scholarly journals Network Pharmacology Analysis and Molecular Characterization of the Herbal Medicine Formulation Qi-Fu-Yin for the Inhibition of the Neuroinflammatory Biomarker iNOS in Microglial BV-2 Cells: Implication for the Treatment of Alzheimer’s Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Fung Yin Ngo ◽  
Weiwei Wang ◽  
Qilei Chen ◽  
Jia Zhao ◽  
Hubiao Chen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Selective Inhibition ◽  
Network Pharmacology ◽  
Herbal Formula ◽  
Active Compounds ◽  
Protein Targets ◽  
Blotting Technique ◽  
Cox 2 ◽  
Angelicae Sinensis

Aberrant microglial activation drives neuroinflammation and neurodegeneration in Alzheimer’s disease (AD). The present study is aimed at investigating whether the herbal formula Qi-Fu-Yin (QFY) could inhibit the inflammatory activation of cultured BV-2 microglia. A network pharmacology approach was employed to predict the active compounds of QFY, protein targets, and affected pathways. The representative pathways and molecular functions of the targets were analyzed by Gene Ontology (GO) and pathway enrichment. A total of 145 active compounds were selected from seven herbal ingredients of QFY. Targets (e.g., MAPT, APP, ACHE, iNOS, and COX-2) were predicted for the selected active compounds based on the relevance to AD and inflammation. As a validation, fractions were sequentially prepared by aqueous extraction, ethanolic precipitation, and HPLC separation, and assayed for downregulating two key proinflammatory biomarkers iNOS and COX-2 in lipopolysaccharide- (LPS-) challenged BV-2 cells by the Western blotting technique. Moreover, the compounds of QFY in 90% ethanol downregulated iNOS in BV-2 cells but showed no activity against COX-2 induction. Among the herbal ingredients of QFY, Angelicae Sinensis Radix and Ginseng Radix et Rhizoma contributed to the selective inhibition of iNOS induction. Furthermore, chemical analysis identified ginsenosides, especially Rg3, as antineuroinflammatory compounds. The herbal formula QFY may ameliorate neuroinflammation via downregulating iNOS in microglia.

scholarly journals Exploring the Mechanisms Underlying the Therapeutic Effect of Xixin Decoction on Alzheimer's Disease Based on Network Pharmacology and Molecular Docking

2021 ◽  
Author(s):  
Zhuo Zhang ◽  
Jiang-lin Xu ◽  
Ming-qing Wei ◽  
Ting Li ◽  
Jing Shi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Docking ◽  
Signaling Pathway ◽  
Therapeutic Effect ◽  
Mapk Signaling ◽  
Network Pharmacology ◽  
Receptor Interaction ◽  
Ppi Network ◽  
Active Compounds

Abstract Background and objective: Alzheimer’s disease (AD) has been a worldwide problem, not only the treatment but also the prevention. As a commonly used Chinese Herbal Formula, Xixin Decoction (XXD) has significant therapeutic effect on AD but without clear mechanism. This study was aimed to predict the main active compounds and targets of XXD in the treatment of AD and to explore the potential mechanism by using network pharmacology and molecular docking. Methods: The compounds of XXD were searched in the TCMSP and the TCMID database, and the active compounds were screened based on the ADME model and SwissADME platform. SwissTargetPrediction platform was used to search for the primary candidate targets of XXD. The common targets related to AD obtained by two databases (GeneCards and DisGeNET) were determined as candidate proteins involved in AD. To acquire the related targets of XXD in the treatment of AD, the target proteins related to AD were intersected with the predicted targets of XXD. Then these overlapping targets were imported into the STRING database to build PPI network including hub targets; Cytoscape 3.7.2 software was used to construct the topology analysis for the herb-compound-target network diagram while one of it’s plug-in called CytoNCA was used to calculate degree value to screen the main active compounds of XXD. GO and KEGG pathway enrichment analyses were conducted to explore the core mechanism of action and biological pathways associated with the decoction via Metascape platform. We used AutoDock Vina and PyMOL 2.4.0 softwares for molecular docking of hub targets and main compounds.Results: We determined 114 active compounds which meet the conditions of ADME screening, 973 drug targets, and 973 disease targets. However, intersection analysis screened out 208 shared targets. PPI network identified 9 hub targets, including TP53, PIK3CA, MAPK1, MAPK3, STAT3, AKT1, etc. The 10 main active compounds play a major role in treatment of AD by XXD. Hub targets were found to be enriched in 10 KEGG pathways, involving the Pathways in cancer, AGE-RAGE signaling pathway in diabetic complications, Alzheimer's disease, Neuroactive ligand-receptor interaction, Dopaminergic synapse, Serotonergic synapse and MAPK signaling pathway. The docking results indicated that the 8 hub targets exhibit good binding activity with the 9 main active compounds of XXD.Conclusions: We found the advantages of multi-compounds-multi-targets-multi-pathways regulation to reveal the mechanism of XXD for treating AD based on network pharmacology and molecular docking. Our study provided a theorical basis for further clinical application and experimental research of XXD for anti-AD in the future.

