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Aim: We investigated the effects and target of gastrodin (GAS) for treating depression through network pharmacology combined with experimentation. Methods: The therapeutic target and signal of GAS for depression were analyzed by network pharmacology. Depression in mice was mimicked with a chronic unpredictable mouse stress (CUMS) model. Through open field, elevated plus maze, forced swimming, and tail suspension tests, the effects of GAS on the CUMS mice behaviors were examined, and the levels of neurotransmitters were detected. The histopathological changes were assayed by H&E and IHC staining, and the protein expressions were detected by Western blotting. Small molecule‐protein docking and molecular dynamics experiments were conducted to simulate the binding mode between GAS and Caspase‐3. Results: Network pharmacological analysis revealed that Caspase‐3 was the action target of GAS. GAS could improve depression‐like behaviors in CUMS mice, elevate their neurotransmitter levels, ameliorate their nerve cell injury, and inhibit their Caspase‐3 expression. After knocking out Caspase‐3, the effects of GAS were inhibited. Molecular dynamics simulation and small molecule‐protein docking found that GAS bound to Caspase‐3 at SER25, inhibiting the maturation and activation of Caspase‐3. Conclusion: We find that GAS can act as a Caspase‐3 inhibitor, which improves depression‐like behaviors and nerve cell injury in CUMS mice by inhibiting Caspase‐3‐mediated apoptosis. [ABSTRACT FROM AUTHOR]

Aim: We investigated the mechanism, whereby tumor necrosis factor‐like ligand 1A (TL1A) mediates the A1 differentiation of astrocytes in postoperative cognitive dysfunction (POCD). Methods: The cognitive and behavioral abilities of mice were assessed by Morris water maze and open field tests, while the levels of key A1 and A2 astrocyte factors were detected by RT‐qPCR. Immunohistochemical (IHC) staining was used to examine the expression of GFAP, western blot was used to assay the levels of related proteins, and enzyme‐linked immunosorbent assay (ELISA) was used to detect the levels of inflammatory cytokines. Results: The results showed that TL1A could promote the progression of cognitive dysfunction in mice. Astrocytes differentiated into A1 phenotype, while unobvious changes were noted in astrocyte A2 biomarkers. Knockout of NLRP3 or intervention with NLRP3 inhibitor could inhibit the effect of TL1A, improving the cognitive dysfunction and suppressing the A1 differentiation. Conclusion: Our results demonstrate that TL1A plays an important role in POCD in mice, which promotes the A1 differentiation of astrocytes through NLRP3, thereby exacerbating the progression of cognitive dysfunction. [ABSTRACT FROM AUTHOR]