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Alleviating Cellular Oxidative Stress through Treatment with Superoxide-Triggered Persulfide Prodrugs.

ABSTRACT: Overproduction of superoxide anion (O₂ ^.- ), the primary cellular reactive oxygen species (ROS), is implicated in various human diseases. To reduce cellular oxidative stress caused by overproduction of superoxide, we developed a compound that reacts with O₂ ^.- to release a persulfide (RSSH), a type of reactive sulfur species related to the gasotransmitter hydrogen sulfide (H₂ S). Termed SOPD-NAC, this persulfide donor reacts specifically with O₂ ^.- , decomposing to generate N-acetyl cysteine (NAC) persulfide. To enhance persulfide delivery to cells, we conjugated the SOPD motif to a short, self-assembling peptide (Bz-CFFE-NH₂ ) to make a superoxide-responsive, persulfide-donating peptide (SOPD-Pep). Both SOPD-NAC and SOPD-Pep delivered persulfides/H₂ S to H9C2 cardiomyocytes and lowered ROS levels as confirmed by quantitative in vitro fluorescence imaging studies. Additional in vitro studies on RAW 264.7 macrophages showed that SOPD-Pep mitigated toxicity induced by phorbol 12-myristate 13-acetate (PMA) more effectively than SOPD-NAC and several control compounds, including common H₂ S donors.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7719095 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Alleviating Cellular Oxidative Stress through Treatment with Superoxide-Triggered Persulfide Prodrugs.

Wang Yin Y Dillon Kearsley M KM Li Zhao Z Winckler Ethan W EW Matson John B JB

Angewandte Chemie (International ed. in English) 20200723 38

Overproduction of superoxide anion (O2.- ), the primary cellular reactive oxygen species (ROS), is implicated in various human diseases. To reduce cellular oxidative stress caused by overproduction of superoxide, we developed a compound that reacts with O2.- to release a persulfide (RSSH), a type of reactive sulfur species related to the gasotransmitter hydrogen sulfide (H2 S). Termed SOPD-NAC, this persulfide donor reacts specifically with ...[more]

PMID: 32592216

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Project description:BackgroundThe currently available treatment methods are ineffective in reducing mortality or improving outcomes in acute lung injury (ALI). The activation of protein kinase C alpha (PKCα) has recently been implicated in ALI development. We explored the potential therapeutic outcomes of PKCα inhibition in cases of ALI and to elucidate the related mechanisms.MethodsIndexes of lung inflammation and injury were examined in lipopolysaccharide (LPS)-treated C57BL/6J mice (male) and macrophages after pretreatment with a PKCα inhibitor. Tissues were collected to assess lung injury by hematoxylin and eosin (H&E) staining. Bronchoalveolar lavage fluid was used to measure the pulmonary edema, hyperinflammatory response, and oxidative stress by bicinchoninic acid (BCA) method and enzyme-linked immunosorbent assay (ELISA). We tested the effect of PKCα inhibition on LPS-induced proliferation, cytotoxicity, oxidative damage, and the release of inflammatory cytokines in macrophages using the Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) cytotoxicity assay kit, flow cytometry, quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and ELISA. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway related proteins were detected by Western blot, immunohistochemistry (IHC), and immunofluorescence staining.ResultsWe observed that LPS upregulated PKCα phosphorylation, induced a hyperinflammatory response, and caused lung injury. However, PKCα inhibition effectively attenuated the changes caused by LPS. Moreover, we confirmed that inhibiting PKCα weakened the activity of the NF-κB pathway under LPS-induced ALI. These findings indicated that inhibition of PKCα is protective against LPS-induced hyperinflammatory response in ALI, this effect is likely to attributed to the downregulation of NF-κB signaling pathways.ConclusionsThe results showed that PKCα inhibition could attenuate ALI which may closely related to its anti-inflammatory and anti-oxidative effects.

Dataset Information

Alleviating Cellular Oxidative Stress through Treatment with Superoxide-Triggered Persulfide Prodrugs.

Publications

Alleviating Cellular Oxidative Stress through Treatment with Superoxide-Triggered Persulfide Prodrugs.

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