Identification of Key Pathways and Targets of Kai Xin San in The Treatment of Alzheimer's Disease Based On a Network Pharmacology Approach and Experimental Validation

Abstract Background: Alzheimer's disease (AD) is the commonest neurodegenerative disease characterized with a progressive loss of cognitive functions and memory decline. Kai Xin San (KXS), a traditional Chinese herbal classic prescription, has been used to ameliorate cognitive dysfunction for thousands of years. However, its specific pharmacological molecular mechanisms have not been fully clarified.Methods: The ingredients of KXS and their corresponding targets were firstly screened from ETCM database. AD-related target proteins were obtained from Malacards database and DisGeNet database. Venn diagram was used to intersect the common targets between KXS and AD. Then, key ingredients and key targets were identified from compound-target-disease network and protein-protein interaction (PPI) network analysis respectively. Moreover, the binding affinity between the key ingredients and targets were verified by molecular docking. KEGG enrichment analysis further predicted the potential key signaling pathway involved in the treatment of KXS on AD, and the predicted signaling pathway was validated via experimental approach.Results: A total of 38 ingredients and 469 corresponding targets were screened, and 264 target proteins associated with AD were obtained. Compound-target-disease network and PPI identified the key active ingredients and targets, which correlate with the treatment of KXS on AD. Molecular docking revealed a good binding affinity between key ingredients and targets. KEGG pathway analysis suggested the potential effect of KXS in treatment of AD via Aβ-GSK3β-Tau pathway. Aβ1-42-injected induced a decline in spatial learning and memory and upregulated the expression of GSK3β and CDK5 along with the downregulated PP1 and PP2 expression. However, KXS significantly improve the cognitive deficits induced by Aβ1-42, decrease the GSK3β and CDK5 levels and increase the expression of PP1 and PP2.Conclusions: Our research elucidated that KXS exerted neuroprotective effects through regulating the Aβ-GSK3β-Tau signaling pathway, which provided a novel insight into the therapeutic mechanism of KXS in treatment of AD.

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MOLECULAR DOCKING STUDIES ON THE THERAPEUTIC TARGETS OF ALZHEIMER'S DISEASE (AChE AND BChE) USING NATURAL BIOACTIVE ALKALOIDS

International Journal of Pharmacy and Pharmaceutical Sciences ◽

10.22159/ijpps.2016v8i12.14833 ◽

2016 ◽

Vol 8 (12) ◽

pp. 108

Author(s):

Punabaka Jyothi ◽

Kuna Yellamma

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Docking ◽

Binding Affinity ◽

Neurodegenerative Disorder ◽

Biological Activities ◽

Neuropsychiatric Symptoms ◽

Docking Studies ◽

Kcal Mole ◽

Molecular Docking Studies

Objective: Alzheimer’s disease (AD), a progressive neurodegenerative disorder with many cognitive and neuropsychiatric symptoms, is biochemically characterized by a significant decrease in the brain neurotransmitter Acetylcholine (ACh).Methods: In the present insilico study, six plant bioactive compounds namely Harmol, Vasicine, Harmaline, Harmine, Harmane and Harmalol (from P. Nigellastrum Bunge) were analyzed for their inhibitory role on AChE (Acetylcholinesterase) and BChE (Butyrylcholinesterase) activity by applying the molecular docking studies. Other parameters viz. determination of molecular interaction-based binding affinity values, protein-ligand interactions, Lipinski rule of five, functional properties and biological activities for the above compounds were also calculated by employing the appropriate bioinformatics tools.Results: The results of docking analysis clearly showed that Harmalol has highest binding affinity with AChE (-8.6 kcal/mole) and BChE (-8.0 kcal/mole) but it does not qualified the enzyme inhibitory activity, since it was exerted, and also has least percentage activity on AD and neurodegenerative disease. Whereas, the Harmine has been second qualified binding affinity (-8.4 kcal/mol) and first in other parameters when compared with Harmalol.Conclusion: Based on docking results and other parameters conducted, we are concluding that Harmine is the best compound for further studies to treat AD.Keywords: Alzheimer's disease (AD), Acetylcholinesterase, Butyrylcholinesterase, Lead Molecules

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Study on the Mechanism of Lianpu Drink for the Treatment of Chronic Gastritis Based on Network Pharmacology

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/6693472 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Shuhan Zhou ◽

Yanjun Duan ◽

Yu Deng ◽

Miao Wang ◽

Chaoqun Huang ◽

...

