Nguewa, P.A. (Paul Alain)

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    The most prominent modulated annexins during parasitic infections
    (2023) Muro, A. (Antonio); Ali-Hassanzadeh, M. (Mohammad); Mansouri, R. (Reza); Manzano-Román, R. (Raúl); Nguewa, P.A. (Paul Alain); Rashidi, S. (Sajad)
    Annexins (ANXs) exert different functions in cell biological and pathological processes and are thus known as double or multi-faceted proteins. These sophisticated proteins might express on both parasite structure and secretion and in parasite-infected host cells. In addition to the characterization of these pivotal proteins, describing their mechanism of action can be also fruitful in recognizing their roles in the pathogenesis of parasitic infections. Accordingly, this study presents the most prominent ANXs thus far identified and their relevant functions in parasites and infected host cells during pathogenesis, especially in the most important intracellular protozoan parasitic infections including leishmaniasis, toxoplasmosis, malaria and trypanosomiasis. The data provided in this study demonstrate that the helminth parasites most probably express and secret ANXs to develop pathogenesis while the modulation of the host-ANXs could be employed as a crucial strategy by intracellular protozoan parasites. Moreover, such data highlight that the use of analogs of both parasite and host ANX peptides (which mimic or regulate ANXs physiological functions through various strategies) might suggest novel therapeutic insights into the treatment of parasitic infections. Furthermore, due to the prominent immunoregulatory activities of ANXs during most parasitic infections and the expression levels of these proteins in some parasitic infected tissues, such multifunctional proteins might be also potentially relevant as vaccine and diagnostic biomarkers. We also suggest some prospects and insights that could be useful and applicable to form the basis of future experimental studies.
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    Schistosoma haematobium and Plasmodium falciparum co-infection in Nigeria 2001–2018: A systematic review and meta-analysis
    (Elsevier BV, 2019) Nguewa, P.A. (Paul Alain); Anumudu, C.I. (C.I); Adebayo, A.S. (A.S); Ojo, O.E. (O.E); Awobode, H.O. (H. O.)
    Malaria and schistosomiasis continue to contribute a big burden to infectious disease prevalence in the tropical areas, mainly in sub Saharan African countries. We previously reported high levels of schistosome specific antibody IgG3 in children coinfected with malaria and schistosomiasis. The aim of the current study was to examine the current co-infection rates of these diseases in Nigeria. Published and unpublished studies on coinfection of human urogenital schistosomiasis and malaria carried out in Nigeria between 2001 and August 2018 were retrieved through literature searches in PubMed, Google Scholar, AJOL, and university theses repositories. The filtered and relevant articles were reviewed and combined in a meta-analysis. Studies involving children reported higher rates of coinfection. The fourteen research articles involving 6,559 individuals were combined in a meta-analysis. Our analyses revealed an estimated 15% co-infection for the country, though with wide variability depending on location. In addition, there are few and welldesigned research publications in Nigeria on prevalence and mechanism of malaria and schistosomiasis coinfection.
