Identification of brain‐targeted bioactive dietary quercetin‐3‐<i>O</i>‐glucuronide as a novel intervention for Alzheimer's disease

Ho, Lap; Ferruzzi, Mario G.; Janle, Elsa M.; Wang, Jun; Gong, Bing; Chen, Tzu‐Ying; Lobo, Jessica; Cooper, Bruce R.; Wu, Qin; Talcott, Stephen T.; Percival, Susan S.; Simon, James E.; Pasinetti, Giulio Maria

doi:10.1096/fj.12-212118

Cited by 188 publications

(166 citation statements)

References 79 publications

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“…Many studies report the health benefit of the consumption of anthocyanidin-rich food or beverages, more precisely in the case of cancers (38), cardiovascular diseases (39), and Alzheimer's disease (40). This could be explained by their anti-inflammatory and antioxidative properties and their capacity to improve lipid profiles and to activate specific regulatory pathways.…”

Section: Discussionmentioning

confidence: 99%

Polyphenols Inhibit Hepatitis C Virus Entry by a New Mechanism of Action

Calland

Sahuc

Belouzard

et al. 2015

J Virol

125

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Despite the validation of direct-acting antivirals for hepatitis C treatment, the discovery of new compounds with different modes of action may still be of importance for the treatment of special patient populations. We recently identified a natural molecule, epigallocatechin-3-gallate (EGCG), as an inhibitor of hepatitis C virus (HCV) targeting the viral particle. The aim of this work was to discover new natural compounds with higher anti-HCV activity than that of EGCG and determine their mode of action. Eight natural molecules with structure similarity to EGCG were selected. HCV JFH1 in cell culture and HCV pseudoparticle systems were used to determine the antiviral activity and mechanism of action of the compounds. We identified delphinidin, a polyphenol belonging to the anthocyanidin family, as a new inhibitor of HCV entry. Delphinidin inhibits HCV entry in a pangenotypic manner by acting directly on the viral particle and impairing its attachment to the cell surface. Importantly, it is also active against HCV in primary human hepatocytes, with no apparent cytotoxicity and in combination with interferon and boceprevir in cell culture. Different approaches showed that neither aggregation nor destruction of the particle occurred. Cryo-transmission electron microscopy observations of HCV pseudoparticles treated with delphinidin or EGCG showed a bulge on particles that was not observed under control conditions. In conclusion, EGCG and delphinidin inhibit HCV entry by a new mechanism, i.e., alteration of the viral particle structure that impairs its attachment to the cell surface. IMPORTANCEIn this article, we identify a new inhibitor of hepatitis C virus (HCV) infection, delphinidin, that prevents HCV entry. This natural compound, a plant pigment responsible for the blue-purple color of flowers and berries, belongs to the flavonoid family, like the catechin EGCG, the major component present in green tea extract, which is also an inhibitor of HCV entry. We studied the mode of action of these two compounds against HCV and demonstrated that they both act directly on the virus, inducing a bulging of the viral envelope. This deformation might be responsible for the observed inhibition of virus attachment to the cell surface. The discovery of such HCV inhibitors with an unusual mode of action is important to better characterize the mechanism of HCV entry into hepatocytes and to help develop a new class of HCV entry inhibitors. H epatitis C is a major health problem, with as many as 130 million people chronically infected worldwide (1). It is caused by hepatitis C virus (HCV), which has a high propensity to establish a persistent infection. Chronic hepatitis C can lead to the development of cirrhosis and hepatocellular carcinoma. Recent improvements in the standard of care, with direct-acting antivirals (DAAs) that inhibit HCV NS3/4A protease, NS5B polymerase, or NS5A, and now without interferon (IFN), which causes severe adverse effects, have raised the hope that HCV infection can be managed efficiently in cou...

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Section: Discussionmentioning

confidence: 99%

Polyphenols Inhibit Hepatitis C Virus Entry by a New Mechanism of Action

Calland

Sahuc

Belouzard

et al. 2015

J Virol

125

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“…"Phase II conjugates, sulfates or glucuronides, have been reported to have antioxidative (Terao, 1999), neuroprotective (Ho et al, 2013), and anti-inflammatory (Granica et al, 2013) effects. In addition to a notable immuneenhancing effect, Astragali Radix is also commonly used for treating cardiovascular disorders and has been shown to possess angiogenic effect in previous studies Li et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

The Presystemic Interplay between Gut Microbiota and Orally Administered Calycosin-7-O-β-d-Glucoside

