Neuroprotective Effects of Functionalized Hydrophilic Carbon Clusters: Targeted Therapy of Traumatic Brain Injury in an Open Blast Rat Model.

Unlabelled: Traumatic brain injury (TBI) causes multiple cerebrovascular disruptions and oxidative stress. These pathological mechanisms are often accompanied by serious impairment of cerebral blood flow autoregulation and neuronal and glial degeneration.

Background/objectives: Multiple biochemical cascades are triggered by brain damage, resulting in reactive oxygen species production alongside blood loss and hypoxia.

Pleozymes: Pleiotropic Oxidized Carbon Nanozymes Enhance Cellular Metabolic Flexibility.

Our group has synthesized a pleiotropic synthetic nanozyme redox mediator we term a "pleozyme" that displays multiple enzymatic characteristics, including acting as a superoxide dismutase mimetic, oxidizing NADH to NAD, and oxidizing HS to polysulfides and thiosulfate. Benefits have been seen in acute and chronic neurological disease models. The molecule is sourced from coconut-derived activated charcoal that has undergone harsh oxidization with fuming nitric acid, which alters the structure and chemical characteristics, yielding 3-8 nm discs with broad redox potential.

Harshly Oxidized Activated Charcoal Enhances Protein Persulfidation with Implications for Neurodegeneration as Exemplified by Friedreich's Ataxia.

Harsh acid oxidation of activated charcoal transforms an insoluble carbon-rich source into water-soluble, disc structures of graphene decorated with multiple oxygen-containing functionalities. We term these pleiotropic nano-enzymes as "pleozymes". A broad redox potential spans many crucial redox reactions including the oxidation of hydrogen sulfide (HS) to polysulfides and thiosulfate, dismutation of the superoxide radical (O*), and oxidation of NADH to NAD.

SOD1 Is an Integral Yet Insufficient Oxidizer of Hydrogen Sulfide in Trisomy 21 B Lymphocytes and Can Be Augmented by a Pleiotropic Carbon Nanozyme.

Down syndrome (DS) is a multisystemic disorder that includes accelerated aging caused by trisomy 21. In particular, overexpression of cystathionine-β-synthase (CBS) is linked to excess intracellular hydrogen sulfide (HS), a mitochondrial toxin at higher concentrations, which impairs cellular viability. Concurrent overexpression of superoxide dismutase 1 (SOD1) may increase oxidative stress by generating excess hydrogen peroxide (HO) while also mitigating the toxic HS burden via a non-canonical sulfide-oxidizing mechanism.

Application of validated size-exclusion chromatography method for physicochemical characterization of topical gel formulation of deferoxamine conjugated with PEGylated carbon nanoparticles.

The focus of current research work was to develop and validate size-exclusion chromatography method and develop and evaluate gel formulation of deferoxamine conjugated with PEGylated carbon nanoparticles (DEF-PEG-CNP) for topical delivery. Size-exclusion chromatography-based method was validated as per ICH guidelines. Effect of Carbopol® 974P and Transcutol® on the nanoparticles' permeation was studied by 3-level full factorial design of experiment.

The SOD1 Inhibitor, LCS-1, Oxidizes H2S to Reactive Sulfur Species, Directly and Indirectly, through Conversion of SOD1 to an Oxidase.

LCS-1, a putative selective inhibitor of SOD1, is a substituted pyridazinone with rudimentary similarity to quinones and naphthoquinones. As quinones catalytically oxidize HS to biologically active reactive sulfur species (RSS), we hypothesized LCS-1 might have similar attributes. Here, we examine LCS-1 reactions with HS and SOD1 using thiol-specific fluorophores, liquid chromatography-mass spectrometry, electron paramagnetic resonance (EPR), UV-vis spectrometry, and oxygen consumption.

Hemin-Induced Transient Senescence Via DNA Damage Response: A Neuroprotective Mechanism Against Ferroptosis in Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) poses acute fatality and long-term neurological risks due to hemin and iron accumulation from hemoglobin breakdown. Our observation that hemin induces DNA double-strand breaks (DSBs), prompting a senescence-like phenotype in neurons, necessitating deeper exploration of cellular responses. Using experimental ICH models and human ICH patient tissue, we elucidate hemin-mediated DNA damage response (DDR) inducing transient senescence and delayed expression of heme oxygenase (HO-1).

