Artículos de revista (Inst. Salud Tropical)
Permanent URI for this collectionhttps://hdl.handle.net/10171/52056
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- 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 defensive interactions of prominent infectious protozoan parasites: the host's complement system(2022) Muro, A. (Antonio); Ali-Hassanzadeh, M. (Mohammad); Mansouri, R. (Reza); Manzano-Román, R. (Raúl); Nguewa, P.A. (Paul Alain); Rashidi, S. (Sajad)The complement system exerts crucial functions both in innate immune responses and adaptive humoral immunity. This pivotal system plays a major role dealing with pathogen invasions including protozoan parasites. Different pathogens including parasites have developed sophisticated strategies to defend themselves against complement killing. Some of these strategies include the employment, mimicking or inhibition of host's complement regulatory proteins, leading to complement evasion. Therefore, parasites are proven to use the manipulation of the complement system to assist them during infection and persistence. Herein, we attempt to study the interaction's mechanisms of some prominent infectious protozoan parasites including Plasmodium, Toxoplasma, Trypanosoma, and Leishmania dealing with the complement system. Moreover, several crucial proteins that are expressed, recruited or hijacked by parasites and are involved in the modulation of the host's complement system are selected and their role for efficient complement killing or lysis evasion is discussed. In addition, parasite's complement regulatory proteins appear as plausible therapeutic and vaccine targets in protozoan parasitic infections. Accordingly, we also suggest some perspectives and insights useful in guiding future investigations.
- Burden of infectious disease studies in Europe and the United Kingdom: a review of methodological design choices(2023) Levi, M. (Miriam); Charalampous, P. (Periklis); Yigit, V. (Vahit); Nena, E. (Evangelia); Stevanovic, A. (Aleksandar); Haagsma, J.A. (Juanita A.); Fantke, P. (Peter); Pires, S.M. (Sara M.); Padrón-Monedero, A. (Alicia); Plass, D. (Dietrich); Reina-Ortiz, M. (Miguel); Thygesen, L.C. (Lau Caspar); Gunes, S. (Sezgin); Steiropoulos, P. (Paschalis); Chen-Xu, J. (José); von-der-Lippe, E. (Elena); Unim, B. (Brigid); Sarmiento, R. (Rodrigo); Isola, G. (Gaetano); Santoso, C.M.A. (Cornelia Melinda Adi); AlKerw, A. (Ala’a); Mondello, S. (Stefania); Lauriola, P. (Paolo); Gazzelloni, F. (Federica); Fischer, F. (Florian); Noguer, I. (Isabel); Obradovic, M. (Marija); O'Caoimh, R. (Rónán); Gorasso, V. (Vanessa); Brus, I. (Iris); Pinheiro, V. (Vera); Economou, M. (Mary); Cuschieri, S. (Sarah); Konar, N.M. (Naime Meriç); Kolkhir, P. (Pavel); Milicevic, M.S. (Milena Santric); Arabloo, J. (Jalal); Santos, J.V. (Joao Vasco); Vasic, M. (Milena); Hynds, P. (Paul); Kostoulas, P. (Polychronis); Idavain, J. (Jane); Devleesschauwer, B. (Brecht); Peyroteo, M. (Mariana); Mechili, E.A. (Enkeleint A.); Uysal, H.B. (Hilal Bektas); Chaintoutis, S.C. (Serafeim C.); Chkhaberidze, N. (Nino); Tozija, F. (Fimka); Jakobsen, L.S. (Lea S.); Gissler, M. (Mika); García-González, J.M. (Juan Manuel); Hincapie, C.A. (Cesar A.); Gulmez, H. (Hakan); Niranjan, V. (Vikram); Cilovic-Lagarija, S. (Seila); Corso, B. (Barbara); Bikbov, B. (Boris); Speybroeck, N. (Niko); Muñoz-Laguna, J. (Javier); Ng, E.S.W. (Edmond S. W.); Ilic, I. (Irena); Burazeri, G. (Genc); Freitas, A. (Alberto); Kulimbet, M. (Mukhtar); Majer, M. (Marjeta); Monasta, L. (Lorenzo); Di-Bari, C. (Carlotta); Kabir, Z. (Zubair); Pallari, E. (Elena); Baltazar, A.L. (Ana Lúcia); McDonald, S.A. (Scott A.); Varga, O. (Orsolya); Riva, S. (Silvia); Borrell-Pages, M. (Maria); Nguewa, P.A. (Paul Alain); La-Vecchia, C. (Carlo); Dopelt, K. (Keren); Kamusheva, M. (Maria); Haller, S. (Sebastian); Wyper, G.M.A. (Grant M. A.); Haneef, R. (Romana); Sprügel, M. (Maximilian); Pranjic, N. (Nurka); Schmitt, T. (Tugce); Gkitakou, A. (Artemis); Nola, I.A. (Iskra Alexandra); Assunçao, R. (Ricardo); Ilic, M. (Milena); Emeto, T.I. (Theophilus I.); Vieira, R.J. (Rafael José); Ádám, B. (Balázs)This systematic literature review aimed to provide an overview of the characteristics and methods used in studies applying the disability-adjusted life years (DALY) concept for infectious diseases within European Union (EU)/European Economic Area (EEA)/European Free Trade Association (EFTA) countries and the United Kingdom. Electronic databases and grey literature were searched for articles reporting the assessment of DALY and its components. We considered studies in which researchers performed DALY calculations using primary epidemiological data input sources. We screened 3053 studies of which 2948 were excluded and 105 studies met our inclusion criteria. Of these studies, 22 were multi-country and 83 were single-country studies, of which 46 were from the Netherlands. Food- and water-borne diseases were the most frequently studied infectious diseases. Between 2015 and 2022, the number of burden of infectious disease studies was 1.6 times higher compared to that published between 2000 and 2014. Almost all studies (97%) estimated DALYs based on the incidence- and pathogen-based approach and without social weighting functions; however, there was less methodological consensus with regards to the disability weights and life tables that were applied. The number of burden of infectious disease studies undertaken across Europe has increased over time. Development and use of guidelines will promote performing burden of infectious disease studies and facilitate comparability of the results.
