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Network Pharmacology-Based and Experimental Identification of the Effects of Quercetin on Alzheimer's Disease.

ABSTRACT: Alzheimer's disease (AD) is one of the neurodegenerative brain disorders inducing nearly half of dementia cases, and the diagnosis and treatment of AD are the primary issues clinically. However, there is a lack of effective biomarkers and drugs for AD diagnosis and therapeutics so far. In this study, bioinformatics analysis combined with an experimental verification strategy was used to identify the biomarkers and the quercetin targets for AD diagnosis and treatment. First, differentially expressed genes in the AD brain were identified by microarray data analysis. Second, quercetin, a predominant flavonoid, was used to screen the target genes. Third, the drug-disease network was determined, and the target genes of quercetin treatment were obtained in AD-related HT-22 cell-based assay. Six genes, including MAPT, PIK3R1, CASP8, DAPK1, MAPK1, and CYCS, were validated by the system pharmacology analysis in the hippocampus samples of AD patients. The results suggested that MAPT, PIK3R1, CASP8, and DAPK1 were significantly increased, but MAPK1 and CYCS were significantly decreased in HT-22 cells after A?1-42 treatment. Moreover, MAPK1 and CYCS were markedly increased, but MAPT, PIK3R1, CASP8, and DAPK1 were markedly decreased after quercetin treatment in these HT-22 cells. Altogether, MAPT, PIK3R1, CASP8, DAPK1, MAPK1, and CYCS are all the biomarkers for AD diagnosis and the targets of quercetin treatment, and our findings may provide valuable biomarkers for AD diagnosis and treatment.

SUBMITTER: Qi P

PROVIDER: S-EPMC7645061 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Network Pharmacology-Based and Experimental Identification of the Effects of Quercetin on Alzheimer's Disease.

Qi Pingfang P Li Jing J Gao Shichao S Yuan Yirong Y Sun Yindi Y Liu Na N Li Yuanyuan Y Wang Gang G Chen Ling L Shi Jing J

Frontiers in aging neuroscience 20201023

Alzheimer's disease (AD) is one of the neurodegenerative brain disorders inducing nearly half of dementia cases, and the diagnosis and treatment of AD are the primary issues clinically. However, there is a lack of effective biomarkers and drugs for AD diagnosis and therapeutics so far. In this study, bioinformatics analysis combined with an experimental verification strategy was used to identify the biomarkers and the quercetin targets for AD diagnosis and treatment. First, differentially expres ...[more]

PMID: 33192484

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Project description:BackgroundCurrently, there are no efficient therapies for Alzheimer's disease (AD) among the elderly, although it is the most common etiology of dementia among the elderly. Quercetin, which has a variety of therapeutic properties, may pave the way for novel approaches to AD treatment. In the AD patients' frontal cortex, current study aims to identify the potential mechanisms of quercetin's pharmacological targets.Materials and methodsThe pharmacological targets of quercetin have been studied from DrugBank and SwissTarget. In order to distinguish AD-associated genes targeted by quercetin (Q-ADGs), we utilized an integrated intersection of gene expressions of the frontal cortex in combination with transcriptome analysis. To detect cortex-related Q-ADGs and immune-related Q-ADGs, a drug screening database and the immune infiltration analysis was utilized. The Q-ADGs were then linked with the AD severity scores (MMSE scores) to find severity-associated Q-ADGs. In addition, the miRNA-seq datasets were examined to identify severity-associated Q-ADG-miRNAs. Twelve genes, more frequently related to AD by previous studies among all the genes identified in the present study, were subjected to the verification of qRT-PCR in AD cell model.ResultsIn the frontal lobe of AD, 207 Q-ADGs were discovered and found that axonogenesis, glial differentiation, and other biological processes had been enriched. There were 155 immune-related Q-ADGs (e.g., COX2, NOS2, HMGB1) and 65 cortex-related Q-ADGs (e.g., FOXO1, CXCL16, NOTCH3). Sixteen Q-ADGs (e.g., STAT3, RORA, BCL6) and 28 miRNAs (e.g., miR-142-5p, miR-17-5p) were found to be related to MMSE scores. In the qRT-PCR results, six out of twelve genes were significantly regulated by quercetin. DYRK1A, FOXO1, NOS2, NGF, NQO1, and RORA genes were novel target of quercetin in AD. DYRK1A, NOS2, and NQO1 genes targeted by quercetin have benefits in the treatment of AD. However, FOXO1, NGF, and RORA genes targeted by quercetin might have a negative impact on AD.ConclusionThe role of quercetin in AD appears to be multifaceted, and it can affect patients' frontal cortex in a variety of pathways, such as axonogenesis, immune infiltration, and glial cell differentiation. DYRK1A, NOS2, and NQO1 might be potential novel effective drug targets for quercetin in AD.

