Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Dual-targeted carbon-dot-drugs nanoassemblies for modulating Alzheimer's related amyloid-β aggregation and inhibiting fungal infection.

ABSTRACT: Amyloid aggregation and fungal infection, especially amyloid beta (Aβ) peptide and Candida albicans are considered as two of the crucial pathogenic agents in Alzheimer's disease (AD). In this work, we propose an innovative treatment strategy for AD, targeting at not only Aβ aggregation but also Candida albicans infection. Here, a high-performance nanomaterial, namely gCDs-E, have been prepared by self-assembled of glycosylated carbon dots (gCDs) and epigallocatechin-3-gallate (EGCG). Surprisingly, gCDs-E can not only suppress the fibrillation of Aβ and disaggregate Aβ fibrils, but also effectively inhibit the activity of Candida albicans. More importantly, the prepared gCDs-E can effectively cut down the cytotoxicity of amyloid aggregations, and the cell viability reached to 99.2%. In addition, the capability of the gCDs-E for blood brain barrier (BBB) penetration was also observed using a normal mice model. Above all, the gCDs-E greatly cleaned Aβ deposition and improved memory impairment in APP/PS1 transgenic AD model mice, confirming its potential as therapeutic agent for AD treatment.

SUBMITTER: Yan C

PROVIDER: S-EPMC8639470 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Neuronal heparan sulfates promote amyloid pathology by modulating brain amyloid-? clearance and aggregation in Alzheimer's disease.

Project description:Accumulation of amyloid-? (A?) peptide in the brain is the first critical step in the pathogenesis of Alzheimer's disease (AD). Studies in humans suggest that A? clearance from the brain is frequently impaired in late-onset AD. A? accumulation leads to the formation of A? aggregates, which injure synapses and contribute to eventual neurodegeneration. Cell surface heparan sulfates (HSs), expressed on all cell types including neurons, have been implicated in several features in the pathogenesis of AD including its colocalization with amyloid plaques and modulatory role in A? aggregation. We show that removal of neuronal HS by conditional deletion of the Ext1 gene, which encodes an essential glycosyltransferase for HS biosynthesis, in postnatal neurons of amyloid model APP/PS1 mice led to a reduction in both A? oligomerization and the deposition of amyloid plaques. In vivo microdialysis experiments also detected an accelerated rate of A? clearance in the brain interstitial fluid, suggesting that neuronal HS either inhibited or represented an inefficient pathway for A? clearance. We found that the amounts of various HS proteoglycans (HSPGs) were increased in postmortem human brain tissues from AD patients, suggesting that this pathway may contribute directly to amyloid pathogenesis. Our findings have implications for AD pathogenesis and provide insight into therapeutic interventions targeting A?-HSPG interactions.

| S-EPMC5512541 | biostudies-literature

Disease-modifying anti-Alzheimer's drugs: inhibitors of human cholinesterases interfering with ?-amyloid aggregation.

Project description:AIMS:We recently described multifunctional tools (2a-c) as potent inhibitors of human Cholinesterases (ChEs) also able to modulate events correlated with A? aggregation. We herein propose a thorough biological and computational analysis aiming at understanding their mechanism of action at the molecular level. METHODS:We determined the inhibitory potency of 2a-c on A?1-42 self-aggregation, the interference of 2a with the toxic A? oligomeric species and with the postaggregation states by capillary electrophoresis analysis and transmission electron microscopy. The modulation of A? toxicity was assessed for 2a and 2b on human neuroblastoma cells. The key interactions of 2a with A? and with the A?-preformed fibrils were computationally analyzed. 2a-c toxicity profile was also assessed (human hepatocytes and mouse fibroblasts). RESULTS:Our prototypical pluripotent analogue 2a interferes with A? oligomerization process thus reducing A? oligomers-mediated toxicity in human neuroblastoma cells. 2a also disrupts preformed fibrils. Computational studies highlighted the bases governing the diversified activities of 2a. CONCLUSION:Converging analytical, biological, and in silico data explained the mechanism of action of 2a on A?1-42 oligomers formation and against A?-preformed fibrils. This evidence, combined with toxicity data, will orient the future design of safer analogues.

| S-EPMC6493034 | biostudies-literature

Small Peptides for Inhibiting Serum Amyloid A Aggregation.