- 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 ...
- Mining the proteome of Toxoplasma parasites seeking vaccine and diagnostic candidates(2022) Sánchez-Montejo, J. (Javier); Ali-Hassanzadeh, M. (Mohammad); Bahreini, M.S. (Mohammad Saleh); Karimazar, M. (Mohammadreza); Mansouri, R. (Reza); Manzano-Román, R. (Raúl); Savardashtaki, A. (Amir); Nguewa, P.A. (Paul Alain); Rashidi, S. (Sajad)Simple Summary The One Health concept to toxoplasmosis highlights that the health of humans is closely related to the health of animals and our common environment. Toxoplasmosis outcomes might be severe and fatal in patients with immunodeficiency, diabetes, and pregnant women and infants. Consequently, the development of effective vaccine and diagnostic strategies is urgent for the elimination of this disease. Proteomics analysis has allowed the identification of key proteins that can be utilized in the development of novel disease diagnostics and vaccines. This work presents relevant proteins found in the proteome of the life cycle-specific stages of Toxoplasma parasites. In fact, it brings together the main functionality key proteins from Toxoplasma parasites coming from proteomic approaches that are most likely to be useful in improving the disease management, and critically proposes innovative directions to finally develop promising vaccines and diagnostics tools. Toxoplasma gondii is a pathogenic protozoan parasite that infects the nucleated cells of warm-blooded hosts leading to an infectious zoonotic disease known as toxoplasmosis. The infection outcomes might be severe and fatal in patients with immunodeficiency, diabetes, and pregnant women and infants. The One Health approach to toxoplasmosis highlights that the health of humans is closely related to the health of animals and our common environment. The presence of drug resistance and side effects, the further improvement of sensitivity and specificity of serodiagnostic tools and the potentiality of vaccine candidates to induce the host immune response are considered as justifiable reasons for the identification of novel targets for the better management of toxoplasmosis. Thus, the identification of new critical proteins in the proteome of Toxoplasma parasites can also be helpful in designing and test more effective drugs, vaccines, and diagnostic tools. Accordingly, in this study we present important proteins found in the proteome of the life cycle-specific stages of Toxoplasma parasites that are potential diagnostic or vaccine candidates. The current study might help to understand the complexity of these parasites and provide a possible source of strategies and biomolecules that can be further evaluated in the pathobiology of Toxoplasma parasites and for diagnostics and vaccine trials against this disease.
- 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.
- The novel serine/threonine protein kinase LmjF.22.0810 from leishmania major may be involved in the resistance to drugs such as paromomycin(MDPI AG, 2019) Algarabel, M. (Miriam); Peña-Guerrero, J. (José); Vacas, A. (Andrés); Larrea, E. (Esther); García-Sosa, A.T. (Alfonso T.); Fernández-Rubio, C. (Celia); Nguewa, P.A. (Paul Alain); Formiga, F.R. (Fabio R.)The identification and clarification of the mechanisms of action of drugs used against leishmaniasis may improve their administration regimens and prevent the development of resistant strains. Herein, for the first time, we describe the structure of the putatively essential Ser/Thr kinase LmjF.22.0810 from Leishmania major. Molecular dynamics simulations were performed to assess the stability of the kinase model. The analysis of its sequence and structure revealed two druggable sites on the protein. Furthermore, in silico docking of small molecules showed that aminoglycosides preferentially bind to the phosphorylation site of the protein. Given that transgenic LmjF.22.0810-overexpressing parasites displayed less sensitivity to aminoglycosides such as paromomycin, our predicted models support the idea that the mechanism of drug resistance observed in those transgenic parasites is the tight binding of such compounds to LmjF.22.0810 associated with its overexpression. These results may be helpful to understand the complex machinery of drug response in Leishmania.
- Discovery and validation of Lmj_04_BRCT domain, a novel therapeutic target: identification of candidate drugs for leishmaniasis(2021) Peña-Guerrero, J. (José); Burguete-Mikeo, A. (Aroia); García-Sosa, A.T. (Alfonso T.); El-Dirany, R. (Rima); Fernández-Rubio, C. (Celia); Nguewa, P.A. (Paul Alain)Since many of the currently available antileishmanial treatments exhibit toxicity, low effectiveness, and resistance, search and validation of new therapeutic targets allowing the development of innovative drugs have become a worldwide priority. This work presents a structure-based drug discovery strategy to validate the Lmj_04_BRCT domain as a novel therapeutic target in Leishmania spp. The structure of this domain was explored using homology modeling, virtual screening, and molecular dynamics studies. Candidate compounds were validated in vitro using promastigotes of Leishmania major, L. amazonensis, and L. infantum, as well as primary mouse macrophages infected with L. major. The novel inhibitor CPE2 emerged as the most active of a group of compounds against Leishmania, being able to significantly reduce the viability of promastigotes. CPE2 was also active against the intracellular forms of the parasites and significantly reduced parasite burden in murine macrophages without exhibiting toxicity in host cells. Furthermore, L. major promastigotes treated with CPE2 showed significant lower expression levels of several genes (alpha-tubulin, Cyclin CYCA, and Yip1) related to proliferation and treatment resistance. Our in silico and in vitro studies suggest that the Lmj_04_BRCT domain and its here disclosed inhibitors are new potential therapeutic options against leishmaniasis.