Brain-derived neurotrophic factor overexpression in taste buds diminishes chemotherapy induced taste loss.

Vismodegib is used in patients suffering from advanced basal cell carcinoma (BCC), but 100% of the patients taking it report dysgeusia and 50% discontinue the treatment. Treatment with neurotrophic factors can stimulate neuronal survival and functional improvement in injured organs. Here, we analysed novel transgenic mouse lines in which brain-derived neurotrophic factor (BDNF) is overexpressed in taste buds, to examine whether higher levels of BDNF would reduce or prevent negative side effects of vismodegib in the taste system. BDNF plays crucial roles for development, target innervation, and survival of gustatory neurons and taste buds. The behavioural test in this study showed that vehicle-treated wild-type mice prefered 10 mM sucrose over water, whereas vismodegib treatment in wild-type mice caused total taste loss. Gustducin-BDNF mice had a significantly increased preference for low concentration of sucrose solution over water compared to wild-type mice, and most importantly the transgenic mice were able to detect low concentrations of sucrose following vismodegib treatment. We evaluated taste cell morphology, identity, innervation and proliferation using immunohistochemistry. All drug-treated mice exhibited deficits, but because of a possible functional upcycled priming of the peripheral gustatory system, GB mice demonstrated better morphological preservation of the peripheral gustatory system. Our study indicates that overexpression of BDNF in taste buds plays a role in preventing degeneration of taste buds. Counteracting the negative side effects of vismodegib treatment might improve compliance and achieve better outcome in patients suffering from advanced BCC.

Bioinformatics Analysis of Chicken miRNAs Associated with Monocyte to Macrophage Differentiation and Subsequent IFNγ Stimulated Activation.

BACKGROUND: The goal of this project was to characterize the molecular and cellular roles of various gene targets regulated by miRNAs identified in differentiating and stimulating avian macrophages. Once a monocyte arrives to a site of infection, local signals induce a redistribution of resources into a macrophage phenotype. This may involve upregulating pathogen pattern recognizing receptors and increasing the efficiency of lysosomal biogenesis, while simultaneously recycling components involved in circulatory migration and leukocyte extravasation. a monocyte tooled with chemokine surface receptors and an internal cytoskeletal structure geared towards mobility may efficiently sense, react, and migrate toward a site of infection. METHODS: Peripheral blood derived monocytes were purified and cultured from young chickens. RNA sequencing was performed on both peripheral blood monocytes during differentiation into macrophages and on mature macrophages following stimulation with interferon gamma. A set of microRNAs were identified and investigated using bioinformatics methods to ascertain their potential role in avian macrophage biology. RESULTS: Among a number of miRNAs that are found to be expressed in avian macrophages, we focused on eight specific miRNAs (miR-1618, miR-1586, miR-1633, miR-1627, miR-1646, miR-1649, miR-1610, miR-1647) associated with macrophage differentiation and activation. Expression profiles of microRNAs were characterized during differentiation and activation. Candidate miRNA targets were implicated in processes including Wnt signaling, ubiquitination, PPAR mediated macrophage function, vesicle mediated cytokine trafficking, and WD40 domain protein functions. CONCLUSION: A global theme for macrophage function that may be modulated by microRNAs is the comprehensive redistribution of the cell's protein repertoire. This redistribution involves two processes: 1) the degradation and recycling of unneeded cytoplasmic and membrane components and 2) the mobilization of newly synthesized cellular components via vesicular trafficking. Generally, it appears that macrophages need to closely regulate gene expression for differentiation to be able to activate successfully in response to a pathogen. This is a process in which miRNAs participate by affecting several pathways critical for both, differentiation and activation.