Keyword(s):

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Signaling Pathway ◽

Chronic Gastritis ◽

Mechanisms Of Action ◽

Network Pharmacology ◽

Biological Pathway ◽

Disease Network ◽

Target Disease ◽

Compound Target

Chronic gastritis (CG) places a considerable burden on the healthcare system worldwide. Traditional Chinese Medicine (TCM) formulas characterized by multicompounds and multitargets have been acknowledged with striking effects in the treatment of CG in China’s history. Nevertheless, their accurate mechanisms of action are still ambiguous. In this study, we analyzed the effective compounds, potential targets, and related biological pathway of Lianpu Drink (LPD), a TCM formula which has been reported to have a therapeutic effect on CG, by contrasting a “compound-target-disease” network. According to the results, 92 compounds and 5762 putative targets of LPD were screened; among them, 8 compounds derived from different herbs in LPD and 30 common targets related to LPD and CG were selected as candidate compounds and precision targets, respectively. Meanwhile, the predicted common targets were verified by Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analysis and pharmacological experiments. The results demonstrated that quercetin, ephedrine, trigonelline, crocetin, and β-sitosterol were major effective compounds of LPD responsible for the CG treatment by inhibiting the activation of the JAK 2-STAT 3 signaling pathway to reduce the expressions of cyclin D1 and Bcl-2 proteins. The study provides evidence for the mechanism of understanding of LPD for the treatment of CG.

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Study on the Mechanism of Acori Graminei Rhizoma in the Treatment of Alzheimer’s Disease Based on Network Pharmacology and Molecular Docking

BioMed Research International ◽

10.1155/2021/5418142 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Yi Kuan Du ◽

Yue Xiao ◽

Shao Min Zhong ◽

Yi Xing Huang ◽

Qian Wen Chen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Docking ◽

Signaling Pathway ◽

Target Prediction ◽

Enrichment Analysis ◽

The Elderly ◽

Estrogen Signaling ◽

Network Pharmacology ◽

Active Components

Alzheimer’s disease is a common neurodegenerative disease in the elderly. This study explored the curative effect and possible mechanism of Acori graminei rhizoma on Alzheimer’s disease. In this paper, 8 active components of Acori graminei rhizoma were collected by consulting literature and using the TCMSP database, and 272 targets were screened using the PubChem and Swiss Target Prediction databases. Introduce it into the software of Cytoscape 3.7.2 and establish the graph of “drug-active ingredient-ingredient target.” A total of 276 AD targets were obtained from OMIM, Gene Cards, and DisGeNET databases. Import the intersection targets of drugs and diseases into STRING database for enrichment analysis, and build PPI network in the Cytoscape 3.7.2 software, whose core targets involve APP, AMPK, NOS3, etc. GO analysis and KEGG analysis showed that there were 195 GO items and 30 AD-related pathways, including Alzheimer’s disease pathway, serotonin synapse, estrogen signaling pathway, dopaminergic synapse, and PI3K-Akt signaling pathway. Finally, molecular docking was carried out to verify the binding ability between Acori graminei rhizoma and core genes. Our results predict that Acori graminei rhizoma can treat AD mainly by mediating Alzheimer’s signal pathway, thus reducing the production of Aβ, inhibiting the hyperphosphorylation of tau protein, regulating neurotrophic factors, and regulating the activity of kinase to change the function of the receptor.

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

10.21203/rs.3.rs-562321/v1 ◽

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.

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The Network Pharmacology Study And Molecular Docking To Investigate The Potential Mechanism of Acoritataninowii Rhizoma Against Alzheimer's Disease

10.21203/rs.3.rs-793765/v1 ◽

2021 ◽

Author(s):

Jiali Pang ◽

Zhi-Kun Qiu

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Docking ◽

Fluid Shear Stress ◽

Venn Diagram ◽

Network Pharmacology ◽

Epstein Barr Virus Infection ◽

Overlapping Genes ◽

Potential Mechanism ◽

Bioactive Ingredients

Abstract Background and objective: Alzheimer's Disease (AD) is considered as a progressively developing neurodegenerative disease with an insidious onset that induces increased cost of social burden and decreased quality of life. Acoritataninowii Rhizoma produced the effects of resuscitating and eliminating phlegm, dispelling dampness and appetizing, refreshing mind and nourishing the mind, and exerted the activities of anti-dementia and improving learning and memory. while little was relevant to its anti-AD mechanism. The present study explored the potential mechanism of Acoritataninowii Rhizoma defend AD by network pharmacology and molecular docking.Methods: The bioactive ingredients of Acoritataninowii Rhizoma were screened by absorption, distribution, metabolism as well as excretion evaluation and obtained from databases retrieval. Genes associated with AD or ingredients were searching by databases, and the overlapping genes between AD and ingredients were analyzed by the Venn diagram. Moreover, the network of Acoritataninowii Rhizoma-ingredients-targets-AD was visualized by cytoscape software. Furthermore, protein-protein interaction, gene ontology, pathway enrichment and molecular docking were conducted to evaluate potential factors of Acoritataninowii Rhizoma against AD.Results: 4 potential compounds were considered as bioactive ingredients after screening ADME. 81 ingredients-related genes and 6765 AD-related genes were screened by databases with 61 overlapping genes. The bioactive ingredients derived from Acoritataninowii Rhizoma (e.g Cycloartenol, (1R,3aS,4R,6aS)-1,4-bis(3,4-dimethoxyphenyl)-1,3,3a,4,6,6a-hexahydrofuro[4,3-c]furan, 8-Isopentenyl-kaempferol, kaempferol) and target proteins (e.g AKT1, JUN, ESR1, CASP3, MAPK14, RELA) with high degree in the network were associated with in mitogen-activated protein kinase (MAPK) of DNA-binding transcription factor. Moreover, Acoritataninowii Rhizoma might play a significant in the treatment of AD which induced Fluid shear stress and atherosclerosis, Kaposi sarcoma-associated herpesvirus infection, Epstein-Barr virus infection, AGE-RAGE signaling pathway in diabetic complications.Conclusion: The bioactive ingredients and potential mechnism of Acoritataninowii Rhizoma defended AD was analyzed by network pharmacology and molecular docking. This study provided a research basis and scientific evidence for supporting the activities of Acoritataninowii Rhizoma against AD.

