Department of Pharmacology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
Molecules. 2019 Jun 16;24(12):2249. doi: 10.3390/molecules24122249.
Methylglyoxal (MG) acts as a reactive precursor of advanced glycation end products (AGEs). This compound is often connected with pathologies such as diabetes, neurodegenerative processes and diseases of aging. 2-iodo-4'-methoxychalcone (CHA79), a synthetic halogen-containing chalcone derivative, has been reported its anti-diabetic activity. This study aims to investigate the potential protective capability of CHA79 against MG-mediated neurotoxicity in SH-SY5Y cells. Results indicated CHA79 increased viability of cells and attenuated the rate of apoptosis in MG-exposed SH-SY5Y. CHA79 up-regulated expression of anti-apoptotic protein (Bcl-2) and down-regulated apoptotic proteins (Bax, cytochrome , caspase-3, caspase-9). Moreover, CHA79 significantly up-regulated expression of neurotrophic factors, including glucagon-like peptide-1 receptor (GLP-1R), brain derived neurotrophic factor (BDNF), p75NTR, p-TrkB, p-Akt, p-GK-3β and p-CREB. CHA79 attenuated MG-induced ROS production and enhanced the antioxidant defense including nuclear factor erythroid 2-related factor 2 (Nrf2), HO-1, SOD and GSH. Furthermore, CHA79 attenuated MG-induced reduction of glyoxalase-1 (GLO-1), a vital enzyme on removing AGE precursors. In conclusion, CHA79 is the first novel synthetic chalcone possessing the GLP-1R and GLO-1 activating properties. CHA 79 also exhibits neuroprotective effects against MG toxicity by enhancing neurotrophic signal, antioxidant defense and anti-apoptosis pathway.
甲基乙二醛（MG）作为糖基化终产物（AGEs）的反应前体而起作用。这种化合物通常与糖尿病、神经退行性过程和衰老疾病等病理学有关。2-碘-4'-甲氧基查耳酮（CHA79）是一种合成含卤素的查耳酮衍生物，已报道其具有抗糖尿病活性。本研究旨在探讨 CHA79 对 SH-SY5Y 细胞中 MG 介导的神经毒性的潜在保护能力。结果表明，CHA79 增加了细胞活力，并减轻了 MG 暴露的 SH-SY5Y 细胞的凋亡率。CHA79 上调了抗凋亡蛋白（Bcl-2）的表达，并下调了凋亡蛋白（Bax、细胞色素 C、caspase-3、caspase-9）的表达。此外，CHA79 还显著上调了神经生长因子的表达，包括胰高血糖素样肽-1 受体（GLP-1R）、脑源性神经营养因子（BDNF）、p75NTR、p-TrkB、p-Akt、p-GK-3β 和 p-CREB。CHA79 减弱了 MG 诱导的 ROS 产生，并增强了抗氧化防御，包括核因子红细胞 2 相关因子 2（Nrf2）、HO-1、SOD 和 GSH。此外，CHA79 减弱了 MG 诱导的糖氧酶-1（GLO-1）减少，GLO-1 是去除 AGE 前体的重要酶。总之，CHA79 是第一个具有 GLP-1R 和 GLO-1 激活特性的新型合成查尔酮。CHA79 还通过增强神经营养信号、抗氧化防御和抗细胞凋亡途径对 MG 毒性具有神经保护作用。
