Intervention in chronically activated microglia-mediated neuroinflammation is a novel approach to treat Alzheimer's disease (AD). The low permeability of the blood‒brain barrier (BBB) and non-selective distribution in the brain severely restrict AD drugs' disease-modifying efficacy. Here, an immunosuppressant TREM2-lowing antisense oligonucleotides (ASOs) and resveratrol co-loaded cationic liposome is developed as an immune reprogramming nanomodulator modified by acid-cleavable BBB-targeting peptide and microglia-targeting peptide (Res@TcMNP/ASO) for AD management. Res@TcMNP/ASO can enter brain endothelial cells via D-T7 peptides. Then D-T7 undergoes an acid-responsive cleavage, facilitating the escape of Res@MNP/ASO from endo/lysosomes to cross the BBB. The detached Res@MNP/ASO specifically targets M1-phenotype microglia via exposed MG1 peptides to prompt the simultaneous delivery of two drugs into activated microglia. This nanomodulator can not only restore the immune function of microglia through TREM2-lowing ASO but also mitigate the immune stimulation to microglia caused by reactive oxygen species (ROS) through resveratrol, thereby synergistically inhibiting the chronic activation of microglia to alleviate neuroinflammation in AD. Our results indicate that this combination treatment can achieve significant behavioral and cognitive improvements in late APP/PS1 mice.

Objective To compare the efficacy of programmed intermittent epidural bolus and continuous epidural infusion of ropivacaine in labor analgesia.Methods From May 2014 to May 2017,170 patients,24 -32 years,for full-term primipara in the Maternal and Child Health Care Hospital of Quzhou were selected as study objects,and they were randomly divided into intermittent epidural injection group (T group) and continuous epidural pump group(C group) by computer random software,with 85 cases in each group.All patients were epidurally injected 2%lidocaine 3mL and 0.2% ropivacaine 2mL at the opening of the uterus,less than 3cm.T group was given programmed intermittent epidural bolus 0.1% ropivacaine 6mL/h.C group was given continuous epidural infusion 0.1%ropivacaine 6mL/h.The pain of maternal(NRS score) and motor block situation of maternal (Bromage score) were monitored.The number of PCEA,PCEA pressure times,the rate of instrumental delivery and APGAR score were also recorded.Results The number of Bromage score≥2 in C group was higher than that of T group at 4-10h after labor analgesia (3 cases vs.11 cases,3 cases vs.15 cases,4 cases vs.17 cases,4 cases vs.18 cases,6 cases vs. 19 cases,6 cases vs.21 cases,7 cases vs.22 cases;χ2＝4.982,8.947,9.182,10.230,7.926,9.907,9.354,all P＜0.05).There was no statistically significant difference in NRS score between the two groups (P＞0.05).The number of PCEA,PCEA pressure times and the rate of instrumental delivery in T group were lower than those in C group [8 cases vs.18 cases,22 cases vs.41 cases,(3.5 ±1.5) times vs.(4.9 ±2.2) times;χ2＝4.541,9.104;t＝2.666,all P＜0.05].There was no statistically significant difference in Apgar score between the two groups (P＞0.05).Conclusion Compared with continuous epidural infusion,programmed intermittent bolus of ropivacaine for labor analgesia exerts good analgesic effect,it has minor effects on exercise function and can decrease the rate of instrumental delivery .