Silver(I) and Copper(II) Complexes of 1,10-Phenanthroline-5,6-Dione Against Phialophora Verrucosa: A Focus on the Interaction With Human Macrophages and Galleria Mellonella Larvae

Phialophora verrucosa is a dematiaceous fungus that causes mainly chromoblastomycosis, but also disseminated infections such as phaeohyphomycosis and mycetoma. These diseases are extremely hard to treat and often refractory to current antifungal therapies. In this work, we have evaluated the effect of 1,10-phenanthroline-5,6-dione (phendione) and its metal-based complexes, [Ag (phendione)2]ClO4 and [Cu(phendione)3](ClO4)2.4H2O, against P. verrucosa, focusing on (i) conidial viability when combined with amphotericin B (AmB); (ii) biofilm formation and disarticulation events; (iii) in vitro interaction with human macrophages; and (iv) in vivo infection of Galleria mellonella larvae. The combination of AmB with each of the test compounds promoted the additive inhibition of P. verrucosa growth, as judged by the checkerboard assay. During the biofilm formation process over polystyrene surface, sub-minimum inhibitory concentrations (MIC) of phendione and its silver(I) and copper(II) complexes were able to reduce biomass and extracellular matrix production. Moreover, a mature biofilm treated with high concentrations of the test compounds diminished biofilm viability in a concentration-dependent manner. Pre-treatment of conidial cells with the test compounds did not alter the percentage of infected THP-1 macrophages; however, [Ag(phendione)2]ClO4 caused a significant reduction in the number of intracellular fungal cells compared to the untreated system. In addition, the killing process was significantly enhanced by post-treatment of infected macrophages with the test compounds. P. verrucosa induced a typically cell density-dependent effect on G. mellonella larvae death after 7 days of infection. Interestingly, exposure to the silver(I) complex protected the larvae from P. verrucosa infection. Collectively, the results corroborate the promising therapeutic potential of phendione-based drugs against fungal infections, including those caused by P. verrucosa

Notes on the algebraic curves in (p,q) minimal string theory

Loop amplitudes in (p,q) minimal string theory are studied in terms of the continuum string field theory based on the free fermion realization of the KP hierarchy. We derive the Schwinger-Dyson equations for FZZT disk amplitudes directly from the W_{1+\infty} constraints in the string field formulation and give explicitly the algebraic curves of disk amplitudes for general backgrounds. We further give annulus amplitudes of FZZT-FZZT, FZZT-ZZ and ZZ-ZZ branes, generalizing our previous D-instanton calculus from the minimal unitary series (p,p+1) to general (p,q) series. We also give a detailed explanation on the equivalence between the Douglas equation and the string field theory based on the KP hierarchy under the W_{1+\infty} constraints.Comment: 61 pages, 1 figure, section 2.5 and Appendix B added, references added, final version to appear in JHE

A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers.

Long noncoding RNAs are emerging players in the epigenetic machinery with key roles in development and diseases. Here we uncover a complex network comprising a promoter-associated noncoding RNA (paRNA), microRNA and epigenetic regulators that controls transcription of the tumour suppressor E-cadherin in epithelial cancers. E-cadherin silencing relies on the formation of a complex between the paRNA and microRNA-guided Argonaute 1 that, together, recruit SUV39H1 and induce repressive chromatin modifications in the gene promoter. A single nucleotide polymorphism (rs16260) linked to increased cancer risk alters the secondary structure of the paRNA, with the risk allele facilitating the assembly of the microRNA-guided Argonaute 1 complex and gene silencing. Collectively, these data demonstrate the role of a paRNA in E-cadherin regulation and the impact of a noncoding genetic variant on its function. Deregulation of paRNA-based epigenetic networks may contribute to cancer and other diseases making them promising targets for drug discovery