Investigating mechanism of Jiang-zhi-dai-pao-cha for treatment of hyperlipidemia by network pharmacology

Objective:To collect the main components and targets of Jiang-zhi-dai-pao-cha(JZDPC)and investigate the mechanism of JZDPC for the treatment of hyperlipidemia by network pharmacology.Methods:The components and targets of JZDPC were searched from ETCM databases,the targets related to hyperlipidemia were searched from DisGeNET and GeneCards databases,and then the intersection targets and corresponding key components were obtained.Cytoscape 3.8.2 software was used to construct and analyze networks,and then Metascape online database was applied for gene ontology(GO)enrichment analysis and Kyoto Encyclopedia of genes and genomes(KEGG)pathway enrichment analysis of core putative targets.Results:There were 99 overlapping targets between JZDPC and hyperlipidemia,among which NR3C1,ESR1,NR1I2,NFKB1,ESR2,ALOX5,PTGS1,PPARA,RXRA,LPL,PLA2G1B,PYGM,CYP2C9 were the core putative targets,and many members of nuclear receptor 1(NR1)subfamily were included.The core components of JZDPC,such as Ursolic Acid,β-Sitosterol,Resveratrol,Arirubic Acid,Alisol A,Oleanolic Acid,Rhein,Chrysophanol and Emodin,can regulate blood lipid by regulating a series of signaling pathways including the above core potential targets,such as non-alcoholic fatty liver disease(NAFLD)signaling pathway,pathways in cancer,arachidonic acid(AA)metabolism signaling pathway and peroxisome proliferator activated receptor(PPAR)signaling pathway,Starch and sucrose metabolism signaling pathway,etc.They play many roles in the treatment of hyperlipidemia by participating in lipid synthesis and metabolism,anti inflammation,anti oxidative stress,regulating hormone levels and carbohydrate metabolism.Conclusion:Network pharmacology provides a theoretical basis for investigating the mechanism of action of JZDPC,and the NAFLD signaling pathway is one of the most valuable pathways.

Distinct Rab7-related Endosomal-Autophagic-Lysosomal Dysregulation Observed in Cortex and Hippocampus in APPswe/PSEN1dE9 Mouse Model of Alzheimer＇s Disease

Background：Amyloid-β deposition and accumulation of autophagic vacuoles are pathologic features of Alzheimer＇s disease （AD）.Dysregulation of the endosomal-autophagic-lysosomal （EAL） pathway,which impairs amyloid precursor protein processing,is one of the earliest changes in AD.However,the precise role of EAL pathway in neurodegeneration remains unclear.This study aimed to investigate the role of EAL pathway in AD and further study the mechanism of EAL dysfunction.Methods：We used 3-,7-,and 12-month-old APPswe/PSEN1dE9 （APP/PS1） mice to model different stages of AD with age-and gender-matched wild-type littermates as controls （4-7 mice per group） and detected the changes of EAL markers,endosomal organizers Rab5 and Rab7,autophagosome marker LC3B,and lysosomal proteins Lamp 1/2 in cortex and hippocampus by immunohistochemistry and Western blotting analysis.To further explore the mechanism of EAL dysregulation in AD,components of the class Ⅲ phosphatidylinositol 3-kinase （PI3KC3） complex,activators ofRab7 （Beclin1 and UVRAG）,and the negative regulator of Rab7 （Rubicon） were also measured in this two brain regions.Results：In 7-month-old APP/PS1 brain that amyloid beta initiated to accumulate intracellularly,EAL pathway,and related PI3KC3 members,UVRAG and Beclin1 were upregulated both in cortex and hippocampus （all P 〈 0.05）.By the age of 12 months old,when abundant amyloid plaques formed,EAL markers,UVRAG,and Beclin 1 were also upregulated in the cortex （all P 〈 0.05）.However,Rab7 was decreased significantly （P =0.0447）,accompanied by a reduction of its activating PI3KC complex component Beclin1 （P =0.0215） and enhancement of its inhibiting component Rubicon （P =0.0055） in the hippocampus.Conclusions：Our study implies that EAL pathway,represented as Rab7 and its PI3KC3 regulators＇ expressions,showed temporal and spatial variation in brains at different stages of AD.It provides new insights into the role of EAL pathway in pathogenesis and indicates potential therapeutic targets in neurodegenerative diseases.