Suchergebnisse

This work was financially supported by the Ministry of Economy and Competitiveness of Spain co-financed with European Regional Development Funds (References: CGL2015-71709-R and SAF2015-71714-R) and the fellowship PEJ2018-004702-A. The European Union also collaborated in the funding of this study (Euronanomed programme, Reference: TARBRAINFECT, and Innovative Medicines Initiative IMI2, Reference: 3TR-831434), as well as the Health Institute Carlos III as the local management institution (Reference: AC18/00008). A.S.L. and V.S.M. were supported by a fellowship from the Ministry of Education, Culture and Sport (FPU 17/05413 and FPU 16/05822), and the results presented in this article are part of A.S.L's doctoral thesis. M.O.G acknowledges for the funds received by the F.P.U. fellowship provided by University of Almeria. ; Next generation sequencing methods are widely used in evaluating the structure and functioning of microbial communities, especially those centered on 16S rRNA subunit. Since Illumina Miseq, the most used sequencing platform, does not allow the full sequencing of 16S rRNA gene, this study aims to evaluate whether the choice of different target regions might affect the outcome of microbiome studies regarding soil and saliva samples. V1V3, V3V4, V4V5 and V6V8 domains were studied, finding that while some regions showed differences in the detection of certain bacterial taxa and in the calculation of alpha diversity, especially in soil samples, the overall effect did not compromise the differentiation of any sample type in terms of taxonomic analysis at the genus level. 16S rRNA target regions did affect the detection of specific bacteria related to soil quality and development, and microbial genera used as health biomarkers in saliva. V1V3 region showed the closest similarity to internal sequencing control mock community B, suggesting it might be the most preferable choice regarding data reliability. ; European Union (EU) 3TR-831434 ; Instituto de Salud Carlos III AC18/00008 ; Ministry of Education, Culture and Sport FPU 17/05413 FPU 16/05822 ; University of Almeria ; Ministry of Economy and Competitiveness of Spain ; European Union (EU) CGL2015-71709-R SAF2015-71714-R PEJ2018-004702-A

African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs. ; JAGS was funded by the European Union, grant FP7-HEALTH-2007-B-2.3.4-1.223048, NANOTRYP and Ministerio de Economía y Competitividad, Spain Plan Nacional de Investigación grant SAF2011- 30528. JLA was funded by Instituto de Salud Carlos III, Spain, grant FIS. 11/02571. HPdK was supported by a grant from the Medical Research Council (84733).

Natural phenolic compounds have gained momentum for the prevention and treatment of cancer, but their antitumoral mechanism of action is not yet well understood. In the present study, we screened the antitumoral potential of several phenolic compounds in a cellular model of colorectal cancer (CRC).We selected gallic acid (GA) as a candidate in terms of potency and selectivity and extensively evaluated its biological activity. We report on the role of GA as a ligand of DNA G-quadruplexes (G4s), explaining several of its antitumoral effects, including the transcriptional inhibition of ribosomal and CMYC genes. In addition, GA shared with other established G4 ligands some effects such as cell cycle arrest, nucleolar stress, and induction of DNA damage. We further confirmed the antitumoral and G4-stabilizing properties of GA using a xenograft model of CRC. Finally, we succinctly demonstrate that GA could be explored as a therapeutic agent in a patient cohort with CRC. Our work reveals that GA, a natural bioactive compound present in the diet, affects gene expression by interaction with G4s both in vitro and in vivo and paves the way towards G4s targeting with phenolic compounds. ; Instituto de Salud Carlos III ; European Commission PI21/00497 AC18/00008 ; Next generation EU, Plan de Recuperacion Transformacion y Resiliencia, Agencia Estatal de Investigacion PLEC2021-008094 ; Ministerio de Ciencia e Innovacion from Government of Spain PID2019-104416RB-I00 PID2020-120481RB-I00 ; Ministerio de Universidades from Government of Spain FPU16/05822 FPU17/05413 FPU20/03952 ; University of Almeria FPI-201102

Sleeping sickness or African trypanosomiasis is a serious health concern with an added socio-economic impact in sub-Saharan Africa due to direct infection in both humans and their domestic livestock. There is no vaccine available against African trypanosomes and its treatment relies only on chemotherapy. Although the current drugs are effective, most of them are far from the modern concept of a drug in terms of toxicity, specificity and therapeutic regime. In a search for new molecules with trypanocidal activity, a high throughput screening of 2000 microbial extracts was performed. Fractionation of one of these extracts, belonging to a culture of the fungus Amesia sp., yielded a new member of the curvicollide family that has been designated as curvicollide D. The new compound showed an inhibitory concentration 50 (IC50) 16-fold lower in Trypanosoma brucei than in human cells. Moreover, it induced cell cycle arrest and disruption of the nucleolar structure. Finally, we showed that curvicollide D binds to DNA and inhibits transcription in African trypanosomes, resulting in cell death. These results constitute the first report on the activity and mode of action of a member of the curvicollide family in T. brucei. ; European Union (Euronanomed programme, Reference: TARBRAINFECT) ; Health Carlos III as the local management institution AC18/00008 ; Ministry of Science, Innovation and Universities from Spain PID2020-120481RB-I00 ; Ministry of Education, Culture and Sport FPU 17/05413 FPU 16/05822 FPU 20/03952 ; University of Almeria FPI-201102 PPUENTE2021-006