scholarly journals Prostaglandin EP2 receptor antagonist ameliorates neuroinflammation in a two-hit mouse model of Alzheimer’s disease

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Avijit Banik ◽  
Radhika Amaradhi ◽  
Daniel Lee ◽  
Michael Sau ◽  
Wenyi Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Complete Blood Count ◽  
Cardiovascular Effects ◽  
Mrna Levels ◽  
Proinflammatory Mediators ◽  
Model Of Alzheimer’S Disease ◽  
Cox 2 ◽  
5Xfad Mice

Abstract Background Alzheimer’s disease (AD) causes substantial medical and societal burden with no therapies ameliorating cognitive deficits. Centralized pathologies involving amyloids, neurofibrillary tangles, and neuroinflammatory pathways are being investigated to identify disease-modifying targets for AD. Cyclooxygenase-2 (COX-2) is one of the potential neuroinflammatory agents involved in AD progression. However, chronic use of COX-2 inhibitors in patients produced adverse cardiovascular effects. We asked whether inhibition of EP2 receptors, downstream of the COX-2 signaling pathway, can ameliorate neuroinflammation in AD brains in presence or absence of a secondary inflammatory stimuli. Methods We treated 5xFAD mice and their non-transgenic (nTg) littermates in presence or absence of lipopolysaccharide (LPS) with an EP2 antagonist (TG11-77.HCl). In cohort 1, nTg (no-hit) or 5xFAD (single-hit—genetic) mice were treated with vehicle or TG11-77.HCl for 12 weeks. In cohort 2, nTg (single-hit—environmental) and 5xFAD mice (two-hit) were administered LPS (0.5 mg/kg/week) and treated with vehicle or TG11-77.HCl for 8 weeks. Results Complete blood count analysis showed that LPS induced anemia of inflammation in both groups in cohort 2. There was no adverse effect of LPS or EP2 antagonist on body weight throughout the treatment. In the neocortex isolated from the two-hit cohort of females, but not males, the elevated mRNA levels of proinflammatory mediators (IL-1β, TNF, IL-6, CCL2, EP2), glial markers (IBA1, GFAP, CD11b, S110B), and glial proteins were significantly reduced by EP2 antagonist treatment. Intriguingly, the EP2 antagonist had no effect on either of the single-hit cohorts. There was a modest increase in amyloid–plaque deposition upon EP2 antagonist treatment in the two-hit female brains, but not in the single-hit genetic female cohort. Conclusion These results reveal a potential neuroinflammatory role for EP2 in the two-hit 5xFAD mouse model. A selective EP2 antagonist reduces inflammation only in female AD mice subjected to a second inflammatory insult.

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

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.

Network pharmacology-based analysis of Chinese herbal Naodesheng formula for application to Alzheimer's disease

2018 ◽  
Vol 16 (1) ◽  
pp. 53-62 ◽  
Author(s):  
Xiao-Cong PANG ◽  
De KANG ◽  
Jian-Song FANG ◽  
Ying ZHAO ◽  
Lv-Jie XU ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Network Pharmacology ◽  
Chinese Herbal

Virtual Screening in Chinese Herbs with Multi-Target Effect on Alzheimer's Disease

2013 ◽  
Vol 765-767 ◽  
pp. 256-260
Author(s):  
Yan Ling Zhang ◽  
Yuan Ming Wang ◽  
Yan Jiang Qiao
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Virtual Screening ◽  
Glycogen Synthase ◽  
Chinese Herbs ◽  
Multiple Targets ◽  
Active Compounds ◽  
Ache Inhibitors ◽  
Gsk 3Β ◽  
Pharmacophore Models

Multiple targets which closely related to Alzheimer's disease (AD) pathogenesis were selected for pharmacophore models generation and virtual screening in Chinese herbs. The targets comprised Acetylcholinesterase (AchE), muscarinic receptor 1 (M1), γ-secretase and glycogen synthase kinase 3β (GSK-3β). The pharmacophore models, which of AchE inhibitors, M1 agonists, γ-secretase inhibitors and GSK-3β inhibitors, were constructed by distance comparison method. Four testing databases for the evaluation of pharmacophore models were constructed with the active compounds with clearly marked activity on each target. The metric CAI (Comprehensive Appraisal Index) was then used to evaluate and obtain the best pharmacophore models of each target, which were then applied to screen the Traditional Chinese Medicine Database for potential active compounds in Chinese herbs. Four common used herbs were obtained, which contain the active compounds and can act on multiple targets, and were expected to have multiple activity of anti-AD disease.

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