Biflavonoids Are Superior to Monoflavonoids in Inhibiting Amyloid-β Toxicity and Fibrillogenesis via Accumulation of Nontoxic Oligomer-like Structures
ABSTRACT Polymerization of monomeric amyloid-β peptides (Aβ) into soluble oligomers and insoluble fibrils is one of the major pathways triggering the pathogenesis of Alzheimer's disease (AD). Using small molecules to prevent the polymerization of Aβ peptides can, therefore, be an effective therapeutic strategy for AD. In this study, we investigate the effects of mono- and biflavonoids in Aβ42-induced toxicity and fibrillogenesis and find that the biflavonoid taiwaniaflavone (TF) effectively and specifically inhibits Aβ toxicity and fibrillogenesis. Compared to TF, the monoflavonoid apigenin (AP) is less effective and less specific. Our data show that differential effects of the mono- and biflavonoids in Aβ fibrillogenesis correlate with their varying cytoprotective efficacies. We also find that other biflavonoids, namely, 2',8''-biapigenin, amentoflavone, and sumaflavone, can also effectively inhibit Aβ toxicity and fibrillogenesis, implying that the participation of two monoflavonoids in a single biflavonoid molecule enhances their activity. Biflavonoids, while strongly inhibiting Aβ fibrillogenesis, accumulate nontoxic Aβ oligomeric structures, suggesting that these are off-pathway oligomers. Moreover, TF abrogates the toxicity of preformed Aβ oligomers and fibrils, indicating that TF and other biflavonoids may also reduce the toxicity of toxic Aβ species. Altogether, our data clearly show that biflavonoids, possibly because of the possession of two Aβ binders separated by an appropriate size linker, are likely to be promising therapeutics for suppressing Aβ toxicity.
- SourceAvailable from: Jing-Ke Weng
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- "Besides monomeric flavonoids, Selaginella is a rich source for biflavonoids (Setyawan, 2011). Medicinally, biflavonoids associate with assorted pharmacological properties including antimicrobial, antiviral, anticancer, anti-inflammatory, and anti-fibrillogenesis activities (Ma et al., 2001; Tang et al., 2003; Pan et al., 2005; Setyawan, 2011; Thapa et al., 2011). "
ABSTRACT: Early plants began colonizing the terrestrial earth approximately 450 million years ago. Their success on land has been partially attributed to the evolution of specialized metabolic systems from core metabolic pathways, the former yielding structurally and functionally diverse chemicals to cope with a myriad of biotic and abiotic ecological pressures. Over the past two decades, functional genomics, primarily focused on flowering plants, has begun cataloging the biosynthetic players underpinning assorted classes of plant specialized metabolites. However, the molecular mechanisms enriching specialized metabolic pathways during land plant evolution remain largely unexplored. Selaginella is an extant lycopodiophyte genus representative of an ancient lineage of tracheophytes. Notably, the lycopodiophytes diverged from euphyllophytes over 400 million years ago. The recent completion of the whole-genome sequence of an extant lycopodiophyte, S. moellendorffii, provides new genomic and biochemical resources for studying metabolic evolution in vascular plants. 400 million years of independent evolution of lycopodiophytes and euphyllophytes resulted in numerous metabolic traits confined to each lineage. Surprisingly, a cadre of specialized metabolites, generally accepted to be restricted to seed plants, have been identified in Selaginella. Initial work suggested that Selaginella lacks obvious catalytic homologs known to be involved in the biosynthesis of well-studied specialized metabolites in seed plants. Therefore, these initial functional analyses suggest that the same chemical phenotypes arose independently more commonly than anticipated from our conventional understanding of the evolution of metabolism. Notably, the emergence of analogous and homologous catalytic machineries through convergent and parallel evolution, respectively, seems to have occurred repeatedly in different plant lineages.Frontiers in Plant Science 05/2013; 4:119. DOI:10.3389/fpls.2013.00119 · 3.95 Impact Factor
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- "This result is similar to that reported using heme to prevent amyloid formation of the double mutant form of sperm whale apomyoglobin (Iannuzzi et al., 2007). The " remodeling " ability of some ligands that results into formation of non-toxic unstructured aggregates instead of the toxic species formed during the amyloidogenic process, has recently been reported for resveratrol (Ladiwala et al., 2010), biflavonoids (Thapa et al., 2011) and rifamycin (Woods et al., 2011). More generally, depending on their structures, aromatic small molecules are believed to act on the amyloidogenic process through different mechanisms, resulting in formation of various non-fibrillar structures (Ladiwala et al., 2011). "
ABSTRACT: A number of ligands with affinities for the heme binding site of apomyoglobin were tested to control amorphous and fibrillar aggregation in the protein. Several techniques, including fluorescence, dynamic light scattering, transmission electron microscopy, dot blot analysis combined with viability studies were employed for structural characterization and cytotoxicity assessment of the intermediate and final protein structures formed during the aggregation process. Of the small molecules investigated, chrysin and Nile red with high structural similarities to heme were chosen for further studies. Only fibril formation was found to be prevented by Nile red, while chrysin, with a greater structural flexibility, was able to prevent both types of aggregate formation. The two ligands were found to influence aggregation at different stages of intermediate structure formation, an ability determined by their degrees of similarities with heme. Based on structural characterization and toxicity studies, it is concluded that ligands similar in structure to heme may be effective in influencing various stages of aggregate formation and toxicity potencies of the protein structures. Since metalloproteins constitute more than thirty percent of all known proteins, it is concluded that the present strategy may be of general significance.The international journal of biochemistry & cell biology 10/2012; 45(2). DOI:10.1016/j.biocel.2012.10.004 · 4.24 Impact Factor
Phytochemicals - A Global Perspective of Their Role in Nutrition and Health, 03/2012; , ISBN: 978-953-51-0296-0
- "CD is also routinely used to study the interaction of many flavonoids with biomolecules, providing valuable information on biomolecule-drug interaction, such as DNA binding of quercetin (Ahmadi et al., 2011), binding to serum albumin (di Bari et al., 2009) and hemoglobin (Chauduri et al., 2011), inhibition of β-amyloid toxicity and fibrillogenesis (Thapa et al., 2011). "