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Gamma-hexalactone flavoring causes DNA lesion and modulates cytokines secretion at non-cytotoxic concentrations.
BMC Pharmacology and Toxicology ( IF 2.8 ) Pub Date : 2019-12-19 , DOI: 10.1186/s40360-019-0359-x
Luísa Zuravski 1 , Taiane A Escobar 1 , Elizandra G Schmitt 2 , Queila D F Amaral 3 , Fávero R Paula 2, 3 , Thiago Duarte 4 , Marta M M F Duarte 5 , Michel M Machado 2, 3 , Luís F S Oliveira 2, 3 , Vanusa Manfredini 1, 2
Affiliation  

BACKGROUND The γ-hexalactone is a flavoring agent for alcoholic beverages, teas, breads, dairy products, coffees, buttery products among others. It presents low molecular weight and exhibits sweet fruity aroma with nuances of nuts. As far as we know, both literature and government regulations have gaps regarding the safe use of the γ-hexalactone. In this context, the main objective of this work was to evaluate the effects of γ-hexalactone through in silico and in vitro approaches. METHODS The in silico analysis was performed through four free online platforms (admetSAR, Osiris Property Explorer®, pkCSM platform and PreADMET) and consisted of comparative structural analysis with substances present in databases. The computational prediction was performed in the sense of complement and guide the in vitro tests. Regarding in vitro investigations, screening of cytotoxicity (assessed by cell proliferation and viability parameters) in lymphocytes exposed to γ-hexalactone for 72 h were carried out previously to determine non-cytotoxic concentrations. Following this screening, concentrations of 5.15, 0.515, and 0.0515 μM were selected for the study of the respective potentials: genotoxic (assessed by DNA comet assay), chromosomal mutation (analysis of micronucleus frequency) and immunomodulatory (cytokine quantification using ELISA immunoassay). The results of in vitro assays were compared by one-way analysis of variance (ANOVA), followed by Bonferroni's post hoc test, conducted by statistic software. RESULTS The platform PreADMET pointed out that γ-hexalactone is potentially mutagenic and carcinogenic. The comet assay data corroborate with these results demonstrating that γ-hexalactone at 5.15 μM caused lymphocytes DNA damage. In relation to cytokine secretion, the results indicate that lymphocytes were activated by γ-hexalactone at non-cytotoxic concentrations, involving an increase in the IL-1 levels in all tested concentrations, ranging from approximately 56 to 93%. The γ-hexalactone only at 5.15 μM induced increase in the levels of IL-6 (~ 60%), TNF-α (~ 68%) and IFN-γ (~ 29%), but decreased IL-10 (~ 46%) in comparison with the negative control (p < 0.05). No change was observed in total lymphocytes or in cell viability at the concentrations tested. CONCLUSIONS In summary, the γ-hexalactone demonstrated immunomodulatory and genotoxic effects at non-cytotoxic concentrations in healthy lymphocytes.

中文翻译:

