Angeloni Cristina, Malaguti Marco, Rizzo Benedetta, Barbalace Maria Cristina, Fabbri Daniele, Hrelia Silvana
Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Bologna, Italy.
Chem Res Toxicol. 2015 Jun 15;28(6):1234-45. doi: 10.1021/acs.chemrestox.5b00067. Epub 2015 May 11.
Glycation, an endogenous process that leads to the production of advanced glycation end products (AGEs), plays a role in the etiopathogenesis of different neurodegenerative diseases, such as Alzheimer's disease (AD). Methylglyoxal is the most potent precursor of AGEs, and high levels of methylglyoxal have been found in the cerebrospinal fluid of AD patients. Methylglyoxal may contribute to AD both inducing extensive protein cross-linking and mediating oxidative stress. The aim of this study was to investigate the role of sulforaphane, an isothiocyanate found in cruciferous vegetables, in counteracting methylglyoxal-induced damage in SH-SY5Y neuroblastoma cells. The data demonstrated that sulforaphane protects cells against glycative damage by inhibiting activation of the caspase-3 enzyme, reducing the phosphorylation of MAPK signaling pathways (ERK1/2, JNK, and p38), reducing oxidative stress, and increasing intracellular glutathione levels. For the first time, we demonstrate that sulforaphane enhances the methylglyoxal detoxifying system, increasing the expression and activity of glyoxalase 1. Sulforaphane modulated brain-derived neurotrophic factor and its pathway, whose dysregulation is related to AD development. Moreover, sulforaphane was able to revert the reduction of glucose uptake caused by methylglyoxal. In conclusion, sulforaphane demonstrates pleiotropic behavior thanks to its ability to act on different cellular targets, suggesting a potential role in preventing/counteracting multifactorial neurodegenerative diseases such as Alzheimer's.
糖基化是一种导致晚期糖基化终产物（AGEs）产生的内源性过程，在不同神经退行性疾病（如阿尔茨海默病（AD））的发病机制中起作用。甲基乙二醛是AGEs最有效的前体，在AD患者的脑脊液中发现了高水平的甲基乙二醛。甲基乙二醛可能通过诱导广泛的蛋白质交联和介导氧化应激而导致AD。本研究的目的是探讨十字花科蔬菜中发现的异硫氰酸盐萝卜硫素在对抗甲基乙二醛诱导的SH-SY5Y神经母细胞瘤细胞损伤中的作用。数据表明，萝卜硫素通过抑制半胱天冬酶-3酶的激活、减少MAPK信号通路（ERK1/2、JNK和p38）的磷酸化、减轻氧化应激以及提高细胞内谷胱甘肽水平来保护细胞免受糖基化损伤。我们首次证明，萝卜硫素增强了甲基乙二醛解毒系统，增加了乙二醛酶1的表达和活性。萝卜硫素调节了脑源性神经营养因子及其信号通路，其失调与AD的发展有关。此外，萝卜硫素能够逆转甲基乙二醛引起的葡萄糖摄取减少。总之，萝卜硫素由于其作用于不同细胞靶点的能力而表现出多效性，提示其在预防/对抗多因素神经退行性疾病如阿尔茨海默病方面具有潜在作用。
