Artículos de revista (Inst. Salud Tropical)
Permanent URI for this collectionhttps://hdl.handle.net/10171/52056
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Results
- Highlighting the interplay of microRNAs from Leishmania parasites and infected-host cells(Cambridge University Press, 2021) Carrera-Silva, E.A. (Eugenio Antonio); Ali-Hassanzadeh, M. (Mohammad); Ghani, E. (Esmaeel); Karimazar, M. (Mohammadreza); Mansouri, R. (Reza); Barazesh, A. (Afshin); Nguewa, P.A. (Paul Alain); Rashidi, S. (Sajad)Leishmania parasites, the causative agents of leishmaniasis, are protozoan parasites with the ability to modify the signalling pathway and cell responses of their infected host cells. These parasite strategies alter the host cell environment and conditions favouring their replication, survival and pathogenesis. Since microRNAs (miRNAs) are able to post-transcriptionally regulate gene expression processes, these biomolecules can exert critical roles in controlling Leishmania-host cell interplay. Therefore, the identification of relevant miRNAs differentially expressed in Leishmania parasites as well as in infected cells, which affect the host fitness, could be critical to understand the infection biology, pathogenicity and immune response against these parasites. Accordingly, the current review aims to address the differentially expressed miRNAs in both, the parasite and infected host cells and how these biomolecules change cell signalling and host immune responses during infection. A deep understanding of these processes could provide novel guidelines and therapeutic strategies for managing and treating leishmaniasis.
- Mixed micelles and gels of a hydrophilic poloxamine (Tetronic 1307) and miltefosine: Structural characterization by small-angle neutron scattering and in vitro evaluation for the treatment of leishmaniasis(Elsevier, 2023) González-Gaitano, G. (Gustavo); El-Dirany, R. (Rima); Nguewa, P.A. (Paul Alain); Smith, G.N. (Gregory N.); Dirany, Z. (Zeinab)Hypothesis/background: Tetronic is a family of four-armed amphiphilic block copolymers of polyethylene oxide (PEO) and polypropylene oxide (PPO) that self-aggregate to form micelles and hydrogels. Due to their temperature and pH-responsiveness, they are emerging as smart nanomaterials in the area of drug delivery. Here we propose the use of Tetronic 1307 (T1307) as a nanocarrier of miltefosine (MF), a zwitterionic alkylphospholipid highly active against leishmaniasis, one of the most threating neglected tropical diseases. Given the amphiphilic nature of the drug, both surfactants can combine to form mixed micelles, reducing the cytotoxicity of MF by lowering its dose and improving its internalization, hence its antileishmanial effect. Experiments: The structure of the T1307 micelles, MF micelles, mixed micelles and hydrogels, formed in buffered solution (pH = 7.4) at different concentrations has been investigated in-depth by a combination of small-angle neutron scattering (SANS), dynamic light scattering (DLS), fluorescence spectroscopy and nuclear magnetic resonance methods (1D, 2D NOESY, and diffusion NMR). The cytotoxicity of the aggregates in macrophages has been assessed, as well as the antileishmanial activity in both Leishmania major promastigotes and amastigotes. Findings: T1307 and MF combine into mixed aggregates over a wide range of temperatures and compositions, forming ellipsoidal core–shell mixed micelles. The shell is highly hydrated and comprises most of the PEO blocks, while the hydrophobic core contains the PO blocks and the MF along with a fraction of EO and water molecules, depending on the molar ratio in the mixture. The combination with T1307 amplified the leishmanicidal activity of the drug against both forms of the parasite and dramatically reduced drug cytotoxicity. T1307 micelles also showed a considerable leishmanicidal activity without exhibiting macrophage toxicity. These results support the use of T1307 as a MF carrier for the treatment of human and animal leishmaniasis, in its different clinical forms.
