Integrated network pharmacology analysis and serum metabolomics to reveal the cognitive improvement effect of Bushen Tiansui formula on Alzheimer's disease

Objective. To explore the mechanisms of the volatiles of Wendan granule (WDG) for the treatment of Alzheimer’s disease, network pharmacology method integrating absorption, distribution, metabolism, and excretion (ADME) screening, target fishing, network constructing, pathway analysing, and correlated diseases prediction was applied. Methods. Twelve small molecular compounds of WDG were selected as the objects from 74 volatiles with the relative abundances above 2 %, and their ADME parameters were collected from Traditional Chinese Medicine Systems Pharmacology platform (TCMSP), and the corresponding targets, genes, pathways, and diseases were predicted according to the data provided by TCMSP, DrugBank, Uniport, and the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Then the related pathways and correlation analysis were explored by the Kyoto Encyclopedia and Genomes (KEGG) database. Finally, the networks of compound target, target pathway, and pathway disease of WDG were constructed by Cytoscape software. Results. Twelve compounds interacted with 49 targets, of which top three targets were gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1), prostaglandin G/H synthase 2 (PGHS-2), and sodium-dependent noradrenaline transporter. Interestingly, these targets were highly associated with depression, insomnia, and Alzheimer’s disease that mainly corresponded to mental and emotional illnesses. Conclusion. The integrated network pharmacology method provides precise probe to illuminate the molecular mechanisms of the main volatiles of WDG for relieving senile dementia related syndromes, which will also facilitate the application of traditional Chinese medicine as an alternative or supplementary to conventional treatments of AD, as well as follow-up studies such as upgrading the quality standard of clinically applied herbal medicine and novel drug development.

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Therapeutic Potential of Curcumin on the Cognitive Decline in Alzheimer’s Disease: A Study Integrated Meta-Analysis, Network Pharmacology, and Molecular Docking

10.21203/rs.3.rs-590600/v1 ◽

2021 ◽

Author(s):

Zheyu Zhang ◽

Hongli Li ◽

Shan Hui ◽

Min Yi ◽

Xin Chen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Docking ◽

Cognitive Deficits ◽

Therapeutic Potential ◽

Meta Analysis ◽

Scientific Basis ◽

Network Pharmacology ◽

Integrated Network ◽

Positive Effects

Abstract Background: Curcumin, a polyphenol derived from the herb turmeric, has emerged as a promising potential therapy in the management of Alzheimer’s disease (AD). However, the efficacy and potential therapeutic mechanisms remains largely unknown. Objective: To systematically meta-analysis the eﬀect and to investigate the potential pharmacological mechanisms of curcumin on cognitive deficits in AD. Methods: A systematic collection of curcumin studies was performed from MEDLINE’s database, PubMed, Web of Science, and Google Scholar until October 31th, 2020. Following quality assessment of study eligibility, stratified meta-analysis and meta-regression analyses were undertaken to recognize and control the heterogeneity in meta-analysis. An integrated network pharmacology and molecular docking approach were applied to decipher the potential pharmacological mechanisms of curcumin on AD. Results: A meta-analysis of 29 publications showed that curcumin exerts significantly positive eﬀects on cognitive performance. For acquisition, the global estimated effect of curcumin was -2.027 (95% CI: -2.435 to -1.619, p<0.001); For retention, the global estimated effect of curcumin was 1.606 (95% CI: 1.101 to 2.111, p<0.001). Stratified meta-analysis demonstrated that an increased effect size depended on various study characteristics. Network pharmacology analysis identified 63 genes targets, and STAT3, CHEK1, AKT1, EGFR, MMP9, hsp90AA1, and EP300 were core target proteins. Molecular docking showed that curcumin can closely bind with these seven targets. Besides, 69 potential pathways of curcumin were identified, like nitrogen metabolism.Conclusions: Our findings suggested that curcumin may reduce cognitive deficits in AD through multi-target and multi-pathway mechanism, providing a scientific basis for further experimental and clinical application.

