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Characterization of the Inducible and Slow-Releasing Hydrogen Sulfide and Persulfide Donor P*: Insights into Hydrogen Sulfide Signaling.

ABSTRACT: Hydrogen sulfide (H₂S) is an important mediator of inflammatory processes. However, controversial findings also exist, and its underlying molecular mechanisms are largely unknown. Recently, the byproducts of H₂S, per-/polysulfides, emerged as biological mediators themselves, highlighting the complex chemistry of H₂S. In this study, we characterized the biological effects of P*, a slow-releasing H₂S and persulfide donor. To differentiate between H₂S and polysulfide-derived effects, we decomposed P* into polysulfides. P* was further compared to the commonly used fast-releasing H₂S donor sodium hydrogen sulfide (NaHS). The effects on oxidative stress and interleukin-6 (IL-6) expression were assessed in ATDC5 cells using superoxide measurement, qPCR, ELISA, and Western blotting. The findings on IL-6 expression were corroborated in primary chondrocytes from osteoarthritis patients. In ATDC5 cells, P* not only induced the expression of the antioxidant enzyme heme oxygenase-1 via per-/polysulfides, but also induced activation of Akt and p38 MAPK. NaHS and P* significantly impaired menadione-induced superoxide production. P* reduced IL-6 levels in both ATDC5 cells and primary chondrocytes dependent on H₂S release. Taken together, P* provides a valuable research tool for the investigation of H₂S and per-/polysulfide signaling. These data demonstrate the importance of not only H₂S, but also per-/polysulfides as bioactive signaling molecules with potent anti-inflammatory and, in particular, antioxidant properties.

SUBMITTER: Trummer M

PROVIDER: S-EPMC8300844 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundSpinal cord ischemia‒reperfusion injury (SCIRI) can lead to paraplegia, which leads to permanent motor function loss. It is a disastrous complication of surgery and causes tremendous socioeconomic burden. However, effective treatments for SCIRI are still lacking. PANoptosis consists of three kinds of programmed cell death, pyroptosis, apoptosis, and necroptosis, and may contribute to ischemia‒reperfusion-induced neuron death. Previous studies have demonstrated that hydrogen sulfide (H2S) exerts a neuroprotective effect in many neurodegenerative diseases. However, whether H2S is anti-PANoptosis and neuroprotective in the progression of acute SCIRI remains unclear. Thus, in this study we aimed to explore the role of H2S in SCIRI and its underlying mechanisms.MethodsMeasurements of lower limb function, neuronal activity, microglia/macrophage function histopathological examinations, and biochemical levels were performed to examine the efficacy of H2S and to further demonstrate the mechanism and treatment of SCIRI.ResultsThe results showed that GYY4137 (a slow-releasing H2S donor) treatment attenuated the loss of Nissl bodies after SCIRI and improved the BBB score. Additionally, the number of TUNEL-positive and cleaved caspase-3-positive cells was decreased, and the upregulation of expression of cleaved caspase-8, cleaved caspase-3, Bax, and Bad and downregulation of Bcl-2 expression were reversed after GYY4137 administration. Meanwhile, both the expression and activation of p-MLKL, p-RIP1, and p-RIP3, along with the number of PI-positive and RIP3-positive neurons, were decreased in GYY4137-treated rats. Furthermore, GYY4137 administration reduced the expression of NLRP3, cleaved caspase-1 and cleaved GSDMD, decreased the colocalization NeuN/NLRP3 and Iba1/interleukin-1β-expressing cells, and inhibited proinflammatory factors and microglia/macrophage polarization.ConclusionsH2S ameliorated spinal cord neuron loss, prevented motor dysfunction after SCIRI, and exerted a neuroprotective effect via the inhibition of PANoptosis and overactivated microglia-mediated neuroinflammation in SCIRI.

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Characterization of the Inducible and Slow-Releasing Hydrogen Sulfide and Persulfide Donor P*: Insights into Hydrogen Sulfide Signaling.

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