Browsing by Author "Mouli, Karthik"

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    Harshly Oxidized Activated Charcoal Enhances Protein Persulfidation with Implications for Neurodegeneration as Exemplified by Friedreich’s Ataxia
    (MDPI, 2024) Vo, Anh T. T.; Khan, Uffaf; Liopo, Anton V.; Mouli, Karthik; Olson, Kenneth R.; McHugh, Emily A.; Tour, James M.; Pooparayil Manoj, Madhavan; Derry, Paul J.; Kent, Thomas A.; Smalley-Curl Institute;Rice Advanced Materials Institute;The NanoCarbon Center
    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 (H2S) to polysulfides and thiosulfate, dismutation of the superoxide radical (O2−*), and oxidation of NADH to NAD+. The oxidation of H2S is predicted to enhance protein persulfidation—the attachment of sulfur to cysteine residues. Persulfidated proteins act as redox intermediates, and persulfidation protects proteins from irreversible oxidation and ubiquitination, providing an important means of signaling. Protein persulfidation is believed to decline in several neurological disorders and aging. Importantly, and consistent with the role of persulfidation in signaling, the master antioxidant transcription factor Nrf2 is regulated by Keap1’s persulfidation. Here, we demonstrate that pleozymes increased overall protein persulfidation in cells from apparently healthy individuals and from individuals with the mitochondrial protein mutation responsible for Friedreich’s ataxia. We further find that pleozymes specifically enhanced Keap1 persulfidation, with subsequent increased accumulation of Nrf2 and Nrf2’s antioxidant targets.
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    Oxidation of Hydrogen Sulfide to Polysulfide and Thiosulfate by a Carbon Nanozyme: Therapeutic Implications with an Emphasis on Down Syndrome
    (Wiley, 2024) Derry, Paul J.; Liopo, Anton V.; Mouli, Karthik; McHugh, Emily A.; Vo, Anh T. T.; McKelvey, Ann; Suva, Larry J.; Wu, Gang; Gao, Yan; Olson, Kenneth R.; Tour, James M.; Kent, Thomas A.; Smalley-Curl Institute; Welch Institute for Advanced Materials; The NanoCarbon Center
    Hydrogen sulfide (H2S) is a noxious, potentially poisonous, but necessary gas produced from sulfur metabolism in humans. In Down Syndrome (DS), the production of H2S is elevated and associated with degraded mitochondrial function. Therefore, removing H2S from the body as a stable oxide could be an approach to reducing the deleterious effects of H2S in DS. In this report we describe the catalytic oxidation of hydrogen sulfide (H2S) to polysulfides (HS2+n−) and thiosulfate (S2O32−) by poly(ethylene glycol) hydrophilic carbon clusters (PEG-HCCs) and poly(ethylene glycol) oxidized activated charcoal (PEG-OACs), examples of oxidized carbon nanozymes (OCNs). We show that OCNs oxidize H2S to polysulfides and S2O32− in a dose-dependent manner. The reaction is dependent on O2 and the presence of quinone groups on the OCNs. In DS donor lymphocytes we found that OCNs increased polysulfide production, proliferation, and afforded protection against additional toxic levels of H2S compared to untreated DS lymphocytes. Finally, in Dp16 and Ts65DN murine models of DS, we found that OCNs restored osteoclast differentiation. This new action suggests potential facile translation into the clinic for conditions involving excess H2S exemplified by DS.
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    Pleozymes: Pleiotropic Oxidized Carbon Nanozymes Enhance Cellular Metabolic Flexibility
    (MDPI, 2024) Vo, Anh T. T.; Mouli, Karthik; Liopo, Anton V.; Lorenzi, Philip; Tan, Lin; Wei, Bo; Martinez, Sara A.; McHugh, Emily A.; Tour, James M.; Khan, Uffaf; Derry, Paul J.; Kent, Thomas A.; Smalley-Curl Institute;Rice Advanced Materials Institute;The NanoCarbon Center
    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 H2S 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. Prior work showed pleozymes localize to mitochondria and increase oxidative phosphorylation and glycolysis. Here, we measured cellular NAD+ and NADH levels after pleozyme treatment and observed increased total cellular NADH levels but not total NAD+ levels. A 13C-glucose metabolic flux analysis suggested pleozymes stimulate the generation of pyruvate and lactate glycolytically and from the tricarboxylic acid (TCA) cycle, pointing to malate decarboxylation. Analysis of intracellular fatty acid abundances suggests pleozymes increased fatty acid β-oxidation, with a concomitant increase in succinyl- and acetyl-CoA. Pleozymes increased total ATP, potentially via flexible enhancement of NAD+-dependent catabolic pathways such as glycolysis, fatty acid β-oxidation, and metabolic flux through the TCA cycle. These effects may be favorable for pathologies that compromise metabolism such as brain injury.
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    SOD1 Is an Integral Yet Insufficient Oxidizer of Hydrogen Sulfide in Trisomy 21 B Lymphocytes and Can Be Augmented by a Pleiotropic Carbon Nanozyme
    (MDPI, 2024) Mouli, Karthik; Liopo, Anton V.; Suva, Larry J.; Olson, Kenneth R.; McHugh, Emily A.; Tour, James M.; Derry, Paul J.; Kent, Thomas A.; Smalley-Curl Institute;NanoCarbon Center;Rice Advanced Materials Institute
    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 (H2S), 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 (H2O2) while also mitigating the toxic H2S burden via a non-canonical sulfide-oxidizing mechanism. We investigated the phenotypic variability in basal H2S levels in relation to DS B lymphocyte cell health and SOD1 in H2S detoxification. The H2S levels were negatively correlated with the DS B lymphocyte growth rates but not with CBS protein. Pharmacological inhibition of SOD1 using LCS-1 significantly increased the H2S levels to a greater extent in DS cells while also decreasing the polysulfide products of H2S oxidation. However, DS cells exhibited elevated H2O2 and lipid peroxidation, representing potential toxic consequences of SOD1 overexpression. Treatment of DS cells with a pleiotropic carbon nanozyme (pleozymes) decreased the total oxidative stress and reduced the levels of the H2S-generating enzymes CBS and 3-mercaptopyruvate sulfurtransferase (MPST). Our results indicate that pleozymes may bridge the protective and deleterious effects of DS SOD1 overexpression on H2S metabolism and oxidative stress, respectively, with cytoprotective benefits.