Statin and aspirin use in parasitic infections as a potential therapeutic strategy: A narrative review

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AF: acetate fibers of the filter." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "María del Pilar Núñez, Matias Butler, Leonardo Matias Majul, Luis Alberto Diorio, Laura Noemi Levin, Sonia Rosenfeldt" "autores" => array:6 [ 0 => array:2 [ "nombre" => "María del Pilar" "apellidos" => "Núñez" ] 1 => array:2 [ "nombre" => "Matias" "apellidos" => "Butler" ] 2 => array:2 [ "nombre" => "Leonardo Matias" "apellidos" => "Majul" ] 3 => array:2 [ "nombre" => "Luis Alberto" "apellidos" => "Diorio" ] 4 => array:2 [ "nombre" => "Laura Noemi" "apellidos" => "Levin" ] 5 => array:2 [ "nombre" => "Sonia" "apellidos" => "Rosenfeldt" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0325754123000044?idApp=UINPBA00004N" "url" => "/03257541/0000005500000003/v1_202309280755/S0325754123000044/v1_202309280755/en/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S0325754123000251" "issn" => "03257541" "doi" => "10.1016/j.ram.2023.02.003" "estado" => "S300" "fechaPublicacion" => "2023-07-01" "aid" => "539" "copyright" => "Asociación Argentina de Microbiología" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Rev Argent Microbiol. 2023;55:272-7" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Brief report" "titulo" => "Ureaplasma diversum–Ureaplasma sp. alone or concomitantly with Mycoplasma hyopneumoniae in pig lungs with and without pneumonia: A descriptive exploratory study in abattoirs" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:3 [ 0 => "en" 1 => "en" 2 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "272" "paginaFinal" => "277" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Presencia de Ureaplasma diversum-Ureaplasma sp. solo o junto con Mycoplasma hyopneumoniae en pulmones de cerdos con y sin neumonía: un estudio exploratorio descriptivo en frigorífico" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Jimena Seitz, Claudina Vissio, Judith Bertone, Lucas Marques, Julián Parada, Alicia Carranza, Gabriel Di Cola, Roberto Ambrogi, Pablo Tamiozzo" "autores" => array:9 [ 0 => array:2 [ "nombre" => "Jimena" "apellidos" => "Seitz" ] 1 => array:2 [ "nombre" => "Claudina" "apellidos" => "Vissio" ] 2 => array:2 [ "nombre" => "Judith" "apellidos" => "Bertone" ] 3 => array:2 [ "nombre" => "Lucas" "apellidos" => "Marques" ] 4 => array:2 [ "nombre" => "Julián" "apellidos" => "Parada" ] 5 => array:2 [ "nombre" => "Alicia" "apellidos" => "Carranza" ] 6 => array:2 [ "nombre" => "Gabriel" "apellidos" => "Di Cola" ] 7 => array:2 [ "nombre" => "Roberto" "apellidos" => "Ambrogi" ] 8 => array:2 [ "nombre" => "Pablo" "apellidos" => "Tamiozzo" ] ] ] ] "resumen" => array:1 [ 0 => array:3 [ "titulo" => "Highlights" "clase" => "author-highlights" "resumen" => "<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">•Ureaplasma sp.–Ureaplasma diversum were detected in 17.1% of pig lungs.</li><li class="elsevierStyleListItem" id="lsti0010">•Ureaplasma sp.–U. diversum and M. hyopneumoniae were detected in 12.5% of lungs.</li><li class="elsevierStyleListItem" id="lsti0015">•In the 27.3% of EP-like lesions Ureaplasma sp.–Ureaplasma diversum were detected.</li></ul>" ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0325754123000251?idApp=UINPBA00004N" "url" => "/03257541/0000005500000003/v1_202309280755/S0325754123000251/v1_202309280755/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Special article" "titulo" => "Statin and aspirin use in parasitic infections as a potential therapeutic strategy: A narrative review" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "278" "paginaFinal" => "288" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Valentina Burgess, Juan D. Maya" "autores" => array:2 [ 0 => array:3 [ "nombre" => "Valentina" "apellidos" => "Burgess" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:4 [ "nombre" => "Juan D." "apellidos" => "Maya" "email" => array:1 [ 0 => "jdmaya@uchile.cl" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Escuela de Medicina, Facultad de Medicina, Universidad de Chile, Independencia, Santiago, Chile" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Independencia, Santiago, Chile" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Uso de estatinas y aspirina en infecciones parasitarias como potencial estrategia terapéutica: Una revisión narrativa" ] ] "textoCompleto" => "IntroductionThe treatment and prevention of infections focus on eradicating the microorganisms that cause them using a broad pharmacological arsenal of highly effective antibiotics and vaccines generating a sense of safety and confidence in reaching the end of infectious diseases<a class="elsevierStyleCrossRef" href="#bib0770">43</a>. The COVID-19 pandemic and the spread of resistant pathogens capable of evading the immune system demonstrated that this goal is still far from being achieved. Moreover, the lack of safer and more effective drugs for the treatment of parasitic diseases, especially those causing chronic conditions, underscores this situation. Furthermore, the transformation of microbiological ecosystems and the global interconnection of societies have accelerated the evolution of microorganisms and infections<a class="elsevierStyleCrossRefs" href="#bib0770">43,106</a>, including the emergence of new threats. Moreover, the epidemiological behavior of traditional zoonotic diseases (as seen, for example, in the increase in congenital and transfusion transmission of Chagas disease in non-endemic countries) is changing. Thus, new therapeutic approaches are required for the treatment of infectious diseases.The inflammatory response against pathogens is a self-limiting process. In general, tissue damage or invasion by pathogens triggers local activation of macrophages through recognizing pathogen-associated molecular patterns (PAMPs) by specialized Toll-like receptors (TLRs)<a class="elsevierStyleCrossRef" href="#bib1050">99</a>. Thus, the secretion of several interleukins (Ils), prostaglandins and leukotrienes, tumor necrosis factor-alpha (TNF-α), and gamma interferon (IFN-γ), among others, is promoted, depending on the type of pathogen involved. Free radicals are also generated, facilitating phagocytosis<a class="elsevierStyleCrossRefs" href="#bib0605">10,97</a>, triggering the inflammatory process. Although essential for eliminating pathogens, the prompt re-establishment of homeostasis is required through the resolution of inflammation. When this resolution is inadequate, inflammation gets out of control, causing further tissue damage or installing chronic processes, with or without active infection<a class="elsevierStyleCrossRefs" href="#bib1040">97,102</a>.The resolution of inflammation is a highly regulated process orchestrated by multiple mediators, the so-called specialized pro-resolving mediators (SPMs)<a class="elsevierStyleCrossRef" href="#bib0785">46</a>, a superfamily of lipid molecules derived from the ω-3 and ω-6 polyunsaturated fatty acids of the plasma membrane, grouped into four classes: lipoxins A4 and B4 (LXA4, LXB4), derived from arachidonic acid; resolvins (Rv) D1-6, protectins (PD) and maresins (MaR), derived from docosahexaenoic acid (DHA); and Rv E1-4, derived from eicosapentaenoic acid (EPA)<a class="elsevierStyleCrossRefs" href="#bib0645">18,48</a>. SPMs are described as potent anti-inflammatory molecules with an immunoregulatory role<a class="elsevierStyleCrossRef" href="#bib0795">48</a>.SPMs are synthesized by several lipooxygenases in different cell types, including neutrophils and macrophages, and act on various G protein-coupled receptors, such as Formyl Peptide Receptor-2 (FPR2) or G protein-coupled receptor 32 (GPR32)<a class="elsevierStyleCrossRef" href="#bib0990">87</a>. The process is initiated during the exudate formation in the active phase of inflammation. The classic initiators, prostaglandins and leukotrienes, are key in the subsequent switch of lipid mediators<a class="elsevierStyleCrossRef" href="#bib1005">90</a>, activating the expression of the enzymes necessary for producing SPMs<a class="elsevierStyleCrossRef" href="#bib0850">59</a>. During this process, LXs<a class="elsevierStyleCrossRef" href="#bib0990">87</a> appear first, followed by Rvs and, finally, PDs and MaRs<a class="elsevierStyleCrossRef" href="#bib0995">88</a>; however, the resolution is more a result of the concerted action of these mediators than of the time course of their secretion; although it is clear that their early appearance guarantees the self-limiting nature of the inflammation<a class="elsevierStyleCrossRef" href="#bib1015">92</a>.The resolution of inflammation is aimed, in part, at clearing the pathogenic load through the SPMs. These are also responsible for promoting local neutrophil apoptosis, reducing the systemic inflammatory response by decreasing the production of cytokines and other Nuclear Factor κB (NFκB)-associated products, and increasing the production of IL-10 and nitric oxide in macrophages<a class="elsevierStyleCrossRef" href="#bib0790">47</a>. In addition, they increase phagocytosis of apoptotic leukocytes (efferocytosis) and pathogen clearance by tissue macrophages<a class="elsevierStyleCrossRefs" href="#bib0790">47,102</a>. For these reasons, SPMs have high therapeutic potential in managing inflammation<a class="elsevierStyleCrossRef" href="#bib1000">89</a>, including the possibility of circumventing the adverse reactions and immunosuppression associated with the treatment of hyperinflammatory states triggered by severe infections, such as sepsis or COVID-19<a class="elsevierStyleCrossRef" href="#bib0925">74</a>.Interestingly, the synthesis of SPMs can be triggered by the prostaglandin production inhibitor aspirin since cyclooxygenase 2 (COX2) acetylation blocks prostaglandin synthesis and, at the same time, confers the ability to produce the epimer intermediates 15R-HETE from arachidonic acid, 18R-HEPE from EPA and 17R-HDHA from DHA. Neutrophils transform these intermediates into lipoxins, resolvins, and protectins triggered by aspirin<a class="elsevierStyleCrossRef" href="#bib1010">91</a>. Likewise, statins, inhibitors of 3-hydroxy-methyl-glutaryl coenzyme A reductase, lower blood cholesterol levels and have other effects, called pleiotropic, by decreasing the synthesis of isoprenoids, intermediates in the mevalonate pathway<a class="elsevierStyleCrossRef" href="#bib0985">86</a>. These effects include regulation of endothelial function, coagulation, and anti-inflammatory actions such as reduced leukocyte migration and proinflammatory cytokine generation<a class="elsevierStyleCrossRef" href="#bib0830">55</a>. Statins induce COX2 nitrosylation, generating the same epimer intermediates of SPMs as aspirin but causing S-nitrosylation<a class="elsevierStyleCrossRef" href="#bib0800">49</a>, explaining, in part, the anti-inflammatory effects of statins<a class="elsevierStyleCrossRef" href="#bib0660">21</a>.SPMs are relevant in acute infections because they shorten the inflammatory interval and increase the elimination of bacteria and other microorganisms; eventually, allowing the decrease in antibiotic doses<a class="elsevierStyleCrossRefs" href="#bib0640">17,90</a>. Therefore, the relationship between infection and resolution is attractive due to the immunosuppressive potential of some anti-inflammatory agents<a class="elsevierStyleCrossRef" href="#bib0705">30</a>. For example, in self-limited Escherichia coli infections, resolution programs are activated, and PD1 and RvD1, and D5 levels are elevated<a class="elsevierStyleCrossRefs" href="#bib0660">21,22</a>. In addition, LXA4, Rv D1, and MaR1 increase the survival of mice with experimental sepsis<a class="elsevierStyleCrossRefs" href="#bib0635">16,50,107</a>; moreover, LXA4 decreases biofilm formation by Pseudomonas aeruginosa while increasing the ability of ciprofloxacin and imipenem to kill this bacterium<a class="elsevierStyleCrossRef" href="#bib1060">101</a>. Interestingly, a recent report links the protective effect of the antimalarial artesunate to the activation of GPR32, another SPM receptor, mimicking the effects of PD1 on macrophages in the context of murine Plasmodium infections and Listeria sepsis<a class="elsevierStyleCrossRef" href="#bib0585">6</a>. Thus, given the importance of antimicrobial resistance, a pharmacological intervention of resolution could provide a different approach to decreasing exposure to antibiotics<a class="elsevierStyleCrossRef" href="#bib0640">17</a>.Modulating the host response with statins or aspirin may be helpful in the therapeutics of infections with significant inflammatory components. It could contribute to managing antimicrobial resistance or prevent referral to potentially harmful chronic courses. Thus, it is interesting to ask whether the modulation of relevant host factors with aspirin or a statin could be beneficial for the adjuvant treatment of parasitic infections caused by systemic protozoa such as the causative agents of malaria, leishmaniasis, toxoplasmosis or Chagas disease. Therefore, we performed a systematic search and a narrative review of the state-of-of-the-art in the use of statins or aspirin as potential therapies to modify host factors in treating parasitic diseases, the most neglected of all infectious diseases, to identify the potential benefits of aspirin or statins in the treatment of these parasitic diseases, based on their properties for modulating the inflammatory response.MethodologyThe present work was structured as a narrative review based on a systematic search for articles on the use of aspirin or statins in experimental models or clinical studies of parasitic infections caused by Plasmodium, Leishmania, Toxoplasma or Trypanosoma.The database used for the search was PUBMED (<a href="https://pubmed.ncbi.nlm.nih.gov/">https://pubmed.ncbi.nlm.nih.gov/</a>). The parasitic diseases included in this study were Chagas disease, leishmaniasis, malaria, and toxoplasmosis. These infectious diseases were included because of their epidemiological importance or the difficulties in finding an effective therapy.The search strategy was designed using terms included in “all fields” or as a medical subject heading (MeSH). The subheading “pharmacological action” was used as an additional descriptor.For the aspirin search, the terms “aspirin” or “acetylsalicylic acid” were used. For the statin search, “statin” OR “lovastatin”, “simvastatin”, “pravastatin”, “atorvastatin”, “fluvastatin”, “rosuvastatin”, and “pitavastatin”.For the parasitic diseases, the keywords used were “Trypanosoma cruzi”, “Chagas disease”, “Trypanosomabrucei”, “African trypanosomiasis”, “Toxoplasma gondii”, “toxoplasmosis”, “malaria”, “Plasmodium falciparum”, “Plasmodium vivax”, “Plasmodium malariae”, “Plasmodium ovale”, “leishmaniasis”, “Leishmania tropica”, “Leishmania donovani”, “Leishmania major”, “Leishmania Mexicana”, “Leishmania amazonensis” and “Leishmania infantum”.Inclusion criteria were (1) English language of publication, (2) articles published between 2015 and 2022, (3) original article, (4) in vitro or in vivo study design. The in vivo studies included animal or human models (prospective or retrospective clinical trials).Two hundred thirty-two (232) hits were retrieved, and after applying the inclusion criteria, 38 studies were obtained and included in this narrative review (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>When necessary, works before 2011 were mentioned to contextualize the concepts discussed.Role of aspirin and statins in the therapy of some parasitic diseases of medical interestMalaria infectionsMalaria, caused by protozoa of the Plasmodium genus, is the most important parasitic disease in the world, with a high burden of disease and mortality<a class="elsevierStyleCrossRef" href="#bib0950">79</a>. P. falciparum is responsible for 95% of morbidity and mortality, including severe manifestations derived from brain involvement, reaching a mortality rate of 10–20%<a class="elsevierStyleCrossRef" href="#bib0950">79</a>. Although its incidence has been decreasing<a class="elsevierStyleCrossRef" href="#bib0655">20</a>, one of the main problems of this disease is the emergence of resistance to pharmacological treatment and insecticides used for vector control; therefore, its control has not been easy<a class="elsevierStyleCrossRefs" href="#bib1075">104,109</a>. Moreover, it is necessary to create new treatment strategies with consistent efficiency and new drug combinations to protect and reduce severe and resistant forms of malaria<a class="elsevierStyleCrossRef" href="#bib1100">109</a>. Thus, statins or aspirin could play a role in modulating the inflammatory response to infection by the Plasmodium parasite.From 2015 to date, only two articles were found reporting the effectiveness of lovastatin or atorvastatin in reducing the cerebral inflammatory response to P. berghei infection in a cerebral malaria model<a class="elsevierStyleCrossRefs" href="#bib0620">13,68</a>. For this reason, the search was extended to cover a longer period of 10 years (2011–2022). This strategy yielded 20 articles, only eight of which studied the modulation of host factors with statins. The remaining articles fell beyond the focus of the present review because they report the activity of statins or their analogs directly on Plasmodium in vitro models.The concept of the use of statins in malaria is not without controversy. On the one hand, in 2009, Helmers et al. reported that statins do not protect against cerebral malaria in an experimental murine model<a class="elsevierStyleCrossRef" href="#bib0755">40</a>; moreover, in a preclinical trial, the administration of atorvastatin did not alter the course of infection with P. bergei, although it acted synergistically with methylene blue<a class="elsevierStyleCrossRef" href="#bib0675">24</a>. On the other hand, preliminary in vitro studies suggest a direct effect of statins on the parasite<a class="elsevierStyleCrossRef" href="#bib0935">76</a>. However, importantly, there is preclinical evidence pointing to the control of neuroinflammation by decreasing endothelial damage<a class="elsevierStyleCrossRefs" href="#bib0620">13,68,98</a> and even improving cognitive alterations caused by cerebral malaria<a class="elsevierStyleCrossRef" href="#bib0955">80</a>. Moreover, the combined therapy of atorvastatin with artemeter<a class="elsevierStyleCrossRef" href="#bib1080">105</a>, dihydroartemisinin<a class="elsevierStyleCrossRef" href="#bib0680">25</a> or mefloquine<a class="elsevierStyleCrossRef" href="#bib1030">95</a> can alter the course of cerebral infection, reducing mortality from this cause in murine models infected with P.bergei<a class="elsevierStyleCrossRefs" href="#bib0680">25,95</a>.Only one article met inclusion criteria for aspirin in malaria. Although it sounds logical to think that prostaglandin synthesis inhibition could influence the host response in malaria, considering the endothelial and platelet alterations observed during plasmodial infection, studies in this regard are scarce and controversial. Indeed, it has been suggested that prostaglandins may protect against endothelial damage<a class="elsevierStyleCrossRef" href="#bib1095">108</a>; moreover, following a prospective, randomized study in 97 patients with P. falciparum infection, aspirin did not alter the course of the disease<a class="elsevierStyleCrossRef" href="#bib0760">41</a>. However, in a recent study in a murine model of P. yoelii-induced renal failure, aspirin prevented renal cell damage, especially in mice subjected to monocytic depletion<a class="elsevierStyleCrossRef" href="#bib1055">100</a>. Therefore, further preclinical studies are needed to support aspirin as an adjuvant in malaria therapy.Toxoplasma gondii infectionsToxoplasma gondii is an apicomplexan intracellular parasite that can infect humans, producing a generally asymptomatic infection, but with the persistence of the parasite in tissues in the form of cysts<a class="elsevierStyleCrossRef" href="#bib0820">53</a>, which can be activated by immunosuppression<a class="elsevierStyleCrossRef" href="#bib0765">42</a>. The most severe consequences of congenital infection in the fetus are observed during pregnancy<a class="elsevierStyleCrossRef" href="#bib0875">64</a>, in addition to severe ocular sequelae in immunosuppressed patients<a class="elsevierStyleCrossRef" href="#bib0690">27</a>. It is a public health concern whose pharmacological treatment is ineffective due to the persistence of cysts in infected tissues. However, in symptomatic and congenital cases, a combination of pyrimethamine and sulfadiazine is used, which blocks folate synthesis, with the consequent risk of causing hematological toxicity in the host due to the high doses required and the prolonged duration of treatments<a class="elsevierStyleCrossRef" href="#bib0740">37</a>. However, trimethoprim–sulfamethoxazole, which is less toxic, is an affordable alternative for some patients<a class="elsevierStyleCrossRef" href="#bib1070">103</a>. Therefore, the search for alternative treatments is necessary<a class="elsevierStyleCrossRef" href="#bib0560">1</a>. Modifying host factors has been proposed owing to the manipulation performed by the parasite for its continuous replication and survival in the host cell<a class="elsevierStyleCrossRef" href="#bib0825">54</a>. However, few studies analyze the effect of aspirin and statins in toxoplasmosis.The use of statins as an experimental pharmacological strategy for the modification of host factors in models of toxoplasmosis is reported in six articles published in the last seven years. The availability of isoprenoids in both parasite and host had been previously suggested<a class="elsevierStyleCrossRef" href="#bib0825">54</a>, being essential for establishing the pathogen-host relationship, which can be altered using atorvastatin. However, it has been recently reported that only high doses of atorvastatin inhibited enteric cell invasion, suggesting that de novo synthesis of isoprenoids is not essential for replication<a class="elsevierStyleCrossRef" href="#bib0855">60</a>. Moreover, when atorvastatin is combined with bisphosphonates, there is a synergistic effect on isoprenoid production and, therefore, on decreasing the parasite load by reducing its replicative capacity<a class="elsevierStyleCrossRefs" href="#bib0820">53,54</a>. Furthermore, rosuvastatin inhibited intracellular replication of T. gondii in HeLa cells<a class="elsevierStyleCrossRef" href="#bib0975">84</a>. Still, in addition, pravastatin and simvastatin, combined with low doses of pyrimethamine-sulfadiazine, synergistically decreased tachyzoite infection in HeLa cells<a class="elsevierStyleCrossRef" href="#bib0970">83</a>, reducing the host levels of cytokines IL-6 and IL-7, responsible, in part, for the spread of the disease<a class="elsevierStyleCrossRef" href="#bib0965">82</a>. These findings are supported by a recent study in which rosuvastatin decreased brain parasite load and local inflammation in a murine model of toxoplasmosis<a class="elsevierStyleCrossRef" href="#bib0910">71</a> and improved the neurological alterations produced by the infection, including memory disorders<a class="elsevierStyleCrossRef" href="#bib0685">26</a>. Those findings suggest that rosuvastatin could be helpful in the treatment of chronic toxoplasmosis.The search strategy for the use of aspirin did not yield results in the last seven years. However, preliminary reports link PGE2 production and IL-10 secretion with a neuroprotective effect against T. gondii infection<a class="elsevierStyleCrossRef" href="#bib0960">81</a>. In addition, this same effect could contribute to regulating the innate immune response since when mice were treated with T. gondii extracts, a significant increase in the production of lipoxin A4 was reported. Lipoxin A4-epimer can be induced by aspirin, related to the suppression of cytokine signaling mediated by SOCS2<a class="elsevierStyleCrossRef" href="#bib0860">61</a>.Leishmania spp. infectionsLeishmaniasis is a group of endemic diseases caused by different species of parasites of the genus Leishmania. They are obligate intracellular parasites infecting host macrophages, causing significant morbidity and mortality worldwide<a class="elsevierStyleCrossRef" href="#bib0785">46</a>. They are transmitted to humans by the bite of female insects of the Phlebotomus and Lutzomyia genus, generating a cutaneous infection in most cases and, less frequently, affecting the liver and spleen, which can be fatal if left untreated<a class="elsevierStyleCrossRefs" href="#bib0565">2,43</a>. To date, no effective vaccines exist, and the pharmacological treatment includes pentavalent antimonial agents<a class="elsevierStyleCrossRef" href="#bib0770">43</a>. However, the antifungal amphotericin B, the aminoglycoside paromomycin, and the phospholipid metabolism inhibitor miltefosine have also shown efficacy. They are directed against the parasite but require monitoring and evaluation of serious adverse effects or the emergence of resistance<a class="elsevierStyleCrossRef" href="#bib0770">43</a>. Therefore, it is of utmost importance for searching drugs with antiparasitic activity, as well as adjuvants or those that control the inflammatory process of the host and could intervene in the parasite invasion in macrophages<a class="elsevierStyleCrossRef" href="#bib0745">38</a>.In this regard, only three studies were identified using the search strategy described above in the context of Leishmania infections. An in vitro study with L. donovani highlights the importance of an adequate cholesterol level in host cells for optimal parasite entry because chronic cholesterol depletion caused by lovastatin reduced promastigote binding to the macrophage surface, with a consequently lower intracellular amastigote load<a class="elsevierStyleCrossRef" href="#bib0785">46</a>. This finding suggests that lowering cholesterol content with statins in the host cell membrane could be effective for infection control<a class="elsevierStyleCrossRef" href="#bib0785">46</a>. Moreover, Haughan et al. previously reported that inhibition of sterol synthesis with lovastatin and miconazole is synergistic<a class="elsevierStyleCrossRef" href="#bib0750">39</a>. However, Ghosh et al. found that an atherogenic diet in mice could be protective against L. donovani infection since the parasite extracts cholesterol from the membrane preventing T-cell activation<a class="elsevierStyleCrossRef" href="#bib0715">32</a>; thus, statin-induced cholesterol depletion could increase susceptibility to infection. However, the intracellular parasite load did not improve, suggesting a role of statin in controlling parasite growth<a class="elsevierStyleCrossRef" href="#bib0715">32</a>, as sterol synthesis by the parasite can be inhibited by mevastatin, the first statin of its kind, affecting cell replication<a class="elsevierStyleCrossRef" href="#bib0670">23</a>. The use of simvastatin in a model of cutaneous leishmaniasis caused by L. major decreased the local parasite load and inflammation by accelerating phagosome maturation and enhancing the oxidative burst in macrophages<a class="elsevierStyleCrossRef" href="#bib0930">75</a>; which had been previously described with pravastatin in a murine model with L.amazoniensis<a class="elsevierStyleCrossRefs" href="#bib0775">44,45,70</a>.Only one recent report suggests that aspirin decreases the parasite load in macrophages, improves the phagocytic activity of these cells and modulates cytokine secretion<a class="elsevierStyleCrossRef" href="#bib0580">5</a>. However, more research on this drug is needed for leishmaniasis.Trypanosoma cruzi infectionT. cruzi is the protozoan responsible for Chagas disease, an endemic illness in Latin America, which is treated with benznidazole and nifurtimox<a class="elsevierStyleCrossRef" href="#bib0695">28</a>. Both agents have high toxicity and limited efficacy, especially in the chronic phase of the disease<a class="elsevierStyleCrossRef" href="#bib0945">78</a>. In 30% of cases, without adequate treatment, the disease may progress to a chronic inflammatory stage, causing heart failure, arrhythmias, and death<a class="elsevierStyleCrossRef" href="#bib0570">3</a>. Different therapeutic strategies have been sought, where statins and aspirin could be candidates for repositioning<a class="elsevierStyleCrossRef" href="#bib0595">8</a>.Seven experimental studies had been identified since 2015 to date, in which a statin was tested in murine models. Considering that T. cruzi has an affinity for cholesterol and that the parasite uses the LDL receptor as part of the mechanism to infect cells, the role of atorvastatin in lipid metabolism is studied, reporting a deleterious effect on the course of the disease, especially in subjects fed a high-fat diet<a class="elsevierStyleCrossRef" href="#bib1105">110</a>. However, Soares de Souza et al. observed that simvastatin can mitigate disease progression in a similar model<a class="elsevierStyleCrossRef" href="#bib0665">22</a>. Notwithstanding the role that statins may have on the mechanics of T. cruzi infection, it is more likely that their actions in the chronic phase are related to the modulation of inflammation induced by the persistence of the parasite. Thus, it has been suggested that simvastatin could have anti-inflammatory potential in models of acute Chagas disease<a class="elsevierStyleCrossRef" href="#bib1020">93</a>. Moreover, Campos-Estrada et al. proposed that simvastatin triggers the production of 15-epi-LXA4 in endothelial cell models<a class="elsevierStyleCrossRef" href="#bib0615">12</a>, although without causing a synergistic effect with benznidazole. However this synergism could exist, according to Araujo-Lima et al., who also highlights the low cardiotoxigenic potential of atorvastatin<a class="elsevierStyleCrossRef" href="#bib0575">4</a>, probably facilitating parasite clearance in cardiac tissue induced by the resolution of inflammation<a class="elsevierStyleCrossRef" href="#bib0720">33</a>. Moreover, treating T. cruzi-infected human umbilical vein endothelial cells (HUVEC) with simvastatin promotes the differential expression of inflammation-related genes. Furthermore, simvastatin treatment of human umbilical vein endothelial cells infected with T. cruzi promotes the differential expression of inflammation-related genes. It also influences the Notch1<a class="elsevierStyleCrossRef" href="#bib0610">11</a> pathway, which is related to cardiac development in the embryo and may also participate in the cardiac protective effect of simvastatin during the chronic phase of the disease<a class="elsevierStyleCrossRef" href="#bib0730">35</a>.Cyclooxygenase (COX) is a relevant player in the pathophysiology of T. cruzi infection<a class="elsevierStyleCrossRef" href="#bib0725">34</a>, and much has been studied since the publication of the relationship of prostaglandins and the phagocytosis of apoptotic bodies<a class="elsevierStyleCrossRef" href="#bib0700">29</a>. Since 2015, 12 studies have been published linking aspirin as a potential modulator of the course of T. cruzi infection. During the acute phase and as an evasive measure, the parasite modifies the macrophage response, generating an anti-inflammatory environment resulting from the production of prostaglandin E2 and the activation of TGF-β, especially in the presence of apoptotic T lymphocyte apoptotic bodies<a class="elsevierStyleCrossRef" href="#bib0700">29</a>. Additionally, COX inhibition has been reported to facilitate parasite survival in the host<a class="elsevierStyleCrossRefs" href="#bib0890">67,69</a>. Furthermore, COX involvement in the invasion process has been recently demonstrated in a process inhibited by aspirin<a class="elsevierStyleCrossRefs" href="#bib0630">15,56,69</a>.In an in vivo model of chronic Chagas disease, it was observed that aspirin treatment during the acute phase was able to prevent damage to esophageal nitrergic myenteric neurons<a class="elsevierStyleCrossRef" href="#bib0870">63</a>. Those findings were corroborated in another study comparing aspirin administration during the acute or chronic phase, which showed a significant decrease in colonic inflammatory foci associated with a neuroprotective effect on myenteric neurons<a class="elsevierStyleCrossRefs" href="#bib0870">63,72,96</a>. Moreover, it has been reported that aspirin could have some beneficial impact on the neurological manifestations of Chagas disease, as it prevents behavioral alterations in mice acutely infected with T.cruzi<a class="elsevierStyleCrossRef" href="#bib1025">94</a>. Moreover, the early use of aspirin in combination with benznidazole proved effective in preventing chronic heart disease<a class="elsevierStyleCrossRef" href="#bib0945">78</a>. Its use during the chronic phase of the disease can prevent the progression of cardiomyopathy, decreasing endothelial activation, cardiac inflammatory infiltrate, and fibrosis, probably by generating pro-resolving lipid mediators of inflammation such as 15-epi-LXA4 and AT-RvD1, among others<a class="elsevierStyleCrossRefs" href="#bib0625">14,58,65,66,73</a>. In a pilot study in humans, aspirin showed efficacy in reducing the symptoms associated with microvascular abnormalities caused by Chagas heart disease<a class="elsevierStyleCrossRef" href="#bib0940">77</a>.Despite the controversy about the role of COX inhibitors in T. cruzi infection<a class="elsevierStyleCrossRef" href="#bib0650">19</a>, there is abundant evidence supporting the immunomodulatory role of aspirin in the context of Chagas disease<a class="elsevierStyleCrossRefs" href="#bib0840">57,62</a>. However, there are still no clinical studies to corroborate this. On the other hand, there are no studies evaluating the use of statins or aspirin in the context of T. brucei infections during the period analyzed.ConclusionsThe relationship between a pathogen and its host determines the course of infection and defines whether the infection progresses or is effectively contained. Progression of infection can have deleterious consequences for the host because it can lead to disability or death. Immunity is one of these major determinants in the host–pathogen relationship. Parasitosis is not excluded from this interaction. However, therapeutic development to expand the antiparasitic pharmacological arsenal is insufficient, slow, or non-existent. Programs such as the Drugs for Neglected Diseases initiative seek to correct this scenario. The active search for compounds capable of modifying key aspects of the inflammatory process that are already approved for use in humans, have proven to be safe and reasonably priced, and a sound strategy<a class="elsevierStyleCrossRef" href="#bib0600">9</a>. In the present review, we present state-of-the-art agents such as aspirin and statins, which induce the production of inflammation-resolving agents and, therefore, could eventually change the course of infections, not only parasitic, as we have seen, but also bacterial or fungal infections. The uncontrolled nature of the inflammatory response in severe SARS-CoV2 infections, leading to patient death in many cases<a class="elsevierStyleCrossRef" href="#bib0925">74</a>, boosted the field for exploring the use of agents to modulate the host factors<a class="elsevierStyleCrossRef" href="#bib0980">85</a>. The prevention of organ damage induced by the persistence of the pathogen and the functional recovery of the innate immune response that prevents chronic inflammation are elements that can help to improve the efficacy of specific anti-infective treatments.Undoubtedly other strategies to modify the host response would make more sense because they are more direct and probably broader in the spectrum, such as the direct blockade of TNF-α action or interferon-γ administration<a class="elsevierStyleCrossRef" href="#bib1110">111</a>. However, these agents are not without adverse events, producing increased susceptibility to infections or severe arthropathy, respectively. Moreover, in many cases, they are also expensive. On the other hand, the use of vaccines for managing and preventing parasitic infections is far from optimal, and little progress has been made in this field, except for the RTS S/AS01 malaria vaccine<a class="elsevierStyleCrossRef" href="#bib0655">20</a>.Unfortunately, the evidence supporting the utility of aspirin in inducing inflammation resolution is not strong. Moreover, the potential for severe reactions such as, for example, bleeding or gastric intolerance considerably diminishes the attractiveness of its use in humans, especially in parasitic diseases, mainly if they are chronic such as in Chagas disease or leishmaniasis. However, this drug may be helpful for further study of the phenomena of inflammation resolution in parasitic infections, as well as other immunopathogenic mechanisms that can be further modified with immunomodulatory drugs.Furthermore, although our literature review mainly focused on in vitro and in vivo experimental models, a beneficial effect is glimpsed with statins as adjuvant therapy through their cholesterol lowering-independent effects, also called pleiotropic. Although the isoprenoid metabolism in parasites can be directly inhibited by statins, halting their growth, there is no doubt that modulating the host response to the pro-inflammatory effects of infection is an attractive alternative. This effect must necessarily be proven in human studies. The study of modulating the resolution of inflammation with statins is a very active field in which they have also been tested for viral<a class="elsevierStyleCrossRef" href="#bib0810">51</a> and bacterial infections<a class="elsevierStyleCrossRef" href="#bib0590">7</a>, including tuberculosis<a class="elsevierStyleCrossRef" href="#bib0815">52</a>, COVID-19<a class="elsevierStyleCrossRef" href="#bib0980">85</a>, and septicemia<a class="elsevierStyleCrossRef" href="#bib0710">31</a>.Thus, the modulation of host factors is an attractive tool to help combat these diseases in a context of emerging treatment resistance and spread to non-endemic areas, with the consequent risk of severe epidemic outbreaks. Because it is still controversial<a class="elsevierStyleCrossRef" href="#bib0705">30</a>, it is necessary to improve the strength of evidence, determine the most effective statin, and, most importantly, analyze the clinical outcomes to further understand statin use in parasitic diseases.FundingThis work was funded by Agencia Nacional de Investigacion y Desarrollo (ANID) programa FONDECYT, grant number 1210359.Conflict of interestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1976953" "titulo" => "Highlights" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:3 [ "identificador" => "xres1976954" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 2 => array:2 [ "identificador" => "xpalclavsec1700525" "titulo" => "Keywords" ] 3 => array:3 [ "identificador" => "xres1976955" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0015" ] ] ] 4 => array:2 [ "identificador" => "xpalclavsec1700524" "titulo" => "Palabras clave" ] 5 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 6 => array:2 [ "identificador" => "sec0010" "titulo" => "Methodology" ] 7 => array:3 [ "identificador" => "sec0015" "titulo" => "Role of aspirin and statins in the therapy of some parasitic diseases of medical interest" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Malaria infections" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Toxoplasma gondii infections" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Leishmania spp. infections" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Trypanosoma cruzi infection" ] ] ] 8 => array:2 [ "identificador" => "sec0040" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0045" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflict of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2022-07-28" "fechaAceptado" => "2023-01-26" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1700525" "palabras" => array:6 [ 0 => "Parasitic diseases" 1 => "Resolution of inflammation" 2 => "Lipoxins" 3 => "Resolvins" 4 => "Aspirin" 5 => "Statins" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1700524" "palabras" => array:6 [ 0 => "Parasitosis" 1 => "Resolución de la inflamación" 2 => "Lipoxinas" 3 => "Resolvinas" 4 => "Aspirina" 5 => "Estatinas" ] ] ] ] "tieneResumen" => true "highlights" => array:2 [ "titulo" => "Highlights" "resumen" => "<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">•Aspirin or statins through pro-resolving lipids may improve inflammation in parasitosis.</li><li class="elsevierStyleListItem" id="lsti0010">•Statins in cerebral malaria reduce mortality in murine models of infection.</li><li class="elsevierStyleListItem" id="lsti0015">•In toxoplasmosis, statin use is controversial, although it decreases cytokines.</li><li class="elsevierStyleListItem" id="lsti0020">•In leishmaniasis, statins decrease local inflammation.</li><li class="elsevierStyleListItem" id="lsti0025">•In Chagas disease, aspirin or statins decrease cardiac inflammation in murine models.</li></ul>" ] "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Infections, including zoonoses, constitute a threat to human health due to the spread of resistant pathogens. These diseases generate an inflammatory response controlled by a resolving mechanism involving specialized membrane lipid-derived molecules called lipoxins, resolvins, maresins, and protectins. The production of some of these molecules can be triggered by aspirin or statins. Thus, it is proposed that modulation of the host response could be a useful therapeutic strategy, contributing to the management of resistance to antiparasitic agents or preventing drift to chronic, host-damaging courses. Therefore, the present work presents the state of the art on the use of statins or aspirin for the experimental management of parasitic infections such as Chagas disease, leishmaniasis, toxoplasmosis or malaria. The methodology used was a narrative review covering original articles from the last seven years, 38 of which met the inclusion criteria. Based on the publications consulted, modulation of the resolution of inflammation using statins may be feasible as an adjuvant in the therapy of parasitic diseases. However, there was no strong experimental evidence on the use of aspirin; therefore, further studies are needed to evaluate its role inflammation resolution process in infectious diseases." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Las infecciones, incluyendo las zoonosis, constituyen una amenaza a la salud humana debido a la diseminación de patógenos resistentes. Estas enfermedades generan una respuesta inflamatoria controlada por un mecanismo de resolución, en el que participan moléculas especializadas derivadas de lípidos de membrana llamadas lipoxinas, resolvinas, maresinas y protectinas. La producción de algunas de estas moléculas puede ser gatillada por aspirina o estatinas. Así, se propone que la modulación de la respuesta del hospedero podría ser una estrategia terapéutica útil, que contribuye al manejo de la resistencia a agentes antiparasitarios o que puede prevenir la derivación hacia cursos crónicos, dañinos para el hospedero. En esta revisión se presenta una puesta al día sobre el uso de estatinas o aspirina para el manejo experimental de infecciones parasitarias, como enfermedad de Chagas, leishmaniasis, toxoplasmosis y malaria. Se hizo una revisión narrativa, buscando artículos originales de los últimos siete años, se encontraron 38 que cumplieron con los criterios de inclusión. De acuerdo con las publicaciones consultadas, la resolución de la inflamación modulada mediante estatinas podría ser un adyuvante en la terapia de enfermedades parasitarias. Por otro lado, no se observó una evidencia experimental fuerte con respecto al uso de aspirina, por lo que se recomiendan más estudios para evaluar su rol en el proceso de resolución de la inflamación en enfermedades infecciosas." ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="8" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Total HITS: 232</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="4" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Aspirin108</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="4" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Statins124</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Chagas disease36 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Leishmaniasis9 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Toxoplasmosis8 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Malaria53 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Chagas disease34 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Leishmaniasis24 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Toxoplasmosis53 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Malaria13 \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="8" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">After applying the inclusion criteria</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12<a class="elsevierStyleCrossRefs" href="#bib0625">14,15,19,22,34,56,63,72,73,77,78,94,96</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1<a class="elsevierStyleCrossRef" href="#bib0580">5</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1<a class="elsevierStyleCrossRef" href="#bib1055">100</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7<a class="elsevierStyleCrossRefs" href="#bib0575">4,11,12,22,33,36,110</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3<a class="elsevierStyleCrossRefs" href="#bib0670">23,46,75</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6<a class="elsevierStyleCrossRefs" href="#bib0685">26,53,60,71,82–84</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRef" href="#tblfn0005">*</a>8<a class="elsevierStyleCrossRefs" href="#bib0620">13,24,25,68,80,95,98,105</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3290895.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "*" "nota" => "From 2015 to 2022 two articles were retrieved, and six additional articles were retrieved from 2011 to 2014." ] ] ] "descripcion" => array:1 [ "en" => "Selection of articles after applying the search strategy and inclusion criteria." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:111 [ 0 => array:3 [ "identificador" => "bib0560" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Drugs in development for toxoplasmosis: advances, challenges, and current status" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2147/DDDT.S60973" "Revista" => array:6 [ "tituloSerie" => "Drug Des Devel Ther" "fecha" => "2017" "volumen" => "11" "paginaInicial" => "273" "paginaFinal" => "293" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0565" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Behaviors and perceptions related to cutaneous leishmaniasis in endemic areas of the world: a review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.actatropica.2021.106090" "Revista" => array:4 [ "tituloSerie" => "Acta Trop" "fecha" => "2021" "volumen" => "223" "paginaInicial" => "106090" ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0570" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Systematic review of historical and current trends in Chagas disease" "autores" => 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Uso de estatinas y aspirina en infecciones parasitarias como potencial estrategia terapéutica: Una revisión narrativa

Valentina Burgessa, Juan D. Mayab,

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jdmaya@uchile.cl

Corresponding author.

a Escuela de Medicina, Facultad de Medicina, Universidad de Chile, Independencia, Santiago, Chile

b Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Independencia, Santiago, Chile

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among others&#44; is promoted&#44; depending on the type of pathogen involved&#46; Free radicals are also generated&#44; facilitating phagocytosis<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">10&#44;97</span></a>&#44; triggering the inflammatory process&#46; Although essential for eliminating pathogens&#44; the prompt re-establishment of homeostasis is required through the resolution of inflammation&#46; When this resolution is inadequate&#44; inflammation gets out of control&#44; causing further tissue damage or installing chronic processes&#44; with or without active infection<a class="elsevierStyleCrossRefs" href="#bib1040"><span class="elsevierStyleSup">97&#44;102</span></a>&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The resolution of inflammation is a highly regulated process orchestrated by multiple mediators&#44; the so-called specialized pro-resolving mediators &#40;SPMs&#41;<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">46</span></a>&#44; a superfamily of lipid molecules derived from the &#969;-3 and &#969;-6 polyunsaturated fatty acids of the plasma membrane&#44; grouped into four classes&#58; lipoxins A4 and B4 &#40;LXA4&#44; LXB4&#41;&#44; derived from arachidonic acid&#59; resolvins &#40;Rv&#41; D1-6&#44; protectins &#40;PD&#41; and maresins &#40;MaR&#41;&#44; derived from docosahexaenoic acid &#40;DHA&#41;&#59; and Rv E1-4&#44; derived from eicosapentaenoic acid &#40;EPA&#41;<a class="elsevierStyleCrossRefs" href="#bib0645"><span class="elsevierStyleSup">18&#44;48</span></a>&#46; SPMs are described as potent anti-inflammatory molecules with an immunoregulatory role<a class="elsevierStyleCrossRef" href="#bib0795"><span class="elsevierStyleSup">48</span></a>&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">SPMs are synthesized by several lipooxygenases in different cell types&#44; including neutrophils and macrophages&#44; and act on various G protein-coupled receptors&#44; such as Formyl Peptide Receptor-2 &#40;FPR2&#41; or G protein-coupled receptor 32 &#40;GPR32&#41;<a class="elsevierStyleCrossRef" href="#bib0990"><span class="elsevierStyleSup">87</span></a>&#46; The process is initiated during the exudate formation in the active phase of inflammation&#46; The classic initiators&#44; prostaglandins and leukotrienes&#44; are key in the subsequent switch of lipid mediators<a class="elsevierStyleCrossRef" href="#bib1005"><span class="elsevierStyleSup">90</span></a>&#44; activating the expression of the enzymes necessary for producing SPMs<a class="elsevierStyleCrossRef" href="#bib0850"><span class="elsevierStyleSup">59</span></a>&#46; During this process&#44; LXs<a class="elsevierStyleCrossRef" href="#bib0990"><span class="elsevierStyleSup">87</span></a> appear first&#44; followed by Rvs and&#44; finally&#44; PDs and MaRs<a class="elsevierStyleCrossRef" href="#bib0995"><span class="elsevierStyleSup">88</span></a>&#59; however&#44; the resolution is more a result of the concerted action of these mediators than of the time course of their secretion&#59; although it is clear that their early appearance guarantees the self-limiting nature of the inflammation<a class="elsevierStyleCrossRef" href="#bib1015"><span class="elsevierStyleSup">92</span></a>&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The resolution of inflammation is aimed&#44; in part&#44; at clearing the pathogenic load through the SPMs&#46; These are also responsible for promoting local neutrophil apoptosis&#44; reducing the systemic inflammatory response by decreasing the production of cytokines and other Nuclear Factor &#954;B &#40;NF&#954;B&#41;-associated products&#44; and increasing the production of IL-10 and nitric oxide in macrophages<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">47</span></a>&#46; In addition&#44; they increase phagocytosis of apoptotic leukocytes &#40;efferocytosis&#41; and pathogen clearance by tissue macrophages<a class="elsevierStyleCrossRefs" href="#bib0790"><span class="elsevierStyleSup">47&#44;102</span></a>&#46; For these reasons&#44; SPMs have high therapeutic potential in managing inflammation<a class="elsevierStyleCrossRef" href="#bib1000"><span class="elsevierStyleSup">89</span></a>&#44; including the possibility of circumventing the adverse reactions and immunosuppression associated with the treatment of hyperinflammatory states triggered by severe infections&#44; such as sepsis or COVID-19<a class="elsevierStyleCrossRef" href="#bib0925"><span class="elsevierStyleSup">74</span></a>&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Interestingly&#44; the synthesis of SPMs can be triggered by the prostaglandin production inhibitor aspirin since cyclooxygenase 2 &#40;COX2&#41; acetylation blocks prostaglandin synthesis and&#44; at the same time&#44; confers the ability to produce the epimer intermediates 15R-HETE from arachidonic acid&#44; 18R-HEPE from EPA and 17R-HDHA from DHA&#46; Neutrophils transform these intermediates into lipoxins&#44; resolvins&#44; and protectins triggered by aspirin<a class="elsevierStyleCrossRef" href="#bib1010"><span class="elsevierStyleSup">91</span></a>&#46; Likewise&#44; statins&#44; inhibitors of 3-hydroxy-methyl-glutaryl coenzyme A reductase&#44; lower blood cholesterol levels and have other effects&#44; called pleiotropic&#44; by decreasing the synthesis of isoprenoids&#44; intermediates in the mevalonate pathway<a class="elsevierStyleCrossRef" href="#bib0985"><span class="elsevierStyleSup">86</span></a>&#46; These effects include regulation of endothelial function&#44; coagulation&#44; and anti-inflammatory actions such as reduced leukocyte migration and proinflammatory cytokine generation<a class="elsevierStyleCrossRef" href="#bib0830"><span class="elsevierStyleSup">55</span></a>&#46; Statins induce COX2 nitrosylation&#44; generating the same epimer intermediates of SPMs as aspirin but causing S-nitrosylation<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">49</span></a>&#44; explaining&#44; in part&#44; the anti-inflammatory effects of statins<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">21</span></a>&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">SPMs are relevant in acute infections because they shorten the inflammatory interval and increase the elimination of bacteria and other microorganisms&#59; eventually&#44; allowing the decrease in antibiotic doses<a class="elsevierStyleCrossRefs" href="#bib0640"><span class="elsevierStyleSup">17&#44;90</span></a>&#46; Therefore&#44; the relationship between infection and resolution is attractive due to the immunosuppressive potential of some anti-inflammatory agents<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">30</span></a>&#46; For example&#44; in self-limited <span class="elsevierStyleItalic">Escherichia coli</span> infections&#44; resolution programs are activated&#44; and PD1 and RvD1&#44; and D5 levels are elevated<a class="elsevierStyleCrossRefs" href="#bib0660"><span class="elsevierStyleSup">21&#44;22</span></a>&#46; In addition&#44; LXA4&#44; Rv D1&#44; and MaR1 increase the survival of mice with experimental sepsis<a class="elsevierStyleCrossRefs" href="#bib0635"><span class="elsevierStyleSup">16&#44;50&#44;107</span></a>&#59; moreover&#44; LXA4 decreases biofilm formation by <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> while increasing the ability of ciprofloxacin and imipenem to kill this bacterium<a class="elsevierStyleCrossRef" href="#bib1060"><span class="elsevierStyleSup">101</span></a>&#46; Interestingly&#44; a recent report links the protective effect of the antimalarial artesunate to the activation of GPR32&#44; another SPM receptor&#44; mimicking the effects of PD1 on macrophages in the context of murine <span class="elsevierStyleItalic">Plasmodium</span> infections and <span class="elsevierStyleItalic">Listeria</span> sepsis<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">6</span></a>&#46; Thus&#44; given the importance of antimicrobial resistance&#44; a pharmacological intervention of resolution could provide a different approach to decreasing exposure to antibiotics<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">17</span></a>&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Modulating the host response with statins or aspirin may be helpful in the therapeutics of infections with significant inflammatory components&#46; It could contribute to managing antimicrobial resistance or prevent referral to potentially harmful chronic courses&#46; Thus&#44; it is interesting to ask whether the modulation of relevant host factors with aspirin or a statin could be beneficial for the adjuvant treatment of parasitic infections caused by systemic protozoa such as the causative agents of malaria&#44; leishmaniasis&#44; toxoplasmosis or Chagas disease&#46; Therefore&#44; we performed a systematic search and a narrative review of the state-of-of-the-art in the use of statins or aspirin as potential therapies to modify host factors in treating parasitic diseases&#44; the most neglected of all infectious diseases&#44; to identify the potential benefits of aspirin or statins in the treatment of these parasitic diseases&#44; based on their properties for modulating the inflammatory response&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Methodology</span><p id="par0070" class="elsevierStylePara elsevierViewall">The present work was structured as a narrative review based on a systematic search for articles on the use of aspirin or statins in experimental models or clinical studies of parasitic infections caused by <span class="elsevierStyleItalic">Plasmodium</span>&#44; <span class="elsevierStyleItalic">Leishmania</span>&#44; <span class="elsevierStyleItalic">Toxoplasma</span> or <span class="elsevierStyleItalic">Trypanosoma</span>&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">The database used for the search was PUBMED &#40;<a href="https://pubmed.ncbi.nlm.nih.gov/">https&#58;&#47;&#47;pubmed&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;</a>&#41;&#46; The parasitic diseases included in this study were Chagas disease&#44; leishmaniasis&#44; malaria&#44; and toxoplasmosis&#46; These infectious diseases were included because of their epidemiological importance or the difficulties in finding an effective therapy&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The search strategy was designed using terms included in &#8220;all fields&#8221; or as a medical subject heading &#40;MeSH&#41;&#46; The subheading &#8220;pharmacological action&#8221; was used as an additional descriptor&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">For the aspirin search&#44; the terms &#8220;aspirin&#8221; or &#8220;acetylsalicylic acid&#8221; were used&#46; For the statin search&#44; &#8220;statin&#8221; OR &#8220;lovastatin&#8221;&#44; &#8220;simvastatin&#8221;&#44; &#8220;pravastatin&#8221;&#44; &#8220;atorvastatin&#8221;&#44; &#8220;fluvastatin&#8221;&#44; &#8220;rosuvastatin&#8221;&#44; and &#8220;pitavastatin&#8221;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">For the parasitic diseases&#44; the keywords used were &#8220;<span class="elsevierStyleItalic">Trypanosoma cruzi</span>&#8221;&#44; &#8220;Chagas disease&#8221;&#44; &#8220;<span class="elsevierStyleItalic">Trypanosoma</span><span class="elsevierStyleItalic">brucei</span>&#8221;&#44; &#8220;African trypanosomiasis&#8221;&#44; &#8220;<span class="elsevierStyleItalic">Toxoplasma gondii</span>&#8221;&#44; &#8220;toxoplasmosis&#8221;&#44; &#8220;malaria&#8221;&#44; &#8220;<span class="elsevierStyleItalic">Plasmodium falciparum</span>&#8221;&#44; &#8220;<span class="elsevierStyleItalic">Plasmodium vivax</span>&#8221;&#44; &#8220;<span class="elsevierStyleItalic">Plasmodium malariae</span>&#8221;&#44; &#8220;<span class="elsevierStyleItalic">Plasmodium ovale</span>&#8221;&#44; &#8220;leishmaniasis&#8221;&#44; &#8220;<span class="elsevierStyleItalic">Leishmania tropica</span>&#8221;&#44; &#8220;<span class="elsevierStyleItalic">Leishmania donovani</span>&#8221;&#44; &#8220;<span class="elsevierStyleItalic">Leishmania major</span>&#8221;&#44; &#8220;<span class="elsevierStyleItalic">Leishmania Mexicana</span>&#8221;&#44; &#8220;<span class="elsevierStyleItalic">Leishmania amazonensis</span>&#8221; and &#8220;<span class="elsevierStyleItalic">Leishmania infantum</span>&#8221;&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Inclusion criteria were &#40;1&#41; English language of publication&#44; &#40;2&#41; articles published between 2015 and 2022&#44; &#40;3&#41; original article&#44; &#40;4&#41; <span class="elsevierStyleItalic">in vitro</span> or <span class="elsevierStyleItalic">in vivo</span> study design&#46; The <span class="elsevierStyleItalic">in vivo</span> studies included animal or human models &#40;prospective or retrospective clinical trials&#41;&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Two hundred thirty-two &#40;232&#41; hits were retrieved&#44; and after applying the inclusion criteria&#44; 38 studies were obtained and included in this narrative review &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">When necessary&#44; works before 2011 were mentioned to contextualize the concepts discussed&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Role of aspirin and statins in the therapy of some parasitic diseases of medical interest</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Malaria infections</span><p id="par0110" class="elsevierStylePara elsevierViewall">Malaria&#44; caused by protozoa of the <span class="elsevierStyleItalic">Plasmodium</span> genus&#44; is the most important parasitic disease in the world&#44; with a high burden of disease and mortality<a class="elsevierStyleCrossRef" href="#bib0950"><span class="elsevierStyleSup">79</span></a>&#46; <span class="elsevierStyleItalic">P&#46; falciparum</span> is responsible for 95&#37; of morbidity and mortality&#44; including severe manifestations derived from brain involvement&#44; reaching a mortality rate of 10&#8211;20&#37;<a class="elsevierStyleCrossRef" href="#bib0950"><span class="elsevierStyleSup">79</span></a>&#46; Although its incidence has been decreasing<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">20</span></a>&#44; one of the main problems of this disease is the emergence of resistance to pharmacological treatment and insecticides used for vector control&#59; therefore&#44; its control has not been easy<a class="elsevierStyleCrossRefs" href="#bib1075"><span class="elsevierStyleSup">104&#44;109</span></a>&#46; Moreover&#44; it is necessary to create new treatment strategies with consistent efficiency and new drug combinations to protect and reduce severe and resistant forms of malaria<a class="elsevierStyleCrossRef" href="#bib1100"><span class="elsevierStyleSup">109</span></a>&#46; Thus&#44; statins or aspirin could play a role in modulating the inflammatory response to infection by the <span class="elsevierStyleItalic">Plasmodium</span> parasite&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">From 2015 to date&#44; only two articles were found reporting the effectiveness of lovastatin or atorvastatin in reducing the cerebral inflammatory response to <span class="elsevierStyleItalic">P&#46; berghei</span> infection in a cerebral malaria model<a class="elsevierStyleCrossRefs" href="#bib0620"><span class="elsevierStyleSup">13&#44;68</span></a>&#46; For this reason&#44; the search was extended to cover a longer period of 10 years &#40;2011&#8211;2022&#41;&#46; This strategy yielded 20 articles&#44; only eight of which studied the modulation of host factors with statins&#46; The remaining articles fell beyond the focus of the present review because they report the activity of statins or their analogs directly on <span class="elsevierStyleItalic">Plasmodium in vitro</span> models&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The concept of the use of statins in malaria is not without controversy&#46; On the one hand&#44; in 2009&#44; Helmers et al&#46; reported that statins do not protect against cerebral malaria in an experimental murine model<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">40</span></a>&#59; moreover&#44; in a preclinical trial&#44; the administration of atorvastatin did not alter the course of infection with <span class="elsevierStyleItalic">P&#46; bergei</span>&#44; although it acted synergistically with methylene blue<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">24</span></a>&#46; On the other hand&#44; preliminary <span class="elsevierStyleItalic">in vitro</span> studies suggest a direct effect of statins on the parasite<a class="elsevierStyleCrossRef" href="#bib0935"><span class="elsevierStyleSup">76</span></a>&#46; However&#44; importantly&#44; there is preclinical evidence pointing to the control of neuroinflammation by decreasing endothelial damage<a class="elsevierStyleCrossRefs" href="#bib0620"><span class="elsevierStyleSup">13&#44;68&#44;98</span></a> and even improving cognitive alterations caused by cerebral malaria<a class="elsevierStyleCrossRef" href="#bib0955"><span class="elsevierStyleSup">80</span></a>&#46; Moreover&#44; the combined therapy of atorvastatin with artemeter<a class="elsevierStyleCrossRef" href="#bib1080"><span class="elsevierStyleSup">105</span></a>&#44; dihydroartemisinin<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">25</span></a> or mefloquine<a class="elsevierStyleCrossRef" href="#bib1030"><span class="elsevierStyleSup">95</span></a> can alter the course of cerebral infection&#44; reducing mortality from this cause in murine models infected with <span class="elsevierStyleItalic">P&#46;</span><span class="elsevierStyleItalic">bergei</span><a class="elsevierStyleCrossRefs" href="#bib0680"><span class="elsevierStyleSup">25&#44;95</span></a>&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Only one article met inclusion criteria for aspirin in malaria&#46; Although it sounds logical to think that prostaglandin synthesis inhibition could influence the host response in malaria&#44; considering the endothelial and platelet alterations observed during plasmodial infection&#44; studies in this regard are scarce and controversial&#46; Indeed&#44; it has been suggested that prostaglandins may protect against endothelial damage<a class="elsevierStyleCrossRef" href="#bib1095"><span class="elsevierStyleSup">108</span></a>&#59; moreover&#44; following a prospective&#44; randomized study in 97 patients with <span class="elsevierStyleItalic">P&#46; falciparum</span> infection&#44; aspirin did not alter the course of the disease<a class="elsevierStyleCrossRef" href="#bib0760"><span class="elsevierStyleSup">41</span></a>&#46; However&#44; in a recent study in a murine model of <span class="elsevierStyleItalic">P&#46; yoelii</span>-induced renal failure&#44; aspirin prevented renal cell damage&#44; especially in mice subjected to monocytic depletion<a class="elsevierStyleCrossRef" href="#bib1055"><span class="elsevierStyleSup">100</span></a>&#46; Therefore&#44; further preclinical studies are needed to support aspirin as an adjuvant in malaria therapy&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050"><span class="elsevierStyleItalic">Toxoplasma gondii</span> infections</span><p id="par0130" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Toxoplasma gondii</span> is an apicomplexan intracellular parasite that can infect humans&#44; producing a generally asymptomatic infection&#44; but with the persistence of the parasite in tissues in the form of cysts<a class="elsevierStyleCrossRef" href="#bib0820"><span class="elsevierStyleSup">53</span></a>&#44; which can be activated by immunosuppression<a class="elsevierStyleCrossRef" href="#bib0765"><span class="elsevierStyleSup">42</span></a>&#46; The most severe consequences of congenital infection in the fetus are observed during pregnancy<a class="elsevierStyleCrossRef" href="#bib0875"><span class="elsevierStyleSup">64</span></a>&#44; in addition to severe ocular sequelae in immunosuppressed patients<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">27</span></a>&#46; It is a public health concern whose pharmacological treatment is ineffective due to the persistence of cysts in infected tissues&#46; However&#44; in symptomatic and congenital cases&#44; a combination of pyrimethamine and sulfadiazine is used&#44; which blocks folate synthesis&#44; with the consequent risk of causing hematological toxicity in the host due to the high doses required and the prolonged duration of treatments<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">37</span></a>&#46; However&#44; trimethoprim&#8211;sulfamethoxazole&#44; which is less toxic&#44; is an affordable alternative for some patients<a class="elsevierStyleCrossRef" href="#bib1070"><span class="elsevierStyleSup">103</span></a>&#46; Therefore&#44; the search for alternative treatments is necessary<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">1</span></a>&#46; Modifying host factors has been proposed owing to the manipulation performed by the parasite for its continuous replication and survival in the host cell<a class="elsevierStyleCrossRef" href="#bib0825"><span class="elsevierStyleSup">54</span></a>&#46; However&#44; few studies analyze the effect of aspirin and statins in toxoplasmosis&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The use of statins as an experimental pharmacological strategy for the modification of host factors in models of toxoplasmosis is reported in six articles published in the last seven years&#46; The availability of isoprenoids in both parasite and host had been previously suggested<a class="elsevierStyleCrossRef" href="#bib0825"><span class="elsevierStyleSup">54</span></a>&#44; being essential for establishing the pathogen-host relationship&#44; which can be altered using atorvastatin&#46; However&#44; it has been recently reported that only high doses of atorvastatin inhibited enteric cell invasion&#44; suggesting that <span class="elsevierStyleItalic">de novo</span> synthesis of isoprenoids is not essential for replication<a class="elsevierStyleCrossRef" href="#bib0855"><span class="elsevierStyleSup">60</span></a>&#46; Moreover&#44; when atorvastatin is combined with bisphosphonates&#44; there is a synergistic effect on isoprenoid production and&#44; therefore&#44; on decreasing the parasite load by reducing its replicative capacity<a class="elsevierStyleCrossRefs" href="#bib0820"><span class="elsevierStyleSup">53&#44;54</span></a>&#46; Furthermore&#44; rosuvastatin inhibited intracellular replication of <span class="elsevierStyleItalic">T&#46; gondii</span> in HeLa cells<a class="elsevierStyleCrossRef" href="#bib0975"><span class="elsevierStyleSup">84</span></a>&#46; Still&#44; in addition&#44; pravastatin and simvastatin&#44; combined with low doses of pyrimethamine-sulfadiazine&#44; synergistically decreased tachyzoite infection in HeLa cells<a class="elsevierStyleCrossRef" href="#bib0970"><span class="elsevierStyleSup">83</span></a>&#44; reducing the host levels of cytokines IL-6 and IL-7&#44; responsible&#44; in part&#44; for the spread of the disease<a class="elsevierStyleCrossRef" href="#bib0965"><span class="elsevierStyleSup">82</span></a>&#46; These findings are supported by a recent study in which rosuvastatin decreased brain parasite load and local inflammation in a murine model of toxoplasmosis<a class="elsevierStyleCrossRef" href="#bib0910"><span class="elsevierStyleSup">71</span></a> and improved the neurological alterations produced by the infection&#44; including memory disorders<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">26</span></a>&#46; Those findings suggest that rosuvastatin could be helpful in the treatment of chronic toxoplasmosis&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The search strategy for the use of aspirin did not yield results in the last seven years&#46; However&#44; preliminary reports link PGE2 production and IL-10 secretion with a neuroprotective effect against <span class="elsevierStyleItalic">T&#46; gondii</span> infection<a class="elsevierStyleCrossRef" href="#bib0960"><span