A5067062682- HIV Research and Treatment
- Neuroinflammation and Neurodegeneration Mechanisms
- Cancer-related Molecular Pathways
- Cytomegalovirus and herpesvirus research
- Alzheimer's disease research and treatments
- HIV-related health complications and treatments
- HIV/AIDS Research and Interventions
- Neuroscience and Neuropharmacology Research
- Endoplasmic Reticulum Stress and Disease
- Neurogenesis and neuroplasticity mechanisms
- Epigenetics and DNA Methylation
- Tryptophan and brain disorders
- Genomics, phytochemicals, and oxidative stress
- Genetics and Neurodevelopmental Disorders
- Genomics and Chromatin Dynamics
- Retinoids in leukemia and cellular processes
- RNA Research and Splicing
- Adenosine and Purinergic Signaling
- Nuclear Receptors and Signaling
- Mosquito-borne diseases and control
- RNA regulation and disease
- interferon and immune responses
- Calcium signaling and nucleotide metabolism
- Neurological Complications and Syndromes
- Amyotrophic Lateral Sclerosis Research
University of Pennsylvania
2016-2025
Philadelphia University
2023
California University of Pennsylvania
2022
Translational Therapeutics (United States)
2020
Children's Hospital of Philadelphia
2011-2019
Drexel University
2019
Children's Hospital of Los Angeles
2011
University of Southern California
2011
University of Dental Medicine
2011
University of Pittsburgh Medical Center
2004
In response to oxidative stress, the nuclear factor E2-related 2 (Nrf2) transcription translocates from cytoplasm into nucleus and transactivates expression of genes with antioxidant activity. Despite this cellular mechanism, damage is abundant in Alzheimer Parkinson disease (AD PD). To investigate mechanisms by which Nrf2 activity may be aberrant or insufficient neurodegenerative conditions, we assessed localization affected brain regions AD, Lewy body variant AD (LBVAD), PD. By...
Recent evidence indicates that cyclin-dependent kinases (CDKs, cdks) may be inappropriately activated in several neurodegenerative conditions. Here, we report cdk5 expression and activity are elevated after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin damages the nigrostriatal dopaminergic pathway. Supporting pathogenic significance alterations findings general cdk inhibitor, flavopiridol, or dominant-negative cdk5, to lesser extent cdk2, attenuates loss...
HIV-associated neurocognitive disorder (HAND), characterized by a wide spectrum of behavioral, cognitive, and motor dysfunctions, continues to affect approximately 50 % HIV(+) patients despite the success combination antiretroviral drug therapy (cART) in periphery. Of note, potential toxicity drugs central nervous system (CNS) remains remarkably underexplored may contribute persistence HAND cART era. Previous studies have shown antiretrovirals (ARVs) be neurotoxic peripheral vivo neurons...
Copper is an essential metal nutrient for life that often relies on redox cycling between Cu(I) and Cu(II) oxidation states to fulfill its physiological roles, but alterations in cellular status can lead imbalances copper homeostasis contribute cancer other metalloplasias with metal-dependent disease vulnerabilities. Copper-responsive fluorescent probes offer powerful tools study labile pools, most of these reagents target Cu(I), limited methods monitoring owing potent fluorescence quenching...
Despite antiretroviral therapy (ART), HIV infection promotes cognitive dysfunction and neurodegeneration through persistent inflammation neurotoxin release from infected and/or activated macrophages/microglia. Furthermore, immune activation within both the CNS periphery correlate with disease progression morbidity in ART-treated individuals. Accordingly, drugs targeting these pathological processes systemic compartments are needed for effective, adjunctive therapy. Using our vitro model of...
HIV-associated neurocognitive disorders (HAND) affect over half of HIV-infected individuals, despite antiretroviral therapy (ART). Therapeutically targetable mechanisms underlying HAND remain elusive, partly due to a lack representative model. We developed human-induced pluripotent stem cell (hiPSC)-based model, independently differentiating hiPSCs into neurons, astrocytes, and microglia, systematically combining generate tri-culture with or without HIV infection ART. Single-cell RNA...
The presence of HIV in sequestered reservoirs is a central impediment to functional cure, allowing persist despite life-long antiretroviral therapy (ART), and driving variety comorbid conditions. Our understanding the latent reservoir nervous system incomplete, because difficulties accessing human tissues. Microglia contribute reservoirs, but molecular phenotype HIV-infected microglia poorly understood. We leveraged unique "Last Gift" rapid autopsy program, which people with are closely...
Cellular mechanisms implicated in Parkinson disease (PD) include oxidative stress, inflammatory response, excess dopamine, DNA damage, and loss of trophic support. These stimuli have been observed to induce changes cell cycle proteins several types. One the key regulators progression is retinoblastoma protein (pRb); therefore, we assessed staining for pRb its inactive hyperphosphorylated isoform, ppRb, autopsy tissue from patients with PD. In PD found abundant neuronal cytoplasm substantia...
