The Flavonoid Baicalein Inhibits Fibrillation of α-Synuclein and Disaggregates Existing Fibrils

Zhu, Min; Rajamani, Sudha; Kaylor, Joanna J.; Han, Shubo; Zhou, Feimeng; Fink, Anthony L.

doi:10.1074/jbc.m403129200

Cited by 445 publications

(423 citation statements)

References 35 publications

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“…Based on our knowledge of baicalein, it is reasonable to assume that a catecholic alcohol ligates the iron and causes an inner sphere reduction on the active site iron, with baicalein undergoing oxidation to its quinone form ( Figure 5). 50 Apigenin was also investigated for pseudoperoxidase activity, however, it is not active, indicating apigenin is not a reductive inhibitor. This difference between baicalein and apigenin could be due to their different structures and chelation properties.…”

Section: Insert Figure 4 Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Baicalein is a potent in vitro inhibitor against both reticulocyte 15-human and platelet 12-human lipoxygenases

Deschamps

Kenyon

Holman

2006

Bioorganic & Medicinal Chemistry

143

126

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Abstract. Lipoxygenases (LO) have been implicated in asthma, immune disorders, and various cancers and as a consequence, there is great interest in isolating selective LO isozyme inhibitors.Currently, there is much use of baicalein as a selective human platelet 12-LO (12-hLO) inhibitor however, our current steady-state inhibition data indicates that baicalein is not selective against 12-hLO versus human reticulocyte 15-LO-1 (15-hLO-1) (15/12 = 1.3), in vitro. However, in the presence of detergents baicalein is slightly more selective (15/12 = 7), which may imply greater selectivity in a cell based assay but has yet to be proven. The mechanism of baicalein inhibition of 15-hLO is reductive, which computer docking suggests is through direct binding of the catecholic moiety of baicalein to the iron. A structurally related flavonoid, apigenin, is not reductive, however, computer docking suggests a hydrogen bond with Thr591, may account for its inhibitor potency.

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Section: Insert Figure 4 Discussionmentioning

confidence: 99%

“…Apigenin had an IC 50 of 81 ± 32 µM against 12-hLO and 3.4 ± 0.51µM against 15-hLO-1 ( Table 2). With 0.01% trition-X-100 in the buffer, baicalein had an IC 50 of 0.62 ± 0.19µM against 12-hLO and 38 ± 21 µM against 15-hLO-1. Apigenin had an IC 50 of 32 ± 11 µM against 12-hLO and 3.0 ± 1.4 µM against 15-hLO-1 (Table 3).…”

Section: Expressionmentioning

confidence: 99%

Baicalein is a potent in vitro inhibitor against both reticulocyte 15-human and platelet 12-human lipoxygenases

Deschamps

Kenyon

Holman

2006

Bioorganic & Medicinal Chemistry

143

126

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“…In these disorders, proteins aggregate into long, unbranched fibers after misfolding into a β-sheet-rich conformation 1 . Though there are no approved therapies targeting amyloid formation directly, many organic molecules inhibit fibrillization in vitro [2][3][4][5][6][7] . Some, such as the chelator clioquinol (1), even have activity in vivo 4 .…”