Project description:ObjectiveTo investigate the therapeutic mechanism of resveratrol (RES) for Alzheimer's disease (AD) in light of network pharmacology.MethodsWe searched PubChem, BATMAN-TCM, Genecards, AD, TTD, String 11.0, AlzData, SwissTargetPrediction, Metascape and other databases for the therapeutic targets of RES and human AD-related targets. The intersection was determined using Venny 2.1 to obtain the therapeutic targets of RES for AD. The protein-protein interaction (PPI) network was constructed, the gene ontology (GO) was enriched and the Kyoto Encyclopedia of Genes and Genomes pathway (KEGG pathway) were analyzed. Cytoscape 3.7.1 software was used to construct a target-signaling pathway network of RES in the treatment of AD. Molecular docking verification was carried out on SwissDock (http://www.swissdock.ch/docking). We examined a 293Tau cell model of AD for changes in protein levels of pS396, pS199, Tau5, CDK5, glycogen synthase kinase 3β (GSK3β) and p-GSK3β in response to RES treatment using Western blotting.ResultsWe obtained 182 targets of RES, 525 targets related to AD, and 36 targets of RES for AD treatment, among which 34.6% of the targets were protein-modifying enzymes, 27.7% were metabolite invertase, 13.8% were gene-specific transcriptional regulators, and 10.3% were transporters. The core key targets of RES in the treatment of AD included INS, APP, ESR1, MMP9, IGF1R, CACNA1C, MAPT (microtubule- associated protein Tau), MMP2, TGFB1 and GSK3B. Enrichment analysis of GO biological process suggested that the biological function of RES in AD treatment mainly involved the response to β-amyloid protein, positive regulation of transferase activity, the transmembrane receptor protein tyrosine kinase signaling pathway, regulation of behavior, learning or memory, aging, and transmembrane transport. KEGG pathway enrichment analysis showed that the most significantly enriched signaling pathways were AD pathway, PI3K-AKT signaling pathway, cGMP-PKG signaling pathway, and MAPK signaling pathway. Molecular docking results showed that RES had strong binding with ESR1, GSK3B, MMP9, IGF1R, APP and INS. In the cell model of AD, treatment with 50 μmol/L RES for 12 h significantly reduced the levels of pS396 and pS199 by regulating CDK5 and GSK3β activity (P < 0.001).ConclusionsRES produces therapeutic effects on AD by acting on multiple targets and affecting multiple signaling pathways and improves AD-associated pathologies via a direct action on Aβ and Tau pathological processes.

Project description:BackgroundHuangqi Sijunzi decoction (HQSJZD) is a commonly used conventional Chinese herbal medicine prescription for invigorating Qi, tonifying Yang, and removing dampness. Modern pharmacology and clinical applications of HQSJZD have shown that it has a certain curative effect on Alzheimer's disease (AD).MethodsThe active components and targets of HQSJZD were searched in the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The genes corresponding to the targets were retrieved using UniProt and GeneCard database. The herb-compound-target network and protein-protein interaction (PPI) network were constructed by Cytoscape. The core targets of HQSJZD were analysed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The main active compounds of HQSJZD were docked with acetylcholinesterase (AChE). In vitro experiments were conducted to detect the inhibitory and neuroprotective effects of AChE.ResultsCompound-target network mainly contained 132 compounds and 255 corresponding targets. The main compounds contained quercetin, kaempferol, formononetin, isorhamnetin, hederagenin, and calycosin. Key targets contained AChE, PTGS2, PPARG, IL-1B, GSK3B, etc. There were 1708 GO items in GO enrichment analysis and 310 signalling pathways in KEGG, mainly including the cAMP signalling pathway, the vascular endothelial growth factor (VEGF) signalling pathway, serotonergic synapses, the calcium signalling pathway, type II diabetes mellitus, arginine and proline metabolism, and the longevity regulating pathway. Molecular docking showed that hederagenin and formononetin were the top 2 compounds of HQSJZD, which had a high affinity with AChE. And formononetin has a good neuroprotective effect, which can improve the oxidative damage of nerve cells.ConclusionHQSJZD was found to have the potential to treat AD by targeting multiple AD-related targets. Formononetin and hederagenin in HQSJZD may regulate multiple signalling pathways through AChE, which might play a therapeutic role in AD.

Project description:There is yet no effective drug for Alzheimer's disease (AD) which is one of the world's most common neurodegenerative diseases. The Qin-Zhi-Zhu-Dan Formula (QZZD) is derived from a widely used Chinese patent drug-Qing-Kai-Ling Injection. It consists of Radix Scutellariae, Fructus Gardeniae, and Pulvis Fellis Suis. Recent study showed that QZZD and its effective components played important roles in anti-inflammation, antioxidative stress and preventing brain injury. It was noted that QZZD had protective effects on the brain, but the mechanism remained unclear. This study aims to investigate the mechanism of QZZD in the treatment of AD combining network pharmacology approach with experimental validation. In the network pharmacology analysis, a total of 15 active compounds of QZZD and 135 putative targets against AD were first obtained. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were then applied to clarify the biological mechanism. The anti-inflammatory mechanism of QZZD was proved, and a synthetic pathway-TNFR1-ERK1/2-NF-κBp65 signaling pathway was obtained. On the basis of the above discoveries, we further validated the protective effects QZZD on neurons with an APP/PS1 double transgenic mouse model. Weight change of the mice was monitored to assess QZZD's influence on the digestive system; water maze experiment was used for evaluating the effects on spatial learning and memory; Western blotting and immunohistochemistry analysis were used to detect the predicted key proteins in network pharmacology analysis, including Aβ, IL-6, NF-κBp65, TNFR1, p-ERK1/2, and ERK1/2. We proved that QZZD could improve neuroinflammation and attenuate neuronal death without influencing the digestive system in APP/PS1 double transgenic mice with dementia. Combining animal pharmacodynamic experiments with network pharmacology analysis, we confirmed the importance of inflammation in pathogenesis of AD, clarified the pharmacodynamic characteristics of QZZD in treating AD, and proved its neuroprotective effects through the regulation of TNFR1-ERK1/2-NF-κBp65 signaling pathway, which might provide reference for studies on treatment of AD in the future.

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Network Pharmacology-Based and Experimental Identification of the Effects of Quercetin on Alzheimer's Disease.

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Network Pharmacology-Based and Experimental Identification of the Effects of Quercetin on Alzheimer's Disease.

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