Neuronal damage in human immunodeficiency virus type 1 (HIV-1) infection the brain is thought to occur at least part through NMDA receptor (NMDAR) excitation initiated by soluble neurotoxins from HIV-infected macrophages. Furthermore, regions enriched NMDAR-2A (NR2A) and NMDAR-2B (NR2B) subunits, such as hippocampus, are particularly vulnerable. Using cultured rat hippocampal cells HIV-1-infected monocyte-derived macrophages (HIV/MDM), we examined role of NR2A NR2B HIV/MDM-induced neuronal...
Heme oxygenase-1 (HO-1) is an inducible, detoxifying enzyme that critical for limiting oxidative stress, inflammation, and cellular injury within the CNS other tissues. Here, we demonstrate a deficiency of HO-1 expression in brains HIV-infected individuals. This correlated with cognitive dysfunction, HIV replication CNS, neuroimmune activation. In vitro analysis macrophages, primary reservoir along microglia, demonstrated decrease as increased. increased culture supernatant glutamate...
J. Neurochem. (2011) 118 , 1113–1123. Abstract Excitotoxic neuronal damage via over‐activation of the NMDA receptor has been implicated in many neurodegenerative diseases. In vitro modeling excitotoxic injury shown that activation G‐protein coupled receptors (GPCRs) counteracts such through modulation pro‐survival pathways and/or signaling. We have previously demonstrated GPCR APJ and its endogenous neuropeptide ligand apelin can protect neurons against excitotoxicity, but mechanism(s) this...
Despite effective viral suppression through combined antiretroviral therapy (cART), approximately half of HIV-positive individuals have HIV-associated neurocognitive disorders (HAND). Studies antiretroviral-treated patients revealed persistent white matter abnormalities including diffuse myelin pallor, diminished tracts, and decreased protein mRNAs. Loss can contribute to dysfunction because the membrane generated by oligodendrocytes is essential for rapid signal transduction axonal...
A number of mechanisms have been proposed to contribute the selective neuronal cell loss observed during Alzheimer disease (AD). These include formation and accumulation amyloid-β (Aβ)-containing plaques, neurofibrillary tangles (NFTs), inflammatory processes mediated by astrocytes microglia. Neuronal responses such insults in AD brain increased protein levels immunoreactivity for kinases known regulate cycle progression. One downstream target these regulatory proteins, Retinoblastoma...
We have previously shown that Actinobacillus actinomycetemcomitans cytolethal-distending toxin (Cdt) is a potent immunosuppressive agent induces G2/M arrest in human lymphocytes. In this study, we explored the possibility Cdt-mediated immunotoxicity involves lipid membrane microdomains. first determined following treatment of Jurkat cells with Cdt holotoxin all three subunits localize to these Laser confocal microscopy was employed colocalize GM1-enriched regions which are characteristic...
The prevalence of HIV‐associated neurocognitive impairment (NCI), which includes dementia (HAD) and minor cognitive motor disorder (MCMD), has been increasing. HIV‐infected and/or activated macrophages/microglia in the brain initiate neurodegeneration seen NCI via soluble neurotoxic mediators, including reactive oxygen species, viral proteins excitotoxins. Neurotoxic factors released by injure neurones directly alter astrocytic homeostatic functions, can lead to excitotoxicity oxidative...
Accumulating evidence suggests that O3 exposure may contribute to CNS dysfunction. Here, we posit inflammatory and acute-phase proteins in the circulation increase after systemically convey signals of CNS. To model acute exposure, female Balb/c mice were exposed 3 ppm or forced air for 2 h studied 6 24 h. Of 23 cytokines chemokines, only KC/CXCL1 was increased blood exposure. The protein serum amyloid A (A-SAA) significantly by h, whereas C-reactive unchanged. A-SAA correlated with total...
Secoisolariciresinol diglucoside (SDG), the main lignan in flaxseed, is known for its beneficial effects inflammation, oxidative stress, heart disease, tumor progression, atherosclerosis, and diabetes. SDG might be an attractive natural compound that protects against neuroinflammation. Yet, there are no comprehensive studies to date investigating of on brain endothelium using relevant vivo vitro models. We evaluated orally administered neuroinflammatory responses imaging microvasculature...
Cell cycle proteins regulate processes as diverse cell division and death. Recently their role in neuronal death has been reported several models of neurodegeneration. We have previously that two key regulators the cycle, retinoblastoma susceptibility gene product (pRb) transcription factor E2F1, exhibit altered immunostaining patterns simian immunodeficiency virus encephalitis (SIVE). Here we show E2F1 inactivated, hyperphosphorylated form pRb (ppRb) also human (HIVE). Quantification ppRb...
Abstract Although the specific mechanism of neuronal damage in human immunodeficiency virus (HIV) ‐associated dementia is not known, a prominent role for NMDA receptor (NMDAR)‐induced excitotoxicity has been demonstrated neurons exposed to HIV‐infected/activated macrophages. We hypothesized NMDAR‐mediated activation calcium‐dependent protease, calpain, would contribute cell death by induction cyclin‐dependent kinase 5 (CDK5) activity. Using an vitro model HIV neurotoxicity, which primary rat...