Selisistat

A novel antioxidant peptide AFYRW was previously isolated and identified from tartary buckwheat albumin in our laboratory. Human immortalized keratinocytes (HaCaT) are the main epidermal cells, and play a critical role in maintaining skin barrier function and mediating inflammatory and immune responses. This study explored the protective effect of AFYRW against oxidative damage in HaCaT cells and clarified the underlying molecular mechanism related to the SIRT1 pathway. HaCaT cells were divided into control, H₂O₂ model, and low/high-dose AFYRW intervention groups. A series of cytological and molecular biological assays were performed to detect cell viability, ROS levels, migration, apoptosis, and the expression of pathway-related proteins and genes. The results showed that AFYRW had no cytotoxicity, and dose-dependently reversed H₂O₂-induced cell viability decline, ROS overproduction, migration inhibition, inflammation and apoptosis. Mechanistically, AFYRW restored intracellular NAD⁺ content and enhanced SIRT1 activity, thereby reducing the acetylation levels of NF-κB p65 (Lys310) and p53 (Lys381). Furthermore, the SIRT1-specific inhibitor EX527 abolished the above protective effects of AFYRW. In conclusion, AFYRW alleviates H₂O₂-induced oxidative damage in HaCaT cells via activating SIRT1-mediated deacetylation, providing a theoretical basis for its application in skin-protective functional foods and cosmetics.

Postoperative cognitive dysfunction (POCD) is a prevalent and clinically significant complication in elderly surgical patients, yet effective therapeutic interventions remain scarce. Mitochondrial dysfunction, particularly impaired biogenesis, has been implicated as a central mechanism. LANCL1 is known for its neuroprotective properties against oxidative stress, but its role in POCD has not been explored. Here, we observed marked downregulation of LANCL1 in the hippocampi of aged mice following surgical trauma, correlating with cognitive decline and neuronal damage. Hippocampal-specific overexpression of Lancl1 via lentiviral vector significantly ameliorated cognitive deficits, including novel object recognition impairment, reduced neuronal injury, restored mitochondrial ultrastructure. Moreover, LANCL1 overexpression increased hippocampal ATP content and elevated the ratios of mitochondrial DNA-encoded genes (16S rRNA and ND1) relative to the nuclear gene HK2, indicating enhanced mitochondrial biogenesis. Histological analyses further revealed increased neuronal survival in the CA1 and CA3 subfields. Single-cell sequencing data demonstrated that LANCL1 expression in neurons was specifically reduced after LPS challenge compared to saline controls, supporting its vulnerability to inflammatory stress. LANCL1 overexpression also reduced hippocampal MDA levels and restored SOD activity, mitigating oxidative stress. Mechanistically, LANCL1 overexpression was associated with upregulation of the SIRT1/PGC-1α signaling axis and its downstream transcription factors NRF1 and TFAM essential for mitochondrial biogenesis. Importantly, co-administration of the SIRT1-specific inhibitor EX-527 completely abolished the protective effects of LANCL1, including the restoration of ATP levels, mtDNA copy number, neuronal survival, and cognitive performance, demonstrating that SIRT1 activity is required for LANCL1-mediated protection. Collectively, these findings establish LANCL1 as a critical regulator of mitochondrial health in the postoperative brain and highlight its therapeutic potential for mitigating POCD via enhancing SIRT1/PGC-1α-mediated mitochondrial biogenesis.