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INSILICO METHOD FOR PREDICTION OF MAXIMUM BINDING AFFINITY AND LIGAND – PROTEIN INTERACTION STUDIES ON ALZHEIMER’S DISEASE

International Journal of Research -GRANTHAALAYAH ◽

10.29121/granthaalayah.v8.i11.2020.2472 ◽

2020 ◽

Vol 8 (11) ◽

pp. 362-370

Author(s):

Karthika Perampattu Baskaran ◽

Arunagiri Arumugam ◽

Ruckmani Kandasamy ◽

Shanmugarathinam Alagarsamy

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Docking ◽

Protein Structure ◽

Binding Affinity ◽

Protein Interactions ◽

Protein Crystal ◽

Hydrogen Bond Formation ◽

Discovery Studio ◽

Protein Crystal Structure

The aim of this study is to perform the molecular docking, identifying the drug likeness, ADME properties of drugs, Ligand-Protein interactions using different softwares. Due to the excess activity of Acetylcholinesterase, plaque formation and tau protein aggregation in the brain is the main cause for the Alzheimer’s disease. The interaction of Donepezil, Rivastigmine and Chlorzoxazone against AChE protein crystal structure (4EY5, 4EY6, 4EY7) using molecular docking were analyzed. Docking results of Rivastigmine and Chlorzoxazone were compared with Donepezil (widely used drug for Alzheimer’s disease) to identify the binding affinity. To verify whether Chlorzoxazone could act similarly as effective drug of Donepezil and also finding in which protein structure, ligands could bind effectively were employed using BIOVIA Discovery Studio software. Among those ligands interaction with all protein structure, 4EY7 on Rivastigmine (-7.1 kcal/mol) exhibits maximum binding affinity. The interactions of three ligands were compared with one another, in that Hydrogen bond formation of Chlorzoxazone and Donepezil with 4EY6 and 4EY7 interacting the similar aminoacids residues (4EY6-ARG165; 4EY7-ASP74) were studied using insilico studies .

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Analysing the role of Saraswatarishta in the treatment of neurological disorders based on network pharmacology

Neuroscience Research Notes ◽

10.31117/neuroscirn.v3i5.106 ◽

2021 ◽

Vol 3 (5) ◽

pp. 23-35

Author(s):

Vrinda Jethalia ◽

Sanjana Varada Hasyagar ◽

Kasturi Bhamidipati ◽

Jhinuk Chatterjee

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Neurological Disorders ◽

Network Pharmacology ◽

Therapeutic Effects ◽

Target Disease ◽

Compound Target

Ayurvedic medications originated centuries ago and are still prevalent today. Saraswatarishta (SWRT) is a well-known ayurvedic formulation that is often prescribed to control the manifestations of neurological illnesses and disorders such as slurred speech, anxiety, Parkinson's disease (PD) and Alzheimer's disease(AD). However, scientific research on its mode of action has not been studied extensively. Therefore, this study employs network pharmacology to understand better the neuroprotective role of Saraswatarishta (SWRT) in neurological disorders. Out of the 18 ingredients in SWRT, five were considered in this study due to their elevated therapeutic action in neurological disorders. Further, nine active phytoconstituents were chosen from the five selected ingredients. The gene targets of the active phytoconstituents were screened and selected using STITCH, SwissTargetPrediction and ChEMBL. Protein-Protein interaction and Gene Ontology (GO) enrichment analysis were carried out using STRING and g:Profiler, respectively. Cytoscape 3.7.2 was used to create three networks-the compound-target, the target-disease and the compound-target-disease network. Molinspiration and admetSAR2.0 were used to obtain the bioactivity scores and the blood-brain barrier (BBB) probability scores. The three networks indicated that all nine phytoconstituents were linked to the gene targets that encode proteins involved in the pathways of 10 major neurological disorders. This includes Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington disease, epilepsy, schizophrenia, spinocerebellar ataxia, amyotrophic lateral sclerosis (ALS), multiple sclerosis and attention deficit hyperactivity disorder (ADHD). The gene targets were expressed significantly in various central nervous system regions such as the cerebral cortex, cerebellum and amygdala. The bioactivity scores of the phytoconstituents were in the active range along with high BBB probability scores, indicating that the phytoconstituents can potentially cross the BBB and impart therapeutic effects.

