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1. Redox and Nucleophilic Reactions of Naphthoquinones with Small Thiols and Their Effects on Oxidization of H2S to Inorganic and Organic Hydropolysulfides and Thiosulfate

   https://doi.org/10.3390/ijms24087516  

   Olson, Kenneth R. ; Clear, Kasey J. ; Gao, Yan ; Ma, Zhilin ; Cieplik, Nathaniel M. ; Fiume, Alyssa R. ; Gaziano, Dominic J. ; Kasko, Stephen M. ; Luu, Jennifer ; Pfaff, Ella ; et al ( April 2023 , International Journal of Molecular Sciences)

   Naphthoquinone (1,4-NQ) and its derivatives (NQs, juglone, plumbagin, 2-methoxy-1,4-NQ, and menadione) have a variety of therapeutic applications, many of which are attributed to redox cycling and the production of reactive oxygen species (ROS). We previously demonstrated that NQs also oxidize hydrogen sulfide (H2S) to reactive sulfur species (RSS), potentially conveying identical benefits. Here we use RSS-specific fluorophores, mass spectroscopy, EPR and UV-Vis spectrometry, and oxygen-sensitive optodes to examine the effects of thiols and thiol-NQ adducts on H2S-NQ reactions. In the presence of glutathione (GSH) and cysteine (Cys), 1,4-NQ oxidizes H2S to both inorganic and organic hydroper-/hydropolysulfides (R2Sn, R=H, Cys, GSH; n = 2–4) and organic sulfoxides (GSnOH, n = 1, 2). These reactions reduce NQs and consume oxygen via a semiquinone intermediate. NQs are also reduced as they form adducts with GSH, Cys, protein thiols, and amines. Thiol, but not amine, adducts may increase or decrease H2S oxidation in reactions that are both NQ- and thiol-specific. Amine adducts also inhibit the formation of thiol adducts. These results suggest that NQs may react with endogenous thiols, including GSH, Cys, and protein Cys, and that these adducts may affect both thiol reactions as well as RSS production from H2S. 

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2. Naphthoquinones Oxidize H2S to Polysulfides and Thiosulfate, Implications for Therapeutic Applications

   https://doi.org/10.3390/ijms232113293  

   Olson, Kenneth R. ; Clear, Kasey J. ; Derry, Paul J. ; Gao, Yan ; Ma, Zhilin ; Cieplik, Nathaniel M. ; Fiume, Alyssa ; Gaziano, Dominic J. ; Kasko, Stephen M. ; Narloch, Kathleen ; et al ( November 2022 , International Journal of Molecular Sciences)

   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. The approximate efficacy of NQs (in decreasing order) is, 1,4-NQ ≈ juglone ≈ plumbagin > 2-methoxy-1,4-NQ ≈ menadione >> phylloquinone ≈ anthraquinone ≈ menaquinone ≈ lawsone. We propose that the most probable reactions are an initial two-electron oxidation of H2S to S0 and reduction of NQ to NQH2. S0 may react with H2S or elongate H2Sn in variety of reactions. Reoxidation of NQH2 likely involves a semiquinone radical (NQ·−) intermediate via several mechanisms involving oxygen and comproportionation to produce NQ and superoxide. Dismutation of the latter forms hydrogen peroxide which then further oxidizes RSS to sulfoxides. These findings provide the chemical background for novel sulfur-based approaches to naphthoquinone-directed therapies. 

