Neuroprotective effects of butyrolactone II from Aspergillus terreus via Nrf-2/SKN-1 pathway modulation in Caenorhabditis elegans

Fourteen compounds were isolated from the fermentation broth of Aspergillus terreus, all of which were isolated from A. terreus for the first time. Among them, butyrolactone II (A9) had excellent DPPH radical scavenging activity, with an EC₅₀ value of 42.05 µM superior to positive control drug BHT. Further neuroprotective activity evaluation of in Caenorhabditis elegans CL2355 revealed that butyrolactone II could alleviate Aβ, causing chemotaxis disorder, prolonging lifespan of C. elegans, and reducing 5-HT sensitivity. Butyrolactone II treatment significantly elevated the chemotaxis index of genotyped nematode CL2355 by 15.06% (P<0.05), and reduced the sensitivity of nematodes to 5-HT, decreasing the paralysis rate by 9.8% (P<0.05). Moreover, it significantly increased median lifespan and maximum lifespan by 20% and 26% respectively. In the RNA transcriptome, Butyrolactone II caused upregulation of 277 differentially expressed genes and downregulation of 171 differentially expressed genes, inducing the entry of transcription factor SKN-1 into the nucleus and changes in its downstream genes. The annotation and enrichment of GO and KEGG pathways indicated that differentially expressed genes might be related to pathways such as metabolic detoxification, oxidative stress, and lysosomal autophagy. The qRT-PCR validation of gene expression was consistent with transcriptomics. Butyrolactone II could significantly increase the expression of mitochondrial fission factor (mff-2), downstream genes related to SKN-1 (dod-17, gst-38), heat shock protein genes (hsp-17, hsp-12.6), and oxidative stress related genes (cyp-14A5) in nematodes, while having no significant effect on the expression level of gst-33 gene. Taken conclusion, butyrolactone II exerts neuroprotective effects by modulating the Nrf-2/SKN-1 pathway and regulating metabolic pathways, underscoring its potential as a therapeutic strategy for Alzheimer's disease and other related neurodegenerative disorders.