RVG-modified exosomes derived from mesenchymal stem cells rescue memory deficits by regulating inflammatory responses in a mouse model of Alzheimer's disease.

BACKGROUND: Exosomes are lipid-bilayer enclosed nano-sized vesicles that transfer functional cellular proteins, mRNA and miRNAs. Mesenchymal stem cells (MSCs) derived exosomes have been demonstrated to prevent memory deficits in the animal model of Alzheimer's disease (AD). However, the intravenously injected exosomes could be abundantly tracked in other organs except for the targeted regions in the brain. Here, we proposed the use of central nervous system-specific rabies viral glycoprotein (RVG) peptide to target intravenously-infused exosomes derived from MSCs (MSC-Exo) to the brain of transgenic APP/PS1 mice. MSC-Exo were conjugated with RVG through a DOPE-NHS linker. RESULTS: RVG-tagged MSC-Exo exhibited improved targeting to the cortex and hippocampus after being administered intravenously. Compared with the group administered MSC-Exo, in the group administered RVG-conjugated MSC-Exo (MSC-RVG-Exo) plaque deposition and Aß levels were sharply decreased and activation of astrocytes was obviously reduced. The brain targeted exosomes derived from MSCs was better than unmodified exosomes to improve cognitive function in APP/PS1 mice according to Morris water maze test. Additionally, although MSC-Exo injected intravenously reduced the expression of pro-inflammatory mediators TNF-α, IL-ß, and IL-6, but the changes of anti-inflammatory factors IL-10 and IL-13 were not obvious. However, administration of MSC-RVG-Exo significantly reduced the levels of TNF-α, IL-ß, and IL-6 while significantly raised the levels of IL-10, IL-4 and IL-13. CONCLUSIONS: Taken together, our results demonstrated a novel method for increasing delivery of exosomes for treatment of AD. By targeting exosomes to the cortex and hippocampus of AD mouse, there was a significant improvement in learning and memory capabilities with reduced plaque deposition and Aß levels, and normalized levels of inflammatory cytokines.

[Rhizoma Panacis majori reduces toxicity of chemotherapy in S180-bearing mice].

OBJECTIVE: To observe the attenuating effect of Rhizoma Panacis majoris (RPM) on toxicity of 5-fluorouracil (5-FU) chemotherapy in S180-bearing mice. METHODS: S180 cells were subcutaneously injected to the right armpit of the mice to establish the S180-bearing model, and thirty mice were randomly divided into untreated group, 5-FU group and 5-FU combined with RPM group (5-FU plus RPM group). The general condition of S180-bearing mice was observed. The white blood cells, red blood cells, and reticulocytes in the peripheral blood were counted, and the ratio of reticulocytes was measured too. The life-span of the S180-bearing mice was recorded. RESULTS: The white blood cell count and the ratio of reticulocytes in 5-FU plus RPM group were higher than those in 5-FU group (P<0.01). The average lifespan of 5-FU plus RPM group was 32.5 days and that of the 5-FU group was 23.5 days; there was a significant difference in the lifespan between the two groups (P<0.01). CONCLUSION: RPM can reduce the toxic effect of 5-FU and prolong the lifespan of S180-bearing mice.

Effects of 5-hydroxymethyl furfural extracted from Rehmannia glutinosa Libosch on the expression of signaling molecules relevant to learning and memory among hippocampal neurons exposed to high concentration of corticosterone.

OBJECTIVE: To determine the effects of 5-hydroxymethyl furfural (5-HMF), an extract of Rehmannia glutinosa Libosch, on several down-regulated signaling molecules involved in learning and memory in hippocampal neurons. METHODS: After cultured for 7 days, primary hippocampal neurons were divided into 5 groups: normal, corticosterone model, RU38486, 5-HMF, and donepezil group. Neuron survival rates were calculated 24 h later using SYTO13-PI double-fluorescence staining and an 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. ß-galactosidase activity was also assayed. Protein expressed by the glucocorticoid receptor (GCR), brainderived neurotrophic factor (BDNF), and N-methyl-D-aspartate receptor 2B (NR2B), as well as phosphorylationcyclic adenosine monophosphate (cAMP) response element binding protein (p-CREB), phosphorylation-extracellular signal-regulated kinase (p-ERK), and phosphorylation-synapsin (p-synapsin) were quantified with Western blot. RESULTS: Hippocampal neuron survival rates and the above-mentioned proteins were dramatically decreased (P<0.05), ß-galactosidase activity was significantly increased in the model group. but the effect was reversed by 5-HMF, RU38486, and to a lesser extent by donepezil (P<0.05). CONCLUSION: 5-HMF extracts from the Chinese herb Rehmannia glutinosa Libosch could protect hippocampal neurons from glucocorticoid injury and from down-regulated signaling molecules in the GCR-BDNF-NR2B-p-ERK-p-CREB-p-synapsin signal transduction pathway.