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Cognitive Improvement by Photic Stimulation in a Mouse Model of Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205012666150710115755 ◽

2015 ◽

Vol 12 (9) ◽

pp. 860-869 ◽

Cited By ~ 2

Author(s):

Yu Zhang ◽

Furong Wang ◽

Xianwen Luo ◽

Li Wang ◽

Peng Sun ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Photic Stimulation ◽

Cognitive Improvement ◽

Model Of Alzheimer’S Disease

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Cortical plasticity is correlated with cognitive improvement in Alzheimer’s disease patients after rTMS treatment

Brain Stimulation ◽

10.1016/j.brs.2021.01.012 ◽

2021 ◽

Vol 14 (3) ◽

pp. 503-510 ◽

Cited By ~ 1

Author(s):

Xingxing Li ◽

Gangqiao Qi ◽

Chang Yu ◽

Guomin Lian ◽

Hong Zheng ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cortical Plasticity ◽

Cognitive Improvement

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Shotgun lipidomics of liver and brain tissue of Alzheimer’s disease model mice treated with acitretin

Scientific Reports ◽

10.1038/s41598-021-94706-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Anna A. Lauer ◽

Daniel Janitschke ◽

Malena dos Santos Guilherme ◽

Vu Thu Thuy Nguyen ◽

Cornel M. Bachmann ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Amyloid Β ◽

Lipid Homeostasis ◽

Medical Surveillance ◽

Shotgun Lipidomics ◽

App Processing ◽

Cognitive Improvement ◽

The Impact

AbstractAlzheimer’s disease (AD) is a very frequent neurodegenerative disorder characterized by an accumulation of amyloid-β (Aβ). Acitretin, a retinoid-derivative and approved treatment for Psoriasis vulgaris, increases non-amyloidogenic Amyloid-Precursor-Protein-(APP)-processing, prevents Aβ-production and elicits cognitive improvement in AD mouse models. As an unintended side effect, acitretin could result in hyperlipidemia. Here, we analyzed the impact of acitretin on the lipidome in brain and liver tissue in the 5xFAD mouse-model. In line with literature, triglycerides were increased in liver accompanied by increased PCaa, plasmalogens and acyl-carnitines, whereas SM-species were decreased. In brain, these effects were partially enhanced or similar but also inverted. While for SM and plasmalogens similar effects were found, PCaa, TAG and acyl-carnitines showed an inverse effect in both tissues. Our findings emphasize, that potential pharmaceuticals to treat AD should be carefully monitored with respect to lipid-homeostasis because APP-processing itself modulates lipid-metabolism and medication might result in further and unexpected changes. Moreover, deducing effects of brain lipid-homeostasis from results obtained for other tissues should be considered cautiously. With respect to acitretin, the increase in brain plasmalogens might display a further positive probability in AD-treatment, while other results, such as decreased SM, indicate the need of medical surveillance for treated patients.

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Disruption of a RAC1-centred network is associated with Alzheimer’s disease pathology and causes age-dependent neurodegeneration

Human Molecular Genetics ◽

10.1093/hmg/ddz320 ◽

2020 ◽

Vol 29 (5) ◽

pp. 817-833 ◽

Cited By ~ 1

Author(s):