Project description:Deposition of human serum amyloid A (SAA) amyloids in blood vessels, causing inflammation, thrombosis, and eventually organ damage, is commonly seen as a consequence of certain cancers and inflammatory diseases and may also be a risk after SARS-COV-2 infections. Several attempts have been made to develop peptide-based drugs that inhibit or at least slow down SAA amyloidosis. We use extensive all-atom molecular dynamic simulations to compare three of these drug candidates for their ability to destabilize SAA fibrils and to propose for the best candidate, the N-terminal sequence SAA1-5, a mechanism for inhibition. As the lifetime of peptide drugs can be increased by replacing l-amino acids with their mirror d-amino acids, we have also studied corresponding d-peptides. We find that DRI-SAA1-5, formed of d-amino acids with the sequence of the peptide reversed, has similar inhibitory properties compared to the original l-peptide and therefore may be a promising candidate for drugs targeting SAA amyloidosis.

| S-EPMC8521652 | biostudies-literature

Novel harmine derivatives as potent acetylcholinesterase and amyloid beta aggregation dual inhibitors for management of Alzheimer's disease.

Project description:In this study, a series of potential ligands for the treatment of AD were synthesised and characterised as novel harmine derivatives modified at position 9 with benzyl piperazinyl. In vitro studies revealed that the majority of the derivatives exhibited moderate to potent inhibition against hAChE and Aβ1 - 42 aggregation. Notably, compounds 13 and 17d displayed potent drug - likeness and ADMET properties, demonstrating remarkable inhibitory activities towards AChE (IC50 = 58.76 nM and 89.38 nM, respectively) as well as Aβ aggregation (IC50 = 9.31 μM and 13.82 μM, respectively). More importantly, compounds 13 and 17d showed exceptional neuroprotective effects against Aβ1 - 42-induced SH - SY5Y damage, while maintaining low toxicity in SH - SY5Y cells. Further exploration of the mechanism through kinetic studies and molecular modelling confirmed that compound 13 could interact with both the CAS and the PAS of AChE. These findings suggested that harmine derivatives hold great potential as dual - targeted candidates for treating AD.

| S-EPMC10653770 | biostudies-literature

Dual-target ligand discovery for Alzheimer's disease: triphenylphosphoranylidene derivatives as inhibitors of acetylcholinesterase and β-amyloid aggregation.

Project description:Alzheimer disease (AD) is one of the major neurodegenerative diseases that could not be prevented or completely cured and may lead to death. Here, we target AChE and β-amyloid proteins. Synthesising new triphenylphosphporanylidene derivatives based on the surveyed literature and testing their biological activity revealed promising results especially for the acetyl triphenylphosphoranylidene derivative 8c, which showed good inhibitor activity against AChE enzyme with IC50 in the nanomolar range (97.04 nM); on the other hand, it showed poor selectivity for AChE versus butyrylcholinesterase but with some futural structural modification, this selectivity can be improved. 8c showed MMP-2 IC50 of 724.19 nM and Aβ1-42 aggregation IC50 of 302.36 nM. A kinetic study demonstrated that compound 8c uncompetitively inhibited AChE. Moreover, derivative 8c showed low cytotoxicity, good in vivo behavioural studies including Y-maze and passive avoidance tests with activity similar to that of donepezil. Finally, in silico studies for 8c predict its good penetration into BBB and good binding affinity in the AChE binding site.

| S-EPMC9879200 | biostudies-literature

Linking folding with aggregation in Alzheimer's beta-amyloid peptides.

Project description:Growing evidence suggests that the beta-amyloid (Abeta) peptides of Alzheimer's disease are generated in early endosomes and that small oligomers are the principal toxic species. We sought to understand whether and how the solution pH, which is more acidic in endosomes than the extracellular environment, affects the conformational processes of Abeta. Using constant pH molecular dynamics simulations of two model peptides, Abeta(1-28) and Abeta(10-42), we found that the folding landscape of Abeta is strongly modulated by pH and is most favorable for hydrophobically driven aggregation at pH 6. Thus, our theoretical findings substantiate the possibility that Abeta oligomers develop intracellularly before secretion into the extracellular milieu, where they may disrupt synaptic activity or act as seeds for plaque formation.

| S-EPMC2040412 | biostudies-literature

In Silico Drug Design and Analysis of Dual Amyloid-Beta and Tau Protein-Aggregation Inhibitors for Alzheimer's Disease Treatment.