γ-己内酯调味剂会引起DNA损伤,并在非细胞毒性浓度下调节细胞因子的分泌。

背景技术γ-六内酯是用于酒精饮料,茶,面包,乳制品,咖啡,黄油产品等的调味剂。它具有较低的分子量,并显示出甜美的水果香气和坚果的细微差别。据我们所知,文献和政府法规在安全使用γ-六内酯方面均存在差距。在这种情况下,这项工作的主要目的是通过计算机和体外方法评估γ-己内酯的作用。方法计算机分析是通过四个免费的在线平台(admetSAR,Osiris PropertyExplorer®,pkCSM平台和PreADMET)进行的,包括数据库中存在的物质的比较结构分析。从互补的意义上进行计算预测,并指导体外测试。关于体外调查,以前对暴露于γ-己内酯72小时的淋巴细胞进行了细胞毒性(通过细胞增殖和活力参数评估)的筛选,以确定非细胞毒性浓度。筛选后,选择5.15、0.515和0.0515μM的浓度用于研究各自的潜力:遗传毒性(通过DNA彗星分析评估),染色体突变(微核频率分析)和免疫调节(使用ELISA免疫分析的细胞因子定量)。通过单向方差分析(ANOVA),然后通过统计软件进行Bonferroni的事后检验,比较了体外测定的结果。结果PreADMET平台指出,γ-己内酯具有潜在的致突变性和致癌性。彗星试验数据证实了这些结果,表明5.15μM的γ-己内酯引起淋巴细胞DNA损伤。关于细胞因子的分泌,结果表明,淋巴细胞在非细胞毒性浓度下被γ-己内酯激活,在所有测试浓度下,IL-1含量均增加,范围约为56%至93%。仅在5.15μM时的γ-六内酯会导致IL-6(〜60%),TNF-α(〜68%)和IFN-γ(〜29%)的水平增加,但IL-10(〜46%)降低)与阴性对照相比(p <0.05)。在所测试的浓度下,未观察到总淋巴细胞或细胞活力的变化。结论总之,在健康淋巴细胞中,γ-六内酯在非细胞毒性浓度下具有免疫调节和遗传毒性作用。关于细胞因子的分泌,结果表明,淋巴细胞在非细胞毒性浓度下被γ-己内酯激活,在所有测试浓度下,IL-1含量均增加,范围约为56%至93%。仅在5.15μM时的γ-六内酯会导致IL-6(〜60%),TNF-α(〜68%)和IFN-γ(〜29%)的水平增加,但IL-10(〜46%)降低)与阴性对照相比(p <0.05)。在所测试的浓度下,未观察到总淋巴细胞或细胞活力的变化。结论总之,在健康淋巴细胞中,γ-六内酯在非细胞毒性浓度下具有免疫调节和遗传毒性作用。关于细胞因子的分泌,结果表明,淋巴细胞在非细胞毒性浓度下被γ-己内酯激活,在所有测试浓度下,IL-1含量均增加,范围约为56%至93%。仅在5.15μM时的γ-六内酯会导致IL-6(〜60%),TNF-α(〜68%)和IFN-γ(〜29%)的水平增加,但IL-10(〜46%)降低)与阴性对照相比(p <0.05)。在所测试的浓度下,未观察到总淋巴细胞或细胞活力的变化。结论总之,在健康淋巴细胞中,γ-六内酯在非细胞毒性浓度下具有免疫调节和遗传毒性作用。包括所有测试浓度的IL-1水平升高,范围从约56%到93%。仅在5.15μM时的γ-六内酯会导致IL-6(〜60%),TNF-α(〜68%)和IFN-γ(〜29%)的水平增加,但IL-10(〜46%)降低)与阴性对照相比(p <0.05)。在所测试的浓度下,未观察到总淋巴细胞或细胞活力的变化。结论总之,在健康淋巴细胞中,γ-六内酯在非细胞毒性浓度下具有免疫调节和遗传毒性作用。包括所有测试浓度的IL-1水平升高,范围从约56%到93%。仅在5.15μM时的γ-六内酯会导致IL-6(〜60%),TNF-α(〜68%)和IFN-γ(〜29%)的水平增加,但IL-10(〜46%)降低)与阴性对照相比(p <0.05)。在所测试的浓度下,未观察到总淋巴细胞或细胞活力的变化。结论总之,在健康淋巴细胞中,γ-六内酯在非细胞毒性浓度下具有免疫调节和遗传毒性作用。在所测试的浓度下,未观察到总淋巴细胞或细胞活力的变化。结论总之,在健康淋巴细胞中,γ-六内酯在非细胞毒性浓度下具有免疫调节和遗传毒性作用。在所测试的浓度下,未观察到总淋巴细胞或细胞活力的变化。结论总之,在健康淋巴细胞中,γ-六内酯在非细胞毒性浓度下具有免疫调节和遗传毒性作用。
更新日期:2020-04-22
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