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    Characterization of Leishmania parasites isolated from naturally infected mammals
    (2023) Carasa-Buj, B. (Belén); Peña-Guerrero, J. (José); Burguete-Mikeo, A. (Aroia); El-Dirany, R. (Rima); Gainza, L. (Leonardo); Fernández-Rubio, C. (Celia); Nguewa, P.A. (Paul Alain)
    Simple Summary Leishmaniasis is a group of parasitic diseases that affect humans and animals. Climate change and increased travel and migration have contributed to the spread of leishmaniasis in Europe, which may allow the introduction of new exotic Leishmania species or change the profile of known strains. Therefore, it is a priority to continue isolating and characterizing Leishmania strains from hosts. In this study, we analyzed and characterized two Leishmania isolates (NAV and TDL) obtained from naturally infected mammals (dogs). We identified Leishmania infantum parasites, the main agents responsible for the disease in Spain and Europe. We focused on the analysis of growth rate, treatment response, infection capacity, and gene expression, comparing these isolates with the widely studied strain L. infantum BCN 150. Considering that these isolates showed different profiles, both NAV and TDL could be useful for in vitro and in vivo assays that might shed some light on the biology of the parasite. Leishmaniasis is spreading in Europe, especially in endemic countries such as Italy and Spain, in part due to ongoing climate change and the increase in travel and migration. Although Leishmania infantum is the main agent responsible for this disease in humans and animals, other species and hybrids have been detected. This highlights the need to continue isolating and characterizing Leishmania strains from biological samples of infected hosts. In this study, we characterized the recently isolated parasites L. infantum NAV and L. infantum TDL, obtained from naturally infected mammals (dogs), and we compared them with the widely distributed and studied strain L. infantum BCN 150. Both NAV and TDL promastigotes showed a slower growth rate than BCN 150 and were significantly more sensitive to amphotericin B and miltefosine. Furthermore, the expression of the CYCA gene (involved in cell cycle and proliferation) was significantly downregulated in NAV and TDL isolates. On the other hand, CYC6 (implicated in treatment resistance) and APG9 (related to the recycling of protein under stress conditions and/or while undergoing a differentiation process and treatment resistance) levels were upregulated, compared to those measured in BCN 150. Both isolates displayed a higher infection capacity (>3 amastigotes per macrophage and >70% of infected macrophages) compared to controls (<2 amastigotes/cells and <50% of infected macrophages). Finally, a higher susceptibility to miltefosine treatment was observed in intracellular NAV and TDL amastigotes. In conclusion, TDL and NAV are novel Leishmania isolates that might be useful for in vitro and in vivo assays that will allow a better understanding of the parasite biology in Mediterranean areas.
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    Identification of importin (IPO-8) as the most accurate reference gene for the clinicopathological analysis of lung specimens
    (BioMed Central, 2008-11-17) Pajares, M.J. (María José); Pio, R. (Rubén); Lozano, M.D. (María Dolores); Gomez-Roman, J. (Javier); Agorreta, J. (Jackeline); Rodriguez, M.J. (María José); Sanchez, B.A. (Blas A.); Blanco, D. (Daniel); Montuenga-Badia, L.M. (Luis M.); Valles, I. (Iñaki); Nguewa, P.A. (Paul Alain); Calvo-González, A. (Alfonso)
    Abstract Background: The accurate normalization of differentially expressed genes in lung cancer is essential for the identification of novel therapeutic targets and biomarkers by real time RT-PCR and microarrays. Although classical "housekeeping" genes, such as GAPDH, HPRT1, and beta-actin have been widely used in the past, their accuracy as reference genes for lung tissues has not been proven. Results: We have conducted a thorough analysis of a panel of 16 candidate reference genes for lung specimens and lung cell lines. Gene expression was measured by quantitative real time RTPCR and expression stability was analyzed with the softwares GeNorm and NormFinder, mean of |ΔCt| (= |Ct Normal-Ct tumor|) ± SEM, and correlation coefficients among genes. Systematic comparison between candidates led us to the identification of a subset of suitable reference genes for clinical samples: IPO8, ACTB, POLR2A, 18S, and PPIA. Further analysis showed that IPO8 had a very low mean of |ΔCt| (0.70 ± 0.09), with no statistically significant differences between normal and malignant samples and with excellent expression stability. Conclusion: Our data show that IPO8 is the most accurate reference gene for clinical lung specimens. In addition, we demonstrate that the commonly used genes GAPDH and HPRT1 are inappropriate to normalize data derived from lung biopsies, although they are suitable as reference genes for lung cell lines. We thus propose IPO8 as a novel reference gene for lung cancer samples.
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    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.
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    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.
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    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.
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    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.
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    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.
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    Desarrollo integral en la primera infancia. Cuidado nutricional del niño
    (Servicio de Publicaciones de la Universidad de Navarra, 2022) Lara-Apolinario, C. (Carmen); Aguilera-Buenosvinos, I. (Inmaculada); Nguewa, P.A. (Paul Alain)
    Este manual está dividido en 5 etapas de edad: embarazo, 0-6 meses, 6-24 meses, 1-3 años, 1-5 años. En cada etapa habrá información y consejos para cuidar el estado nutricional de su hijo. Todas las recomendaciones de este libro se deben hacer siempre bajo supervisión de un adulto y con previa ayuda y guía de un profesional