RESUMO
Anti-Aß therapy has dominated clinical trials for the prevention and treatment of Alzheimer's disease (AD). However, suppressing Aß aggregation and disintegrating mature fibrils simultaneously remains a great challenge. In this work, we developed a new strategy using a charged tubular supramolecule (CTS) with pillar[5]arene as the backbone and modifying amino and carboxyl groups at the tubular terminals (noted as CTS-A, CTS-A/C, and CTS-C, respectively) to suppress Aß fibrillation for the first time. According to the spectroscopic and microscopic characterizations, Aß40 fibrillation can be efficiently suppressed by CTS-A in a very low inhibitor:peptide (I:P) molar ratio (1:10). A greatly alleviated cytotoxic effect of Aß peptides after the inhibition or disaggregation process is further disclosed. The well-organized supramolecular structure drives multivalent interaction and gains enhanced efficiency on amyloid fibrillar modulation. These results open a new path for the design of supramolecules in the application of AD treatment.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Amiloide/química , Peptídeos beta-Amiloides/química , Humanos , Fragmentos de PeptídeosRESUMO
We developed a voltage-sensitive artificial transmembrane channel by mimicking the dipolar structure of natural alamethicin channel. The artificial channel featured a zwitterionic structure and could undergo voltage-driven flipping in the lipid bilayers. Importantly, this flipping of the channel could lead to their directional alignment in the bilayers and rectifying behavior for ion transport.
Assuntos
Canais Iônicos/química , Bicamadas Lipídicas/química , Condutividade Elétrica , Transporte de Íons , Estrutura Molecular , Prata/química , Compostos de Prata/químicaRESUMO
Artificial aquaporins are synthetic molecules that mimic the structure and function of natural aquaporins (AQPs) in cell membranes. The development of artificial aquaporins would provide an alternative strategy for treatment of AQP-related diseases. In this report, an artificial aquaporin has been constructed from an amino-terminated tubular molecule, which operates in a unimolecular mechanism. The artificial channel can work in cell membranes with high water permeability and selectivity rivaling those of AQPs. Importantly, the channel can restore wound healing of the cells that contain function-lost AQPs.
Assuntos
Aquaporinas/farmacologia , Cicatrização/efeitos dos fármacos , Aquaporinas/química , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Modelos Moleculares , Simulação de Dinâmica Molecular , Estrutura Molecular , Imagem Individual de MoléculaRESUMO
BACKGROUND: Although anxiety disorders are one of the most common mental illness in population, antianxiety drugs often only have single action targets, require long-term use, and are associated with many adverse reactions and dependencies. Professor Yan Zhaojun from Shandong Provincial Hospital of Traditional Chinese Medicine (TCM) has applied the modified Renshu Powder, a TCM formula, to treat anxiety disorders, with satisfactory outcomes. Here, we investigated the mechanism of action of two core herbs (prepared Rehmannia root and Chinese arborvitae kernel) in the Renshu Powder in the treatment of anxiety disorders by using network pharmacology approaches. METHODS: Candidate compounds of the herb pair of prepared Rehmannia root-Chinese arborvitae kernel were extracted via the Traditional Chinese Medicine Systems Pharmacology (TCMSP) platform. The targets of action of the main compounds were collected using the SwissTargetPrediction database. Targets associated with anxiety disorders were retrieved from DisGeNET, Online Mendelian Inheritance in Man (OMIM), DrugBank, GeneCards, and Comparative Toxicogenomics Database (CTD) databases. The compound-target interaction network was constructed by Cytoscape 3.7.2 software, and the protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) platform. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses the data by using Metascape. RESULTS: The main active compounds of the herb pair included arachidonic acid, stigmasterol, and beta-sitosterol. The key targets included Nitric Oxide Synthase 3 (NOS3), Epidermal growth factor (EGF), Prostaglandin-Endoperoxide Synthase 2 (PTGS2), Caspase 3 (CASP3), Mitogen-Activated Protein Kinase 1 (MAPK1), Peroxisome proliferator-activated receptor gamma (PPARG), RELA Proto-Oncogene, NF-KB Subunit (RELA), Estrogen Receptor 1 (ESR1), Solute Carrier Family 6 Member 4 (SLC6A4), and Phosphatase and Tensin homolog deleted on chromosome 10 (PTEN). Anxiety disorder-related GO analysis mainly involved synaptic signaling, neurotransmitter receptor activity, and G protein-coupled neurotransmitter receptor activity. The KEGG pathways involved neuroactive ligand-receptor interaction, serotonergic synapse, PI3K/AKT/mTOR signaling pathway, and MAPK signaling pathway. CONCLUSIONS: The mechanism of action of the prepared Rehmannia root-Chinese arborvitae kernel in treating anxiety disorders involves multiple ingredients, multiple targets, and pathways.
Assuntos
Medicamentos de Ervas Chinesas , Rehmannia , Thuja , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/genética , China , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Fosfatidilinositol 3-Quinases , Proto-Oncogene Mas , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
BACKGROUND: Tourette's syndrome (TS) is a neurodevelopmental condition characterized by multiple motor and vocal tics. Qiangzhi decoction (QD), a well-known herbal decoction, has been used in treating TS in China for decades. We have found relevance between the indications of QD and the classic symptoms of TS. The pharmacological mechanisms of QD in treating TS are still unclear. METHODS: The active compounds of QD were extracted from multi-database, including TCMSP (the Traditional Chinese Medicine Systems Pharmacology database), and potential targets of the compounds were compiled by target fishing. The TS target database was established, and then the protein-protein interaction (PPI) network was constructed to analyze the interactions between the potential targets of compounds in QD and targets associated with TS and screened the core targets by topology. The DAVID bioinformatics database was used to conduct the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. RESULTS: 59 active molecules and 585 potential targets of QD were selected. The consequences of the DAVID enrichment analysis show that 36 cellular biological processes (FDR <0.01) and 65 pathways (FDR <0.01) of QD chiefly took part in the convoluted treating effects relevant to the dopamine system, inflammation, and infection, and miRNA pathway. Fourteen core targets of QD were found as potential targets of the treatment of TS. CONCLUSIONS: QD could relieve the symptoms of TS through the molecular mechanisms predicted by network pharmacology. This study supplies insight into how network pharmacology can predict traditional Chinese herbal medicine's possible molecular mechanisms (TCHM).