Studying numerous biologically important species simultaneously is crucial to understanding cellular functions and the root causes of related diseases.D irect visualization of endogenous biothiols in biological systems is of great value to understanding their biological roles.H erein, an ovel multisignal fluorescent probe was rationally designed and exploited for the simultaneous sensing of homocysteine (Hcy), cysteine (Cys), and glutathione (GSH) using different emission channels.T his probe was successfully applied to the simultaneous discrimination between and visualization of endogenous Hcy, Cys,GSH, and their transformation in living cells.

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are chronic neurodegenerative diseases with high morbidity and mortality. Homocysteine (Hcy), cysteine (Cys), and glutathione (GSH) are closely related to AD and PD. However, the dynamics of Hcy, Cys, and GSH in the brain tissues and the potential pathogenesis between Cys/Hcy/GSH with AD and PD remain unclear. Herein, a novel fluorescent probe 1 with multiple binding sites was rationally designed and exploited for the direct quantification of serum total Hcy and Cys along with superior optical properties. Importantly, differentiation and simultaneity fluorescence imaging of Cys, Hcy, and GSH dynamics were achieved in living cells, tissues, and mouse models of AD and PD with this probe, providing direct evidences for the relationship between Hcy/Cys/GSH and AD/PD for the first time. In addition, pathogenesis studies demonstrated that elevated Hcy and Cys levels are closely related to imbalanced redox homeostasis, increased amyloid aggregates, and nerve cell cytotoxicity. These findings will greatly promote the understanding of the functions of Hcy/Cys/GSH in Alzheimer’s and Parkinson’s diseases, demonstrating clinical promise for the early diagnosis and prevention of AD and PD.

An ovel fluorescent probe was developed by integrating chlorinated coumarin and benzothiazolylacetonitrile and exploited for simultaneous detection of cysteine (Cys), homocysteine (Hcy), and glutathione (GSH). Featuring four binding sites and different reaction mechanisms for different biothiols,t his probe exhibited rapid fluorescence turn-on for distinguishing Cys,H cy,a nd GSH with 108-, 128-, 30-fold fluorescence increases at 457, 559, 529 nm, respectively,across different excitation wavelengths.F urthermore,t he probe was successfully applied to the fluorescence imaging of endogenous Cys and GSH and exogenous Cys,H cy,a nd GSH in living cells.

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