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To investigate the material foundation and mechanism of Zi Bu Pi Yin Recipe in the prevention and treatment of mild cognitive impairment. The integrated pharmacology platform was used to study the active ingredients, drug targets, and disease targets of 12 Chinese traditional medicines of Zi Bu Pi Yin Recipe, and to construct the target of"Zi Bu Pi Yin Recipe-Chinese herbal medicine-chemical composition-core Target-the key path "of the visual network and network analysis. Results:The platform screened 687 kinds of active ingredients of Zi Bu Pi Yin Recipe including glycosides, sugars and alcohols. and 595 key targets for treating mild cognitive impairment, Including HADHA, HADH, NAD (P) -dependent steroid dehydrogenase-like (NSDHL), and et al. The enrichment analysis of GO and KEGG showed that these key targets were mainly localized in the cytoplasm and mitochondria. The most common molecular functions were ATP binding and protein binding, and participated in purine metabolism, nucleotide metabolism, carbon metabolism pathway, Carbohydrate metabolism and so on. The platform could predict the key target of Zi Bu Pi Yin Recipe in preventing and treating Mild Cognitive Impairment and its related pathways, which lay a good foundation for further revealing its mechanism.
ABSTRACT
Objective To explore the mechanism of Zibu Piyin Recipe (ZBPYR) on spleen yin deficiency diabetes-associated cognitive disorder (DACD). Methods The rats were randomly divided into control group, diabetes mellitus (DM) group, spleen yin deficiency group, spleen yin deficiency DM group and spleen yin deficiency DM+ZBPYR group (treatment group). Type 2 DM models were established by high-fat food feeding and low dose STZ intraperitoneal injection for 4 weeks. Then the classical compound method was used to construct spleen yin deficiency rat models by improper diet, over exertion and yin fluids exhaustion. The treatment group was given ZBPYR by gavage for 15 days, and the other groups were given the same amount of normal saline. Then cerebral cortex, hippocampus, stomach and liver were obtained and the changes of protein expression of PDHE1α in them were observed by Western Blot. Results The protein expression of PDHE1αin cortex of DM group and spleen yin deficiency DM group were lower than control group (P<0.05). PDHE1α expression of treatment group in cortex and stomach increased more significantly than spleen yin deficiency DM group (P<0.05). The expression of PDHE1α protein showed no significant difference among all groups in hippocampus and liver. Conclusion ZBPYR improved spleen yin deficiency DACD by regulating PDHE1αin cortex and stomach.
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This study was aimed to observe changes of key molecular in insulin signaling pathway in the hypothala-mus of rats to explore the mechanism of spleen yin deficiency diabetes-associated cognitive decline (DACD) and Zibu Piyin Recipe (ZBPYR) in order to provide new ideas and new clues for treatment of DACD. Rats were randomly divided into five groups, which were the control (Cont) group, diabetes (DM) group, spleen yin deficiency (pi) group, spleen yin deficiency diabetes (piDM) group and the ZBPYR group. Insulin receptor substrate 1 (IRS-1) serine phos-phorylation levels and protein kinase B (PKB/Akt) serine phosphorylation levels which were involved in the insulin signaling were observed by western blotting in the hypothalamus to determine whether there were insulin signaling obstacles in the hypothalamus of rats. The results showed that the expression of p-IRS-1ser in the DM group, pi group and piDM group was increased compared with the Cont group (P< 0.05); while the p-Akt expression of the DM group and piDM group was decreased (P< 0.05). The expression of p-IRS-1ser in the ZBPYR group decreased compared with the DM group and piDM group (P< 0.05); while the level of p-Akt increased compared with the DM group and piDM group (P < 0.05). It was concluded that insulin signaling was not transduced normally in the hy-pothalamus of the DM group, pi group and piDM group. Insulin resistance may occur in the hypothalamus. And ZBPYR can correct insulin signaling transduction disorder.