Oxidation of Hydrogen Sulfide to Polysulfide and Thiosulfate by a Carbon Nanozyme: Therapeutic Implications with an Emphasis on Down Syndrome.

Hydrogen sulfide (H S) is a noxious, potentially poisonous, but necessary gas produced from sulfur metabolism in humans. In Down Syndrome (DS), the production of H S is elevated and associated with degraded mitochondrial function. Therefore, removing H S from the body as a stable oxide could be an approach to reducing the deleterious effects of H S in DS.

Oxidized Activated Charcoal Nanozymes: Synthesis, and Optimization for In Vitro and In Vivo Bioactivity for Traumatic Brain Injury.

Carbon-based superoxide dismutase (SOD) mimetic nanozymes have recently been employed as promising antioxidant nanotherapeutics due to their distinct properties. The structural features responsible for the efficacy of these nanomaterials as antioxidants are, however, poorly understood. Here, the process-structure-property-performance properties of coconut-derived oxidized activated charcoal (cOAC) nano-SOD mimetics are studied by analyzing how modifications to the nanomaterial's synthesis impact the size, as well as the elemental and electrochemical properties of the particles.

Naphthoquinones Oxidize HS to Polysulfides and Thiosulfate, Implications for Therapeutic Applications.

1,4-Napththoquinones (NQs) are clinically relevant therapeutics that affect cell function through production of reactive oxygen species (ROS) and formation of adducts with regulatory protein thiols. Reactive sulfur species (RSS) are chemically and biologically similar to ROS and here we examine RSS production by NQ oxidation of hydrogen sulfide (H2S) using RSS-specific fluorophores, liquid chromatography-mass spectrometry, UV-Vis absorption spectrometry, oxygen-sensitive optodes, thiosulfate-specific nanoparticles, HPLC-monobromobimane derivatization, and ion chromatographic assays. We show that NQs, catalytically oxidize H2S to per- and polysulfides (H2Sn, n = 2−6), thiosulfate, sulfite and sulfate in reactions that consume oxygen and are accelerated by superoxide dismutase (SOD) and inhibited by catalase.

Using Mobile Video-Teleconferencing to Deliver Secondary Stroke Prevention Interventions: A Pilot Study.

Objectives: Patient self-management support (SMS) interventions help stroke survivors control stroke risk factors and assist with secondary prevention. We examined utility and preliminary effectiveness of mobile video-teleconferencing (VT) to deliver SMS to stroke survivors in rural and low-income urban Texas communities.

Methods: We applied a within-subjects design to assess improvement in self-management behaviors and stroke risk factors among stroke survivors receiving SMS intervention through mobile VT.

SARS-CoV-2 and the central nervous system: Emerging insights into hemorrhage-associated neurological consequences and therapeutic considerations.

Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to impact our lives by causing widespread illness and death and poses a threat due to the possibility of emerging strains. SARS-CoV-2 targets angiotensin-converting enzyme 2 (ACE2) before entering vital organs of the body, including the brain. Studies have shown systemic inflammation, cellular senescence, and viral toxicity-mediated multi-organ failure occur during infectious periods.

The Effects of Antioxidant Nutraceuticals on Cellular Sulfur Metabolism and Signaling.

Nutraceuticals are ingested for health benefits, in addition to their general nutritional value. These dietary supplements have become increasingly popular since the late 20th century and they are a rapidly expanding global industry approaching a half-trillion U.S.

Thrombolysis Experience in Costa Rica Compared Against Individual Patient Data from two Randomized Controlled Trials.

Objectives: We sought to compare thrombolysis outcomes from the Costa Rican Stroke Registry Program (CRSRP) with published individual patient data from NINDS and CLOTBUST-ER trials using matching and outcome modeling from randomized clinical trials (RCTs).

Materials And Methods: A retrospective observational study matching subjects on baseline characteristics, from the CRSRP, the control arm of CLOTBUST-ER, and the interventional arm of NINDS trials. Day 7-10/discharge modified Rankin Score (mRS), and early mortality was compared between matched subjects.

Coenzyme Q and related quinones oxidize HS to polysulfides and thiosulfate.

In the canonical pathway for mitochondrial HS oxidation electrons are transferred from sulfide:quinone oxidoreductase (SQR) to complex III via ubiquinone (CoQ). We previously observed that a number of quinones directly oxidize HS and we hypothesize that CoQ may have similar properties. Here we examine HS oxidation by CoQ and more hydrophilic, truncated forms, CoQ and CoQ, in buffer using HS and polysulfide fluorophores (AzMC and SSP4), silver nanoparticles to measure thiosulfate (HSO), mass spectrometry to identify polysulfides and O-sensitive optodes to measure O consumption.

The Key Regulator of Necroptosis, RIP1 Kinase, Contributes to the Formation of Astrogliosis and Glial Scar in Ischemic Stroke.

Necroptosis initiation relies on the receptor-interacting protein 1 kinase (RIP1K). We recently reported that genetic and pharmacological inhibition of RIP1K produces protection against ischemic stroke-induced astrocytic injury. However, the role of RIP1K in ischemic stroke-induced formation of astrogliosis and glial scar remains unknown.

The Chemical Basis of Intracerebral Hemorrhage and Cell Toxicity With Contributions From Eryptosis and Ferroptosis.

Intracerebral hemorrhage (ICH) is a particularly devastating event both because of the direct injury from space-occupying blood to the sequelae of the brain exposed to free blood components from which it is normally protected. Not surprisingly, the usual metabolic and energy pathways are overwhelmed in this situation. In this review article, we detail the complexity of red blood cell degradation, the contribution of eryptosis leading to hemoglobin breakdown into its constituents, the participants in that process, and the points at which injury can be propagated such as elaboration of toxic radicals through the metabolism of the breakdown products.

Manage Emotions to Reduce Aggression: A Pilot Study of a Brief Treatment to Help Veterans Reduce Impulsive Aggression.

Veterans with posttraumatic stress disorder (PTSD) report more aggression than civilians with PTSD. Because emotion regulation difficulties mediated the relationship between PTSD symptoms and impulsive aggression in veterans, we developed an intervention to increase emotion regulation skills. This pilot study tested the feasibility and acceptability of a three-session treatment, Manage Emotions to Reduce Aggression (MERA), and examined its effectiveness at reducing aggression and emotion dysregulation.

Pervasive Genomic Damage in Experimental Intracerebral Hemorrhage: Therapeutic Potential of a Mechanistic-Based Carbon Nanoparticle.

Therapy for intracerebral hemorrhage (ICH) remains elusive, in part dependent on the severity of the hemorrhage itself as well as multiple deleterious effects of blood and its breakdown products such as hemin and free iron. While oxidative injury and genomic damage have been seen following ICH, the details of this injury and implications remain unclear. Here, we discovered that, while free iron produced mostly reactive oxygen species (ROS)-related single-strand DNA breaks, hemin unexpectedly induced rapid and persistent nuclear and mitochondrial double-strand breaks (DSBs) in neuronal and endothelial cell genomes and in mouse brains following experimental ICH comparable to that seen with γ radiation and DNA-complexing chemotherapies.

Use of a bioengineered antioxidant in mouse models of metabolic syndrome.

: 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 at10/molecule of PEG-HCC.

Revisiting the intersection of amyloid, pathologically modified tau and iron in Alzheimer's disease from a ferroptosis perspective.

The complexity of Alzheimer's disease (AD) complicates the search for effective treatments. While the key roles of pathologically modified proteins has occupied a central role in hypotheses of the pathophysiology, less attention has been paid to the potential role for transition metals overload, subsequent oxidative stress, and tissue injury. The association of transition metals, the major focus heretofore iron and amyloid, the same can now be said for the likely pathogenic microtubular associated tau (MAPT).