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Prion diseases currently have no effective therapy. These illnesses affect both animal and human populations, and are characterized by the conformational change of a normal self protein PrPC (C for cellular) to a pathological and infectious conformer, PrPSc (Sc for scrapie). We used a well characterized tissue culture model of prion infection, where mouse neuroblastoma cells (N2a) were infected with 22L PrPSc, to screen compounds for anti-prion activity. In a prior study we designed a library of styryl based, potential imaging compounds which were selected for high affinity binding to Alzheimer's disease &bgr;-amyloid plaques and good blood-brain barrier permeability. In the current study we screened this library for activity in the N2a/22L tissue culture system. We also tested the anti-prion activity of two clinically used drugs, trimipramine and fluphenazine, in the N2a/22L system. These were selected based on their structural similarity to quinacrine, which was previously reported to have anti-prion activity. All the compounds were also screened for toxicity in tissue culture and their ability to disaggregate amyloid fibrils composed of PrP and &bgr;-amyloid synthetic peptides in vitro. Two of the imaging agents, 23I and 59, were found to be both effective at inhibiting prion infection in N2a/22L tissue culture and to be non-toxic. These two compounds, as well as trimipramine and fluphenazine were evaluated in vivo using wild-type CD-1 mice infected peripherally with 139A PrPSc. All four agents significantly prolonged the asymptomatic incubation period of prion infection (p<0.0001 log-rank test), as well as significantly reducing the degree of spongiform change, astrocytosis and PrPSc levels in the brains of treated mice. These four compounds can be considered, with further development, as candidates for prion therapy. [ABSTRACT FROM AUTHOR]

Visualization of macrophages in live animals has been of great interest for a better understanding of inflammation. We developed a near infrared (NIR) probe CDnir7 that can selectively detect macrophages and visualize inflammation in vivo using the IVIS spectrum, Fluorescence Molecular Tomography (FMT) and Multi-Spectral Optoacoustic Tomography (MSOT). [ABSTRACT FROM AUTHOR]

Hypochlorous acid (HOCI), as a highly potent oxidant, is well-known as a key "killer" for pathogens in the innate immune system. Recently, mounting evidence indicates that intracellular HOCI plays additional important roles in regulating inflammation and cellular apoptosis. However, the organelle (s) involved in the distribution of HOCI remain unknown, causing difficulty to fully exploit its biological functions in cellular signaling pathways and various diseases. One of the main reasons lies in the lack of effective chemical tools to directly detect HOCI at subcellular levels due to low concentration, strong oxidization, and short lifetime of HOCI. Herein, the first two-photon fluorescent HOCI probe (TP-HOCl 1) and its mitochondria- (MITO-TP) and lysosome- (LYSO-TP) targetable derivatives for imaging mitochondrial and lysosomal HOCI were reported. These probes exhibit fast response (within seconds), good selectivity, and high sensitivity (<20 nM) toward HOCI. In live cell experiments, both probes MITO-TP and LYSO-TP were successfully applied to detect intracellular HOCI in corresponding organelles. In particular, the two-photon imaging of MITO-TP and LYSO-TP in murine model shows that higher amount of HOCI can be detected in both lysosome and mitochondria of macrophage cells during inflammation condition. Thus, these probes could not only help clarify the distribution of subcellular HOCI, but also serve as excellent tools to exploit and elucidate functions of HOCI at subcellular levels. [ABSTRACT FROM AUTHOR]