Investigation of the Hydrogen Sulfide Signaling Pathway in Schwann Cells during Peripheral Nerve Degeneration: Multi-Omics Approaches

Abstract

N-ethylmaleimide (NEM) inhibits peripheral nerve degeneration (PND) by targeting Schwann cells in a hydrogen sulfide (H2S)-pathway-dependent manner, but the underlying molecular and pharmacological mechanisms are unclear. We investigated the effect of NEM, an α,β-unsaturated carboxyl compound, on H2S signaling in in vitro- and ex vivo-dedifferentiated Schwann cells using global proteomics (LC-MS) and transcriptomics (whole-genome and small RNA-sequencing (RNA-seq)) methods. The multi-omics analyses identified several genes and proteins related to oxidative stress, such as Sod1, Gnao1, Stx4, Hmox2, Srxn1, and Edn1. The responses to oxidative stress were transcriptionally regulated by several transcription factors, such as Atf3, Fos, Rela, and Smad2. In a functional enrichment analysis, cell cycle, oxidative stress, and lipid/cholesterol metabolism were enriched, implicating H2S signaling in Schwann cell dedifferentiation, proliferation, and myelination. NEM-induced changes in the H2S signaling pathway affect oxidative stress, lipid metabolism, and the cell cycle in Schwann cells. Therefore, regulation of the H2S signaling pathway by NEM during PND could prevent Schwann cell demyelination, dedifferentiation, and proliferation.

Detection of H2S using a novel fluorescent nanoprobe in plasma and tissue samples from ASD patients and model mice

“…2,3 Emerging studies have proved that H 2 S also has the potential to treat nervous system diseases as a neuroprotective agent. 4 In mammalian cells, the natural biosynthesis of H 2 S requires specific enzymes to produce H 2 S, including cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), cysteine aminotransferase (CAT), and 3-mercaptopyruvate sulfotransferase (3-MST), 5 while in the central nervous system, CBS is the main H 2 S-producing enzyme. 6…”

“…2,3 Emerging studies have proved that H 2 S also has the potential to treat nervous system diseases as a neuroprotective agent. 4 In mammalian cells, the natural biosynthesis of H 2 S requires specific enzymes to produce H 2 S, including cystathionine b-synthase (CBS), cystathionine g-lyase (CSE), cysteine aminotransferase (CAT), and 3-mercaptopyruvate sulfotransferase (3-MST), 5 while in the central nervous system, CBS is the main H 2 S-producing enzyme. 6 The abnormal generation and metabolism of endogenous H 2 S are closely related to nervous system diseases, suggesting that H 2 S participates in the pathological process of many nervous system diseases, such as Alzheimer's disease, Parkinson's disease, Febrile seizures, etc.…”