stem cells may constitute a novel tool for the treatment of epilepsy. Pluripotency and unlimited self-renewal make embryonic stem (ES) cells a particularly versatile donor source for cell transplantation. With the aim to test the feasibility of a stem cell-based delivery system for adenosine, both alleles of adenosine kinase (ADK), the major adenosine-metabolizing enzyme, were disrupted by homologous recombination in ES cells. Adk-/- ES cells were subjected to a glial differentiation protocol and, as a result, gave rise to proliferating glial precursors, which could be further differentiated into mature astrocytes and oligodendrocytes. Thus, a lack of ADK does not compromise the glial differentiation potential of ES cells. The Adk-/- ES cells yielded glial populations with an adenosine release of up to 40.1 +/- 6.0 ng per 10(5) cells per hour, an amount considered to be sufficient for seizure suppression. Our findings indicate that Adk-/- ES cells constitute a potential source for therapeutic adenosine releasing grafts.
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http://dx.doi.org/10.1016/j.neulet.2004.08.031DOI Listing
November 2004

Aging successfully: oral health for the prime of life.

Compend Contin Educ Dent 2002 Oct;23(10 Suppl):4-11

DENTSPLY International York, Pennsylvania, USA.

Aging is a worldwide phenomena. More adults, particularly those in developed countries, are living longer and healthier lives. The average US life expectancy was 47 years in 1900; by 2000, it had increased to 74 years. As the population ages, the number of adults with acute and chronic illnesses increases. The use of medications also increases with age. People over 65 years of age make up about 12% of the US population, but they consume 30% of all prescription medications, many of which can have a negative impact on oral health. Although tooth loss is declining in US adults, the need for various types of dental services in the adult population continues to increase. Data on the use of dental services has shown that dental visits by older adults correlate with the presence of teeth, not age. Research on the epidemiology of periodontal disease in older adults suggests that the disease in older adults is probably not due to greater susceptibility but, instead, the result of cumulative disease progression over time. Data on root caries has shown that exposed root surfaces, in combination with compromised health status and the use of multiple medications, can increase an older adult's risk for root caries. Oral candidiasis commonly occurs in immunocompromised individuals of any age, but in older adults, nursing home residents are particularly susceptible. Oral cancer is a disease of older adults, with a median age of 64 at diagnosis. Tobacco and alcohol use are the most common risk factors. Mental or physical impairments, such as dementing illnesses, or impaired dexterity as a result of arthritis or stroke, can impair an adult's ability to perform adequate oral self-care. Preventing oral diseases in older adults requires an understanding of the risk factors for oral diseases and how these risk factors change over time. Of particular concern are nursing home residents, who remain the most vulnerable of elders. Incorporating preventive oral health strategies into dental treatment and nursing home care will play a critical role in maintaining oral health for a lifetime. Oral health education of family, caregivers, and nursing home staff is essential if oral diseases are to be avoided later in life.
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October 2002

Oral health in the elderly with non-insulin-dependent diabetes mellitus.

Spec Care Dentist 2002 May-Jun;22(3):94-8

Geriatric Dental Programs, Department of Veteran Affairs, Medical Center at Perry Point, MD, USA.

Non-insulin-dependent diabetes mellitus (NIDDM) is a common endocrine disease affecting the elderly in particular. Long-term complications involve the vasculature; vision, renal, and neural function; and the periodontium. Knowledge about the oral health of the elderly and the effects of NIDDM is limited. The objective of this study was to compare the oral health of patients aged 60+ years, who have NIDDM, with patients who do not have NIDDM. To evaluate oral health, we recorded retention and condition of the teeth, periodontal health, and condition of the oral mucosa. We also assessed oral hygiene, smoking history, regularity of dental checkups, and medication use. The study group was selected from among patients who came to the ambulatory care clinic at University of Medicine and Dentistry, New Jersey, Center for Aging with a diagnosis of NIDDM. The control group, which did not have NIDDM, was selected from among the same patient group and was matched for age and gender. Patients with severe dementia, those having fewer than 10 teeth or those who were in need of antibiotic prophylaxis were excluded from the study. Patients underwent a short interview and a clinical evaluation. Our study involved 32 elderly adults with NIDDM and 40 elderly adults who did not have NIDDM. Both groups had similar oral hygiene levels and regularity of professional dental care. In addition, the plasma glucose levels among the study group were well controlled. This study did not show statistically significant differences in oral health parameters between participants with diabetes and those in a control group.
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http://dx.doi.org/10.1111/j.1754-4505.2002.tb01169.xDOI Listing
December 2002