Highlighting Cancer Cells with Halochromic Switches.

Halochromic coumarin-oxazine prefluorophores and targeting folate ligands can be connected covalently to the side chains of amphiphilic polymers. The resulting macromolecular constructs assemble into nanoparticles in aqueous environments. The prefluorophores do not produce any detectable fluorescence at neutral pH, but are converted into fluorophores with intense visible emission at acidic pH.

Bioimaging with Macromolecular Probes Incorporating Multiple BODIPY Fluorophores.

Seven macromolecular constructs incorporating multiple borondipyrromethene (BODIPY) fluorophores along a common poly(methacrylate) backbone with decyl and oligo(ethylene glycol) side chains were synthesized. The hydrophilic oligo(ethylene glycol) components impose solubility in aqueous environment on the overall assembly. The hydrophobic decyl chains effectively insulate the fluorophores from each other to prevent detrimental interchromophoric interactions and preserve their photophysical properties.

Fluorescent Kinase Probes Enabling Identification and Dynamic Imaging of HER2(+) Cells.

The human epidermal growth factor receptor, EGFR/ERBB/HER, family of receptor tyrosine kinases is central to many signaling pathways and a validated chemotherapy target in multiple cancers. While EGFR/ERBB-targeted therapies, including monoclonal antibodies, e.g.

One probe, two-channel imaging of nuclear and cytosolic compartments with orange and red emissive dyes.

Several new DNA-targeting probes that exhibit binding-induced 'turn on' fluorescence are presented. Two of the dyes, orange emissive 1, (E)-4-(4(-4-methylpiperazin-1-yl)phenyl)6-(4-(4-methylpi-perazin-1-yl)styryl)pyrimidin-2-ol), and red emissive 2, (E)-4-(4(-4-methyl-piperazin-1-yl)-phenyl)6-(4-(4-methylpiperazin-1-yl)styryl)-1,3-propanedionato-κO,κO']difluoroborane), are brightly fluorescent when bound to DNA, but are virtually non-fluorescent in aqueous solutions. Confocal fluorescence microscopy of live BT474, MCF7 and HEK293 cells demonstrates that both probes are cell permeable and rapidly accumulated intracellularly into cell nuclei and the cytosol.

Binding-induced, turn-on fluorescence of the EGFR/ERBB kinase inhibitor, lapatinib.

We report the photophysical properties, binding-induced turn-on emission, and fluorescence imaging of the cellular uptake and distribution of lapatinib, an EGFR/ERBB inhibitor. Lapatinib, a type II, i.e.

Turn-on, fluorescent nuclear stains with live cell compatibility.

DNA-binding, green and yellow fluorescent probes with excellent brightness and high on/off ratios are reported. The probes are membrane permeable, live-cell compatible, and optimally matched to 405 nm and 514 nm laser lines, making them attractive alternatives to UV-excited and blue emissive Hoechst 33342 and DAPI nuclear stains. Their electronic structure was investigated by optical spectroscopy supported by TD-DFT calculations.

Fluorescent stilbazolium dyes as probes of the norepinephrine transporter: structural insights into substrate binding.

We report the synthesis, binding kinetics, optical spectroscopy and predicted binding modes of a series of sterically demanding, fluorescent norepinephrine transporter (NET) ligands. A series of bulky stilbazolium dyes, including six newly synthesized compounds, were evaluated to determine the effect of extending the molecular probes' 'heads' or 'tails'. Taking advantage of the dyes' characteristic 'turn-on' emission, the kinetic binding parameters, k(on) and k(off) were determined revealing that extension of the molecules' tails is well tolerated while expansion of the head is not.

Effects of oat β-glucan on the macrophage cytokine response to herpes simplex virus 1 infection in vitro.

Oat β-glucan can counteract the increased risk for Herpes Simplex Virus 1 (HSV-1) infection in mice, the effects of which have, at least in part, been attributed to macrophages. However, the specific responses of macrophages to oat β-glucan treatment in this model have yet to be elucidated. We examined the effects of varying doses of oat β-glucan on the pro-inflammatory cytokine response in both peritoneal and lung macrophages with and without exposure to HSV-1 infection in vitro.