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3. Hepatic cell mobilization for protection against ischemic myocardial injury

   https://doi.org/10.1038/s41598-021-94170-z  

   Liu, Shu Q. ; Troy, John B. ; Luan, Chi-Hao ; Guillory, Roger J. ( August 2021 , Scientific Reports)

   The heart is capable of activating protective mechanisms in response to ischemic injury to support myocardial survival and performance. These mechanisms have been recognized primarily in the ischemic heart, involving paracrine signaling processes. Here, we report a distant cardioprotective mechanism involving hepatic cell mobilization to the ischemic myocardium in response to experimental myocardial ischemia–reperfusion (MI-R) injury. A parabiotic mouse model was generated by surgical skin-union of two mice and used to induce bilateral MI-R injury with unilateral hepatectomy, establishing concurrent gain- and loss-of-hepatic cell mobilization conditions. Hepatic cells, identified based on the cell-specific expression of enhanced YFP, were found in the ischemic myocardium of parabiotic mice with intact liver (0.2 ± 0.1%, 1.1 ± 0.3%, 2.7 ± 0.6, and 0.7 ± 0.4% at 1, 3, 5, and 10 days, respectively, in reference to the total cell nuclei), but not significantly in the ischemic myocardium of parabiotic mice with hepatectomy (0 ± 0%, 0.1 ± 0.1%, 0.3 ± 0.2%, and 0.08 ± 0.08% at the same time points). The mobilized hepatic cells were able to express and release trefoil factor 3 (TFF3), a protein mitigating MI-R injury as demonstrated in TFF3^−/−mice (myocardium infarcts 17.6 ± 2.3%, 20.7 ± 2.6%, and 15.3 ± 3.8% at 1, 5, and 10 days, respectively) in reference to wildtype mice (11.7 ± 1.9%, 13.8 ± 2.3%, and 11.0 ± 1.8% at the same time points). These observations suggest that MI-R injury can induce hepatic cell mobilization to support myocardial survival by releasing TFF3.

    

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4. Organelle-Targeted Fluorescent Probes for Sulfane Sulfur Species

   https://doi.org/10.3390/antiox12030590  

   Roy, Biswajit ; Shieh, Meg ; Ramush, Geat ; Xian, Ming ( March 2023 , Antioxidants)

   Sulfane sulfurs, which include hydropersulfides (RSSH), hydrogen polysulfides (H2Sn, n > 1), and polysulfides (RSnR, n > 2), play important roles in cellular redox biology and are closely linked to hydrogen sulfide (H2S) signaling. While most studies on sulfane sulfur detection have focused on sulfane sulfurs in the whole cell, increasing the recognition of the effects of reactive sulfur species on the functions of various subcellular organelles has emerged. This has driven a need for organelle-targeted detection methods. However, the detection of sulfane sulfurs, particularly of RSSH and H2Sn, in biological systems is still a challenge due to their low endogenous concentrations and instabilities. In this review, we summarize the development and design of organelle-targeted fluorescent sulfane sulfur probes, examine their organelle-targeting strategies and choices of fluorophores (e.g., ratiometric, near-infrared, etc.), and discuss their mechanisms and ability to detect endogenous and exogenous sulfane sulfur species. We also present the advantages and limitations of the probes and propose directions for future work on this topic. 

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5. A Case for Hydrogen Sulfide Metabolism as an Oxygen Sensing Mechanism

   https://doi.org/10.3390/antiox10111650  

   Olson, Kenneth R. ( November 2021 , Antioxidants)

   The ability to detect oxygen availability is a ubiquitous attribute of aerobic organisms. However, the mechanism(s) that transduce oxygen concentration or availability into appropriate physiological responses is less clear and often controversial. This review will make the case for oxygen-dependent metabolism of hydrogen sulfide (H2S) and polysulfides, collectively referred to as reactive sulfur species (RSS) as a physiologically relevant O2 sensing mechanism. This hypothesis is based on observations that H2S and RSS metabolism is inversely correlated with O2 tension, exogenous H2S elicits physiological responses identical to those produced by hypoxia, factors that affect H2S production or catabolism also affect tissue responses to hypoxia, and that RSS efficiently regulate downstream effectors of the hypoxic response in a manner consistent with a decrease in O2. H2S-mediated O2 sensing is then compared to the more generally accepted reactive oxygen species (ROS) mediated O2 sensing mechanism and a number of reasons are offered to resolve some of the confusion between the two. 

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