Antibody-Free Determinations of Low-Mass, Soluble Oligomers of Aß42 and Aß40 by Planar Bilayer Lipid Membrane-Based Electrochemical Biosensor.

Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly. Abnormal aggregates of both ß-amyloid peptide (Aß) subtypes, Aß42 and Aß40, are the typical neuropathology hallmarks of AD. However, because of the lack of specific recognition elements such as an antibody and aptamer, it is difficult to differentiate and determine the oligomers of Aß42 and Aß40 in clinic. In this paper, we developed a planar bilayer lipid membrane (BLM)-based electrochemical biosensor. According to the dynamic differences on oligomer-induced BLM damage, both low-mass, soluble oligomers of Aß42 and Aß40 (L-Aß42O and L-Aß40O) were measured in turn by electrochemical impedance spectroscopy. The BLM was supported by a porous 11-mercaptoundecanoic acid layer on a gold electrode, which amplified the impedance signal corresponding to the membrane damage and improved the detection sensitivity. The weakly charged surface of the BLM ensured the low non-specific adsorption of coexisting proteins in cerebrospinal fluid (CSF). Using the electrochemical biosensor, L-Aß42O was determined within 20 min, with a linear range from 5 to 500 pM and a detection limit of 3 pM. Meanwhile, L-Aß40O was determined within 60 min, with a linear range from 60 pM to 6.0 nM and a detection limit of 26 pM. The recoveries in oligomer-spiked artificial CSF and human CSF samples confirmed the accuracy and applicability of this proposed method in clinic. This work provides an antibody-free, highly selective, and sensitive method for simultaneous detections of L-Aß42O and L-Aß40O in real CSF samples, which is significant for the early diagnosis and prognosis of AD.

Paradoxical effects of DNA tumor virus oncogenes on epithelium-derived tumor cell fate during tumor progression and chemotherapy response.

Epstein-Barr virus (EBV) and human papillomavirus (HPV) infection is the risk factors for nasopharyngeal carcinoma and cervical carcinoma, respectively. However, clinical analyses demonstrate that EBV or HPV is associated with improved response of patients, although underlying mechanism remains unclear. Here, we reported that the oncoproteins of DNA viruses, such as LMP1 of EBV and E7 of HPV, inhibit PERK activity in cancer cells via the interaction of the viral oncoproteins with PERK through a conserved motif. Inhibition of PERK led to increased level of reactive oxygen species (ROS) that promoted tumor and enhanced the efficacy of chemotherapy in vivo. Consistently, disruption of viral oncoprotein-PERK interactions attenuated tumor growth and chemotherapy in both cancer cells and tumor-bearing mouse models. Our findings uncovered a paradoxical effect of DNA tumor virus oncoproteins on tumors and highlighted that targeting PERK might be an attractive strategy for the treatment of NPC and cervical carcinoma.

Norepinephrine-Fe(III)-ATP Ternary Complex and Its Relevance to Parkinson's Disease.

The aberrant autoxidation of norepinephrine (NE) in the presence of oxygen, which is accelerated by Fe(III), has been linked to the pathogenesis of the Parkinson's disease (PD). Adenosine triphosphate (ATP), as a neurotransmitter whose release can be stimulated by tissue damage and oxidative stress, is co-stored and often co-released with NE in presynaptic terminals. We have shown previously that ATP inhibits the iron-catalyzed dopamine oxidation, thereby decreasing the production of certain neurotoxins such as 6-hydroxydopamine. Whether ATP plays a similar role in Fe(III)-catalyzed NE oxidation and how it maintains the NE stability have not been investigated. Here, we studied the coordination in a ternary complex among NE, Fe(III), and ATP, and found that Fe(III) is coordinated as a octahedral center by NE and ATP. Voltammetry and mass spectrometry were employed to examine this ternary complex's modulation of the NE autoxidation. NE-Fe(III)-ATP plays a protective role to modulate the autoxidation and Fe(III)-catalyzed oxidation of NE. The ternary complex can be detected in the substantia nigra (SN), locus coeruleus (LC), and striatum regions of C57BL/6 wild-type mice. In contrast, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse brains displayed a significant decrease of the ternary complex in the SN region and an increase in the LC and striatum areas. We posit that the ternary complex is produced by noradrenergic neurons as a protective regulator against neuronal damage and oxidative stress, contributing to the lower vulnerability of LC neurons with respect to that of SN neurons.