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Objective To clarify the pathogenesis of spleen yin deficiency diabetes-associated cognitive decline (DACD) and mechanism of Zinu Piyin Recipe (ZBPYR) by observing the expression of phosphorylated RNA-dependent protein kinase-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor 2α subunit (eIF2α), p-eIF2α, glucose-regulated protein 78 (GRP78) in cerebral cortex of spleen yin deficiency diabetes mellitus rats. Methods The rats were randomly divided into control group, diabetes mellitus group, spleen yin deficiency group, spleen yin deficiency diabetes mellitus group (disease-syndrome group) and spleen yin deficiency diabetes mellitus+ZBPYR group (treatment group). Type 2 diabetes mellitus models were established by high-fat food feeding for 4 weeks and low dose STZ intraperitoneal injection. Then the classical compound method was used to construct spleen yin deficiency rats model by improper diet, over exertion and yin fluids exhaustion. The reatment group was given ZBPYR and other groups were given equal volume of normal saline for 15 days, then cerebral cortex was obtained. The expression of p-PERK, p-eIF2α, eIF2α and GRP78 were observed by Western Blot and RT-PCR. Results The protein expression of p-PERK, p-eIF2α, and mRNA expression of GRP78 of diabetes mellitus group, spleen yin deficiency group and disease-syndrome group was enhanced compared with control group (P<0.05). GRP78 protein expression of diabetes mellitus group, disease-syndrome group was increased compared with control group (P<0.05). The protein expression of p-PERK, p-eIF2α, GRP78 and mRNA expression of GRP78 of treatment group was decreased compared with diabetes mellitus group and disease-syndrome group (P<0.05). Conclusion Endoplasmic reticulum stress is involved in spleen yin deficiency DACD. ZBPYR improves learning and memory ability by reducing endoplasmic reticulum stress.
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Objective To explore the inhibitory effects of Zibu Piyin Recipe(ZBPYR)serum on neuron apoptosis induced by tunieamyein(Tm,5 μg/ml)and its mechamsm in vitro by using sero-pharmacological method.Method Totally 12 healthy adult male SD rats(220～250 g)(SPF)were divided randomly into control group and ZBPYR group,6 in each group,then the blank and ZBPYR serum were prepared.The mouse.neuroblastoma cell line Neum2a cells were treated with Tunicamycin(Tin,an inhibitor of N-glycoslytion)to establish the endoplasmic reticulum(ER)stress model.The cells treated by ZBPYR aerum of different concentrations were interventional groups,and the cells treated by blank serum were control group.The viability of Neuro2a cells was meusurcdd by MTT assay.Flow cytometry wus applied to observe the apoptosis of Neuro2a cells.Western blotting was utilized to detect the protein expressions of two molecules,ER molecular chaperone-ucose regulated protein 78(CRP78)and transcriptional factor CCAAT/enhancer-binding protein-homologous protein(CHOP).The results were analyzed by sNK-q test.Results Compared to Tm group(cell viability 0.1673±0.0213,apoptotic rate 62.7050±1.4056),The cell viability of interventional groups(5%0.5295±0.0373,10%0.5843±0.0428,15%0.6274±0.0324)increased significantly(P<0.05);and the apoptotic rate(5%47.8733±2.8166,10%46.3366±1.2748,15%39.8833±1.0524)reduced significantly(P<0.05).The protein expressions of GRP 78(5%2.1228±0.2251,10%1.3293±0.9443,15%;15%0.0931±0.1168)and CHOP(5%1.1776±0.2927,10%0.7290±0.1708,15%0.6577±0.1883)of interventional groups reduced significantly compared with Tm group(GRP78 2.9149±0.5355;CHOP 1.6611±0.2913)P<0.05.Condusions ZBPYR serurn could increase the cell viability of Neuro2a cells treated with Tm and inhibit cell apoptosis.Thereby it may have neuroprotective effects,and the mechanism may be associated with the inhibition of ER stress and apoptosis pathway.