Folium Hibisci Mutabilis extract, a potent autophagy enhancer, exhibits neuroprotective properties in multiple models of neurodegenerative diseases.

BACKGROUND: Protein aggregates are considered key pathological features in neurodegenerative diseases (NDs). The induction of autophagy can effectively promote the clearance of ND-related misfolded proteins. OBJECTIVE: In this study, we aimed to screen natural autophagy enhancers from traditional Chinese medicines (TCMs) presenting potent neuroprotective potential in multiple ND models. METHODS: The autophagy enhancers were broadly screened in our established herbal extract library using the transgenic Caenorhabditis elegans (C. elegans) DA2123 strain. The neuroprotective effects of the identified autophagy enhancers were evaluated in multiple C. elegans ND models by measuring Aß-, Tau-, α-synuclein-, and polyQ40-induced pathologies. In addition, PC-12 cells and 3 × Tg-AD mice were employed to further validate the neuroprotective ability of the identified autophagy enhancers, both in vitro and in vivo. Furthermore, RNAi bacteria and autophagy inhibitors were used to evaluate whether the observed effects of the identified autophagy enhancers were mediated by the autophagy-activated pathway. RESULTS: The ethanol extract of Folium Hibisci Mutabilis (FHME) was found to significantly increase GFP::LGG-1-positive puncta in the DA2123 worms. FHME treatment markedly inhibited Aß, α-synuclein, and polyQ40, as well as prolonging the lifespan and improving the behaviors of C. elegans, while siRNA targeting four key autophagy genes partly abrogated the protective roles of FHME in C. elegans. Additionally, FHME decreased the expression of AD-related proteins and restored cell viability in PC-12 cells, which were canceled by cotreatment with 3-methyladenine (3-MA) or bafilomycin A1 (Baf). Moreover, FHME ameliorated AD-like cognitive impairment and pathology, as well as activating autophagy in 3 × Tg-AD mice. CONCLUSION: FHME was successfully screened from our natural product library as a potent autophagy enhancer that exhibits a neuroprotective effect in multiple ND models across species through the induction of autophagy. These findings offer a new and reliable strategy for screening autophagy inducers, as well as providing evidence that FHME may serve as a possible therapeutic agent for NDs.

Detrimental effects of long-term elevated serum uric acid on cognitive function in rats.

Uric acid is a powerful antioxidant. However, its elevated levels in association with cardiovascular diseases predispose individuals to cognitive impairment. Uric acid's effects on cognition may be related to its concentration and exposure period. We aimed to explore the effects of long-term elevated serum uric acid on cognitive function and hippocampus. Rats were randomly divided into four groups: NC, M1, M2 and M3 groups. Hyperuricemia was established in rats at week 6 and maintained until week 48 in groups M1, M2 and M3. The rats' spatial learning and memory abilities were assessed by the Morris Water Maze test at weeks 0, 6, 16, 32, and 48. After week 48, we observed pathological changes in right hippocampal CA1 and CA3 regions, and measured levels of oxidative stress, inflammatory cytokines, and ß-amyloid peptide of left hippocampus. Starting from week 6, the serum uric acid level of M3 group > M2 group, the serum uric acid level of M2 group > M1 group, and the serum uric acid level of M1 group > NC group. The rats in M3 and M2 groups had longer escape latencies, longer mean distances to the platform, more extensive pathological damage, stronger inflammation response, higher oxidative stress and ß-amyloid peptide levels than those in NC group. No significant differences were observed between M1 and NC groups. In addition, we also found that oxidative stress significantly correlated with tumour necrosis factor-α and ß-amyloid peptide. Long-term elevated serum uric acid was significantly associated with cognitive impairment risk. Oxidative stress, tumour necrosis factor-α and ß-amyloid peptide may mediate the pathogenesis of the cognitive impairment induced by uric acid. The detrimental effect of elevated serum uric acid on cognitive function was probably expressed when the serum uric acid concentration reached a certain level.