Masataka Kikuchi ◽

Michiko Sekiya ◽

Norikazu Hara ◽

Akinori Miyashita ◽

Ryozo Kuwano ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Model ◽

Neurofibrillary Tangle ◽

Neuronal Cell ◽

Brain Regions ◽

Protein Domain ◽

Expression Data ◽

Integrated Network ◽

Age Dependent

Abstract The molecular biological mechanisms of Alzheimer’s disease (AD) involve disease-associated crosstalk through many genes and include a loss of normal as well as a gain of abnormal interactions among genes. A protein domain network (PDN) is a collection of physical bindings that occur between protein domains, and the states of the PDNs in patients with AD are likely to be perturbed compared to those in normal healthy individuals. To identify PDN changes that cause neurodegeneration, we analysed the PDNs that occur among genes co-expressed in each of three brain regions at each stage of AD. Our analysis revealed that the PDNs collapsed with the progression of AD stage and identified five hub genes, including Rac1, as key players in PDN collapse. Using publicly available as well as our own gene expression data, we confirmed that the mRNA expression level of the RAC1 gene was downregulated in the entorhinal cortex (EC) of AD brains. To test the causality of these changes in neurodegeneration, we utilized Drosophila as a genetic model and found that modest knockdown of Rac1 in neurons was sufficient to cause age-dependent behavioural deficits and neurodegeneration. Finally, we identified a microRNA, hsa-miR-101-3p, as a potential regulator of RAC1 in AD brains. As the Braak neurofibrillary tangle (NFT) stage progressed, the expression levels of hsa-miR-101-3p were increased specifically in the EC. Furthermore, overexpression of hsa-miR-101-3p in the human neuronal cell line SH-SY5Y caused RAC1 downregulation. These results highlight the utility of our integrated network approach for identifying causal changes leading to neurodegeneration in AD.

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Cognitive improvement of compound danshen in an Aβ25-35 peptide-induced rat model of Alzheimer’s disease

BMC Complementary and Alternative Medicine ◽

10.1186/s12906-015-0906-y ◽

2015 ◽

Vol 15 (1) ◽

Cited By ~ 17

Author(s):

Min Liu ◽

Haibiao Guo ◽

Chuyuan Li ◽

Deqin Wang ◽

Jingang Wu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rat Model ◽

Cognitive Improvement ◽

Model Of Alzheimer’S Disease

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Cognitive Improvement is Correlated with Increased Dynamic Functional Connectivity of Default Mode Network by Personalized rTMS in Alzheimer's Disease

10.21203/rs.3.rs-554187/v1 ◽

2021 ◽

Author(s):

Lili Wei ◽

Jintao Wang ◽

Yingchun Zhang ◽

Luoyi Xu ◽

Kehua Yang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Functional Connectivity ◽

Default Mode Network ◽

Present Report ◽

Verbal Learning ◽

Dynamic Functional Connectivity ◽

Default Mode ◽

Cognitive Improvement ◽

Promising Therapeutic Approach

Abstract Background Repetitive transcranial magnetic stimulation (rTMS) is thought to be a promising therapeutic approach for Alzheimer's disease patients. Methods In the present report, a double-blind, randomized, sham-controlled rTMS trial was conducted in mild-to-moderate Alzheimer's disease patients. High-frequency rTMS was delivered to a subject-specific left lateral parietal region that demonstrated highest functional connectivity with the hippocampus using resting-state fMRI. The Mini Mental State Examination (MMSE) and Philadelphia Verbal Learning Test (PVLT) were used to evaluate patients’ cognitive functions. Results Patients receiving active rTMS treatment (n = 31) showed a significant increase in the MMSE, PVLT-Immediate recall, and PVLT-Short Delay recall scores after two weeks of rTMS treatment, whereas patients who received sham rTMS (n = 27) did not show significant changes in these measures. Dynamic functional connectivity (dFC) magnitude of the default mode network (DMN) in the active-rTMS group showed a significant increase after two weeks of rTMS treatment, and no significant changes were found in the sham-rTMS group. There was a significantly positive correlation between changes of the MMSE and changes of the dFC magnitude of DMN in the active-rTMS group, but not the sham-rTMS group. Conclusions Our findings are novel in demonstrating the feasibility and effectiveness of the fMRI-guided rTMS treatment in Alzheimer's disease patients, and DMN might play a vital role in therapeutic effectiveness of rTMS in Alzheimer’s disease. Trial registration: China National Medical Research Platform (http://114.255.48.20/login, No:MR-33-20-004217), retrospectively registered 2020-12-23.

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Network Pharmacology-Based Study of the Underlying Mechanisms of Huangqi Sijunzi Decoction for Alzheimer’s Disease

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/6480381 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Wei Zhang ◽

Mingti Lv ◽

Yating Shi ◽

Yonghui Mu ◽

Zhaoyang Yao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neuroprotective Effect ◽

Signalling Pathway ◽

Signalling Pathways ◽

Network Pharmacology ◽

Neuroprotective Effects ◽

Target Network ◽

Compound Target

Background. Huangqi 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). Methods. The 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. Results. Compound-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. Conclusion. HQSJZD 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.

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