class="elsevierStyleSup">81</span></a>&#46; In addition&#44; this same effect could contribute to regulating the innate immune response since when mice were treated with <span class="elsevierStyleItalic">T&#46; gondii</span> extracts&#44; a significant increase in the production of lipoxin A4 was reported&#46; Lipoxin A4-epimer can be induced by aspirin&#44; related to the suppression of cytokine signaling mediated by SOCS2<a class="elsevierStyleCrossRef" href="#bib0860"><span class="elsevierStyleSup">61</span></a>&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055"><span class="elsevierStyleItalic">Leishmania</span> spp&#46; infections</span><p id="par0145" class="elsevierStylePara elsevierViewall">Leishmaniasis is a group of endemic diseases caused by different species of parasites of the genus <span class="elsevierStyleItalic">Leishmania&#46;</span> They are obligate intracellular parasites infecting host macrophages&#44; causing significant morbidity and mortality worldwide<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">46</span></a>&#46; They are transmitted to humans by the bite of female insects of the <span class="elsevierStyleItalic">Phlebotomus</span> and <span class="elsevierStyleItalic">Lutzomyia</span> genus&#44; generating a cutaneous infection in most cases and&#44; less frequently&#44; affecting the liver and spleen&#44; which can be fatal if left untreated<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">2&#44;43</span></a>&#46; To date&#44; no effective vaccines exist&#44; and the pharmacological treatment includes pentavalent antimonial agents<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">43</span></a>&#46; However&#44; the antifungal amphotericin B&#44; the aminoglycoside paromomycin&#44; and the phospholipid metabolism inhibitor miltefosine have also shown efficacy&#46; They are directed against the parasite but require monitoring and evaluation of serious adverse effects or the emergence of resistance<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">43</span></a>&#46; Therefore&#44; it is of utmost importance for searching drugs with antiparasitic activity&#44; as well as adjuvants or those that control the inflammatory process of the host and could intervene in the parasite invasion in macrophages<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">38</span></a>&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">In this regard&#44; only three studies were identified using the search strategy described above in the context of <span class="elsevierStyleItalic">Leishmania</span> infections&#46; An <span class="elsevierStyleItalic">in vitro</span> study with <span class="elsevierStyleItalic">L&#46; donovani</span> highlights the importance of an adequate cholesterol level in host cells for optimal parasite entry because chronic cholesterol depletion caused by lovastatin reduced promastigote binding to the macrophage surface&#44; with a consequently lower intracellular amastigote load<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">46</span></a>&#46; This finding suggests that lowering cholesterol content with statins in the host cell membrane could be effective for infection control<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">46</span></a>&#46; Moreover&#44; Haughan et al&#46; previously reported that inhibition of sterol synthesis with lovastatin and miconazole is synergistic<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">39</span></a>&#46; However&#44; Ghosh et al&#46; found that an atherogenic diet in mice could be protective against <span class="elsevierStyleItalic">L&#46; donovani</span> infection since the parasite extracts cholesterol from the membrane preventing T-cell activation<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">32</span></a>&#59; thus&#44; statin-induced cholesterol depletion could increase susceptibility to infection&#46; However&#44; the intracellular parasite load did not improve&#44; suggesting a role of statin in controlling parasite growth<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">32</span></a>&#44; as sterol synthesis by the parasite can be inhibited by mevastatin&#44; the first statin of its kind&#44; affecting cell replication<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">23</span></a>&#46; The use of simvastatin in a model of cutaneous leishmaniasis caused by <span class="elsevierStyleItalic">L&#46; major</span> decreased the local parasite load and inflammation by accelerating phagosome maturation and enhancing the oxidative burst in macrophages<a class="elsevierStyleCrossRef" href="#bib0930"><span class="elsevierStyleSup">75</span></a>&#59; which had been previously described with pravastatin in a murine model with <span class="elsevierStyleItalic">L&#46;</span><span class="elsevierStyleItalic">amazoniensis</span><a class="elsevierStyleCrossRefs" href="#bib0775"><span class="elsevierStyleSup">44&#44;45&#44;70</span></a>&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Only one recent report suggests that aspirin decreases the parasite load in macrophages&#44; improves the phagocytic activity of these cells and modulates cytokine secretion<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">5</span></a>&#46; However&#44; more research on this drug is needed for leishmaniasis&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060"><span class="elsevierStyleItalic">Trypanosoma cruzi</span> infection</span><p id="par0160" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">T&#46; cruzi</span> is the protozoan responsible for Chagas disease&#44; an endemic illness in Latin America&#44; which is treated with benznidazole and nifurtimox<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">28</span></a>&#46; Both agents have high toxicity and limited efficacy&#44; especially in the chronic phase of the disease<a class="elsevierStyleCrossRef" href="#bib0945"><span class="elsevierStyleSup">78</span></a>&#46; In 30&#37; of cases&#44; without adequate treatment&#44; the disease may progress to a chronic inflammatory stage&#44; causing heart failure&#44; arrhythmias&#44; and death<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">3</span></a>&#46; Different therapeutic strategies have been sought&#44; where statins and aspirin could be candidates for repositioning<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">8</span></a>&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Seven experimental studies had been identified since 2015 to date&#44; in which a statin was tested in murine models&#46; Considering that <span class="elsevierStyleItalic">T&#46; cruzi</span> has an affinity for cholesterol and that the parasite uses the LDL receptor as part of the mechanism to infect cells&#44; the role of atorvastatin in lipid metabolism is studied&#44; reporting a deleterious effect on the course of the disease&#44; especially in subjects fed a high-fat diet<a class="elsevierStyleCrossRef" href="#bib1105"><span class="elsevierStyleSup">110</span></a>&#46; However&#44; Soares de Souza et al&#46; observed that simvastatin can mitigate disease progression in a similar model<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">22</span></a>&#46; Notwithstanding the role that statins may have on the mechanics of <span class="elsevierStyleItalic">T&#46; cruzi</span> infection&#44; it is more likely that their actions in the chronic phase are related to the modulation of inflammation induced by the persistence of the parasite&#46; Thus&#44; it has been suggested that simvastatin could have anti-inflammatory potential in models of acute Chagas disease<a class="elsevierStyleCrossRef" href="#bib1020"><span class="elsevierStyleSup">93</span></a>&#46; Moreover&#44; Campos-Estrada et al&#46; proposed that simvastatin triggers the production of 15-epi-LXA4 in endothelial cell models<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">12</span></a>&#44; although without causing a synergistic effect with benznidazole&#46; However this synergism could exist&#44; according to Araujo-Lima et al&#46;&#44; who also highlights the low cardiotoxigenic potential of atorvastatin<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">4</span></a>&#44; probably facilitating parasite clearance in cardiac tissue induced by the resolution of inflammation<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">33</span></a>&#46; Moreover&#44; treating <span class="elsevierStyleItalic">T&#46; cruzi</span>-infected human umbilical vein endothelial cells &#40;HUVEC&#41; with simvastatin promotes the differential expression of inflammation-related genes&#46; Furthermore&#44; simvastatin treatment of human umbilical vein endothelial cells infected with <span class="elsevierStyleItalic">T&#46; cruzi</span> promotes the differential expression of inflammation-related genes&#46; It also influences the Notch1<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">11</span></a> pathway&#44; which is related to cardiac development in the embryo and may also participate in the cardiac protective effect of simvastatin during the chronic phase of the disease<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">35</span></a>&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Cyclooxygenase &#40;COX&#41; is a relevant player in the pathophysiology of <span class="elsevierStyleItalic">T&#46; cruzi</span> infection<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">34</span></a>&#44; and much has been studied since the publication of the relationship of prostaglandins and the phagocytosis of apoptotic bodies<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">29</span></a>&#46; Since 2015&#44; 12 studies have been published linking aspirin as a potential modulator of the course of <span class="elsevierStyleItalic">T&#46; cruzi</span> infection&#46; During the acute phase and as an evasive measure&#44; the parasite modifies the macrophage response&#44; generating an anti-inflammatory environment resulting from the production of prostaglandin E2 and the activation of TGF-&#946;&#44; especially in the presence of apoptotic T lymphocyte apoptotic bodies<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">29</span></a>&#46; Additionally&#44; COX inhibition has been reported to facilitate parasite survival in the host<a class="elsevierStyleCrossRefs" href="#bib0890"><span class="elsevierStyleSup">67&#44;69</span></a>&#46; Furthermore&#44; COX involvement in the invasion process has been recently demonstrated in a process inhibited by aspirin<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">15&#44;56&#44;69</span></a>&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">In an <span class="elsevierStyleItalic">in vivo</span> model of chronic Chagas disease&#44; it was observed that aspirin treatment during the acute phase was able to prevent damage to esophageal nitrergic myenteric neurons<a class="elsevierStyleCrossRef" href="#bib0870"><span class="elsevierStyleSup">63</span></a>&#46; Those findings were corroborated in another study comparing aspirin administration during the acute or chronic phase&#44; which showed a significant decrease in colonic inflammatory foci associated with a neuroprotective effect on myenteric neurons<a class="elsevierStyleCrossRefs" href="#bib0870"><span class="elsevierStyleSup">63&#44;72&#44;96</span></a>&#46; Moreover&#44; it has been reported that aspirin could have some beneficial impact on the neurological manifestations of Chagas disease&#44; as it prevents behavioral alterations in mice acutely infected with <span class="elsevierStyleItalic">T&#46;</span><span class="elsevierStyleItalic">cruzi</span><a class="elsevierStyleCrossRef" href="#bib1025"><span class="elsevierStyleSup">94</span></a>&#46; Moreover&#44; the early use of aspirin in combination with benznidazole proved effective in preventing chronic heart disease<a class="elsevierStyleCrossRef" href="#bib0945"><span class="elsevierStyleSup">78</span></a>&#46; Its use during the chronic phase of the disease can prevent the progression of cardiomyopathy&#44; decreasing endothelial activation&#44; cardiac inflammatory infiltrate&#44; and fibrosis&#44; probably by generating pro-resolving lipid mediators of