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1.
Biochim Biophys Acta Gen Subj ; 1862(10): 2226-2235, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30036601

RESUMO

Protein misfolding and aggregation are associated with amyloidosis. The toxic aggregation of amyloid-ß 1-42 (Aß42) may disrupt cell membranes and lead to cell death and is thus regarded as a contributing factor in Alzheimer's disease (AD). 1,4-naphthoquinone (NQ) has been shown to exhibit strong anti-aggregation effects on amyloidogenic proteins such as insulin and α-synuclein; however, its high toxicity and poor solubility limit its clinical application. Menadione sodium bisulfite (MSB, also known as vitamin K3), is used clinically in China to treat hemorrhagic diseases caused by vitamin K deficiency and globally as a vitamin K supplement. We hypothesized that MSB could inhibit amyloid formation since its backbone structure is similar to NQ. To test our hypothesis, we first investigated the effects of MSB on Aß42 amyloid formation in vitro. We found that MSB inhibited Aß42 amyloid formation in a dose dependent manner, delayed the secondary structural conversion of Aß42 from random coil to ordered ß-sheet, and attenuated the ability of Aß42 aggregates to disrupt membranes; moreover, the quinone backbone rather than lipophilicity is esstial for the inhibitory effects of MSB. Next, in cells expressing a pathogenic APP mutation (Osaka mutation) that results in the formation of intraneuronal Aß oligomers, MSB inhibited the intracellular aggregation of Aß. Moreover, MSB treatment significantly extended the life span of Caenorhabditis elegans CL2120, a strain that expresses human Aß42. Together, these results suggest that MSB and its derivatives may be further explored as potential therapeutic agents for the prevention or treatment of AD.


Assuntos
Peptídeos beta-Amiloides/química , Animais Geneticamente Modificados/crescimento & desenvolvimento , Caenorhabditis elegans/crescimento & desenvolvimento , Fragmentos de Peptídeos/química , Agregação Patológica de Proteínas/prevenção & controle , Vitamina K 3/farmacologia , Vitaminas/farmacologia , Peptídeos beta-Amiloides/efeitos dos fármacos , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Humanos , Longevidade , Fragmentos de Peptídeos/efeitos dos fármacos
2.
Food Funct ; 7(1): 409-16, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26456030

RESUMO

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Lewy bodies that are formed by the aggregated α-synuclein are a major pathological feature of PD. Salvia miltiorrhiza has been used as food and as a traditional medicine for centuries in China, with tanshinone I (TAN I) and tanshinone IIA (TAN IIA) as its major bioactive ingredients. Here, we investigated the effects of TAN I and TAN IIA on α-synuclein aggregation both in vitro and in a transgenic Caenorhabditis elegans PD model (NL5901). We demonstrated that TAN I and TAN IIA inhibited the aggregation of α-synuclein as demonstrated by the prolonged lag time and the reduced thioflavin-T fluorescence intensity; TAN I and TAN IIA also disaggregated preformed mature fibrils in vitro. Moreover, the presence of TAN I or TAN IIA affected the secondary structural transformation of α-synuclein from unstructured coils to ß-sheets, and alleviated the membrane disruption caused by aggregated α-synuclein in vitro. Besides, the immuno-dot-blot assay indicated that TAN I and TAN IIA reduce the formation of oligomers and fibrils. We further found that TAN I and TAN IIA extended the life span of NL5901, a strain of transgenic C. elegans that expresses human α-synuclein, possibly by attenuating the aggregation of α-synuclein. Taken together, our results suggested that TAN I and TAN IIA may be explored further as potential candidates for the prevention and treatment of PD.


Assuntos
Abietanos/farmacologia , alfa-Sinucleína/química , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/efeitos dos fármacos , Curcumina , Escherichia coli/genética , Escherichia coli/metabolismo , Humanos , Estrutura Molecular , Doença de Parkinson , Dobramento de Proteína , alfa-Sinucleína/metabolismo
3.
Fitoterapia ; 88: 82-90, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23669033

RESUMO

Three new alkaloids (1-3) and one new phenolic glycoside (4), together with twenty five known alkaloids (5-29), were isolated from the bulbs of Lycoris radiata collected from Huaihua county of Hunan province, China. Their structures were elucidated on the basis of comprehensive NMR and MS spectroscopic analysis. The isolated alkaloids were evaluated for their neuroprotective activities against CoCl2, H2O2 and Aß(25-35)-induced SH-SY5Y cell injuries. Compounds 1-3 showed significant neuroprotective effects against H2O2 or CoCl2-induced SH-SY5Y cell death, while compound 3 exhibited significant neuroprotective effects against Aß(25-35)-induced SH-SY5Y cell injury. The known alkaloids 5-29 also exhibited similar bioactivities of different degrees. These findings highlight the fact that the over 100 Amaryllidaceae alkaloids may have a big potential to neuroprotective activity.


Assuntos
Alcaloides Indólicos/farmacologia , Lycoris/química , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/isolamento & purificação , Alcaloides de Amaryllidaceae/farmacologia , Peptídeos beta-Amiloides , Morte Celular , China , Cobalto , Humanos , Peróxido de Hidrogênio , Alcaloides Indólicos/química , Alcaloides Indólicos/isolamento & purificação , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Extratos Vegetais/química , Raízes de Plantas/química
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