Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 8 de 8
Filter
Add more filters










Database
Language
Publication year range
1.
Expert Opin Investig Drugs ; 29(2): 209-219, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31937152

ABSTRACT

Background: Oxidative stress has been implicated in metabolic syndrome (MetS); however, antioxidants such as vitamin E have had limited success in the clinic. This prompts the question of what effects amore potent antioxidant might produce. A prime candidate is the recently developed bioengineered antioxidant, poly(ethylene glycol)-functionalizedhydrophilic carbon clusters (PEG-HCCs), which are capable of neutralizing the reactive oxygen species (ROS) superoxide anion and hydroxyl radical at106/molecule of PEG-HCC. In this project, we tested the potential of PEG-HCCs as a possible therapeutic for MetS.Results: PEG-HCC treatment lessened lipid peroxidation, aspartate aminotransferase levels, non-fastingblood glucose levels, and JNK phosphorylation inob/ob mice. PEG-HCC-treated WT mice had an increased response to insulin by insulin tolerance tests and adecrease in blood glucose by glucose tolerance tests. These effects were not observed in HFD-fed mice, regardless of treatment. PEG-HCCs were observed in the interstitial space of liver, spleen, skeletal muscle, and adipose tissue. No significant difference was shown in gluconeogenesis or inflammatory gene expression between treatment and dietary groups.Expert Opinion: PEG-HCCs improved some parameters of disease possibly due to a resulting increase in peripheral insulin sensitivity. However, additional studies are needed to elucidate how PEG-HCCsare producing these effects.


Subject(s)
Antioxidants/pharmacology , Metabolic Syndrome/drug therapy , Oxidative Stress/drug effects , Animals , Antioxidants/chemistry , Bioengineering , Blood Glucose/drug effects , Carbon/chemistry , Diet, High-Fat , Disease Models, Animal , Hydrophobic and Hydrophilic Interactions , Insulin/metabolism , Insulin Resistance , Male , Metabolic Syndrome/physiopathology , Mice , Mice, Inbred C57BL , Polyethylene Glycols/chemistry , Reactive Oxygen Species/metabolism
2.
Proc Natl Acad Sci U S A ; 112(8): 2343-8, 2015 Feb 24.
Article in English | MEDLINE | ID: mdl-25675492

ABSTRACT

Many diseases are associated with oxidative stress, which occurs when the production of reactive oxygen species (ROS) overwhelms the scavenging ability of an organism. Here, we evaluated the carbon nanoparticle antioxidant properties of poly(ethylene glycolated) hydrophilic carbon clusters (PEG-HCCs) by electron paramagnetic resonance (EPR) spectroscopy, oxygen electrode, and spectrophotometric assays. These carbon nanoparticles have 1 equivalent of stable radical and showed superoxide (O2 (•-)) dismutase-like properties yet were inert to nitric oxide (NO(•)) as well as peroxynitrite (ONOO(-)). Thus, PEG-HCCs can act as selective antioxidants that do not require regeneration by enzymes. Our steady-state kinetic assay using KO2 and direct freeze-trap EPR to follow its decay removed the rate-limiting substrate provision, thus enabling determination of the remarkable intrinsic turnover numbers of O2 (•-) to O2 by PEG-HCCs at >20,000 s(-1). The major products of this catalytic turnover are O2 and H2O2, making the PEG-HCCs a biomimetic superoxide dismutase.


Subject(s)
Carbon/chemistry , Hydrophobic and Hydrophilic Interactions , Oxygen/chemistry , Superoxides/chemistry , Catalysis , Electron Spin Resonance Spectroscopy , Hydrogen Peroxide/metabolism , Hydrogen-Ion Concentration , Hydroxyl Radical/chemistry , Polyethylene Glycols/chemistry , Sodium Hydroxide/chemistry , Superoxide Dismutase/metabolism
3.
Trends Biotechnol ; 32(10): 501-5, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25175886

ABSTRACT

Oxidative stress reflects an excessive accumulation of reactive oxygen species (ROS) and is a hallmark of several acute and chronic human pathologies. Although many antioxidants have been investigated, most have demonstrated poor efficacy in clinical trials. Here we discuss the limitations of current antioxidants and describe a new class of nanoparticle antioxidants, poly(ethylene glycol)-functionalized hydrophilic carbon clusters (PEG-HCCs). PEG-HCCs show high capacity to annihilate ROS such as superoxide (O2(•-)) and the hydroxyl (HO(•)) radical, show no reactivity toward the nitric oxide radical (NO(•)), and can be functionalized with targeting moieties without loss of activity. Given these properties, we propose that PEG-HCCs offer an exciting new area of study for the treatment of numerous ROS-induced human pathologies.