Probing the functional limits of the norepinephrine transporter with self-reporting, fluorescent stilbazolium dimers.

A series of stilbazolium dimers were synthesized and investigated as sterically demanding ligands targeting the norepinephrine transporter (NET). The environmentally sensitive fluorescence of the dyes enables their use as self-reporting ligands; binding to and displacement from NET can be monitored by fluorescence microscopy.

Fluorescent reporters of monoamine transporter distribution and function.

Serotonin is a monoamine serving as a chemical messenger in diverse brain regions, as well as in blood and various other organs. We synthesized six ethylamine functionalized fluorophores as fluorescent probes for serotonin. The one with best spectral properties and aqueous solubility, 6-amino-2-(2-aminoethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione, was studied in detail both in vivo and in vitro.

Luminescent charge-transfer complexes: tuning emission in binary fluorophore mixtures.

Charge-transfer (CT) complexes composed of a π-electron-poor naphthalene diimide (NDI) derivative combined with a series of π-electron-rich donors were investigated. Solutions of the CT complexes are nonemissive; however, solid-state complexes and aqueous suspensions display emission that is dependent on the energy of the HOMO of the electron donor. Crystallographic analysis of a pyrene-NDI complex reveals columnar packing and a high degree of frontier molecular orbital (FMO) overlap that likely contributes to the observed optical properties.

Fluorescent neuroactive probes based on stilbazolium dyes.

A set of spectrally diverse stilbazolium dyes was identified in an uptake assay using cultured brainstem and cerebellum cells isolated from e19 chicks. Pretreatment of cells with indatraline, a monoamine reuptake inhibitor, allowed identification of dyes that may interact with monoamine transporters. Two structurally related, yet spectrally segregated, probes, (E)-1-methyl-4-[2-(2-naphthalenyl)ethenyl]-pyridinium iodide (NEP+, 3A) and (E)-4-[2-(6-hydroxy-2-naphthalenyl)ethenyl]-1-methyl-pyridinium iodide (HNEP+, 4A), were selected and further investigated using HEK-293 cells selectively expressing dopamine, norepinephrine or serotonin transporters.

Fluorescent mimics of 5-hydroxytryptamine based on N-alkylated derivatives of 6-hydroxycarbostyril.

Fluorescent probes based on a 6-hydroxycarbostyril core accumulate inside neurons and astroglia in the absence of a serotonin uptake inhibitor.

Sexual dimorphism in the effect of sound stress on neutrophil function.

It has been hypothesized that stress contributes to the severity of inflammatory diseases. However, the mechanisms underlying this effect are incompletely understood. In this study we investigated the effects of sound stress on function of the polymorphonuclear neutrophil-immune cells that play key roles in both the acute and chronic inflammatory response.

Effect of IL-6 deficiency on susceptibility to HSV-1 respiratory infection and intrinsic macrophage antiviral resistance.

Cytokines play important roles in the mechanisms of disease development. Interleukin-6 (IL-6) is associated with clearance of herpes simplex virus (HSV) infections and in virus-induced immunopathology. However, the importance of IL-6 in host defense against HSV-1 respiratory infection is unknown.

Stress induces a switch of intracellular signaling in sensory neurons in a model of generalized pain.

Stress dramatically exacerbates pain in diseases such as fibromyalgia and rheumatoid arthritis, but the underlying mechanisms are unknown. We tested the hypothesis that stress causes generalized hyperalgesia by enhancing pronociceptive effects of immune mediators. Rats exposed to nonhabituating sound stress exhibited no change in mechanical nociceptive threshold, but showed a marked increase in hyperalgesia evoked by local injections of prostaglandin E(2) or epinephrine.

beta(2)-Adrenergic receptor-dependent sexual dimorphism for murine leukocyte migration.