- The BRCT domain from the homologue of the oncogene PES1 in Leishmania major (LmjPES) promotes malignancy and drug resistance in mammalian cells(2022) Peña-Guerrero, J. (José); Larrea, E. (Esther); Guruceaga, E. (Elizabeth); Fernández-Rubio, C. (Celia); Nguewa, P.A. (Paul Alain)Around 15% of cancer cases are attributable to infectious agents. Epidemiological studies suggest that an association between leishmaniasis and cancer does exist. Recently, the homologue of PES1 in Leishmania major (LmjPES) was described to be involved in parasite infectivity. Mammalian PES1 protein has been implicated in cellular processes like cell cycle regulation. Its BRCT domain has been identified as a key factor in DNA damage-responsive checkpoints. This work aimed to elucidate the hypothetical oncogenic implication of BRCT domain from LmjPES in host cells. We generated a lentivirus carrying this BRCT domain sequence (lentiBRCT) and a lentivirus expressing the luciferase protein (lentiLuc), as control. Then, HEK293T and NIH/3T3 mammalian cells were infected with these lentiviruses. We observed that the expression of BRCT domain from LmjPES conferred to mammal cells in vitro a greater replication rate and higher survival. In in vivo experiments, we observed faster tumor growth in mice inoculated with lentiBRCT respect to lentiLuc HEK293T infected cells. Moreover, the lentiBRCT infected cells were less sensitive to the genotoxic drugs. Accordingly, gene expression profiling analysis revealed that BRCT domain from LmjPES protein altered the expression of proliferation- (DTX3L, CPA4, BHLHE41, BMP2, DHRS2, S100A1 and PARP9), survival- (BMP2 and CARD9) and chemoresistance-related genes (DPYD, Dok3, DTX3L, PARP9 and DHRS2). Altogether, our results reinforced the idea ...
- Repurposing the antibacterial agents peptide 19-4LF and peptide 19-2.5 for treatment of cutaneous leishmaniasis(2022) Peña-Guerrero, J. (José); Brandenburg, K. (Klaus); Larrea, E. (Esther); Abdel-Sater, F. (Fadi); Espuelas, S. (Socorro); Martinez-de-Tejada, G. (Guillermo); El-Dirany, R. (Rima); Moreno-Amatria, E. (Esther); Fernández-Rubio, C. (Celia); Nguewa, P.A. (Paul Alain)The lack of safe and cost-effective treatments against leishmaniasis highlights the urgent need to develop improved leishmanicidal agents. Antimicrobial peptides (AMPs) are an emerging category of therapeutics exerting a wide range of biological activities such as anti-bacterial, anti-fungal, anti-parasitic and anti-tumoral. In the present study, the approach of repurposing AMPs as antileishmanial drugs was applied. The leishmanicidal activity of two synthetic anti-lipopolysaccharide peptides (SALPs), so-called 19-2.5 and 19-4LF was characterized in Leishmania major. In vitro, both peptides were highly active against intracellular Leishmania major in mouse macrophages without exerting toxicity in host cells. Then, q-PCR-based gene profiling, revealed that this activity was related to the downregulation of several genes involved in drug resistance (yip1), virulence (gp63) and parasite proliferation (Cyclin 1 and Cyclin 6). Importantly, the treatment of BALB/c mice with any of the two AMPs caused a significant reduction in L. major infective burden. This effect was associated with an increase in Th1 cytokine levels (IL-12p35, TNF-¿, and iNOS) in the skin lesion and spleen of the L. major infected mice while the Th2-associated genes were downregulated (IL-4 and IL-6). Lastly, we investigated the effect of both peptides in the gene expression profile of the P2X7 purinergic receptor, which has been reported as a therapeutic target in several diseases. The results showed ...
- Leishmaniasis en Navarra (1976-2018): actualización(Gobierno de Navarra, 2022) Burguete-Mikeo, A. (Aroia); Nguewa, P.A. (Paul Alain)La leishmaniasis es endémica en países de la cuenca mediterránea. En el presente estudio se revisa la información disponible sobre la leishmaniasis en Navarra y en regiones limítrofes en el periodo 1976-2018, y se aporta una visión general de la situación de esta enfermedad a nivel nacional, desde el vector hasta el hombre. La tasa de incidencia de leishmaniasis disminuyó en Aragón entre 2008 y 2018 respecto a la década anterior, mientras que en Navarra y La Rioja casi se duplicaron los casos por 100.000 habitantes; el País Vasco también presentó un aumento en la incidencia. El incremento de casos a nivel nacional ha sido significativo desde 2015, en parte debido a la inclusión de la leishmaniasis como enfermedad de declaración obligatoria. Si bien su incidencia en humanos no parece preocupante, la leishmaniasis es hoy una realidad en España, por lo que es necesario vigilar globalmente su evolución.