Selisistat

Corni fructus are the fruits of Cornus officinalis Sieb. et Zucc. and is widely used in traditional Chinese Medicine for the treatment of dementia. Cornuside, derived from Corni fructus, has been shown to be effective in improving cognition of AD mouse.

In the present study, we investigated the effect of cornuside on cognitive dysfunction and microglial NLRP3 inflammasome activation, as well as explored the underlying mechanism with respect to Sirt1 and autophagy.

AD mice were established and then treated with cornuside (3, 10, and 30 mg/kg) for 2 weeks. A series of behavioral tests were performed to assess cognition, including the Morris water maze, Y maze, nest building, step-down and step-through tests. Nissl staining was used to evaluate neuronal structural damage. LPS-stimulated BV2 cells were used for in vitro experiments. The anti-inflammatory effects of cornuside on cytokines and NLRP3 inflammasome activation were assessed using ELISA, RT-PCR, immunohistochemistry, western blotting, and immunofluorescence assays. To further elucidate the relationship between Sirt1, autophagy, and NLRP3 inflammasome activation, EX527 and 3-MA were used to inhibit Sirt1 and block autophagy flux in vitro, respectively.

Cornuside significantly improved various behavioral performance and inhibited NLRP3 inflammasome activation in LPS-induced mice, as evidenced by decreased levels of NLRP3, ASC, pro-caspase1, caspase1, pro-IL-1β, IL-1β, GSDMD, GSDMD-NT and IL-18. Similar inhibitory effects of cornuside on NLRP3 inflammasome activation was also detected in LPS stimulated BV2 cells. The involvement of Sirt1 and autophagy were further explored in-vivo and in-vitro, revealing that cornuside increased the expression of Sirt1 and enhanced autophagy, with decreased SQSTM1/p62 and increased LC3BII. However, the inhibitory effect of cornuside on NLRP3 inflammasome activation was abrogated by 3-MA, and the effects of cornuside on promoting autophagy and inhibiting NLRP3 inflammasome activation was abolished by EX527.

Cornuside exerts therapeutic effects on LPS induced AD mice by inhibiting microglial activation and NLRP3 inflammasome overactivation. And Sirt1 mediated autophagy activation is a vital mechanism by which cornuside degrades NLRP3 inflammasome, thereby alleviating neuroinflammation and improving cognitive function.

Spermidine (SPD) is an organic compound known for its powerful antioxidant stress and anti-aging properties, and whether SPD has the ability to reduce bone mass in elderly iron overload rats is unknown. The study aimed to assess SPD's impact on iron overload-induced bone loss in elderly rats. In our aged rat model, we found that iron overload negatively influences bone metabolism and remodeling, resulting in decreased bone mineral density and increased bone loss. However, SPD treatment effectively alleviated these harmful effects, as shown by reduced serum levels of MDA and increased SOD and GSH levels. Additionally, SPD-treated rats exhibited enhanced bone mass and higher expression of OC, BMP2, SIRT1, and SOD2 in their bones. Moreover, SPD restored the imbalance in bone metabolism by counteracting the inhibition of osteogenic differentiation and promoting osteoclast differentiation induced by iron overload in MC3T3-E1 and RAW264.7 cells affected by EX527. In summary, our findings suggest that SPD's antioxidant properties may exert anti-osteoporosis effects through activation of the SIRT1/SOD2 signaling pathway.