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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., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

The previous study by our group has found that miRNA‐22 can inhibit pyroptosis by targeting GSDMD and improve the memory and motor ability of mice with Alzheimer's disease (AD) mice by inhibiting inflammatory response. In recent years, stem cells and their exosomes have been reported to have good therapeutic effects on AD; therefore, we hypothesize that miRNA‐22 is likely to play a synergistic therapeutic effect. In this study, adipose‐derived mesenchymal stem cells (ADMSCs) were transfected into miRNA‐22 mimic to obtain miRNA‐22 loaded exosomes (Exo‐miRNA‐22), which was further used for the treatment and nerve repair of AD. In brief, 4‐month‐old APP/PS1 mice were assigned into the control group, Exo and Exo‐miRNA‐22 groups. After exosome transplantation, we observed changes in the motor and memory ability of mice. In addition, ELISA was used to detect the expression of inflammatory factors in cerebrospinal fluid and peripheral blood, Nissl staining was used to assess the survival of mouse nerve cells, immunofluorescence staining was used to determine the activation of microglia, and Western blot was utilized to detect the expression of pyroptosis‐related proteins. As a result, the nerve function and motor ability were significantly higher in mice in the Exo‐miRNA‐22 group than those in the control group and Exo group. Meanwhile, the survival level of nerve cells in mice was higher in the Exo‐miRNA‐22 group, and the expression of inflammatory factors was lower than that of the Exo group, indicating Exo‐miRNA‐22 could significantly suppress neuroinflammation. In vitro culture of PC12 cells, Aβ25‐35‐induced cell damage, detection of PC12 apoptotic level, the release of inflammatory factors and the expression of pyroptosis‐related proteins showed that Exo‐miRNA‐22 could inhibit PC12 apoptosis and significantly decrease the release of inflammatory factors. In this study, we found that miRNA‐22‐loaded ADMSC‐derived exosomes could decrease the release of inflammatory factors by inhibiting pyroptosis, thereby playing a synergetic therapeutic role with exosomes on AD, which is of great significance in AD research. [ABSTRACT FROM AUTHOR]

• Salvianolic acid C improves cerebral ischemia reperfusion injury through suppressing microglial cell M1 polarization. • Salvianolic acid C improves cerebral ischemia reperfusion injury through promoting cerebral angiogenesis. • Salvianolic acid C inhibits microglia polarization through glucose metabolism signals. This study aimed to investigate the mechanism of salvianolic acid C (SAC), the active ingredient in Salvia miltiorrhiza , in improving cerebral ischemia injury. The mouse microglial cells BV2 and mouse endothelial cells bEnd.3 were used as the objects of study. LPS/IFN-γ was applied to simulate the BV2 polarization, and bEnd.3 cells were treated under hypoxic condition. The BV2 cell polarization level was measured through flow cytometry (FCM), the TLR4 and MyD88 expression levels were detected by fluorescence staining, whereas the expression of inflammatory factors TNF-α, IL-6 and IL-1β was analyzed through ELISA. Tubule formation assay was also conducted to observe the tubule formation ability of bEnd.3 cells in vitro, and the level of VEGFR2 was detected by fluorescence staining. Cells were treated with the PKM2 inhibitor IN3, aiming to observe the influence of SAC on glycolysis of BV2 cells. In addition, the mouse model of cerebral ischemia was constructed through the middle cerebral artery occlusion (MCAO) method, and the pathological changes in brain tissues were detected after SAC intervention. Meanwhile, the levels of IBA-1, CD31 and ZO-1 were determined through histochemical staining. Nissl staining to detect nerve cell damage. In BV2 cell experiment, SAC suppressed the M1 polarization of BV2 cells, reduced the inflammatory factor levels, and inhibited the activation of TLR4 signal through suppressing glycolysis. When PKM2 was suppressed, the effects of SAC were antagonized. In the bEnd.3 model, SAC promoted tubule formation in bEnd.3 cells under hypoxic condition, and increased the expression of VEGFR2 and Notch1. In the mouse model, SAC improved the neurological function in MCAO mice, and inhibited the activation of microglial cells and the expression of inflammatory factors. At the same time, SAC up-regulated the expression of ZO-1 and CD31, and maintained the blood-brain barrier (BBB) function. As a major component of Salvia miltiorrhiza , SAC can suppress microglial cell polarization and promote tubule formation in endothelial cells to exert the neurological repair function in cerebral ischemia. SAC is a multi-functional neuroprotective small molecule. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a central degenerative disease characterized by cognitive impairment. Polymerization of β-amyloid has been reported to cause the entanglement of nerve cells, leading to the progressive loss of nerve cells. Accumulative studies have confirmed the important roles of neuroinflammation in the development of AD. In this study, the gut microbiota from AD patients were transplanted into APP/PS1 double transgenic mice. As a result, the expression of NLRP3 was increased in the intestinal tract of mice, and the expression levels of inflammatory factors in peripheral blood were also increased. Consistently, the cognitive impairment was more severe in mice receiving gut microbiota from AD patients than those did not, with activation of microglia in the central hippocampus of mice, and increased expression of neuroinflammatory factors. In APP/PS1 mice transplanted with gut microbiota from AD patients, transplantation of healthy human gut microbiota or oral administration of minocycline was further used to improve the composition of gut microbiota. Consequently, the intestinal expression of NLRP3 was down-regulated, the cognitive ability of mice was improved, the activation of microglia in central hippocampus was suppressed and the expression of neuroinflammatory factors was also down-regulated. After transplantation of gut microbiota from AD patients in C57BL/6 mice, the intestinal expression of NLRP3 was up-regulated. Although the cognitive ability of mice was not significantly changed, the microglia in the hippocampus of mice were still activated and the expression of inflammatory factors was up-regulated. In this study, we found that gut microbiota in AD patients could induce the activation of NLRP3 inflammasome in the intestinal tract of mice, subsequently causing the release of inflammatory factors. The absorption and circulation of inflammatory factors through the intestinal tract could further aggravate the inflammation in the nervous tissues and the activation of microglia. Therefore, improving the composition of gut microbiota in AD patients can further attenuate neuroinflammation, which is considered as a novel idea for AD treatment. • GM in AD patients can promote intestinal inflammatory response by activating intestinal NLRP3 inflammasome. • After reaching the brain tissue through circulation, inflammatory factors can promote microglia activation and inflammatory response in hippocampus, further aggravating the pathological progression of AD, leading to declined cognitive and behavioral abilities. • Improving intestinal bacteria can inhibit the central inflammation caused by NLRP3. [ABSTRACT FROM AUTHOR]