Dataset Information

Network Systems Pharmacology-Based Mechanism Study on the Beneficial Effects of Vitamin D against Psychosis in Alzheimer's Disease.

ABSTRACT: Alzheimer's disease (AD) is a chronic neurodegenerative disease with significant financial costs and negative impacts on quality of life. Psychotic symptoms, i.e., the presence of delusions and/or hallucinations, is a frequent complication of AD. About 50% of AD patients will develop psychotic symptoms (AD with Psychosis, or AD?+?P) and these patients will experience an even more rapid cognitive decline than AD patients without psychosis (AD-P). In a previous analysis on medication records of 776 AD patients, we had shown that use of Vitamin D was associated with delayed time to psychosis in AD patients and Vitamin D was used more by AD-P than AD?+?P patients. To explore the potential molecular mechanism behind our findings, we applied systems pharmacology approaches to investigate the crosstalk between AD and psychosis. Specifically, we built protein-protein interaction (PPI) networks with proteins encoded by AD- and psychosis-related genes and Vitamin D-perturbed genes. Using network analysis we identified several high-impact genes, including NOTCH4, COMT, CACNA1C and DRD3 which are related to calcium homeostasis. The new findings highlight the key role of calcium-related signaling pathways in AD?+?P development and may provide a new direction and facilitate hypothesis generation for future drug development.

SUBMITTER: Fan P

PROVIDER: S-EPMC7145835 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Network Systems Pharmacology-Based Mechanism Study on the Beneficial Effects of Vitamin D against Psychosis in Alzheimer's Disease.

Fan Peihao P Qi Xiguang X Sweet Robert A RA Wang Lirong L

Scientific reports 20200409 1

Alzheimer's disease (AD) is a chronic neurodegenerative disease with significant financial costs and negative impacts on quality of life. Psychotic symptoms, i.e., the presence of delusions and/or hallucinations, is a frequent complication of AD. About 50% of AD patients will develop psychotic symptoms (AD with Psychosis, or AD + P) and these patients will experience an even more rapid cognitive decline than AD patients without psychosis (AD-P). In a previous analysis on medication records of 77 ...[more]

PMID: 32273551

Similar Datasets

Project description:BackgroundEndometrial cancer (EC) is one of the most common gynaecological malignancies, and its incidence has been rising over the past decade. Tetrandrine, a bisbenzylisoquinoline alkaloid, has been isolated from a vine used in traditional Chinese medicine, Stephania tetrandra. However, the key mechanism of tetrandrine in EC is still unclear.PurposeThis research was designed to predict the molecular mechanisms of tetrandrine against EC based on network pharmacology and to further verify these predictions by in vitro experiments.MethodsThe potential therapeutic targets of tetrandrine against EC were predicted by using public databases. Afterwards, the protein-protein interaction (PPI) network of the common targets was constructed, and the key gene targets were obtained. Biological function and pathway enrichment analyses were performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Furthermore, molecular docking and in vitro experiments were carried out to verify the predictions. The cell counting kit‑8 (CCK‑8) assay, Hoechst 33258 staining, flow cytometry analysis, qRT-PCR, Western blot analysis and an immunofluorescence assay were performed.ResultsOur findings identified 111 potential therapeutic targets of tetrandrine against EC. We obtained 7 key gene targets from the PPI network analysis. Furthermore, GO enrichment analysis indicated that these targets were mainly associated with metabolic processes, responses to stimulus, and biological regulation. The KEGG pathway analysis showed that the common targets were mainly distributed in the PI3K/Akt signalling pathway. A potential interaction of tetrandrine with Akt1 was revealed by molecular docking. In addition, in vitro experiments showed that tetrandrine significantly inhibited cell proliferation and induced apoptosis in Ishikawa and HEC-1-B cells in dose- and time-dependent manners. The results also revealed that tetrandrine can downregulate the expression of Bcl-2 and upregulate the expression of Bax at the mRNA level. The mRNA levels of Akt were not significantly different in the various tetrandrine (0, 10 and 20µM) groups. However, Western blot analysis demonstrated that the protein expression ratios of p-Akt/Akt decreased at the protein level. The results were further confirmed by immunofluorescence assays.ConclusionBased on bioinformatic analysis and experimental verification, our findings demonstrated that tetrandrine exerted tumour-suppressive effects on EC by regulating the PI3K/Akt signalling pathway.