Subject(s)
Antioxidants , Biotechnology , Carbon , Nanotechnology , Humans , Hydrophobic and Hydrophilic Interactions , Oxidative Stress
4.
J Neurotrauma ; 30(9): 789-96, 2013 May 01.
Article in English | MEDLINE | ID: mdl-22928502

ABSTRACT

Traumatic brain injury (TBI) involves the elaboration of oxidative stress that causes cerebrovascular dysfunction, including impairment of autoregulation of cerebral blood flow. Currently, there is no clinically effective antioxidant treatment for these pathologies. Most currently available antioxidants act through mechanisms in which the antioxidant either transfers the radical or requires regeneration, both of which are impaired in the toxic post-TBI environment. We previously reported that single-walled carbon nanotubes (SWCNTs) and ultrashort SWCNTs possess antioxidant activity, and their characteristics suggest that radical annihilation is the major mechanism. We have now developed a biologically compatible class of carbon-based nanovectors, poly(ethylene glycol)-functionalized hydrophilic carbon clusters (PEG-HCCs) that can be further functionalized with antibodies, and hence show promise as targeted drug delivery platforms. Here we report that PEG-HCCs possess innate antioxidant activity and can be rapidly targeted via an antibody to the P-selectin antigen in a model of injured cultured brain endothelial cells. One immediate application of this therapy is to vascular dysfunction that accompanies TBI and worsens outcome in the face of systemic hypotension. These in vitro results support the need for further investigation in animal models.


Subject(s)
Antioxidants/pharmacology , Brain Concussion/physiopathology , Carbon/pharmacology , Polyethylene Glycols/pharmacology , Animals , Antioxidants/chemical synthesis , Cells, Cultured , Cerebrovascular Circulation/drug effects , Cerebrovascular Circulation/physiology , Endothelial Cells/drug effects , Mice , Nanotechnology , Oxidative Stress/drug effects , Polyethylene Glycols/chemical synthesis
5.
Mol Neurodegener ; 7: 47, 2012 Sep 19.
Article in English | MEDLINE | ID: mdl-22992283

ABSTRACT

BACKGROUND: The transcription factor NFκB is an important mediator of cell survival and inflammation in the immune system. In the central nervous system (CNS), NFκB signaling has been implicated in regulating neuronal survival following acute pathologic damage such as traumatic brain injury (TBI) and stroke. NFκB is normally bound by the principal inhibitory protein, IκBα, and sequestered in the cytoplasm. Activation of NFκB requires the degradation of IκBα, thereby freeing NFκB to translocate to the nucleus and activate the target genes. Mice deficient in IκBα display deregulated and sustained NFκB activation and early postnatal lethality, highlighting a critical role of IκBα in NFκB regulation. RESULTS: We investigated the role of IκBα in regulating NFκB activity in the brain and the effects of the NFκB/IκBα pathway in mediating neuroinflammation under both physiological and brain injury conditions. We report that astrocytes, but not neurons, exhibit prominent NFκB activity, and that basal NFκB activity in astrocytes is elevated in the absence of IκBα. By generating mice with brain-specific deletion of IκBα, we show that IκBα deficiency does not compromise normal brain development. However, basal neuroinflammation detected by GFAP and Iba1 immunoreactivity is elevated. This leads to impaired inflammatory responses following TBI and worsened brain damage including higher blood brain barrier permeability, increased injury volumes and enlarged ventricle volumes. CONCLUSIONS: We conclude that, in the CNS, astrocyte is the primary cell type subject to NFκB regulation. We further demonstrate that IκBα plays an important role in regulating NFκB activity in the brain and a robust NFκB/IκBα-mediated neuroinflammatory response immediately following TBI is beneficial.


