Structure–Activity Relationship for (+)-Taxifolin Isolated from Silymarin as an Inhibitor of Amyloid β Aggregation

Satô, Mizuho; Murakami, Kazuma; Uno, Mayumi; Ikubo, Haruko; Nakagawa, Yu; Katayama, Soichiro; Akagi, Ken‐ichi; Irie, Kazuhiro

doi:10.1271/bbb.120925

Cited by 46 publications

(53 citation statements)

References 28 publications

(36 reference statements)

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“…In fact, the flavonoids that possessed a catechol moiety had a lower IC 50 than the non-catechol type substances ( Table 1), indicating that the position and number of hydroxyl group on the aromatic ring is important for the determination of aggregation inhibition potency. This result is consistent with previous reports concerning Aβ, 12,13,15,16) but confirmed, in this research, for hIAPP aggregation inhibition.…”

Section: Resultssupporting

confidence: 94%

“…4) The similarities in Aβ and IAPP oligomers can be used to investigate the prevention of oxidative stress and amyloid aggregation inhibition related to AD and T2D, since potent therapeutic agents such as antioxidants with a catechol moiety, proved to inhibit Aβ aggregation, [12][13][14][15][16] may play a key role inhibiting the aggregation of human IAPP (hIAPP) in case of patients with diabetes.…”

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confidence: 99%

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Inhibitory Activities of Antioxidant Flavonoids from <i>Tamarix gallica</i> on Amyloid Aggregation Related to Alzheimer’s and Type 2 Diabetes Diseases

Hmidene

Hanaki

Murakami

et al. 2017

Biological & Pharmaceutical Bulletin

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The prevention of amyloid aggregation is promising for the treatment of age-related diseases such as Alzheimer's (AD) and type 2 diabetes (T2D). Ten antioxidant flavonoids isolated from the medicinal halophyte Tamarix gallica were tested for their amyloid aggregation inhibition potential. Glucuronosylated flavonoids show relatively strong inhibitory activity of Amyloid β (Aβ) and human islet amyloid polypeptide (hIAPP) aggregation compared to their aglycone analogs. Structure-activity relationship of the flavonoids suggests that the catechol moiety is important for amyloid aggregation inhibition, while the methylation of the carboxyl group in the glucuronide moiety and of the hydroxyl group in the aglycone flavonoids decreased it.Key words amyloid aggregation; glucuronosylated flavonoid; Tamarix gallica; Alzheimer's disease; type 2 diabetes The incidence of both disturbances Alzheimer's disease (AD) and type 2 diabetes (T2D) is increasing and has become a major public health concern in many industrialized countries. Despite intense research, best strategies to treat/prevent these costly diseases are still under investigation. However, it is now widely recognized that AD and T2D share many pathophysiological features including increased oxidative stress and amyloid aggregation. 1-4)Amyloid β (Aβ) is the component of the amyloid deposits in the AD brain, 5) while the component of the amyloidogenic peptide deposit in the diabetic pancreatic islets of Langerhans is identified as islet amyloid polypeptide (IAPP), a 37-amino acid peptide. 6,7) Although the amino acid sequences of amyloidogenic proteins are diverse, they all adopt a similar structure in aggregates called cross-β-spine.8) Extensive studies in the past years have found that, similar to Aβ 1-42 , IAPP forms early intermediate assemblies as spherical oligomers 9,10) that are recognized by soluble Aβ oligomers antibody, 11) implicating that these oligomers possess a common folding pattern or conformation.4) The similarities in Aβ 1-42 and IAPP oligomers can be used to investigate the prevention of oxidative stress and amyloid aggregation inhibition related to AD and T2D, since potent therapeutic agents such as antioxidants with a catechol moiety, proved to inhibit Aβ aggregation, 12-16) may play a key role inhibiting the aggregation of human IAPP (hIAPP) in case of patients with diabetes.The powerful antioxidant activity of the medicinal halophyte Tamarix gallica L. has been reported as exhibiting a remarkable spectrum of biochemical and pharmacological activities. Although traditionally used for the treatment of various liver disorders and marketed as a herbal medicine in many countries, [17][18][19] there have been no reports on the use of this plant for the treatment or prevention of AD or T2D. Therefore, the aim of this research is to investigate the protective effect of T. gallica towards both disturbances by isolation and identification of the Aβ and hIAPP aggregation inhibitors with antioxidant potential. MATERIALS AND METHODS MaterialsThe aerial par...

