curcumin and myricetin

Amyloid fibrils are highly ordered protein aggregates associated with many diseases affecting millions of people worldwide. Polyphenols such as Curcumin, Exifone, and Myricetin exhibit modest inhibition toward fibril formation of tau peptide which is associated with Alzheimer's disease. However, the molecular mechanisms of this inhibition remain elusive. We investigated the binding of three polyphenol molecules to the protofibrils of an amyloidogenic fragment VQIVYK of tau peptide by molecular dynamics simulations in explicit solvent. We find that polyphenols induce conformational changes in the oligomer aggregate. These changes disrupt the amyloid H bonding, perturbing the aggregate. While the structural evolution of the control oligomer with no ligand is limited to the twisting of the β-sheets without their disassembly, the presence of polyphenol molecule pushes the β-sheets apart, and leads to a loosely packed structure where two of four β-sheets dissociate in each of the three cases considered here. The H-bonding capacity of polyphenols is responsible for the observed behavior. The calculated binding free energies and its individual components enabled better understanding of the binding. Results indicated that the contribution from Van der Waals interactions is more significant than electrostatic contribution to the binding. The findings from this study are expected to assist in the development of aggregation inhibitors. Significant binding between polyphenols and aggregate oligomer identified in our simulations confirms the previous experimental observations in which polyphenols refold the tau peptide without forming covalent bonds.

Topics: Amino Acid Sequence; Amyloid; Benzophenones; Curcumin; Flavonoids; Humans; Hydrogen Bonding; Models, Molecular; Molecular Conformation; Molecular Dynamics Simulation; Peptide Fragments; Polyphenols; Protein Aggregation, Pathological; Protein Binding; Protein Multimerization; Quantitative Structure-Activity Relationship; tau Proteins

An insight into the complex cancer pathophysiology reveals that a dependable amelioration of the disease could only be envisaged with a multipronged treatment approach. It is highly evident that singular chemotherapeutic agents used in clinical practice have shown limitations like severe side effects, MDR and are often associated with poor QOL while combinations of drugs have yielded better therapeutic outcomes. The current hypothesis takes it a step forward wherein a chemotherapeutic agent is combined with a natural chemosensitizer, both loaded into a nanopotentiated particulate system, which would eventually deliver the drug cargo at the target site with certitude. The encapsulated natural bioactive would then favorably act on the tumor milieu through multiple portals and chemosensibilize the cells towards cytotoxic action of the synthetic drug moiety. This 2C (chemotherapeutic and chemosensitizer) approach along with nanosystem's attributes like high payload, prolonged action and diminished side effects would proffer a more dependable treatment modality. In conclusion, the proposed system would be a value addition to the currently available armamentarium of cancer treatment tools.

Topics: Antineoplastic Agents, Phytogenic; Curcumin; Drug Delivery Systems; Drug Therapy, Combination; Flavonoids; Fluorouracil; Humans; Models, Biological; Nanoparticles; Neoplasms; Resveratrol; Stilbenes

Lewy bodies, mainly composed of α-synuclein (αS), are pathological hallmarks of Parkinson's disease and dementia with Lewy bodies. Epidemiological studies showed that green tea consumption or habitual intake of phenolic compounds reduced Parkinson's disease risk. We previously reported that phenolic compounds inhibited αS fibrillation and destabilized preformed αS fibrils. Cumulative evidence suggests that low-order αS oligomers are neurotoxic and critical species in the pathogenesis of α-synucleinopathies. To develop disease modifying therapies for α-synucleinopathies, we examined effects of phenolic compounds (myricetin (Myr), curcumin, rosmarinic acid (RA), nordihydroguaiaretic acid, and ferulic acid) on αS oligomerization. Using methods such as photo-induced cross-linking of unmodified proteins, circular dichroism spectroscopy, the electron microscope, and the atomic force microscope, we showed that Myr and RA inhibited αS oligomerization and secondary structure conversion. The nuclear magnetic resonance analysis revealed that Myr directly bound to the N-terminal region of αS, whereas direct binding of RA to monomeric αS was not detected. Electrophysiological assays for long-term potentiation in mouse hippocampal slices revealed that Myr and RA ameliorated αS synaptic toxicity by inhibition of αS oligomerization. These results suggest that Myr and RA prevent the αS aggregation process, reducing the neurotoxicity of αS oligomers. To develop disease modifying therapies for α-synucleinopathies, we examined effects of phenolic compounds on α-synuclein (αS) oligomerization. Phenolic compounds, especially Myricetin (Myr) and Rosmarinic acid (RA), inhibited αS oligomerization and secondary structure conversion. Myr and RA ameliorated αS synaptic toxicity on the experiment of long-term potentiation. Our results suggest that Myr and RA prevent αS aggregation process and reduce the neurotoxicity of αS oligomers. Phenolic compounds are good candidates of disease modifying drugs for α-synucleinopathies.