In wild-type FVB mice, leukocyte recruitment to lipopolysaccharide was sexually dimorphic, with a greater number of leukocytes recruited in females. In male beta(2)-adrenergic receptor knock out mice (bred on a congenic FVB background) the number of leukocytes recruited was increased approximately 4-fold, while in females there was no change, eliminating sexual dimorphism in leukocyte migration. While there were significantly fewer recruited CD62L(+) and CD11a(+) leukocytes in wild-type males, only in male beta-adrenergic receptor knock out mice was there an increase in the number of recruited CD11a(+) leukocytes, again eliminating sexual dimorphism.

Oat beta-glucan effects on neutrophil respiratory burst activity following exercise.

Unlabelled: Fatiguing exercise has been associated with a decrease in certain functions of neutrophils, whereas moderate exercise has generally been associated with an increase. Consumption of oat beta-glucan (ObetaG), a soluble fiber and mild immune system enhancer, may offset the immunosuppression associated with intense training and perhaps further enhance the benefits of moderate exercise.

Purpose: To test the effects of ObetaG consumption on neutrophil function and number after both moderate and fatiguing exercise.

Curcumin effects on inflammation and performance recovery following eccentric exercise-induced muscle damage.

Downhill running is associated with fiber damage, inflammation, delayed-onset muscle soreness, and various functional deficits. Curcumin, a constituent of the Indian spice turmeric has been investigated for its anti-inflammatory activity and may offset some of the damage and functional deficits associated with downhill running. This study examined the effects of curcumin on inflammation and recovery of running performance following downhill running in mice.

Role of brain IL-1beta on fatigue after exercise-induced muscle damage.

Brain cytokines, induced by various inflammatory challenges, have been linked to sickness behaviors, including fatigue. However, the relationship between brain cytokines and fatigue after exercise is not well understood. Delayed recovery of running performance after muscle-damaging downhill running is associated with increased brain IL-1beta concentration compared with uphill running.

Gender differences in macrophage antiviral function following exercise stress.

Introduction: In male mice, exhaustive exercise increases susceptibility to respiratory infection following intranasal inoculation with herpes simplex virus-1 (HSV-1), whereas moderate exercise decreases the risk of infection. These responses have been linked with altered macrophage antiviral resistance, among other immune mechanisms. Female mice appear to be better protected from death than male mice following HSV-1 infection, although their response to exercise stress is similar.

Recovery of running performance following muscle-damaging exercise: relationship to brain IL-1beta.

Recovery following muscle-damaging downhill running is associated with increased muscle inflammatory cytokines. Various inflammatory challenges can also increase cytokines in the brain, which have been linked to sickness behaviors, including fatigue, but little is known about the brain cytokine response to stressful exercise. We used a downhill running model to determine the relationship between brain IL-1beta and recovery of running performance.

Effects of oat beta-glucan on innate immunity and infection after exercise stress.

Purpose: To test the effects of oat beta-glucan (ObetaG) on respiratory infection, macrophage antiviral resistance, and NK cytotoxicity.

Methods: Mice were randomly assigned to one of four groups: Ex-H2O, Ex-ObetaG, Con-H2O, or Con-ObetaG. ObetaG was fed in the drinking water for 10 d before intranasal inoculation of HSV-1 or sacrifice.

Gender differences in viral infection after repeated exercise stress.

Unlabelled: Fatiguing exercise can increase susceptibility to respiratory infection after intranasal inoculation with herpes simplex virus-1 (HSV-1) in male mice. Although gender differences in susceptibility to certain pathogens do exist, it is unknown whether female mice will respond differently than males in response to strenuous exercise and HSV-1 infection.

Purpose: To test the effects of gender on susceptibility to HSV-1 respiratory infection after repeated exhaustive exercise.

Effects of short-term exercise training on plasminogen activator inhibitor (PAI-1).

Purpose: To observe the effects of exercise training on plasminogen activator inhibitor, type-1 (PAI-1), tissue plasminogen activator (tPA), and associated metabolic variables in sedentary men and women.

Methods: A randomized, controlled experimental design was used to examine the influence of 10 d of moderate-intensity exercise training on measures of fibrinolysis. Sixteen men and 16 women between the ages of 50 and 70 yr were randomly assigned to exercise (EX) and control groups (CON) that were balanced for gender and hormone replacement therapy.