Subject(s)
Astrocytes/metabolism , Brain Injuries/metabolism , Brain/metabolism , I-kappa B Proteins/deficiency , Recovery of Function/physiology , Animals , Blood-Brain Barrier/physiology , Brain/growth & development , Brain/pathology , Brain Injuries/pathology , Glial Fibrillary Acidic Protein , Inflammation/metabolism , Mice , NF-kappa B/metabolism , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Neurons/pathology , Phosphorylation , Signal Transduction/physiology , Tumor Necrosis Factor-alpha/metabolism
6.
ACS Nano ; 6(9): 8007-14, 2012 Sep 25.
Article in English | MEDLINE | ID: mdl-22866916

ABSTRACT

Injury to the neurovasculature is a feature of brain injury and must be addressed to maximize opportunity for improvement. Cerebrovascular dysfunction, manifested by reduction in cerebral blood flow (CBF), is a key factor that worsens outcome after traumatic brain injury (TBI), most notably under conditions of hypotension. We report here that a new class of antioxidants, poly(ethylene glycol)-functionalized hydrophilic carbon clusters (PEG-HCCs), which are nontoxic carbon particles, rapidly restore CBF in a mild TBI/hypotension/resuscitation rat model when administered during resuscitation--a clinically relevant time point. Along with restoration of CBF, there is a concomitant normalization of superoxide and nitric oxide levels. Given the role of poor CBF in determining outcome, this finding is of major importance for improving patient health under clinically relevant conditions during resuscitative care, and it has direct implications for the current TBI/hypotension war-fighter victims in the Afghanistan and Middle East theaters. The results also have relevancy in other related acute circumstances such as stroke and organ transplantation.


Subject(s)
Antioxidants/administration & dosage , Brain Injuries/drug therapy , Brain Injuries/physiopathology , Cerebrovascular Circulation/drug effects , Intracranial Hypotension/drug therapy , Intracranial Hypotension/physiopathology , Nanotubes, Carbon , Animals , Brain Injuries/complications , Intracranial Hypotension/etiology , Rats , Treatment Outcome
7.
Magn Reson Insights ; 5: 1-6, 2012 Mar 29.
Article in English | MEDLINE | ID: mdl-22639527

ABSTRACT

Oxidative stress and mitochondrial dysfunction have been implicated in the pathogenesis of Alzheimer's disease. We and others have shown that over expression of the mitochondrial antioxidant superoxide dismutase 2 (SOD-2) can improve many of the pathologies in the Tg2576 mouse model of Alzheimer's disease that harbors the Swedish mutation in the amyloid precursor protein. However, it is not clear if these improvements are due to functional improvements or structural/anatomical changes. To answer this question, we used diffusion tensor imaging (DTI) to assess the structural integrity of white matter tracts in the control mice, Tg2576 mouse and Tg2576 mice over expressing SOD-2. We observed minimal differences in diffusion parameters with SOD-2 over expression in this model indicating that the improvements we previously reported are due to functional changes and not any alterations to the white matter tractography.

8.
J Cereb Blood Flow Metab ; 30(6): 1105-9, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20372170

ABSTRACT

Traumatic brain injury (TBI) results in reduced cerebral blood flow (CBF) and low levels of the vasodilator nitric oxide (NO) may be involved. Arginase II negatively regulates NO production through competition for the substrate L-arginine. We determined whether arginase II-deficient (ArgII(-/-)) mice would show improved CBF after TBI through arterial spin-labeling magnetic resonance imaging (MRI). The ArgII(-/-) mice exhibit a significantly improved CBF recovery after trauma in the perilesional brain (P=0.0015) and in various other brain regions. In conclusion, arginase II deficiency leads to a better CBF recovery after TBI and implicates arginase II in hemodynamic processes.


Subject(s)
Arginase , Blood Flow Velocity , Brain Injuries/enzymology , Brain Injuries/physiopathology , Cerebral Cortex/blood supply , Cerebrovascular Circulation , Magnetic Resonance Angiography , Animals , Brain Injuries/diagnostic imaging , Brain Injuries/genetics , Brain Injuries/pathology , Cerebral Cortex/pathology , Male , Mice , Mice, Knockout , Radiography
SELECTION OF CITATIONS
SEARCH DETAIL
...