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, 2024-12-13) Vo, Anh T. T.; Khan, Uffaf; Liopo, Anton V.; Mouli, Karthik; Olson, Kenneth R.; McHugh, Emily A.; Tour, James M.; Manoj, Madhavan Pooparayil; Derry, Paul J.; Kent, Thomas A.; Anatomy, Cell Biology and Physiology, School of Medicine
    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; Suv, Larry J.; Wu, Gang; Gao, Yan; Olson, Kenneth R.; Tour, James M.; Kent, Thomas A.; Cellular and Integrative Physiology, School of Medicine
    Hydrogen sulfide (H2 S) is a noxious, potentially poisonous, but necessary gas produced from sulfur metabolism in humans. In Down Syndrome (DS), the production of H2 S is elevated and associated with degraded mitochondrial function. Therefore, removing H2 S from the body as a stable oxide could be an approach to reducing the deleterious effects of H2 S in DS. In this report we describe the catalytic oxidation of hydrogen sulfide (H2 S) to polysulfides (HS2+n - ) and thiosulfate (S2 O3 2- ) 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 H2 S to polysulfides and S2 O3 2- 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 H2 S 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 H2 S exemplified by DS.
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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, 2024-11-07) Mouli, Karthik; Liopo, Anton V.; Suva, Larry J.; Olson, Kenneth R.; McHugh, Emily A.; Tour, James M.; Derry, Paul J.; Kent, Thomas A.; Anatomy, Cell Biology and Physiology, School of Medicine
    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.
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    The SOD1 Inhibitor, LCS-1, Oxidizes H2S to Reactive Sulfur Species, Directly and Indirectly, through Conversion of SOD1 to an Oxidase
    (MDPI, 2024-08-15) Olson, Kenneth R.; Takata, Tsuyoshi; Clear, Kasey J.; Gao, Yan; Ma, Zhilin; Pfaff, Ella; Mouli, Karthik; Kent, Thomas A.; Jones, Prentiss, Jr.; Fukuto, Jon; Wu, Gang; Straub, Karl D.; Anatomy, Cell Biology and Physiology, School of Medicine
    LCS-1, a putative selective inhibitor of SOD1, is a substituted pyridazinone with rudimentary similarity to quinones and naphthoquinones. As quinones catalytically oxidize H2S to biologically active reactive sulfur species (RSS), we hypothesized LCS-1 might have similar attributes. Here, we examine LCS-1 reactions with H2S and SOD1 using thiol-specific fluorophores, liquid chromatography-mass spectrometry, electron paramagnetic resonance (EPR), UV-vis spectrometry, and oxygen consumption. We show that LCS-1 catalytically oxidizes H2S in buffer solutions to form RSS, namely per- and polyhydrosulfides (H2Sn, n = 2-6). These reactions consume oxygen and produce hydrogen peroxide, but they do not have an EPR signature, nor do they affect the UV-vis spectrum. Surprisingly, LCS-1 synergizes with SOD1, but not SOD2, to oxidize H2S to H2S3-6. LCS-1 forms monothiol adducts with H2S, glutathione (GSH), and cysteine (Cys), but not with oxidized glutathione or cystine; both thiol adducts inhibit LCS-1-SOD1 synergism. We propose that LCS-1 forms an adduct with SOD1 that disrupts the intramolecular Cys57-Cys146 disulfide bond and transforms SOD1 from a dismutase to an oxidase. This would increase cellular ROS and polysulfides, the latter potentially affecting cellular signaling and/or cytoprotection.