Flucofuron as a Promising Therapeutic Agent against Brain-Eating Amoeba.

Primary amoebic meningoencephalitis (PAM) is a rare and fulminant neurodegenerative disease caused by the free-living amoeba Naegleria fowleri. Currently, there is a lack of standardized protocols for therapeutic action. In response to the critical need for effective therapeutic agents, we explored the Global Health Priority Box, a collection of 240 compounds provided by the Medicines for Malaria Venture (MMV). From this pool, flucofuron emerged as a promising candidate, exhibiting high efficacy against trophozoites of both N. fowleri strains (ATCC 30808 IC50 : 2.58 ± 0.64 µM and ATCC 30215 IC50: 2.47 ± 0.38 µM), being even active against the resistant cyst stage (IC50: 0.88 ± 0.07 µM). Moreover, flucofuron induced diverse metabolic events that suggest the triggering of apoptotic cell death. This study highlights the potential of repurposing medications for treating challenging diseases, such as PAM.

Global Health Priority Box: Discovering Flucofuron as a Promising Antikinetoplastid Compound.

Leishmaniasis, produced by Leishmania spp., and Chagas disease, produced by Trypanosoma cruzi, affect millions of people around the world. The treatments for these pathologies are not entirely effective and produce some side effects. For these reasons, it is necessary to develop new therapies that are more active and less toxic for patients. Some initiatives, such as the one carried out by the Medicines for Malaria Venture, allow for the screening of a large number of compounds of different origins to find alternatives to the lack of trypanocide treatments. In this work, 240 compounds were tested from the Global Health Priority Box (80 compounds with confirmed activity against drug-resistant malaria, 80 compounds for screening against neglected and zoonotic diseases and diseases at risk of drug resistance, and 80 compounds with activity against various vector species) against Trypanosoma cruzi and Leishmania amazonensis. Flucofuron, a compound with activity against vectors and with previous activity reported against Staphylococcus spp. and Schistosoma spp., demonstrates activity against L. amazonensis and T. cruzi and produces programmed cell death in the parasites. Flucofuron seems to be a good candidate for continuing study and proving its use as a trypanocidal agent.

Exploring therapeutic approaches against Naegleria fowleri infections through the COVID box.

Naegleria fowleri, known as the brain-eating amoeba, is the pathogen that causes the primary amoebic meningoencephalitis (PAM), a severe neurodegenerative disease with a fatality rate exceeding 95%. Moreover, PAM cases commonly involved previous activities in warm freshwater bodies that allow amoebae-containing water through the nasal passages. Hence, awareness among healthcare professionals and the general public are the key to contribute to a higher and faster number of diagnoses worldwide. Current treatment options for PAM, such as amphotericin B and miltefosine, are limited by potential cytotoxic effects. In this context, the repurposing of existing compounds has emerged as a promising strategy. In this study, the evaluation of the COVID Box which contains 160 compounds demonstrated significant in vitro amoebicidal activity against two type strains of N. fowleri. From these compounds, terconazole, clemastine, ABT-239 and PD-144418 showed a higher selectivity against the parasite compared to the remaining products. In addition, programmed cell death assays were conducted with these four compounds, unveiling compatible metabolic events in treated amoebae. These compounds exhibited chromatin condensation and alterations in cell membrane permeability, indicating their potential to induce programmed cell death. Assessment of mitochondrial membrane potential disruption and a significant reduction in ATP production emphasized the impact of these compounds on the mitochondria, with the identification of increased ROS production underscoring their potential as effective treatment options. This study emphasizes the potential of the mentioned COVID Box compounds against N. fowleri, providing a path for enhanced PAM therapies.

Intention to use physical restraint in paediatric intensive care units and correlated variables: A multicentre and cross-sectional study.

OBJECTIVES: To determine the intention to use physical restraint (PR) and the relationship with sociodemographic and professional variables of the Paediatric Intensive Care Unit (PICU) nurses. RESEARCH METHODOLOGY/DESIGN AND SETTING: A multicentre and correlational study was carried out from October 2021 to December 2023 in five paediatric intensive care units from five maternal and child hospitals in Spain. The Paediatric Physical Restraint-Theory of Planned Behaviour Questionnaire was provided. Moreover, sociodemographic and employment variables were registered. RESULTS: A total of 230 paediatric nurses participated in the study. A total of 87.7 % were females with an average age of 35.5 ± 9.7 years and working experience of 10.5 ± 8.4 years. The mean scores obtained were 21.1 ± 3.8 for attitude, 13.1 ± 5.0 for subjective norms, 14.4 ± 4.3 for perceived behavioural control and 28.0 ± 6.0 for intention. The nurses apply more physical restraint to anxious patients, with scarce analgesics and sedation, those affected with pharmacological withdrawal symptoms and those with a high risk of accidental removal of vital support devices or fall from bed. The sex (p = 0.007) and type of employment contract (p = 0.01) are the variables that are significantly correlated with the intention to use of PR. CONCLUSION: The paediatric nurses analysed had a moderate attitude, social pressure and perceived behavioural control towards the use of PR. IMPLICATIONS FOR CLINICAL PRACTICE: It is important to know the factors that influence the intention to use physical restraint in order to standardise safe practice for critically ill paediatric and to ensure that patients' rights are respected by obtaining informed consent and assessing the prescription, continuation and removal of physical restraint.

Morphology does not matter: WSe2 luminescence nanothermometry unravelled.

Transition metal dichalcogenides, including WSe2, have gained significant attention as promising nanomaterials for various applications due to their unique properties. In this study, we explore the temperature-dependent photoluminescent properties of WSe2 nanomaterials to investigate their potential as luminescent nanothermometers. We compare the performance of WSe2 quantum dots and nanorods synthesized using sonication synthesis and hot injection methods. Our results show a distinct temperature dependence of the photoluminescence, and conventional ratiometric luminescence thermometry demonstrates comparable relative thermal sensitivity (0.68-0.80% K-1) and temperature uncertainty (1.3-1.5 K), irrespective of the morphology of the nanomaterials. By applying multiple linear regression to WSe2 quantum dots, we achieve enhanced thermal sensitivity (30% K-1) and reduced temperature uncertainty (0.1 K), highlighting the potential of WSe2 as a versatile nanothermometer for microfluidics, nanofluidics, and biomedical assays.

Healthcare service use for children with chronic complex diseases: A longitudinal six-year follow-up study.

PURPOSE: The objective was analysed the patterns use of healthcare services of this population and the influence of their clinical and sociodemographic characteristics. DESIGN AND METHODS: A six-year longitudinal follow-up study was performed to evaluate the annual healthcare resources use and clinical data among children with complex chronic diseases in Spain between 2015 and 2021. The sample trends in healthcare usage and the associated factors were analysed using ANCOVA and multivariable linear regression models. RESULTS: Patients had high attendance during the follow-up period, with >15 episodes year. This trend decreased over time, especially in children with oncological diseases compared with other diseases (F (16.75; 825.4) = 32.457; p < 0.001). A multivariable model showed that children with a greater number of comorbidities (ß = 0.17), shorter survival time (ß = -0.23), who had contact with the palliative care unit (ß = 0.16), and whose mothers had a higher professional occupation (ß = 0.14), had a greater use of the healthcare system. CONCLUSIONS: Children with a higher number of comorbidities and the use of medical devices made a greater frequentation of health services, showing a trend of decreasing use over time. Socioeconomic factors such as mothers' occupational status determine healthcare frequentation. These results suggest the existence of persistent gaps in care coordination sustained over time. PRACTICAL IMPLICATIONS: Systematized and coordinated models of care for this population should consider the presence of inequalities in health care use.

Influence of salt and temperature in the growth of pathogenic free-living amoebae.

Introduction: Free-living amoebae are an extensive group of protistans that can be found in a wide variety of environments. Among them, the Acanthamoeba genus and Naegleria fowleri stand out as two of the most pathogenic amoebae and with a higher number of reported cases. N. fowleri is mainly found in warm freshwater water bodies whereas amoebae of the Acanthamoeba genus are broadly distributed through natural and anthropogenic environments. In this regard, the management and the control of the amoebic populations in swimming pools has become a major public health challenge for institutions. Methods: The aim of this work was to evaluate the growth pattern of trophozoites of A. griffini and N. fowleri at different temperatures and salt concentrations. Results and discussion: Our results showed that A. griffini resisted a higher concentration of salt than N. fowleri. Moreover, no trophozoites could withstand the salt levels of the sea in in vitro conditions. This work supports the contention that salinity could represent an important and useful tool for the control of the most pathogenic amoebic populations in recreational water bodies.

Anti-COVID Drugs (MMV COVID Box) as Leishmanicidal Agents: Unveiling New Therapeutic Horizons.

Leishmaniasis, a neglected tropical disease, poses a significant global health challenge, necessitating the urgent development of innovative therapies. In this study, we aimed to identify compounds from the COVID Box with potential efficacy against two Leishmania species, laying the foundation for future chemical development. Four promising molecules were discovered, demonstrating notable inhibitory effects against L. amazonensis and L. donovani. Our study revealed that bortezomib, almitrine, and terconazole induced a significant decrease in mitochondrial membrane potential, while the above compounds and ABT239 induced plasma permeability alterations, chromatin condensation, and reactive oxygen species accumulation, indicating early apoptosis in Leishmania amazonensis promastigotes, preventing inflammatory responses and tissue damage, thereby improving patient outcomes. Furthermore, ADME predictions revealed favorable pharmacokinetic profiles for all compounds, with bortezomib and ABT239 standing out as potential candidates. These compounds exhibited intestinal absorption, blood-brain barrier penetration (excluding bortezomib), and good drug-likeness for bortezomib and ABT239. Toxicity predictions for CYP-inhibition enzymes favored bortezomib as the safest candidate. In conclusion, our study identifies bortezomib as a promising aspirant for leishmaniasis treatment, demonstrating potent antiparasitic activity, favorable pharmacokinetics, and low toxicity. These findings emphasize the potential repurposing of existing drugs for neglected diseases and highlight the importance of the COVID Box in drug discovery against tropical diseases.

Acrylonitrile derivatives: In vitro activity and mechanism of cell death induction against Trypanosoma cruzi and Leishmania amazonensis.

Leishmaniasis and Chagas disease are parasitic infections that affect millions of people worldwide, producing thousands of deaths per year. The current treatments against these pathologies are not totally effective and produce some side effects in the patients. Acrylonitrile derivatives are a group of compounds that have shown activity against these two diseases. In this work, four novels synthetic acrylonitriles were evaluated against the intracellular form and extracellular forms of L. amazonensis and T. cruzi. The compounds 2 and 3 demonstrate to have good selectivity indexes against both parasites, specifically the compound 3 against the amastigote form (SI = 6 against L. amazonensis and SI = 7.4 against T. cruzi). In addition, the parasites treated with these two compounds demonstrate to produce a programmed cell death, since they were positive for the events studied related to this type of death, including chromatin condensation, accumulation of reactive oxygen species and alteration of the mitochondrial membrane potential. In conclusion, this work confirms that acrylonitriles is a source of possible new compounds against kinetoplastids, however, more studies are needed to corroborate this activity.

Adaptation and validation of the Physical Restraint-Theory of Planned Behaviour Questionnaire to the paediatric context.

OBJECTIVE: To create and test psychometrically a paediatric version of the Physical Restraint-Theory of Planned Behaviour Questionnaire to assess paediatric critical care nurses' intention to use physical restraint. DESIGN: A psychometric study. SETTING: Five medical-surgical Paeditric Intensive care Units from five hospitals in Spain. METHODS: The study took place in three phases. In phase 1, the questionnaire was adapted. In phase 2, the content validity of each item was determined, and a pilot test was conducted. In phase 3, we administered the questionnaire and determined its psychometric properties. RESULTS: The assessment of the intention to use physical restraint was extended to all critical paediatric patients, two items were eliminated from the initial questionnaire, four new items were included, and the clinical scenarios of the intention subscale were expanded from three to six. Overall content validity index for the full instrument of 0.96 out of 1. The Paediatric Physical Restraint-Theory of Planned Behaviour Questionnaire is made up of four subscales (attitude, subjective norms (SN), perceived behavioural control (PBC), and intention) subdivided into 7 factors and 51 items. The internal consistency for the attitude subscale obtained a Cronbach's Alpha of 0.80 to 0.73, for the SN it was 0.72 to 0.89, for the PBC it was from 0.80 to 0.73 and for the intention subscale it was 0.75. CONCLUSIONS: The Paediatric Physical Restraint-Theory of Planned Behaviour Questionnaire is an instrument composed of seven factors and 51 items that validly and reliably assesses the intention of paediatric nurses to apply PR in PICUs. RELEVANCE FOR CLINICAL PRACTICE: Having this instrument will help health centres move towards restraint-free care by allowing managers to assess professionals' attitudes, beliefs, and intentions around the use of PR in PICUs.

Salvadoran Celastraceae Species as a Source of Antikinetoplastid Quinonemethide Triterpenoids.

Chagas disease and leishmaniasis are among the most widespread neglected tropical diseases, and their current therapies have limited efficacy and several toxic side effects. The present study reports the chemical and antikinetoplastid profiles of extracts from five Salvadoran Celastraceae species against the Trypanosoma cruzi epimastigotes stage and Leishmania amazonensis and Leishmania donovani promastigote forms. The phytochemical profile evinced the presence of flavonoids, tannins, sterols, and triterpenes as the main components in all plant species, whereas quinonemethide triterpenoids (QMTs) were restricted to the root bark of the studied species. Antikinetoplastid evaluation highlights the root bark extracts from Zinowewia integerrima, Maytenus segoviarum, and Quetzalia ilicina as the most promising ones, exhibiting higher potency against T. cruzi (IC50 0.71-1.58 µg/mL) and L. amazonensis (IC50 0.38-2.05 µg/mL) than the reference drugs, benznidazole (IC50 1.81 µg/mL) and miltefosine (IC50 2.64 µg/mL), respectively. This potent activity was connected with an excellent selectivity index on the murine macrophage J774A.1 cell line. These findings reinforce the potential of QMTs as antikinetoplastid agents for the development of innovative phytopharmaceuticals and the plant species under study as a source of these promising lead compounds.

Amoebicidal effect of synthetic indoles against Acanthamoeba spp.: a study of cell death.

Organic and synthetic chemistry plays a crucial role in drug discovery fields. Moreover, chemical modifications of available molecules to enhance their efficacy, selectivity and safety have been considered as an attractive approach for the development of new bioactive agents. Indoles, a versatile group of natural heterocyclic compounds, have been widely used in pharmaceutical industry due to their broad spectrum of activities including antimicrobial, antitumoral and anti-inflammatory among others. Herein, we report the amoebicidal activity of different indole analogs on Acanthamoeba castellanii Neff. Among the 40 tested derivatives, eight molecules were able to inhibit this protistan parasite. The structure-activity relationship (SAR) analysis of their anti-Acanthamoeba activity would suggest that a carboxylation of C-3 position and the incorporation of halogen as chlorine/fluorine would enhance their biological profile, presumably by increasing their lipophilicity and therefore their ability to cross the cell membrane. Fluorescence image base system was used to investigate the effect of indole 6o c-6 on the cytoskeleton network and various programmed cell death features. We were able to highlight that the methyl 6-chloro-1H-indole-3-carboxylate could induce program cell death by the mitochondrial dysfunction.

Assessment of an intervention for preventing pediatric overweight and obesity through the World Café technique: A qualitative study.

PURPOSE: To evaluate the self-reported perspectives of participants involved in the Previene Cádiz intervention for preventing pediatric overweight and obesity. DESIGN AND METHODS: This qualitative study collected information through the World Café technique. A purposive sample of 40 participants was used, of which 14 were schoolchildren, 12 were teachers, and 14 were parent volunteers. The data were segmented, and concepts were created and grouped into dimensions and categories. RESULTS: The participants confirmed they had learned new information and behaviors about healthy habits. Parental awareness was considered a crucial and necessary element in changing family habits; therefore, increasing the motivation of family members was deemed a critical task in public health interventions conducted in school settings. DISCUSSION: Despite the suitability of qualitative methodology to evaluate the perceptions of the main players in an educational intervention, scientific literature is scarce. Obtaining information from the educational community about an intervention is not always easy, so the perspectives of teachers, students, and families about the Previene Cádiz intervention through the World Café approach is considered a relevant contribution. CONCLUSIONS: The participants considered the intervention positive in terms of learning and fostering increased knowledge, awareness, and healthy behaviors. PRACTICE IMPLICATIONS: Future interventions should encourage the active participation of all social groups involved, integrating dynamic and collaborative training activities that are acceptable to all participants.

Induction of Programmed Cell Death in Acanthamoeba culbertsoni by the Repurposed Compound Nitroxoline.

Acanthamoeba is a ubiquitous genus of amoebae that can act as opportunistic parasites in both humans and animals, causing a variety of ocular, nervous and dermal pathologies. Despite advances in Acanthamoeba therapy, the management of patients with Acanthamoeba infections remains a challenge for health services. Therefore, there is a need to search for new active substances against Acanthamoebae. In the present study, we evaluated the amoebicidal activity of nitroxoline against the trophozoite and cyst stages of six different strains of Acanthamoeba. The strain A. griffini showed the lowest IC50 value in the trophozoite stage (0.69 ± 0.01 µM), while the strain A. castellanii L-10 showed the lowest IC50 value in the cyst stage (0.11 ± 0.03 µM). In addition, nitroxoline induced in treated trophozoites of A. culbertsoni features compatibles with apoptosis and autophagy pathways, including chromatin condensation, mitochondrial malfunction, oxidative stress, changes in cell permeability and the formation of autophagic vacuoles. Furthermore, proteomic analysis of the effect of nitroxoline on trophozoites revealed that this antibiotic induced the overexpression and the downregulation of proteins involved in the apoptotic process and in metabolic and biosynthesis pathways.

Antiparasitic Activity of Compounds Isolated from Ganoderma tuberculosum (Agaricomycetes) from Mexico.

The genus Ganoderma has a long history of use in traditional Asiatic medicine due to its different nutritional and medicinal properties. In Mexico, the species G. tuberculosum is used in indigenous communities, for example, the Wixaritari and mestizos of Villa Guerrero Jalisco for the treatment of diseases that may be related to parasitic infections; however, few chemical studies corroborate its traditional medicinal potential. Thereby, the objective of this study was to isolate and identify anti-parasitic activity compounds from a strain of G. tuberculosum native to Mexico. From the fruiting bodies of G. tuberculosum (GVL-21) a hexane extract was obtained which was subjected to guided fractioning to isolate pure compounds. The in vitro anti-parasitic activity of the pure compound (IC50) was assayed against Leishmania amazonensis, Trypanosoma cruzi, Acanthamoeba castellanii Neff, and Naegleria fowleri. Furthermore, the cytotoxicity (CC50) of the isolated compounds was determined against murine macrophages. The guided fractioning produced 5 compounds: ergosterol (1), ergosta-4,6,8(14),22-tetraen-3-one (2), ergosta-7,22-dien-3ß-ol (3), 3,5-dihydroxy-ergosta-7,22-dien-6-one (4), and ganoderic acid DM (5). Compounds 2 and 5 showed the best anti-parasitic activity in an IC50 range of 54.34 ± 8.02 to 12.38 ± 2.72 µM against all the parasites assayed and low cytotoxicity against murine macrophages. The present study showed for the first time the in vitro anti-parasitic activity of compounds 1-5 against L. amazonensis, T. cruzi, A. castellanii Neff, and N. fowleri, corroborating the medicinal potential of Ganoderma and its traditional applications.

