Laboratory of Biochemistry, Department of Chemistry, "AHEPA" General Hospital Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
1(st) Department of Neurology, "AHEPA" General Hospital Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; Greek Association of Alzheimer's Disease and Related Disorders-GAADRD, Greece; Center for Interdisciplinary Research and Innovation, Laboratory of Neurodegenerative Diseases (LND), 57001, Thermi, Thessaloniki, Greece.
Exp Gerontol. 2021 Dec;156:111621. doi: 10.1016/j.exger.2021.111621. Epub 2021 Nov 5.
Oxidative/nitrative stress that results from the unbalance of the overproduction/clearance of reactive oxygen/nitrogen species (ROS/NOS), originated from a variety of endo- and/or exo-genous sources, can have detrimental effects on DNA and is involved in Alzheimer's disease (AD) pathology. An excellent marker of oxidative DNA lesions is 8-hydroxy-2'-deoxyguanosine (8-OHdG) while of nitrative stress the enzyme NOS2 (Nitric oxide synthase 2). Under massive oxidative stress, poly(ADP-ribose)polymerase 1 (PARP-1) enzyme activity, responsible for restoration of DNA damage, is augmented, DNA repair enzymes are recruited, and cell survival/or death is ensued through PARP-1 activation, which is correlated positively with neurodegenerative diseases. In this biochemical study the levels of PARP-1, 8-oxo-dG, and NOS2, Aβ1-42, and p-tau in their sera determined using Enzyme-Linked Immunosorbent Assay (ELISA). Patients diagnosed with Mild Cognitive Impairment participated in MICOIL clinical trial, were daily administered with 50 ml Extra Virgin Olive Oil (EVOO) for one year. All MCI patients' biomarkers that had consumed EVOO were tantamount to those of healthy participants, contrary to MCI patients who were not administered. EVOO administration in MCI patients resulted in the restoration of DNA damage and of the well-established "hallmarks" AD biomarkers, thanks probably to its antioxidant properties exhibiting a therapeutic potentiality against AD. Molecular docking simulations of the EVOO constituents on the crystal structure of PARP-1 and NOS-2 target enzymes were also employed, to study in silico the ability of the compounds to bind to these enzymes and explain the observed in vitro activity. In silico analysis has proved the binding of EVOO constituents on PARP-1and NOS-2 enzymes and their interaction with crucial amino acids of the active sites. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03362996. MICOIL GOV IDENTIFIER: NCT03362996.
氧化/硝化应激是由于活性氧/氮物种（ROS/NOS）的产生/清除失衡引起的，这种失衡源自各种内源性和/或外源性来源，会对 DNA 产生有害影响，并与阿尔茨海默病（AD）的病理有关。氧化 DNA 损伤的一个极好标志物是 8-羟基-2'-脱氧鸟苷（8-OHdG），而硝化应激的标志物是酶 NOS2（一氧化氮合酶 2）。在大量氧化应激下，负责修复 DNA 损伤的聚（ADP-核糖）聚合酶 1（PARP-1）酶活性增加，DNA 修复酶被招募，细胞通过 PARP-1 激活而存活/死亡，PARP-1 激活与神经退行性疾病呈正相关。在这项生化研究中，使用酶联免疫吸附试验（ELISA）测定了血清中 PARP-1、8-氧代-dG 和 NOS2、Aβ1-42 和 p-tau 的水平。参与 MICOIL 临床试验的轻度认知障碍患者每天接受 50 毫升特级初榨橄榄油（EVOO）治疗一年。与未接受 EVOO 治疗的 MCI 患者相比，所有接受 EVOO 治疗的 MCI 患者的生物标志物都等同于健康参与者的生物标志物。EVOO 治疗 MCI 患者可修复 DNA 损伤和已确立的 AD 生物标志物，这可能归功于其抗氧化特性，显示出对 AD 的治疗潜力。还进行了 EVOO 成分对 PARP-1 和 NOS-2 靶酶晶体结构的分子对接模拟，以研究化合物与这些酶结合的能力并解释体外观察到的活性。计算机分析证明了 EVOO 成分与 PARP-1 和 NOS-2 酶的结合及其与活性位点关键氨基酸的相互作用。临床试验注册：https://clinicaltrials.gov/ct2/show/NCT03362996。MICOIL 政府标识符：NCT03362996。