Project description:Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder that gradually leads to the state of dementia. The main features of AD include the deposition of amyloid-beta peptides (Aβ), forming senile plaques, and the development of neurofibrillary tangles due to the accumulation of hyperphosphorylated Tau protein (p-tau) within the brain cells. In this report, seven dual-inhibitor molecules (L1-7) that can prevent the aggregation of both Aβ and p-tau are suggested. The drug-like features and identification of the target proteins are analyzed by the in silico method. L1-7 show positive results in both Blood-Brain Barrier (BBB) crossing and gastrointestinal absorption, rendering to the results of the permeation method. The molecular docking test performed for L1-7 shows binding energies in the range of -4.9 to -6.0 kcal/mol towards Aβ, and -4.6 to -5.6 kcal/mol for p-tau. The drug's effectiveness under physiological conditions is assessed by the use of solvation models on the investigated systems. Further, the photophysical properties of L1-3 are predicted using TD-DFT studies.

| S-EPMC9919237 | biostudies-literature

Crown ethers attenuate aggregation of amyloid beta of Alzheimer's disease.

Project description:In this report, we reasoned that non-covalent modification of amyloid beta (A?) by crown ethers could inhibit its aggregation. We demonstrated that PiB-C, a conjugate PiB and crown ether, could significantly reduce the aggregation in vitro. Additionally, two-photon imaging showed that PiB-C could efficiently label A? plaques and CAAs in AD mice.

| S-EPMC4617529 | biostudies-literature

Molecular topology as novel strategy for discovery of drugs with aβ lowering and anti-aggregation dual activities for Alzheimer's disease.

Project description:Background and purposeIn this study, we demonstrate the use of Molecular topology (MT) in an Alzheimer's disease (AD) drug discovery program. MT uses and expands upon the principles governing the molecular connectivity theory of numerically characterizing molecular structures, in the present case, active anti-AD drugs/agents, using topological descriptors to build models. Topological characterization has been shown to embody sufficient molecular information to provide strong correlation to therapeutic efficacy.Experimental approachWe used MT to include multiple bioactive properties that allows for the identification of multi-functional single agent compounds, in this case, the dual functions of β-amyloid (Aβ) -lowering and anti-oligomerization. Using this technology, we identified and designed novel compounds in chemical classes unrelated to current anti-AD agents that exert dual Aβ lowering and anti-Aβ oligomerization activities in animal models of AD. AD is a multifaceted disease with different pathological features.Conclusion and implicationsOur study, for the first time, demonstrated that MT can provide novel strategy for discovering drugs with Aβ lowering and anti-aggregation dual activities for AD.

| S-EPMC3966818 | biostudies-literature

Quantum-dot-labeled synuclein seed assay identifies drugs modulating the experimental prion-like transmission.

Project description:Synucleinopathies are neurodegenerative disorders including Parkinson disease (PD), dementia with Lewy body (DLB), and multiple system atrophy (MSA) that involve deposits of the protein alpha-synuclein (α-syn) in the brain. The inoculation of α-syn aggregates derived from synucleinopathy or preformed fibrils (PFF) formed in vitro induces misfolding and deposition of endogenous α-syn. This is referred to as prion-like transmission, and the mechanism is still unknown. In this study, we label α-syn PFF with quantum dots and visualize their movement directly in acute slices of brain tissue inoculated with α-syn PFF seeds. Using this system, we find that the trafficking of α-syn seeds is dependent on fast axonal transport and the seed spreading is dependent on endocytosis and neuronal activity. We also observe pharmacological effects on α-syn seed spreading; clinically available drugs including riluzole are effective in reducing the spread of α-syn seeds and this effect is also observed in vivo. Our quantum-dot-labeled α-syn seed assay system combined with in vivo transmission experiment reveals an early phase of transmission, in which uptake and spreading of seeds occur depending on neuronal activity, and a later phase, in which seeds induce the propagation of endogenous misfolded α-syn.

| S-EPMC9243017 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data