Time measurement validity and reliability of the 4 × 10-m shuttle run test in adult population: The ADULT-FIT project.

OBJECTIVES: The purpose of this study was to analyze the time measurement validity and reliability (between raters and test-retest) of the 4 × 10-m shuttle run test to assess motor fitness in adults, according to gender, age, and physical activity levels. DESIGN: Cross-sectional. A total of 230 adults (86 women) aged 18-64 years participated in the study. METHODS: The time taken to complete the 4 × 10-m shuttle run test was recorded simultaneously by a trained and an untrained rater (inter-rater reliability) and by photoelectric cells (time measurement validity). 48-72 h later, the test was repeated under the same conditions (test-retest reliability). RESULTS: The systematic error for trained rater vs. photocell was close to zero (0.0125, p < 0.01), with an effect size of 0.006; and for both, untrained rater vs. photocell and trained rater vs. untrained rater was ∼0.2 s (p < 0.001) with an effect size of 0.09. For the test-retest reliability, the systematic error was 0.05 s (p < 0.001), with an effect size of 0.26, the intraclass correlation coefficient was 0.998 and the coefficient of variation reported a variability of 0.73 %. Results were not influenced by gender and age, while these improved for active vs. non-active participants. CONCLUSIONS: Findings indicate that measurements with trained raters are a valid and reliable method for assessing the 4 × 10-m shuttle run test in adults. It is highly recommended that raters be trained to minimize the measurement error.

Longitudinal effects of FTO gene polymorphism on body composition, cardiorespiratory fitness, physical activity, inflammatory markers, and cardiovascular risk in children and adolescents. "The UP & DOWN study".

The role of polymorphism rs9939609 of the FTO gene has been related with fat mass and cardiovascular risk in adults, but it remains unclear in children and adolescents. Hence, the main aim of this study was to determine the FTO polymorphism effects on body composition, cardiorespiratory fitness (CRF), physical activity (PA), inflammatory markers, and cardiovascular risk both in cross-sectional analysis and after two-years of follow-up in children and adolescents. A total of 2129 participants were included in this study. The rs9939609 polymorphism was genotyped. Body composition measurements, CRF, and moderate-to-vigorous PA (MVPA) were determined at baseline and after two-year of follow-up. Moreover, plasma leptin and adiponectin were also determined as inflammatory markers. Furthermore, an index of cardiovascular disease risk factors (CVDRF-I) was calculated. Codominant (TT vs. TA vs. AA) and dominant (AA+AT vs. TT) models were applied for statistical analysis. The results showed a main effect of the FTO genotype on body composition measures in both first and third year (p < 0.05), with lower adiposity in TT compared with AA or AA+AT group. These differences were maintained after accounting for pubertal maturity, sex, age, VO2 max, and MVPA. Moreover, lower leptin level was observed in TT compared to AA+AT group in the third year. An interaction in Gene*Time*Sex was found in height and neck circumference in dominant model (p = 0.047; p = 0.020, respectively). No differences were found in CRF, MVPA nor CVDRF-I between groups. Hence, homozygous TT allele could be a protective factor against weight gain from early childhood.

Influence of a Concurrent Exercise Training Program on Health-Related Quality of Life During Advanced Pregnancy: The GESTAFIT Project.