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Section: Resultssupporting

confidence: 94%

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confidence: 99%

Inhibitory Activities of Antioxidant Flavonoids from <i>Tamarix gallica</i> on Amyloid Aggregation Related to Alzheimer’s and Type 2 Diabetes Diseases

Hmidene

Hanaki

Murakami

et al. 2017

Biological & Pharmaceutical Bulletin

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“…Synthesis of (ϩ)-Taxifolin, Dihydrokaempferol, and Pinobanksin-A naturally occurring form of (ϩ)-taxifolin was synthesized (supplemental Scheme S1A) basically according to the previous reports (23,24). Briefly, vanillin was demethylated by treatment with boron tribromide to give 3,4-dihydroxybenzaldehyde quantitatively, whose phenolic hydroxyl groups were protected with methoxymethyl groups.…”

Section: Methodsmentioning

confidence: 99%

“…We also isolated (ϩ)-taxifolin (22), a flavanonol that has a catechol moiety on the B-ring (Fig. 1A), as a component of the extracts that prevents A␤42 aggregation (23). "Aggregation" used in this article means the process of A␤42 monomer to form fibrils by way of oligomer and/or protofibril.…”

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confidence: 99%

Site-specific Inhibitory Mechanism for Amyloid β42 Aggregation by Catechol-type Flavonoids Targeting the Lys Residues

Satô

Murakami²,

Uno³

et al. 2013

Journal of Biological Chemistry

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Background:The inhibitory mechanism of A␤42 aggregation by flavonoid is fully unknown. Results: The oxidant enhanced the inhibitory activity of (ϩ)-taxifolin against A␤42 aggregation by forming A␤42-taxifolin adducts between the Lys residues and oxidized (ϩ)-taxifolin. Conclusion:The inhibitory activity of catechol-type flavonoids requires autoxidation to form an o-quinone to react with Lys. Significance: These may help design promising inhibitors against A␤42 aggregation for Alzheimer disease therapy.

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“…Raloxifene has been licenced since 1997 (Evista, Eli Lilly) and used to treat osteoporosis in postmenopausal women. 28 Raloxifene has already participated in a small clinical trial for AD where it was shown that a large dose of the drug resulted in the reduced risk of cognitive impairment in postmenopausal women. 29 It is already known that the inhibition of ABAD restores the amyloid-β-mediated deregulation of estradiol, 9 and with Raloxifene classed as a selective estrogen receptor modulator this compound proves to be very interesting and its analogues require further investigation as possible therapeutics against ABAD.…”

Section: Primary Validation Screenmentioning

confidence: 99%

In Vitro Assay Development and HTS of Small-Molecule Human ABAD/17β-HSD10 Inhibitors as Therapeutics in Alzheimer’s Disease

et al. 2017

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Structure–Activity Relationship for (+)-Taxifolin Isolated from Silymarin as an Inhibitor of Amyloid β Aggregation

Cited by 46 publications

References 28 publications

Inhibitory Activities of Antioxidant Flavonoids from <i>Tamarix gallica</i> on Amyloid Aggregation Related to Alzheimer’s and Type 2 Diabetes Diseases

Inhibitory Activities of Antioxidant Flavonoids from <i>Tamarix gallica</i> on Amyloid Aggregation Related to Alzheimer’s and Type 2 Diabetes Diseases

Site-specific Inhibitory Mechanism for Amyloid β42 Aggregation by Catechol-type Flavonoids Targeting the Lys Residues

In Vitro Assay Development and HTS of Small-Molecule Human ABAD/17β-HSD10 Inhibitors as Therapeutics in Alzheimer’s Disease

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