Amyloid-ß Oligomer-Induced Electrophysiological Mechanisms and Electrical Impedance Changes in Neurons.

Amyloid plays a critical role in the pathogenesis of Alzheimer's disease (AD) and can aggregate to form oligomers and fibrils in the brain. There is increasing evidence that highly toxic amyloid-ß oligomers (AßOs) lead to tau protein aggregation, hyperphosphorylation, neuroinflammation, neuronal loss, synaptic loss, and dysfunction. Although the effects of AßOs on neurons have been investigated using conventional biochemical experiments, there are no established criteria for electrical evaluation. To this end, we explored electrophysiological changes in mouse hippocampal neurons (HT22) following exposure to AßOs and/or naringenin (Nar, a flavonoid compound) using electrical impedance spectroscopy (EIS). AßO-induced HT22 showed a decreased impedance amplitude and increased phase angle, and the addition of Nar reversed these changes. The characteristic frequency was markedly increased with AßO exposure, which was also reversed by Nar. The AßOs decreased intranuclear and cytoplasmic resistance and increased nucleus resistance and extracellular capacitance. Overall, the innovative construction of the eight-element CPE-equivalent circuit model further reflects that the pseudo-capacitance of the cell membrane and cell nucleus was increased in the AßO-induced group. This study conclusively revealed that AßOs induce cytotoxic effects by disrupting the resistance characteristics of unit membranes. The results further support that EIS is an effective technique for evaluating AßO-induced neuronal damage and microscopic electrical distinctions in the sub-microscopic structure of reactive cells.

The natural flavone acacetin protects against high-fat diet-induced lipid accumulation in the liver via the endoplasmic reticulum stress/ferroptosis pathway.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. To date, no medication has been approved to treat NAFLD. In this study, we evaluated the therapeutic effect of the natural flavone acacetin on high-fat diet (HFD)-induced NAFLD in mice and the underlying mechanisms. We found that acacetin (10, 20, 50 mg/kg/day) suppressed the increase in body weight, serum total cholesterol, triglycerides, low-density lipoprotein, aspartate aminotransferase, and alanine aminotransferase levels in mice fed with HFD with a dose-dependent manner. Hepatic lipid accumulation, iron overload, and lipid peroxidation were significantly alleviated by acacetin. Quantitative PCR and western blotting revealed that acacetin inhibited endoplasmic reticulum (ER) stress, ferroptosis, and expressions of lipid acid synthesis-related genes in the livers of HFD mice. Similar results were observed in HepG2 cells treated with oleic acid and lipopolysaccharide. The suppressive effects of acacetin on triglycerides and expression of lipid acid synthesis genes were abolished by ER stress and the ferroptosis activators, erastin or TU. Interestingly, the action of TU was more potent than that of erastin. Treatment with the ER stress inhibitor GSK and the ferroptosis inhibitor Fer-1 revealed that ER stress was the upstream signal of ferroptosis for hepatic lipid accumulation. These findings suggest the protective effect of acacetin against lipid accumulation via suppressing ER stress and ferroptosis and provide evidence that ER stress is an upstream signal of ferroptosis in lipid accumulation. Acacetin may be a promising candidate agent for NAFLD treatment.