BACKGROUND: Health-related quality of life (HRQoL) may be altered during pregnancy due to pregnancy-related changes in all domains of women's health. HYPOTHESIS: A supervised concurrent exercise-training program from the 17th gestational week until birth positively influences HRQoL. STUDY DESIGN: Randomized controlled trial. LEVEL OF EVIDENCE: Level 1. METHODS: Eighty-six pregnant women (age, 33.1 ± 4.6 years; prepregnancy body mass index, 23.5 kg/m2), divided into exercise (n = 41) and control (n = 45) groups, participated in this study (per-protocol basis). The exercise group followed a 60-min, 3 days/week, concurrent (aerobic + resistance) exercise training program. HRQoL was assessed with the 36-Item Short Form Health Survey (SF-36), where higher scores (0-100) indicate better HRQoL. RESULTS: After adjusting for potential confounders, the exercise group decreased 16.1 points less than the control group in the SF-36 physical functioning domain [between-group differences (B): 95% confidence interval (CI), 9.02 to 23.22; P < 0.01], and 4.5 points less in the SF-36 physical component summary than the control group (between-group differences (B): 95% CI, 0.65 to 8.28; P = 0.02). Intention-to-treat basis analyses depicted similar results, where the exercise group decreased 10.03 points less than the control group the in the SF-36 social functioning domain (between-group differences (B): 95% CI, 0.39 to 19.68; P = 0.04). CONCLUSION: A supervised concurrent exercise training program ameliorates HRQoL decreases along gestation. Although HRQoL decreased throughout pregnancy in both groups, this impact was less in the exercise group, especially in the SF-36 physical functioning, the SF-36 social functioning, and the SF-36 physical component summary. CLINICAL RELEVANCE: Healthcare providers may encourage pregnant women to exercise in this physiological stage for a better HRQoL throughout pregnancy. CLINICALTRIALS.GOV IDENTIFIER: NCT02582567; Date of registration: 20/10/2015.

Repurposing of Nitroxoline as an Alternative Primary Amoebic Meningoencephalitis Treatment.

Among the pathogenic free-living amoebae (FLA), Naegleria fowleri is the etiological agent of a fatal disease known as primary amoebic meningoencephalitis (PAM). Once infection begins, the lesions generated in the central nervous system (CNS) result in the onset of symptoms leading to death in a short period of time. Currently, there is no standardized treatment against the infection, which, due to the high virulence of the parasite, results in a high case fatality rate (>97%). Therefore, it is essential to search for new therapeutic sources that can generate a rapid elimination of the parasite. In recent years, there have already been several successful examples of drug repurposing, such as Nitroxoline, for which, in addition to its known bioactive properties, anti-Balamuthia activity has recently been described. Following this approach, the anti-Naegleria activity of Nitroxoline was tested. Nitroxoline displayed low micromolar activity against two different strains of N. fowleri trophozoites (IC50 values of 1.63 ± 0.37 µM and 1.17 ± 0.21 µM) and against cyst stages (IC50 of 1.26 ± 0.42 µM). The potent anti-parasitic activity compared to the toxicity produced (selectivity index of 3.78 and 5.25, respectively) in murine macrophages and human cell lines (reported in previous studies), together with the induction of programmed cell death (PCD)-related events in N. fowleri make Nitroxoline a great candidate for an alternative PAM treatment.

Marine Meroterpenoids Isolated from Gongolaria abies-marina Induce Programmed Cell Death in Naegleria fowleri.

Naegleria fowleri is the causative agent of a central nervous system affecting disease called primary amoebic meningoencephalitis. It is a fulminant disease with a rapid progression that affects mainly children and young adults who report previous water exposure. Current treatment options are not totally effective and involve several side effects. In this work, six meroterpenoids isolated from the brown algae Gongolaria abies-marina were evaluated against N. fowleri. Gongolarone B (1), 6Z-1'-methoxyamentadione (2), and 1'-methoxyamentadione (3) were the most active molecules against N. fowleri with IC50 values between 13.27 ± 0.96 µM and 21.92 ± 1.60 µM. However, cystomexicone B (6) was the molecule with the highest selectivity index (>8.5). Moreover, all these compounds induced different cellular events compatible with the apoptosis-like PCD process, such as chromatin condensation, damages at the mitochondrial level, cell membrane disruption, and production of reactive oxygen species (ROS). Therefore, G. abies-marina could be considered as a promising source of active molecules to treat the N. fowleri infections.