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.
Highlights
EDTA, L-cysteine, Igepal CA-630, NaHS, N-acetyl cysteine (NAC), neocuproine, and RIPA buffer were purchased from Sigma-Aldrich (Vienna, Austria)
As free thiols are relatively abundant in mammals, we hypothesized that the intracellular amount of thiols thiols would would be be sufficient sufficient to to induce induce H
ELISA and normalized to stimulated cells (Stim) set to 100%, n = 3, * p < 0.05, ** p < 0.01. (b) ATDC5 cells were incubated by ELISA and normalized to stimulated cells (Stim) set to 100%, n = 3, * p < 0.05, ** p < 0.01. (b) ATDC5 cells were incubated with P* for 1 h and stimulated for 24 h
Summary
Osteoarthritis (OA) is a degenerative joint disease characterized by pain, cartilage destruction, and disability. An imbalance occurs between the synthesis and degradation of the extracellular matrix tissue and involves mechanical, metabolic, and inflammatory factors [1,2]. OA represents the most common form of arthritis, but most diseasemodifying OA drugs and therapies have shown little clinical efficacy [3]. Among the non-pharmacological therapies for OA, traditional balneotherapy in hydrogen sulfide (H2 S)-rich water is still widely used and recommended by the guidelines of the OA Research Society International (OARSI) [3]. In different in vitro and in vivo OA models, H2 S exerted anti-inflammatory, antioxidant, and pain-relieving effects [4,5,6,7,8]. The effects of Antioxidants 2021, 10, 1049.
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