Inhibiting 5-hydroxytryptamine receptor 3 alleviates pathological changes of a mouse model of Alzheimer's disease

Extracellular amyloid beta(Aβ) plaques are main pathological feature of Alzheimer’s disease.However,the specific type of neuro ns that produce Aβ peptides in the initial stage of Alzheimer’s disease are unknown.In this study,we found that 5-hydroxytryptamin receptor 3A subunit(HTR3A) was highly expressed in the brain tissue of transgenic amyloid precursor protein and presenilin-1 mice(an Alzheimer’s disease model) and patients with Alzheimer’s disease.To investigate whether HTR3A-positive interneurons are associated with the production of Aβ plaques,we performed double immunostaining and found that HTR3A-positive interneurons were clustered around Aβ plaques in the mouse model.Some amyloid precursor protein-positive or β-site amyloid precursor protein cleaving enzyme-1-positive neurites near Aβ plaques were co-localized with HTR3A interneurons.These results suggest that HTR3A-positive interneurons may partially contribute to the generation of Aβ peptides.We treated 5.0-5.5-month-old model mice with tro pisetron,a HTR3 antagonist,for 8 consecutive weeks.We found that the cognitive deficit of mice was partially reversed,Aβ plaques and neuroinflammation we re remarkably reduced,the expression of HTR3 was remarkably decreased and the calcineurin/nuclear factor of activated T-cell 4 signaling pathway was inhibited in treated model mice.These findings suggest that HTR3A interneurons partly contribute to generation of Aβ peptide at the initial stage of Alzheimer’s disease and inhibiting HTR3 partly reve rses the pathological changes of Alzheimer’s disease.

Lipopolysaccharides protect mesenchymal stem cell against cardiac ischemia-reperfusion injury by HMGB1/STAT3 signaling

BACKGROUND Myocardial ischemia-reperfusion(I/R) is a serious and irreversible injury. Bone marrow-derived mesenchymal stem cells(MSCs) is considered to be a potential therapy for I/R injury due to the paracrine effects. High-mobility group box1(HMGB1) is a novel mediator in MSC and regulates the response of inflammation injury. Signal Transduction and Transcription Activator 3(STAT3) is a critical transcription factor and important for release of paracrine factors. However, the relationship between HMGB1 and STAT3 in paracrine effect of MSC remains unknown.METHODS In vitro, hypoxia/reoxygenation injury model was established by Anaero Pack System and examined by Annexin V flow cytometry, CCK8 assay and morphology observation. Detection of apoptotic proteins and protein expression of HMGB1and STAT3 by Western blot.RESULTS The conditioned medium of MSCs with or without LPS pretreatment was cocultured with H9C2 cells for 24 h before hypoxia treatment and MSC showed obvious cardiomyocytes protect role, as evidence by decreased apoptosis rate and improved cells viability, and LPS pretreated MSC exhibited better protect role than untreated MSC. However, such effect was abolished in HMGB1 deficiency group, silencing HMGB1 decreased the secretion of vascular endothelial growth factor(VEGF), hepatocyte growth factor(HGF), insulin growth factor(IGF), cell viability, and the expression of STAT3. Furthermore, STAT3 silence attenuated the protective effect of LPS in MSC.CONCLUSIONS These findings suggested that LPS improved MSC-mediated cardiomyocytes protection by HMGB1/STAT3signaling.

Biochemical, molecular, and morphological variations of flight muscles before and after dispersal flight in a eusocial termite, Reticulitermes chinensis

Swarming behavior facilitates pair formation,and therefore mating,in many eusocial termites.However,the physiological adjustments and morphological transformations of the flight muscles involved in flying and flightless insect forms are still unclear.Here,we found that the dispersal flight of the eusocial termite Reticulitermes chinensis Snyder led to a gradual decrease in adenosine triphosphate supply from oxidative phospho・rylation,as well as a reduction in the activities of critical mitochondrial respiratory enzymes from preflight to dealation.Correspondingly,using three-dimensional reconstruction and transmission electron microscopy(TEM),the flight muscles were found to be gradually deteriorated during this process.In particular,two tergo-pleural muscles(IItpm5 and IIItpm5)necessary to adjust the rotation of wings for wing shedding behavior were present only in flying alates.These findings suggest that flight muscle systems vary in function and morphology to facilitate the swarming flight procedure,which sheds light on the important role of swarming in successful extension and fecundity of eusocial termites.

Mechanism Research of Chonglou as a Pain Killer by Network Pharmacology

Objective:The objective of this study is to screen the therapeutic targets of pain of traditional Chinese medicine Chonglou and explore the relevant mechanism by network pharmacology techniques and methods.Materials and Methods:The chemical components of Chonglou were collected according to chemistry database and related literature.SwissADME was used to collect the potential active ingredients from all the chemical components of Chonglou and SwissTarget Prediction was utilized to predict their targets.The genes related to pain were collected from GeneCards and Online Mendelian Inheritance in Man databases.Joint genes were uploaded to the online string database for the analysis and the PPI network was constructed.The"Chonglou-active component-target-pain"network was constructed by Cytoscape 3.7.1 software,Gene Ontology(GO)functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were performed for key target proteins.The top three active components with most targets in the network were docked with the target proteins by the molecular docking technique.Results:A total of nine potential active compounds of Chonglou,264 potential target genes,2385 targets of pain disorder,and 128 common targets for drug and disease were screened.One hundred and thirty-one GO items were identified by the GO enrichment analysis,and 23 related signaling pathways were identified by the KEGG pathway enrichment analysis.Molecular-docking results show that pennogenin is the optimal butt ligand of PIK3 CA,STAT3,mitogen-activated protein kinase 14,and ADORA1.Conclusion:It is preliminarily revealed that Chonglou might treat pain through multiple targets,multiple biology processes and multiple pain-related signaling pathways,providing reference for the subsequent experimental research.