inflammation such as 15-epi-LXA4 and AT-RvD1&#44; among others<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">14&#44;58&#44;65&#44;66&#44;73</span></a>&#46; In a pilot study in humans&#44; aspirin showed efficacy in reducing the symptoms associated with microvascular abnormalities caused by Chagas heart disease<a class="elsevierStyleCrossRef" href="#bib0940"><span class="elsevierStyleSup">77</span></a>&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Despite the controversy about the role of COX inhibitors in <span class="elsevierStyleItalic">T&#46; cruzi</span> infection<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">19</span></a>&#44; there is abundant evidence supporting the immunomodulatory role of aspirin in the context of Chagas disease<a class="elsevierStyleCrossRefs" href="#bib0840"><span class="elsevierStyleSup">57&#44;62</span></a>&#46; However&#44; there are still no clinical studies to corroborate this&#46; On the other hand&#44; there are no studies evaluating the use of statins or aspirin in the context of <span class="elsevierStyleItalic">T&#46; brucei</span> infections during the period analyzed&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusions</span><p id="par0185" class="elsevierStylePara elsevierViewall">The relationship between a pathogen and its host determines the course of infection and defines whether the infection progresses or is effectively contained&#46; Progression of infection can have deleterious consequences for the host because it can lead to disability or death&#46; Immunity is one of these major determinants in the host&#8211;pathogen relationship&#46; Parasitosis is not excluded from this interaction&#46; However&#44; therapeutic development to expand the antiparasitic pharmacological arsenal is insufficient&#44; slow&#44; or non-existent&#46; Programs such as the Drugs for Neglected Diseases initiative seek to correct this scenario&#46; The active search for compounds capable of modifying key aspects of the inflammatory process that are already approved for use in humans&#44; have proven to be safe and reasonably priced&#44; and a sound strategy<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">9</span></a>&#46; In the present review&#44; we present state-of-the-art agents such as aspirin and statins&#44; which induce the production of inflammation-resolving agents and&#44; therefore&#44; could eventually change the course of infections&#44; not only parasitic&#44; as we have seen&#44; but also bacterial or fungal infections&#46; The uncontrolled nature of the inflammatory response in severe SARS-CoV2 infections&#44; leading to patient death in many cases<a class="elsevierStyleCrossRef" href="#bib0925"><span class="elsevierStyleSup">74</span></a>&#44; boosted the field for exploring the use of agents to modulate the host factors<a class="elsevierStyleCrossRef" href="#bib0980"><span class="elsevierStyleSup">85</span></a>&#46; The prevention of organ damage induced by the persistence of the pathogen and the functional recovery of the innate immune response that prevents chronic inflammation are elements that can help to improve the efficacy of specific anti-infective treatments&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Undoubtedly other strategies to modify the host response would make more sense because they are more direct and probably broader in the spectrum&#44; such as the direct blockade of TNF-&#945; action or interferon-&#947; administration<a class="elsevierStyleCrossRef" href="#bib1110"><span class="elsevierStyleSup">111</span></a>&#46; However&#44; these agents are not without adverse events&#44; producing increased susceptibility to infections or severe arthropathy&#44; respectively&#46; Moreover&#44; in many cases&#44; they are also expensive&#46; On the other hand&#44; the use of vaccines for managing and preventing parasitic infections is far from optimal&#44; and little progress has been made in this field&#44; except for the RTS S&#47;AS01 malaria vaccine<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">20</span></a>&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Unfortunately&#44; the evidence supporting the utility of aspirin in inducing inflammation resolution is not strong&#46; Moreover&#44; the potential for severe reactions such as&#44; for example&#44; bleeding or gastric intolerance considerably diminishes the attractiveness of its use in humans&#44; especially in parasitic diseases&#44; mainly if they are chronic such as in Chagas disease or leishmaniasis&#46; However&#44; this drug may be helpful for further study of the phenomena of inflammation resolution in parasitic infections&#44; as well as other immunopathogenic mechanisms that can be further modified with immunomodulatory drugs&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Furthermore&#44; although our literature review mainly focused on <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> experimental models&#44; a beneficial effect is glimpsed with statins as adjuvant therapy through their cholesterol lowering-independent effects&#44; also called pleiotropic&#46; Although the isoprenoid metabolism in parasites can be directly inhibited by statins&#44; halting their growth&#44; there is no doubt that modulating the host response to the pro-inflammatory effects of infection is an attractive alternative&#46; This effect must necessarily be proven in human studies&#46; The study of modulating the resolution of inflammation with statins is a very active field in which they have also been tested for viral<a class="elsevierStyleCrossRef" href="#bib0810"><span class="elsevierStyleSup">51</span></a> and bacterial infections<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">7</span></a>&#44; including tuberculosis<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">52</span></a>&#44; COVID-19<a class="elsevierStyleCrossRef" href="#bib0980"><span class="elsevierStyleSup">85</span></a>&#44; and septicemia<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">31</span></a>&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">Thus&#44; the modulation of host factors is an attractive tool to help combat these diseases in a context of emerging treatment resistance and spread to non-endemic areas&#44; with the consequent risk of severe epidemic outbreaks&#46; Because it is still controversial<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">30</span></a>&#44; it is necessary to improve the strength of evidence&#44; determine the most effective statin&#44; and&#44; most importantly&#44; analyze the clinical outcomes to further understand statin use in parasitic diseases&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Funding</span><p id="par0210" class="elsevierStylePara elsevierViewall">This work was funded by <span class="elsevierStyleGrantSponsor" id="gs1">Agencia Nacional de Investigacion y Desarrollo &#40;ANID&#41;</span> programa FONDECYT&#44; grant number <span class="elsevierStyleGrantNumber" refid="gs1">1210359</span>&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflict of interest</span><p id="par0215" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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    "highlights" => array:2 [
      "titulo" => "Highlights"
      "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0005" class="elsevierStylePara elsevierViewall">Aspirin or statins through pro-resolving lipids may improve inflammation in parasitosis&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0010" class="elsevierStylePara elsevierViewall">Statins in cerebral malaria reduce mortality in murine models of infection&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0015" class="elsevierStylePara elsevierViewall">In toxoplasmosis&#44; statin use is controversial&#44; although it decreases cytokines&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8226;</span><p id="par0020" class="elsevierStylePara elsevierViewall">In leishmaniasis&#44; statins decrease local inflammation&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0025" class="elsevierStylePara elsevierViewall">In Chagas disease&#44; aspirin or statins decrease cardiac inflammation in murine models&#46;</p></li></ul></p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Infections&#44; including zoonoses&#44; constitute a threat to human health due to the spread of resistant pathogens&#46; These diseases generate an inflammatory response controlled by a resolving mechanism involving specialized membrane lipid-derived molecules called lipoxins&#44; resolvins&#44; maresins&#44; and protectins&#46; The production of some of these molecules can be triggered by aspirin or statins&#46; Thus&#44; it is proposed that modulation of the host response could be a useful therapeutic strategy&#44; contributing to the management of resistance to antiparasitic agents or preventing drift to chronic&#44; host-damaging courses&#46; Therefore&#44; the present work presents the state of the art on the use of statins or aspirin for the experimental management of parasitic infections such as Chagas disease&#44; leishmaniasis&#44; toxoplasmosis or malaria&#46; The methodology used was a narrative review covering original articles from the last seven years&#44; 38 of which met the inclusion criteria&#46; Based on the publications consulted&#44; modulation of the resolution of inflammation using statins may be feasible as an adjuvant in the therapy of parasitic diseases&#46; However&#44; there was no strong experimental evidence on the use of aspirin&#59; therefore&#44; further studies are needed to evaluate its role inflammation resolution process in infectious diseases&#46;</p></span>"
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        "resumen" => "<span id="abst0015" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Las infecciones&#44; incluyendo las zoonosis&#44; constituyen una amenaza a la salud humana debido a la diseminaci&#243;n de pat&#243;genos resistentes&#46; Estas enfermedades generan una respuesta inflamatoria controlada por un mecanismo de resoluci&#243;n&#44; en el que participan mol&#233;culas especializadas derivadas de l&#237;pidos de membrana llamadas lipoxinas&#44; resolvinas&#44; maresinas y protectinas&#46; La producci&#243;n de algunas de estas mol&#233;culas puede ser gatillada por aspirina o estatinas&#46; As&#237;&#44; se propone que la modulaci&#243;n de la respuesta del hospedero podr&#237;a ser una estrategia terap&#233;utica &#250;til&#44; que contribuye al manejo de la resistencia a agentes antiparasitarios o que puede prevenir la derivaci&#243;n hacia cursos cr&#243;nicos&#44; da&#241;inos para el hospedero&#46; En esta revisi&#243;n se presenta una puesta al d&#237;a sobre el uso de estatinas o aspirina para el manejo experimental de infecciones parasitarias&#44; como enfermedad de Chagas&#44; leishmaniasis&#44; toxoplasmosis y malaria&#46; Se hizo una revisi&#243;n narrativa&#44; buscando art&#237;culos originales de los &#250;ltimos siete a&#241;os&#44; se encontraron 38 que cumplieron con los criterios de inclusi&#243;n&#46; De acuerdo con las publicaciones consultadas&#44; la resoluci&#243;n de la inflamaci&#243;n modulada mediante estatinas podr&#237;a ser un adyuvante en la terapia de enfermedades parasitarias&#46; Por otro lado&#44; no se observ&#243; una evidencia experimental fuerte con respecto al uso de aspirina&#44; por lo que se recomiendan m&#225;s estudios para evaluar su rol en el proceso de resoluci&#243;n de la inflamaci&#243;n en enfermedades infecciosas&#46;</p></span>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Total HITS&#58; 232</th></tr><tr title="table-row"><th class="td" title="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Statins124</th></tr><tr title="table-row"><th class="td" title="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Chagas disease36&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Leishmaniasis9&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Toxoplasmosis8&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 03257541
Original language: English

DOI:10.1016/j.ram.2023.01.006

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