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Systems-Pharmacology-Based Identification of Antitumor Necrosis Factor Effect in Mimeng Flower Decoction for the Treatment of Diabetic Retinopathy

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/5107103 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10

Author(s):

Yingzi Li ◽

Ying Huang ◽

Changsen Tu

Keyword(s):

Diabetic Retinopathy ◽

Binding Affinity ◽

Diabetic Rat ◽

Systems Pharmacology ◽

Disease Network ◽

Active Compounds ◽

Hub Gene ◽

Target Disease ◽

Necrosis Factor ◽

Compound Target

The traditional Chinese medicine of Mimeng flower decoction (MFD) is effective in treating diabetic retinopathy (DR), but the mechanism is still unclear. This study aims at investigating the mechanism of MFD in treating DR. First, active compounds in MFD were filtered out by the systems pharmacology method and used as bait to fish potential targets. The common genes between the targets and DR-related genes were selected to construct the compound-target-disease network and identify the network hub gene as a key gene. Molecular docking was simulated to assess the binding affinity of active compounds towards the gene protein. Streptozotocin- (STZ-) induced diabetic rat model was administered to evaluate the efficacy of MFD in treating DR and its effects on retinal gene expression. Finally, 53 active compounds were screened out from the seven herbs in MFD, with a total of 136 targets. After intersecting with 210 DR-related genes, 21 common genes were applied to construct the network, and tumor necrosis factor (TNF) was identified as the hub gene. The active compounds of acacetin, kaempferol, luteolin, and quercetin showed a good binding affinity towards TNF (C-score ≥ 4). In diabetic rats, MFD treatment reversed the retinal impairment and decreased retinal TNF expression significantly. In conclusion, this study adopted the method of systems pharmacology to screen out active compounds and construct the compound-target-disease network and found that MFD could ameliorate DR by downregulating the network hub gene of TNF.

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A Network Pharmacology Approach to Estimate Potential Targets of the Active Ingredients of Epimedium for Alleviating Mild Cognitive Impairment and Treating Alzheimer’s Disease

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/2302680 ◽

2021 ◽

Vol 2021 ◽

pp. 1-15

Author(s):

Xianwei Gao ◽

Shengnan Li ◽

Chao Cong ◽

Yuejiao Wang ◽

Lianwei Xu

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Molecular Docking ◽

Mild Cognitive Impairment ◽

Signaling Pathway ◽

Enrichment Analysis ◽

Active Ingredients ◽

Depth Analysis ◽

The Common

Background. The present study made use of a network pharmacological approach to evaluate the mechanisms and potential targets of the active ingredients of Epimedium for alleviating mild cognitive impairment (MCI) and treating Alzheimer’s disease (AD). Methods. The active ingredients of Epimedium were acquired from the Traditional Chinese Medicine System Pharmacology database, and potential targets were predicted using the TCMSP target module, SwissTargetPrediction, and PharmMapper database. Target proteins correlating with MCI and AD were downloaded from the GeneCards, DisGeNet, and OMIM databases. The common targets of Epimedium, MCI, and AD were identified using the Jvenn online tool, and a protein-protein interaction (PPI) network was constructed using the String database and Cytoscape. Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the common targets was performed using DAVID, and molecular docking between active ingredients and target genes was modeled using AutoDock Vina. Results. A total of 20 active ingredients were analyzed, and 337 compound-related targets were identified for Epimedium. Out of 236 proteins associated with MCI and AD, 54 overlapped with the targets of Epimedium. The top 30 interacting proteins in this set were ranked by topological analysis. GO and KEGG enrichment analysis suggested that the common targets participated in diverse biological processes and pathways, including cell proliferation and apoptosis, inflammatory response, signal transduction, and protein phosphorylation through cancer pathway, MAPK signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, sphingolipid signaling pathway, FoxO signaling pathway, and TNF signaling pathway. Molecular docking analysis suggested that the 20 active ingredients could bind to the top 5 protein targets. Conclusions. The present study provides theoretical evidence for in-depth analysis of the mechanisms and molecular targets by which Epimedium protects against MCI, AD, and other neurodegenerative diseases and lays the foundation for pragmatic clinical applications and potential new drug development.

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