Topics: alpha-Synuclein; Amyloid; Animals; Antioxidants; Cinnamates; Circular Dichroism; Coumaric Acids; Curcumin; Depsides; Drug Evaluation, Preclinical; Flavonoids; Hippocampus; Long-Term Potentiation; Masoprocol; Mice; Microscopy, Atomic Force; Models, Molecular; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Phenols; Polymerization; Protein Structure, Secondary; Rosmarinic Acid

Combined results of theoretical molecular dynamic simulations and in vitro spectroscopic (circular dichroism and fluorescence) studies are presented, providing the atomistic and secondary structure details of the process by which a selected small molecule may destabilize the β-sheet ordered "amyloid" oligomers formed by the model undecapeptide of amyloid β-peptide 25-35 [Aβ(25-35)]. Aβ(25-35) was chosen because it is the shortest fragment capable of forming large β-sheet fibrils and retaining the toxicity of the full length Aβ(1-40/42) peptides. The conformational transition, that leads to the formation of β-sheet fibrils from soluble unordered structures, was found to depend on the environmental conditions, whereas the presence of myricetin destabilizes the self-assembly and antagonizes this conformational shift. In parallel, we analyzed several molecular dynamics trajectories describing the evolution of five monomer fragments, without inhibitor as well as in the presence of myricetin. Other well-known inhibitors (curcumin and (-)-tetracycline), found to be stronger and weaker Aβ(1-42) aggregation inhibitors, respectively, were also studied. The combined in vitro and theoretical studies of the Aβ(25-35) self-assembly and its inhibition contribute to understanding the mechanism of action of well-known inhibitors and the peptide amino acid residues involved in the interaction leading to a rational drug design of more potent new molecules able to antagonize the self-assembly process.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Circular Dichroism; Curcumin; Flavonoids; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Models, Molecular; Peptide Fragments; Protein Structure, Secondary; Spectrometry, Fluorescence; Temperature; Tetracycline

The accumulation of aggregated β-Amyloid (Aβ) in the brain is a hallmark of Alzheimer's disease and is thought to play a role in the neurotoxicity associated with the disease. The mechanism by which Aβ aggregates induce toxicity is uncertain. Nonetheless, several small molecules have been found to interact with Aβ fibrils and to prevent their toxicity. In this paper we studied the binding of these known toxicity inhibitors to Aβ fibrils, as a means to explore surfaces or loci on Aβ aggregates that may be significant in the mechanism of action of these inhibitors. We believe knowledge of these binding loci will provide insight into surfaces on the Aβ fibrils important in Aβ biological activity. The program DOCK was used to computationally dock the inhibitors to an Aβ fibril. The inhibitors docked at two shared binding loci, near Lys28 and at the C-termini near Asn27 and Val39. The docking predictions were experimentally verified using lysine specific chemical modifications and Aβ fibrils mutated at Asn27. We found that both Congo red and Myricetin, despite being structurally different, bound at the same two sites. Additionally, our data suggests that three additional Aβ toxicity inhibitors may also bind in one of the sites. Identification of these common binding loci provides targets on the Aβ fibril surface that can be tested in the future for their role in Aβ biological activity.

Topics: Amyloid; Binding Sites; Congo Red; Curcumin; Flavonoids; Microscopy, Electron, Transmission; Nicotine; Protein Binding

Inhibition of amyloid-beta (Abeta) aggregation is an attractive therapeutic strategy for Alzheimer's disease (AD). Certain phenolic compounds have been reported to have anti-Abeta aggregation effects in vitro. This study systematically investigated the effects of phenolic compounds on AD model transgenic mice (Tg2576). Mice were fed five phenolic compounds (curcumin, ferulic acid, myricetin, nordihydroguaiaretic acid (NDGA), and rosmarinic acid (RA)) for 10 months from the age of 5 months. Immunohistochemically, in both the NDGA- and RA-treated groups, Abeta deposition was significantly decreased in the brain (P < 0.05). In the RA-treated group, the level of Tris-buffered saline (TBS)-soluble Abeta monomers was increased (P < 0.01), whereas that of oligomers, as probed with the A11 antibody (A11-positive oligomers), was decreased (P < 0.001). However, in the NDGA-treated group, the abundance of A11-positive oligomers was increased (P < 0.05) without any change in the levels of TBS-soluble or TBS-insoluble Abeta. In the curcumin- and myricetin-treated groups, changes in the Abeta profile were similar to those in the RA-treated group, but Abeta plaque deposition was not significantly decreased. In the ferulic acid-treated group, there was no significant difference in the Abeta profile. These results showed that oral administration of phenolic compounds prevented the development of AD pathology by affecting different Abeta aggregation pathways in vivo. Clinical trials with these compounds are necessary to confirm the anti-AD effects and safety in humans.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cinnamates; Coumaric Acids; Curcumin; Depsides; Disease Models, Animal; Female; Flavonoids; Humans; Immunohistochemistry; Masoprocol; Mice; Mice, Transgenic; Phenols; Rosmarinic Acid; Signal Transduction