Rodríguez de Fonseca Fernando, Medina-Paz Francisco, Sapozhnikov Mira, Hurtado-Guerrero Isaac, Rubio Leticia, Martín-de-Las-Heras Stella, Requena-Ocaña Nerea, Flores-López María, Fernández-Arjona María Del Mar, Rivera Patricia, Serrano Antonia, Serrano Pedro, C Zapico Sara, Suárez Juan
Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Málaga, Spain.
Servicio de Neurología, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain.
Toxics. 2024 Feb 29;12(3):190. doi: 10.3390/toxics12030190.
Alcohol use disorder (AUD) is a major component in the etiology of cognitive decline and dementia. Underlying mechanisms by which long-term alcohol abuse causes cognitive dysfunction include excessive oxidative stress and inflammation in the brain, activated by increased reactive oxygen/nitrogen species (ROS/RNS), advanced glycation end-products (AGEs) and high-mobility group box 1 protein (HMGB1). In a pilot study, we examine the potential clinical value of circulating biomarkers of oxidative stress including ROS/RNS, HMGB1, the soluble receptor for AGE (sRAGE), the brain biomarker of aging apolipoprotein D (ApoD), and the antioxidant regulator nuclear factor erythroid 2-related factor 2 (NRF2) as predictive indices for cognitive impairment (CI) in abstinent patients with AUD ( = 25) compared to patients with established Alzheimer's disease (AD, = 26) and control subjects ( = 25). Plasma concentrations of sRAGE were evaluated with immunoblotting; ROS/RNS with a fluorometric kit; and HMGB1, ApoD, and NRF2 by ELISA. Abstinent AUD patients had higher sRAGE, ROS/RNS ( < 0.05), and ApoD ( < 0.01) concentrations, similar to those of AD patients, and lower NRF2 ( < 0.01) concentrations, compared to controls. These changes were remarkable in AUD patients with CI. HMGB1, and sRAGE correlated positively with duration of alcohol use (rho = 0.398, = 0.022; rho = 0.404, = 0.018), whereas sRAGE correlated negatively with periods of alcohol abstinence (rho = -0.340, = 0.045). A predictive model including ROS/RNS, HMGB1, sRAGE, alcohol use duration, and alcohol abstinence periods was able to differentiate AUD patients with CI (92.3% of correct predictions, ROC-AUC= 0.90) from those without CI. In conclusion, we propose ROS/RNS, HMGB1, and sRAGE as stress biomarkers capable of predicting cognitive impairment in AUD patients.
酒精使用障碍（AUD）是认知能力下降和痴呆病因的一个主要组成部分。长期酗酒导致认知功能障碍的潜在机制包括大脑中过度的氧化应激和炎症，这是由活性氧/氮物种（ROS/RNS）、晚期糖基化终产物（AGEs）和高迁移率族蛋白B1（HMGB1）增加所激活的。在一项初步研究中，我们检测了氧化应激循环生物标志物的潜在临床价值，这些标志物包括ROS/RNS、HMGB1、AGE可溶性受体（sRAGE）、衰老脑生物标志物载脂蛋白D（ApoD）以及抗氧化调节因子核因子红细胞2相关因子2（NRF2），将其作为戒酒的AUD患者（n = 25）与已确诊的阿尔茨海默病（AD，n = 26）患者及对照受试者（n = 25）认知障碍（CI）的预测指标。通过免疫印迹法评估sRAGE的血浆浓度；使用荧光试剂盒检测ROS/RNS；通过酶联免疫吸附测定法检测HMGB1、ApoD和NRF2。与对照组相比，戒酒的AUD患者sRAGE、ROS/RNS（P < 0.05）和ApoD（P < 0.01）浓度较高，与AD患者相似，而NRF2浓度较低（P < 0.01）。这些变化在患有CI的AUD患者中尤为明显。HMGB1和sRAGE与饮酒持续时间呈正相关（rho = 0.398，P = 0.022；rho = 0.404，P = 0.018），而sRAGE与戒酒时间呈负相关（rho = -0.340，P = 0.045）。一个包含ROS/RNS、HMGB1、sRAGE、饮酒持续时间和戒酒时间的预测模型能够区分患有CI的AUD患者（正确预测率92.3%，ROC-AUC = 0.90）和未患CI的患者。总之，我们提出ROS/RNS、HMGB1和sRAGE作为能够预测AUD患者认知障碍的应激生物标志物。