Ruan

et al. 2015

Drug Metab Dispos

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Presystemic interactions with gut microbiota might play important roles in the holistic action of herbal medicines in their traditional oral applications. However, research interests usually focus on biologic activities of the in vivo available herb-derived components and their exposure in circulation. In this study, we illustrated the importance of studying the presystemic interplay with gut microbiota for understanding the holistic actions of medicinal herbs by using calycosin-7-O-b-D-glucoside (C7G), the most abundant flavonoid and chemical marker in Astragali Radix, as a model compound. When C7G was orally administrated to rats, calycosin-39-O-glucuronide (G2) was the major circulating component in the blood together with a minor calycosin but not C7G. Rat gut microbiota hydrolyzed C7G in vitro rapidly and produced its aglycone calycosin. Calycosin exhibited higher permeability than C7G and further underwent extensive glucuronidation to yield 3ʹ-glucuronide as the dominant metabolite. Bioactivity assays revealed that G2 exhibited similar or more potent proangiogenic effects than calycosin in human umbilical vein endothelial cells in vitro and in the vascular endothelial growth factor receptor tyrosine kinase inhibitor II-induced blood vessel loss model in zebrafish. More interestingly, the incubation of C7G with gut microbiota from both normal and colitic rats showed a probiotics-like effect through stimulating the growth of the beneficial bacteria Lactobacillus and Bifidobacterium. In conclusion, C7G interacts reciprocally with gut microbiota after oral dosing, which makes it not only an angiogenic prodrug but also a modulator of gut microbiota.

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“…Da mesma forma, o resveratrol possui potencial modulador da neuropatologia da DA por meio de alguns mecanismos, incluindo a modulação da oxidação, catabolismo e oligomerização ou diretamente influenciando nas atividades cerebrais (HO et al, 2013).…”

Section: Doença De Alzheimerunclassified

Efeito Protetor Do Resveratrol Na Doença De Alzheimer

Rosa

Machado

Frusciante

et al. 2017

RBM

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ResumoA Doença de Alzheimer (DA) é uma doença neurodegenerativa e progressiva, caracterizada por alterações comportamentais e cognitivas, apresenta como principais características neuropatológicas a presença de placas senis e emaranhados neurofibrilares. A presença de placas senis está relacionada com o metabolismo anormal da proteína precursora de amiloide (APP) e os emaranhados neurofibrilares são formados a partir da hiperfosforilação da proteína tau. O resveratrol, um potente antioxidante pertencente à família dos estilbenos, parece atuar como fator protetor na neurodegeneração da DA. O presente estudo tem como objetivo realizar uma revisão da literatura sobre o efeito protetor do resveratrol na DA, uma vez que não existe um tratamento efetivo para esta doença, portanto se necessita de uma busca de substâncias que poderiam ser adjuvantes terapêuticos nesta patologia. Palavras-chave:Resveratrol; Doença de Alzheimer; Antioxidantes. Protective Effect Of Resveratrol In Alzheimer's Disease AbstractAlzheimer's Disease (AD) is a neurodegenerative and progressive disease characterized by behavioral and cognitive changes and presents as major neuropathological features the presence of senile plaques and neurofibrillary tangles. The presence of senile plaques is related to the abnormal metabolism of amyloid precursor protein (APP) and neurofibrillary tangles are formed from hyperphosphorylation of tau protein.Resveratrol, a potent antioxidant belonging to the family of stilbenes, seems to act as a protective factor in the neurodegeneration of AD. The present study aims to conduct a literature review on the protective effect of resveratrol in AD, since there is no effective treatment for this disease, so there is anecessity to search for substances that could be therapeutic adjuvants in this pathology. Keywords: Resveratrol; Alzheimer's disease; Antioxidants IntroduçãoA Doença de Alzheimer (DA) é reconhecida atualmente como uma das formas mais comuns de demência em todo o mundo. Nos países desenvolvidos aproximadamente uma em cada dez pessoas acima dos 65 anos sofre de uma forma de demência, números que aumentam para mais de um terço naqueles acima dos 85 anos (POVOVA et al., 2012). Embora as causas da DA ainda sejam debatidas, duas características patológicas são cruciais no diagnóstico da doença, são elas: a presença de placas senis e os emaranhados neurofibrilares, sendo que estes últimos são formados pela hiperfosforilação da proteína tau (CRESPO et al., 2014). Agentes infecciosos, metais como alumínio e zinco, espécies reativas de oxigênio e proteínas associados também apresentam relação com o surgimento da DA (BOLOGNIN et al., 2013;FROZZA et al., 2013). A procura de abordagens terapêuticas da doença focou-se em compostos que têm como alvo as vias das proteínas β-amiloide e da proteína tau, a neuroinflamação e o dano oxidativo (HONG-QI et al., 2012). Entretanto, até o momento só existem tratamentos paliativos para a doença, logo,a busca por novas terapias e adjuvantes terapêuticos tem sido alvo de diversas pesqu...

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Identification of brain‐targeted bioactive dietary quercetin‐3‐O‐glucuronide as a novel intervention for Alzheimer's disease

Cited by 188 publications

References 79 publications

Polyphenols Inhibit Hepatitis C Virus Entry by a New Mechanism of Action

Polyphenols Inhibit Hepatitis C Virus Entry by a New Mechanism of Action

The Presystemic Interplay between Gut Microbiota and Orally Administered Calycosin-7-O-β-d-Glucoside

Efeito Protetor Do Resveratrol Na Doença De Alzheimer

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