An Inhibitor of NF-κB and an Agonist of AMPK: Network Prediction and Multi-Omics Integration to Derive Signaling Pathways for Acteoside Against Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most frequent type of dementia. Acteoside (ACT) is a compound isolated from Cistanche tubulosa, which possesses excellent neuroprotective properties. However, the underlying mechanism of ACT in regulating microglia polarization remains ill-defined. Therefore, a computational network model was established to identify the driving targets of ACT and predict its mechanism by integrating multiple available databases. The AlCl3-induced AD model in zebrafish larvae was successfully constituted to demonstrate the therapeutic efficacy of ACT. Subsequently, LPS-induced BV-2 cells uncovered the positive role of ACT in M1/M2 polarization. The NF-κB and AMPK pathways were further confirmed by transcriptomic analysis, metabolomics analysis, molecular biology techniques, and molecular docking. The research provided an infusive mechanism of ACT and revealed the connection between metabolism and microglia polarization from the perspective of mitochondrial function. More importantly, it provided a systematic and comprehensive approach for the discovery of drug targets, including the changes in genes, metabolites, and proteins.

The pharmacokinetic property and pharmacological activity of acteoside: A review

“… [98] BV-2 Acts as an inhibitor of NF-κB and an agonist of AMPK. [99] Rats Increases Glut1, Glut3, and Glut4 expression, reduces ROS production, and protects against ICV-STZ-induced learning and cognitive impairment. [102] Zebrafish Protects against 6-OHDA-induced movement disorders and dopaminergic neuron death.…”

“…A computational network model has been analyzed and verified that AC acts as an inhibitor of NF-κB and an agonist of AMPK in AlCl 3 -induced AD and LPS-treated BV-2 cells. AC inhibits M1 polarization, stimulates M2 polarization, and ameliorates mitochondrial dysfunction by mediating NF-κB and AMPK/PGC-1α/UCP2 signaling pathways [99] ( Fig. 5 ).…”

Analysis of the Molecular Mechanism of Punicalagin in the Treatment of Alzheimer’s Disease by Computer-Aided Drug Research Technology

“…KEGG enrichment analysis revealed that the main active component of Pun exerts therapeutic effects against AD by mediating proteoglycan, lipid, and atherosclerosis in cancer. Proteoglycans in cancer, including hyaluronic acid, heparan sulfate proteoglycan, chondroitin sulfate/dermatan sulfate proteoglycan, form dense lattice perineural networks (PNNs) to regulate neural activity and plasticity following a central nervous system injury . Pun may act on PNNs, enhance neuronal activity and synaptic plasticity, and promote recovery from central nervous degenerative diseases.…”

“…Proteoglycans in cancer, including hyaluronic acid, heparan sulfate proteoglycan, chondroitin sulfate/dermatan sulfate proteoglycan, form dense lattice perineural networks (PNNs) to regulate neural activity and plasticity following a central nervous system injury. 18 Pun may act on PNNs, enhance neuronal activity and synaptic plasticity, and promote recovery from central nervous degenerative diseases. Atherosclerosis is a lipid-driven arterial immune inflammatory disease and a major risk factor for cognitive impairment.…”

Celastrol Alleviates Autoimmune Hepatitis Through the PI3K/AKT Signaling Pathway Based on Network Pharmacology and Experiments

“…Docking studies were conducted between celastrol and key targets using Autodock 4.2. The structure modification process included ligand and water removal, hydrogen addition, amino acid optimization, and patching ( Pradeepkiran et al, 2015 ; Yin et al, 2020 ; Li et al, 2021 ; Venkataramaiah et al, 2021 ).…”