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:BackgroundScrophulariae Radix (SR) is a commonly used medicinal plant. Alzheimer's disease (AD) is a neurodegenerative disease for which there is no effective treatment. This study aims to initially clarify the potential mechanism of SR in the treatment of AD based on network pharmacology and molecular docking techniques.MethodsThe principal components and corresponding protein targets of SR were conducted by HPLC analysis and searched on TCMSP. AD targets were searched on DrugBank, Chemogenomics, TTD, OMIM and GeneCards databases. The compound-target network was constructed by Cytoscape3.8.2. The intersection of compound target and disease target was obtained and the coincidence target was imported into STRING database to construct a PPI network. We further performed GO and KEGG enrichment analysis on the targets. Meanwhile, molecular docking study and cell experiments were approved for the core target and the active compound.ResultsThrough multidatabase retrieval and integration, it was found that 17 components of SR could exert anti-AD effects against 40 targets. KEGG enrichment analysis indicated that Alzheimer's disease (hsa05010) was one of the most significant AD enrichment signalling pathways. Combined with the gene expression profile information in the AlzData database, 15 targets were found to be associated with tau or beta-amyloid protein (Aβ). GO analysis indicated that the primary molecular functions of SR in the treatment of AD were neurotransmitter receptor activity (GO:0007268), postsynaptic neurotransmitter receptor activity (GO:0070997), and acetylcholine receptor activity (GO:0050435). Moreover, we explored the anti-AD effects of SR extract and ursolic acid (UA) using SH-SY5Y cells. Treatment of SH-SY5Y cells with 20 μM UA significantly reduced the oxidative damage to these neuronal cells.ConclusionThis study reveals the active ingredients and potential molecular mechanism of SR in the treatment of AD, and provides a theoretical basis for further basic research and clinical application.

Project description:Background: Non-alcoholic fatty liver disease (NAFLD) is a burgeoning health problem but no drug has been approved for its treatment. Animal experiments and clinical trials have demonstrated the beneficial of saffron on NAFLD. However, the bioactive ingredients and therapeutic targets of saffron on NAFLD are unclear. Purpose: This study aimed to identify the bioactive ingredients of saffron responsible for its effects on NAFLD and explore its therapy targets through network pharmacology combined with experimental tests. Methods: Various network databases were searched to identify bioactive ingredients of saffron and identify NAFLD-related targets. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were conducted to enrich functions and molecular pathways of common targets and the STRING database was used to establish a protein-protein interaction network (PPI). The effect of crocetin (CCT) on NAFLD was evaluated in a mouse model of NAFLD by measuring the biomarkers of lipid, liver and renal function, oxidative stress, and inflammation. Liver histopathology was performed to evaluate liver injury. Nuclear factor erythroid-related factor (Nrf2) and hemeoxygenase-1 (HO-1) were examined to elucidate underlying mechanism for the protective effect of saffron against NAFLD. Results: A total of nine bioactive ingredients of saffron, including CCT, with 206 common targets showed therapeutic effects on NAFLD. Oxidative stress and diabetes related signaling pathways were identified as the critical signaling pathways mediating the therapeutic effects of the active bioactive ingredients on NAFLD. Treatment with CCT significantly reduced the activities of aspartate aminotransferase (AST), alanine transaminase (ALT), and the levels of total cholesterol (TC), triglyceride (TG), malondialdehyde (MDA), blood urea nitrogen (BUN), creatinine (CR), and uric acid (UA). CCT significantly increased the activities of superoxide dismutase (SOD), and catalase (CAT). Histological analysis showed that CCT suppressed high-fat diet (HFD) induced fat accumulation, steatohepatitis, and renal dysfunctions. Results of ELISA assay showed that CCT decreased the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and increased the expression of HO-1 and Nrf2. Conclusion: This study shows that CCT is a potential bioactive ingredient of saffron that treats NAFLD. Its mechanism of action involves suppressing of oxidative stress, mitigating inflammation, and upregulating Nrf2 and HO-1 expression.

Dataset Information

Network Systems Pharmacology-Based Mechanism Study on the Beneficial Effects of Vitamin D against Psychosis in Alzheimer's Disease.

Publications

Network Systems Pharmacology-Based Mechanism Study on the Beneficial Effects of Vitamin D against Psychosis in Alzheimer's Disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets