Hydrogen Sulfide Inhibits Formaldehyde-Induced Senescence in HT-22 Cells via Upregulation of Leptin Signaling

• Published in: Neuromolecular medicine 2019-06, Vol.21 (2), p.192-203
• Main Authors: Zhu, Wei-Wen, Ning, Min, Peng, Yi-Zhu, Tang, Yi-Yun, Kang, Xuan, Zhan, Ke-Bin, Zou, Wei, Zhang, Ping, Tang, Xiao-Qing
• Format: Article
• Language: English
• Subjects: Aging; Animals; Apoptosis; Apoptosis - drug effects; Biomedical and Life Sciences; Biomedicine; Cell Division - drug effects; Cell Line; Cell proliferation; Cell viability; Cellular Senescence - drug effects; Cholecystokinin; Cyclin-Dependent Kinase Inhibitor p16 - biosynthesis; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - biosynthesis; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Environmental Pollutants - antagonists & inhibitors; Environmental Pollutants - toxicity; Flow cytometry; Formaldehyde; Formaldehyde - antagonists & inhibitors; Formaldehyde - toxicity; Gene Expression Regulation - drug effects; Genes, p16; Hippocampus - cytology; Hormones; Hydrogen sulfide; Hydrogen Sulfide - pharmacology; INK4a protein; Internal Medicine; Leptin - antagonists & inhibitors; Leptin - biosynthesis; Leptin - genetics; Leptin - physiology; Mice; Neurodegenerative Diseases - chemically induced; Neurology; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Neurosciences; Neurotoxicity; Original Paper; p16 Protein; Receptors, Leptin - biosynthesis; Receptors, Leptin - genetics; Senescence; Signal Transduction - drug effects; Sulfides - pharmacology; Up-regulation; Up-Regulation - drug effects; β-Galactosidase
• ISSN: 1535-1084; 1559-1174
• DOI: 10.1007/s12017-019-08536-8

It has been previously demonstrated that hydrogen sulfide (H 2 S) prevents formaldehyde (FA)-induced neurotoxicity. However, the exact mechanisms underlying this protection remain to be fully elucidated. Neuronal senescence is involved in FA-induced neurotoxicity. Leptin signaling has anti-aging function. The present work was to investigate the protection of H 2 S against FA-induced neuronal senescence and the mediatory role of leptin signaling. FA-exposed HT-22 cells were used as the vitro model of FA-induced neuronal senescence. The senescence-associated β-galactosidase (SA-β-Gal) positive cell was detected by β-galactosidase staining. The expressions of P16 INK4a , P21 CIP1 , leptin, and lepRb (leptin receptor) were measured by western blot. The proliferation, viability, and apoptosis of cells were evaluated by Trypan blue exclusion assay, Cell Counting Kit-8 (CCK-8) assay, and Flow cytometry analysis, respectively. We found that H 2 S suppressed FA-induced senescence, as evidenced by the decrease in SA-β-Gal positive cells, the downregulations of P16 INK4a and P21 CIP1 , as well as decrease in cell growth arrest, in HT-22 cells. Also, H 2 S upregulated the expressions of leptin and lepRb in FA-exposed HT-22 cells. Furthermore, leptin tA (a specific inhibitor of the leptin) abolished the protective effects of H 2 S on FA-induced senescence and neurotoxicity (as evidenced by the increase in cell viability and the decrease in cell apoptosis) in HT-22 cells. These results indicated that H 2 S prevents FA-induced neuronal senescence via upregulation of leptin signaling. Our findings offer a novel insight into the mechanisms underlying the protection of H 2 S against FA-induced neurotoxicity. Graphical Abstract FA upregulates the expressions of P16 INK4a and P21 CIP1 via inhibiting leptin signaling, which in turn induces senescence in HT-22 cells; H 2 S downregulates the expressions of P16 INK4a and P21 CIP1 via reversing FA-downregulated leptin signaling, which in turn prevents FA-induced senescence in HT-22 cells.