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Semisynthetic quercetin-quinone mitigates BV-2 microglia activation through modulation of Nrf2 pathway.
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2020-03-04 , DOI: 10.1016/j.freeradbiomed.2020.02.030 Martin Škandík 1 , Nataša Mrvová 1 , Štefan Bezek 1 , Lucia Račková 1
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2020-03-04 , DOI: 10.1016/j.freeradbiomed.2020.02.030 Martin Škandík 1 , Nataša Mrvová 1 , Štefan Bezek 1 , Lucia Račková 1
Affiliation
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During brain ageing, microglia, the resident immune cells of the CNS, are immunologically activated and contribute to neuroinflammation, a vicious cycle that supports development of neurological disorders. Therapeutic approaches focus mainly on downregulation of their pro-inflammatory activated state that is associated with health benefits. Electrophilic compounds, such as natural quinones and their reduced pro-electrophilic precursors, flavonoids, represent a wide group of diverse substances with important biological effects. They can cause considerable cytotoxicity when used at higher dosages, but on the other hand, they have versatile health benefits at lower dosages. In this study, we investigated the cytotoxicity and prooxidant profile of synthetic conjugate of two electrophilic compounds, quercetin and 1,4-naphthoquinone, 4'-O-(2-chloro-1,4-naphthoquinone-3-yloxy) quercetin (CHNQ), and its attenuation of inflammatory responses and modulation of Nrf2 pathway in BV-2 microglial cells. CHNQ showed higher cytotoxicity than its precursors, accompanied by promotion of production of reactive oxygen species along with G2/M cell cycle arrest at higher concentrations tested. Nevertheless, at a lower non-toxic concentration, CHNQ, more significantly than did its precursors, downregulated LPS-stimulated microglia cells as documented by decreased iNOS, COX-2 and TNFα protein levels. Moreover, CHNQ most effectively upregulated expression of phase II antioxidant enzyme HO-1 and β5 subunit of constitutive proteasome. The enhanced anti-inflammatory effect of CHNQ was accompanied by prominent increase in cytosolic expression of Nrf2 and c-Jun, however, induction effect on nuclear Nrf2 translocation was comparable to QUER. Moreover, a conditioned medium from activated BV-2 cells co-treated with quercetin and CHNQ maintained viability of neuron-like PC12 cells. The compounds tested did not show any disturbance of phagocytosis of live or dead PC12 cells. The present experimental data predict a preventive and therapeutic potential of semisynthetic derivative CHNQ in ageing and related pathologies, mediated by activation of proteins of the antioxidant response.
中文翻译：
半合成槲皮素醌通过调节Nrf2途径减轻BV-2小胶质细胞的活化。
在脑衰老过程中，中枢神经系统的固有免疫细胞小胶质细胞被免疫激活并促进神经发炎，这是支持神经系统疾病发展的恶性循环。治疗方法主要集中在下调其促炎激活状态，这与健康有益。诸如天然醌之类的亲电化合物及其还原的亲电前体，类黄酮代表了具有重要生物学效应的多种多样的物质。当以较高剂量使用时，它们可引起相当大的细胞毒性，但另一方面，以较低剂量使用时，它们具有多种健康益处。在这项研究中，我们研究了两种亲电子化合物槲皮素和1,4-萘醌4'的合成共轭物的细胞毒性和促氧化剂谱 -O-（2-氯-1,4-萘醌-3-基氧基）槲皮素（CHNQ）及其在BV-2小胶质细胞中减轻炎症反应和调节Nrf2途径。CHNQ显示出比其前体更高的细胞毒性，并伴随着更高浓度的G2 / M细胞周期阻滞促进了活性氧的产生。尽管如此，在较低的无毒浓度下，CHNQ比其前体更显着，下调了LPS刺激的小胶质细胞，如iNOS，COX-2和TNFα蛋白水平的降低所证明。此外，CHNQ最有效地上调了组成型蛋白酶体的II期抗氧化酶HO-1和β5亚基的表达。CHNQ的增强抗炎作用伴随Nrf2和c-Jun的胞浆表达显着增加，但是，Nrf2核易位的诱导作用与QUER相当。此外，来自用槲皮素和CHNQ共同处理过的活化BV-2细胞的条件培养基保持了神经元样PC12细胞的活力。测试的化合物没有显示出活的或死的PC12细胞吞噬作用的任何干扰。目前的实验数据预测了半合成衍生物CHNQ在衰老和相关病理中的预防和治疗潜力，这是由抗氧化反应蛋白的激活介导的。
更新日期：2020-03-04
中文翻译：
半合成槲皮素醌通过调节Nrf2途径减轻BV-2小胶质细胞的活化。
在脑衰老过程中，中枢神经系统的固有免疫细胞小胶质细胞被免疫激活并促进神经发炎，这是支持神经系统疾病发展的恶性循环。治疗方法主要集中在下调其促炎激活状态，这与健康有益。诸如天然醌之类的亲电化合物及其还原的亲电前体，类黄酮代表了具有重要生物学效应的多种多样的物质。当以较高剂量使用时，它们可引起相当大的细胞毒性，但另一方面，以较低剂量使用时，它们具有多种健康益处。在这项研究中，我们研究了两种亲电子化合物槲皮素和1,4-萘醌4'的合成共轭物的细胞毒性和促氧化剂谱 -O-（2-氯-1,4-萘醌-3-基氧基）槲皮素（CHNQ）及其在BV-2小胶质细胞中减轻炎症反应和调节Nrf2途径。CHNQ显示出比其前体更高的细胞毒性，并伴随着更高浓度的G2 / M细胞周期阻滞促进了活性氧的产生。尽管如此，在较低的无毒浓度下，CHNQ比其前体更显着，下调了LPS刺激的小胶质细胞，如iNOS，COX-2和TNFα蛋白水平的降低所证明。此外，CHNQ最有效地上调了组成型蛋白酶体的II期抗氧化酶HO-1和β5亚基的表达。CHNQ的增强抗炎作用伴随Nrf2和c-Jun的胞浆表达显着增加，但是，Nrf2核易位的诱导作用与QUER相当。此外，来自用槲皮素和CHNQ共同处理过的活化BV-2细胞的条件培养基保持了神经元样PC12细胞的活力。测试的化合物没有显示出活的或死的PC12细胞吞噬作用的任何干扰。目前的实验数据预测了半合成衍生物CHNQ在衰老和相关病理中的预防和治疗潜力，这是由抗氧化反应蛋白的激活介导的。
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