Neuregulin-1 preconditioning protects the heart against ischemia/reperfusion injury through a PI3K/Akt-dependent mechanism

Background Neuregulin-1 （NRG-1）, the ligand of the myocardial ErbB receptor, is a protein mediator with regulatory actions in the heart. This study investigated whether NRG-1 preconditioning has protective effects on myocardial ischemia/reperfusion （I/R） injury and its potential mechanism.Methods We worked with an in vivo rat model with induced myocardial ischemia （45 minutes） followed by reperfusion （3 hours）. NRG-1 message was detected in the heart using RT-PCR and the protein levels of NRG-1 and ErbB4 were detected by Western blotting analysis. Infarct size was assessed using the staining agent triphenyltetrazolium chloride and cardiac function was continuously monitored. The levels of creatine kinase and lactate dehydrogenase in plasma were analyzed to assess the degree of cardiac injury. The extent of cardiac apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling （TUNEL） assay and by Western blotting analysis of cleaved caspase-3. We examined the phosphorylation of Akt in the myocardium and the effect of PI3K/Akt inhibition on NRG-1-induced cardioprotection.Results Transcription and expression of NRG-1 and phosphorylation of its ErbB4 receptor were significantly upregulated in the I/R hearts. NRG-1 pretreatment reduced the infarct size following cardiac I/R in a concentration-dependent manner with an optimal concentration of 4 μg/kg in vivo. NRG-1 pretreatment with 4 μg/kg, i.v.markedly reduced the plasma creatine kinase and lactate dehydrogenase levels. Pretreatment with NRG-1 also significantly reduced the percentage of TUNEL positive myocytes and the level of cleaved caspase-3 in the I/R hearts.Pretreatment with NRG-1 significantly increased phosphorylation of Akt following I/R. Furthermore, the cardioprotective effect limiting the infarct size that was induced by NRG-1 was abolished by co-administration of the PI3K inhibitor LY294002.Conclusions The concentration of NRG-1, a new autacoid, was rapidly upregulated after myocardial I/R. NRG-1 preconditioning has cardioprotective effects against I/R injury through a PI3K/Akt-dependent mechanism in vivo.

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.