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Effects of several quinones on insulin aggregation.

ABSTRACT: Protein misfolding and aggregation are associated with more than twenty diseases, such as neurodegenerative diseases and metabolic diseases. The amyloid oligomers and fibrils may induce cell membrane disruption and lead to cell apoptosis. A great number of studies have focused on discovery of amyloid inhibitors which may prevent or treat amyloidosis diseases. Polyphenols have been extensively studied as a class of amyloid inhibitors, with several polyphenols under clinical trials as anti-neurodegenerative drugs. As oxidative intermediates of natural polyphenols, quinones widely exist in medicinal plants or food. In this study, we used insulin as an amyloid model to test the anti-amyloid effects of four simple quinones and four natural anthraquinone derivatives from rhubarb, a traditional herbal medicine used for treating Alzheimer's disease. Our results demonstrated that all eight quinones show inhibitory effects to different extent on insulin oligomerization, especially for 1,4-benzoquinone and 1,4-naphthoquinone. Significantly attenuated oligomerization, reduced amount of amyloid fibrils and reduced hemolysis levels were found after quinones treatments, indicating quinones may inhibit insulin from forming toxic oligomeric species. The results suggest a potential action of native anthraquinone derivatives in preventing protein misfolding diseases, the quinone skeleton may thus be further explored for designing effective anti-amyloidosis compounds.

SUBMITTER: Gong H

PROVIDER: S-EPMC4090620 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Effects of several quinones on insulin aggregation.

Gong Hao H He Zihao Z Peng Anlin A Zhang Xin X Cheng Biao B Sun Yue Y Zheng Ling L Huang Kun K

Scientific reports 20140710

Protein misfolding and aggregation are associated with more than twenty diseases, such as neurodegenerative diseases and metabolic diseases. The amyloid oligomers and fibrils may induce cell membrane disruption and lead to cell apoptosis. A great number of studies have focused on discovery of amyloid inhibitors which may prevent or treat amyloidosis diseases. Polyphenols have been extensively studied as a class of amyloid inhibitors, with several polyphenols under clinical trials as anti-neurode ...[more]

PMID: 25008537

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Project description:Substances containing a phenolic moiety are often metabolized to quinones whose high reactivity makes them difficult to study. Some of these precursors have clear health benefits, and some quinones themselves are used in cancer therapy, whereas others are deleterious. For example, dietary intake of phytoestrogen, genistein (Gen), seems to play a preventive role in breast cancer (BC) whereas prolonged exposure to chemically similar mammalian estrogens is clearly associated with elevated incidence of BC. Although both can be metabolized to reactive quinones, the catechol estrogen quinones (CEQs) modify DNA by redox cycling and/or depurination via a Michael addition. Here, we report an investigation of the chemical reactivity of Gen and estrone quinones to determine the chemical differences of these two biologically important molecules. The catechol genistein quinone (CGenQ), has a half-life of 4 +/- 1 s under physiological condition, as determined by glutathione trapping. It disappears by reacting with H2O to give a dihydrate, CGenQ x (H2O)2, whose structure was proved by NMR. Under reductive conditions, CGenQ x (H2O)2 is readily reduced to reform the catechol genistein (CGen). This reversible oxidation of CGen to CGenQ and the prompt moderation of its reactivity by hydration to CGenQ x (H2O)2 effectively hinders any redox cycling or depurination reaction of CGenQ with DNA. Catechol estrogen quinones, on the other hand, are sufficiently long-lived that they can damage DNA via a Michael addition or by redox cycling. Although the reactivity of CEQ in a nonaqueous solvent is similar to that of CGenQ, its reactivity in aqueous media with the free Ade base is more than 600 times that of CGenQ. These results suggest that rapid hydration of a quinone can moderate its reactivity toward biomolecules, allowing them to express, for example, estrogen-like properties without exhibiting the deleterious properties of redox cycling or directly damaging DNA via depurination reactions.

Project description:BackgroundThe prevalence, pathology, and existence of malnutrition-associated diabetes remain uncertain, especially with respect to adult-acquired undernutrition.ObjectiveThe aim was to investigate the association of prior undernutrition (low BMI, in kg/m2), acquired in adulthood and insulin during an oral glucose tolerance test (OGTT).MethodsWe followed up 630 adults recruited 7-14 y previously for other studies. Plasma insulin was measured fasting and at 30 and 120 min during an OGTT. The main exposure was BMI measured 7-14 y prior. The main outcome of interest was plasma insulin, controlling for time during the OGTT using generalized estimating equations, and exploratory outcomes were early insulin response (relative change in insulin and glucose from 0-30 min) and relative insulin and glucose AUCs from 0 to 120 min. Current confounding factors were age, sex, BMI, HIV, socioeconomic status, and physical activity.ResultsIn unadjusted analyses, increasing severity of prior malnutrition was associated with lower insulin concentration. In multivariate adjusted analyses, only current BMI was a strong predictor of overall insulin concentration. Associations with prior BMI of insulin responses accounting for glucose were also seen in unadjusted but not adjusted analyses. For insulin concentration but not the outcomes accounting for glucose, there was a sex interaction with prior BMI such that only men had lower insulin if previously malnourished: insulin (pmol/L) at 120 min was 311 (95% CI: 272, 351) for prior BMI ≥18.5, 271 (95% CI: 221, 321) for prior BMI 17.0-18.5, and 237 (95% CI: 194, 297) for prior BMI <17.0; P = 0.03. HIV status showed limited and variable associations with insulin.ConclusionsInsulin concentration, fasting and during an OGTT, was normalized in women more than in men several years after adult malnutrition. Chronic malnutrition, as indicated by low prior and current BMI, may contribute to diabetes through low insulin secretion.

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Effects of several quinones on insulin aggregation.

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Effects of several quinones on insulin aggregation.

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