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confidence: 99%

Small-molecule aggregates inhibit amyloid polymerization

et al. 2008

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Many amyloid inhibitors resemble molecules that form chemical aggregates, which are known to inhibit many proteins. Eight known chemical aggregators inhibited amyloid formation of the yeast and mouse prion proteins Sup35 and recMoPrP in a manner characteristic of colloidal inhibition. Similarly, three known anti-amyloid molecules inhibited β-lactamase in a detergent-dependent manner, which suggests that they too form colloidal aggregates. The colloids localized to preformed fibers and prevented new fiber formation in electron micrographs. They also blocked infection of yeast cells with Sup35 prions, which suggests that colloidal inhibition may be relevant in more biological milieus.The aggregation of proteins into amyloid fibers is associated with a growing list of diseases, including diabetes, Alzheimer's, Parkinson's, Huntington's and the prion diseases. In these disorders, proteins aggregate into long, unbranched fibers after misfolding into a β-sheet-rich conformation 1 . Though there are no approved therapies targeting amyloid formation directly, many organic molecules inhibit fibrillization in vitro [2][3][4][5][6][7] . Some, such as the chelator clioquinol (1), even have activity in vivo 4 . These results have inspired the hope of therapeutic applications for some molecules 3-5 . Curiously, many fibrillization inhibitors resemble molecules known to form promiscuous chemical aggregates. These colloidal particles are composed of small organic molecules and range in size from 50 to over 600 nm 8 . Once formed, they physically sequester proteins and inhibit enzymes nonspecifically 8,9 . Like many inhibitors of amyloid polymerization, these colloidal inhibitors are typically highly conjugated, hydrophobic and dye-like (Supplementary Table 1 online) 8,9 . A good example is the amyloid inhibitor Congo red (2), a dye that was one of the first molecules observed to exhibit colloidal inhibition 8 . The flavonoid baicalein (3), an inhibitor of α-synuclein polymerization 6 , resembles the known chemical aggregator quercetin (4), and 4,5-dianilinophthalimide (DAPH, 5), an inhibitor of Alzheimer's amyloid formation 2 , resembles the aggregator bisindoylmaleimide (6 ; Supplementary Fig. 1 online).Given that chemical aggregates function through enzyme sequestration, we wondered whether they might also sequester protein molecules from each other, thereby preventing amyloid polymerization. Here, we investigate this hypothesis in two classic amyloid-forming proteins: the yeast prion protein Sup35 (ref. 10 ) and the recombinant mouse prion protein recMoPrP 89-230 (ref. 11 ). We ask whether known chemical aggregators can inhibit amyloid fiber formation, whether known fibrillization inhibitors form colloidal aggregates and whether amyloid inhibition by these molecules is in fact mediated via colloidal aggregation.Eight known chemical aggregators and two known nonaggregators 8,9 were tested for inhibition of Sup35 fibrillization in a thioflavin T (ThT, 7) fluorescence assay. All eight inhibited Sup35 fibrillization b...

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“…Here, we examined the effects of two representative ionic liquids, 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [BIMbF 3 Im] and 1-butyl-3-methylimidazolium tetrafluoroborate [BIMBF 4 ], on the fibril formation of a-synuclein and its tandem repeat (a-TR). The chemical structures of [BIMbF 3 Im] and [BIMBF 4 ], which have the same cationic components but different anionic parts, are shown in Fig 1A. In addition, EGCG and baicalein, which were reported to inhibit the fibril formation of a-synuclein [17,18], were used in this study (Fig. 1B).…”

Section: Resultsmentioning

confidence: 99%

“…Based on the previous reports concerning the disaggregating activities of polyphenols on the preformed fibrils of Ab or a-synuclein [17,18,21], we investigated the effects of epigallocatechin gallate (EGCG) and baicalein for the disaggregation of a-synuclein fibrils. Various concentrations of EGCG and baicalein were added to the a-synuclein fibrils prepared by [BIMbF 3 Im], and the disaggregation kinetics was investigated.…”

Section: Resultsmentioning

confidence: 99%

Amyloid formation and disaggregation of α-synuclein and its tandem repeat (α-TR)

Bae

Kim

Hwang

et al. 2010

Biochemical and Biophysical Research Communications

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The Flavonoid Baicalein Inhibits Fibrillation of α-Synuclein and Disaggregates Existing Fibrils

Cited by 445 publications

References 35 publications

Baicalein is a potent in vitro inhibitor against both reticulocyte 15-human and platelet 12-human lipoxygenases

Baicalein is a potent in vitro inhibitor against both reticulocyte 15-human and platelet 12-human lipoxygenases

Small-molecule aggregates inhibit amyloid polymerization

Amyloid formation and disaggregation of α-synuclein and its tandem repeat (α-TR)

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