Nerve growth factor (NGF) binds to TrkA receptor and triggers activation of numerous signaling cascades, which play critical roles in neuronal plasticity, survival, and neurite outgrowth. To mimic NGF functions pharmacologically, we developed a high-throughput screening assay to identify small-molecule agonists for TrkA receptor. The most potent compound, gambogic amide, selectively binds to TrkA, but not TrkB or TrkC, and robustly induces its tyrosine phosphorylation and downstream signaling activation, including Akt and MAPKs. Further, it strongly prevents glutamate-induced neuronal cell death and provokes prominent neurite outgrowth in PC12 cells. Gambogic amide specifically interacts with the cytoplasmic juxtamembrane domain of TrkA receptor and triggers its dimerization. Administration of this molecule in mice substantially diminishes kainic acid-triggered neuronal cell death and decreases infarct volume in the transient middle cerebral artery occlusion model of stroke. Thus, gambogic amide might not only establish a powerful platform for dissection of the physiological roles of NGF and TrkA receptor but also provide effective treatments for neurodegenerative diseases and stroke.neurotrophic effect ͉ nerve growth factor ͉ ligand ͉ receptor dimerization

ABSTRACTOral candidiasis is often accompanied by severe inflammation, resulting in a decline in the quality of life of immunosuppressed individuals and elderly people. To develop a new oral therapeutic option for candidiasis, a nonpathogenic commensal oral probiotic microorganism,Streptococcus salivariusK12, was evaluated for its ability to modulateCandida albicansgrowthin vitro, and its therapeutic activity in an experimental oral candidiasis model was tested.In vitroinhibition of mycelial growth ofC. albicanswas determined by plate assay and fluorescence microscopy. Addition ofS. salivariusK12 to modified RPMI 1640 culture medium inhibited the adherence ofC. albicansto the plastic petri dish in a dose-dependent manner. Preculture ofS. salivariusK12 potentiated its inhibitory activity for adherence ofC. albicans. Interestingly,S. salivariusK12 was not directly fungicidal but appeared to inhibitCandidaadhesion to the substratum by preferentially binding to hyphae rather than yeast. To determine the potentially anti-infective attributes ofS. salivariusK12 in oral candidiasis, the probiotic was administered to mice with orally induced candidiasis. Oral treatment withS. salivariusK12 significantly protected the mice from severe candidiasis. These findings suggest thatS. salivariusK12 may inhibit the process of invasion ofC. albicansinto mucous surfaces or its adhesion to denture acrylic resins by mechanisms not associated with the antimicrobial activity of the bacteriocin.S. salivariusK12 may be useful as a probiotic as a protective tool for oral care, especially with regard to candidiasis.

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We examined the therapeutic effects of cinnamaldehyde and the potentiation of those effects with cassia and cinnamaldehyde when combined with the food additive methylcellulose against murine oral candidiasis. When 19.5 mg/ml of cinnamaldehyde was administered in the oral cavity of Candida infected mice, the oral symptoms were improved. Furthermore, when either a cassia or a cinnamaldehyde preparation in combination with methylcellulose was administered to oral candidiasis-inflicted mice, the therapeutic effects of cassia or cinnamaldehyde potentiated. Methylcellulose itself did not affect the oral symptoms or the viable number of C. albicans cells. GC/MS analysis showed that the dose of cinnamaldehyde remaining in the tongue tissue of mice treated with the cinnamaldehyde-methylcellulose mixture was higher than that in mice administered cinnamaldehyde alone, and also showed that cinnamaldehyde was not detected in the blood of any of the tested mice. These findings suggested that the combination of cassia or cinnamaldehyde and methylcellulose may be a useful prophylactic or therapeutic tool against oral candidiasis.

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