benzofurans and Protein-Aggregation--Pathological

Neuroinflammation and mitochondrial impairment play important roles in the neuropathogenesis of Parkinson's disease (PD). The activation of NLRP3 inflammasome and the accumulation of α-synuclein (α-Syn) are strictly correlated to neuroinflammation. Therefore, the regulation of NLRP3 inflammasome activation and α-Syn aggregation might have therapeutic potential. It has been indicated that Dl-3-n-butylphthalide (NBP) produces neuroprotection against some neurological diseases such as ischemic stroke. We here intended to explore whether NBP suppressed NLRP3 inflammasome activation and reduced α-Syn aggregation, thus protecting dopaminergic neurons against neuroinflammation.. In our study, we established a MPTP-induced mouse model and 6-OHDA-induced SH-SY5Y cell model to examine the neuroprotective actions of NBP. We then performed behavioral tests to examine motor dysfunction in MPTP-exposed mice after NBP treatment. Western blotting, immunofluorescence staining, flow cytometry and RT-qPCR were conducted to investigate the expression of NLRP3 inflammasomes, neuroinflammatory cytokines, PARP1, p-α-Syn, and markers of microgliosis and astrogliosis.. The results showed that NBP exerts a neuroprotective effect on experimental PD models.. In summary, NBP rescued dopaminergic neurons by reducing NLRP3 inflammasome activation and ameliorating mitochondrial impairments and increases in p-α-Syn levels. This current study may provide novel neuroprotective mechanisms of NBP as a potential therapeutic agent.

Topics: alpha-Synuclein; Animals; Apoptosis; Benzofurans; Cell Line; Disease Models, Animal; Dopaminergic Neurons; Humans; Inflammasomes; Mice; Mitochondria; Neuroprotective Agents; NLR Family, Pyrin Domain-Containing 3 Protein; Parkinson Disease; Protein Aggregation, Pathological

A series of benzofuran piperidine derivatives were designed, synthesized and evaluated as multifunctional Aβ antiaggregant to treat Alzheimer's disease (AD). In vitro results revealed that all of them are very good Aβ antiaggregants and some of the compounds are potent acetylcholinesterase (AChE) inhibitors with moderate antioxidant property. Selected compounds were also tested for neuroprotection activity, LDH release, ATP production and inhibitory activity to prevent Aβ peptides binding to the cell membrane. The different modifications introduced in the structure of our lead compound 3 (hAChE IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Benzofurans; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Humans; Models, Molecular; Molecular Structure; Neuroprotective Agents; Piperidines; Protein Aggregates; Protein Aggregation, Pathological; Structure-Activity Relationship

Recent studies indicated that seeded fibril formation and toxicity of α-synuclein (α-syn) play a main role in the pathogenesis of certain diseases including Parkinson's disease (PD), multiple system atrophy, and dementia with Lewy bodies. Therefore, examination of compounds that abolish the process of seeding is considered a key step towards therapy of several synucleinopathies.. Using biophysical, biochemical and cell-culture-based assays, assessment of eleven compounds, extracted from Chinese medicinal herbs, was performed in this study for their effect on α-syn fibril formation and toxicity caused by the seeding process.. Salvianolic acid B and dihydromyricetin were the two compounds that strongly inhibited the fibril growth and neurotoxicity of α-syn. In an in-vitro cell model, these compounds decreased the insoluble phosphorylated α-syn and aggregation. Also, in primary neuronal cells, these compounds showed a reduction in α-syn aggregates. Both compounds inhibited the seeded fibril growth with dihydromyricetin having the ability to disaggregate preformed α-syn fibrils. In order to investigate the inhibitory mechanisms of these two compounds towards fibril formation, we demonstrated that salvianolic acid B binds predominantly to monomers, while dihydromyricetin binds to oligomeric species and to a lower extent to monomers. Remarkably, these two compounds stabilized the soluble non-toxic oligomers lacking β-sheet content after subjecting them to proteinase K digestion.. Eleven compounds were tested but only two showed inhibition of α-syn aggregation, seeded fibril formation and toxicity in vitro. These findings highlight an essential beginning for development of new molecules in the field of synucleinopathies treatment.

Topics: alpha-Synuclein; Animals; Benzofurans; Drugs, Chinese Herbal; Flavonols; HEK293 Cells; Humans; Mice; Molecular Structure; Plant Extracts; Protein Aggregation, Pathological; Synucleinopathies

Both amyloid-β (Aβ) and insulin are amyloidogenic peptides, and they play a critical role in Alzheimer's disease (AD) and type-2 diabetes (T2D). Misfolded or aggregated Aβ and glycated insulin are commonly found in AD and T2D patients, respectively, and exhibit neurotoxicity and oxidative stress. The present study examined the anti-Aβ

Topics: Amyloid beta-Peptides; Benzofurans; Dioxins; Glycation End Products, Advanced; Lipid Peroxidation; Molecular Docking Simulation; Molecular Structure; Phaeophyceae; Phloroglucinol; Protein Aggregation, Pathological

Viticultural residues from commercial viticultural activities represent a potentially important source of bioactive stilbenes such as resveratrol. The main aim of the present study was therefore to isolate, identify and perform biological assays against amyloid-β peptide aggregation of original stilbenes from Vitis vinifera shoots.. A new resveratrol oligomer, (Z)-cis-miyabenol C (3), was isolated from Vitis vinifera grapevine shoots together with two newly reported oligostilbenes from Vitis vinifera shoots, vitisinol C (1) and (E)-cis-miyabenol C (2), and six known compounds: piceatannol, resveratrol, (E)-ε-viniferin (trans-ε-viniferin), ω-viniferin, vitisinol C and (E)-miyabenol C. The structures of these resveratrol derivatives were established on the basis of detailed spectroscopic analysis including nuclear magnetic resonance experiments. All the newly reported compounds were tested for their anti-aggregative activity against amyloid-β fibril formation. Vitisinol C was found to exert a significant activity against amyloid-β aggregation.. Vitis vinifera grapevine shoots are potentially interesting as a source of new bioactive stilbenes, such as vitisinol C.

Topics: Agriculture; Amyloid beta-Peptides; Benzofurans; Chromatography, High Pressure Liquid; Drug Discovery; France; Humans; Industrial Waste; Molecular Structure; Neuroprotective Agents; Nootropic Agents; Peptide Fragments; Phenols; Plant Extracts; Plant Shoots; Protein Aggregates; Protein Aggregation, Pathological; Spectrometry, Mass, Electrospray Ionization; Stereoisomerism; Stilbenes; Stilbestrols; Vitis