Activation of angiotensin II type 2 receptor leads to preservation of primary cilia in tubular cells during renal ischaemia-reperfusion injury.

Ischaemia-reperfusion (IR)-associated acute kidney injury (AKI) is a severe clinical condition that lacks effective pharmacological treatments. Our recent research revealed that pretreatment with the angiotensin II type 2 receptor (AT2R) agonist C21 alleviates kidney damage during IR. Primary cilia are organelles crucial for regulation of epithelial cell homeostasis, which are significantly affected by IR injury. This study aimed to evaluate the impact of AT2R activation on cilia integrity during IR and to identify pathways involved in the nephroprotective effect of C21. Rats were subjected to 40 min of unilateral ischaemia followed by 24 h of reperfusion. Immunofluorescence analysis of the kidneys showed that the nephroprotective effect of C21 was associated with preservation of cilia integrity in tubular cells. AT2R agonists increased α-tubulin acetylation in primary cilia in tubular cells in vivo and in a cell model. Analysis of ERK phosphorylation indicated that AT2R activation led to diminished activation of ERK1/2 in tubular cells. Similar to AT2R agonists, inhibitors of α-tubulin deacetylase HDAC6 or inhibitors of ERK activation ameliorated IR-induced cell death and preserved cilia integrity. Immunofluorescence analysis of tubular cells revealed significant ERK localization at primary cilia and demonstrated that ERK inhibition increased cilia levels of acetylated α-tubulin. Overall, our findings demonstrate that C21 elicits a preconditioning effect that enhances cilia stability in renal tubular cells, thereby preserving their integrity when exposed to IR injury. Furthermore, our results indicate that this effect might be mediated by AT2R-induced inhibition of ERK activation. These findings offer potential insights for the development of pharmacological interventions to mitigate IR-associated AKI. KEY POINTS: The AT2R agonist C21 prevents primary cilia shortening and tubular cell deciliation during renal ischaemia-reperfusion. AT2R activation inhibits ERK1/2 in renal tubular cells. Both AT2R agonists and ERK1/2 inhibitors increase alpha-tubulin acetylation at the primary cilium in tubular cells. AT2R activation, ERK1/2 inhibition or inhibition of alpha-tubulin deacetylation elicit protective effects in tubular cells subjected to ischaemia-reperfusion injury.

Feeding practices and weight status of children with congenital Zika syndrome: A longitudinal study in Brazil.

OBJECTIVE: The objective of this study was to describe feeding practices and weight status in a cohort of children with congenital Zika syndrome (CZS) in northeastern Brazil. METHODS: This longitudinal study of children with CZS (N = 156) included data collection on child feeding practices and weight status at five timepoints between 2018 and 2022. The average age of the children was 32.1 months at enrollment and 76.6 months at the fifth assessment. Multilevel models, with repeated observations nested within children, were used to estimate time-related differences in each outcome. RESULTS: Use of enteral feeding, such as gastrostomy, increased from 19.2% to 33.3% over 4 years (p < .001). Among children who did not exclusively use an enteral feeding method, the percentage experiencing at least one dysphagia-associated behavior, such as coughing or gagging, increased from 73.9% to 85.3% (p = .030) while consuming liquids and from 36.2% to 73.5% (p = .001) while consuming solids. Based on weight-for-age z-scores, the percentage of children who were moderately or severely underweight increased from 42.5% to 46.1% over the 4 years but was not statistically significant. Children exclusively using an enteral feeding method had significantly decreased odds of being underweight at assessments 3, 4, and 5. CONCLUSIONS: These data highlight the ongoing and increasing challenges of feeding young children with CZS. Our findings elucidate the physiological reasons children with CZS may be underweight and point to intervention targets, such as enteral feeding, to improve their feeding practices.

Antifungal Activity of Morinda citrifolia Methanolic Extract against Candida albicans: An In Vitro Study.

Aim: Natural medicine used as an alternative and/or complementary treatment to counteract diseases is of great importance in public health. Therefore, the purpose of the present study was to assess the in vitro antifungal activity of Morinda citrifolia methanolic extract of peel, pulp, and seed against Candida albicans. Materials and Methods: The present study was experimental in vitro and cross-sectional. Eight replicates were prepared in Sabouraud dextrose agar with five wells each, where 0.12% chlorhexidine, distilled water, and methanolic extract of seed, peel, and pulp of Morinda citrifolia fruit were placed at concentrations of 10,690, 8,270, and 6,430 mg/mL, respectively, to evaluate sensitivity according to Duraffourd's scale. In addition, the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) were determined by dilution and agar seeding method. Statistical analysis was performed by analysis of variance (ANOVA) and Tukey's post hoc test, considering a significance level of P < 0.05. Results: The inhibition halos of Morinda citrifolia methanolic extract of seed, peel, and pulp against Candida albicans measured on average 15.94, 11.94, and 11.56 mm, respectively. The MIC of seed, peel, and pulp extract were 1366.25, 2067.5, and 1607.5 mg/mL respectively, whereas the MFC for seed, peel, and pulp extract were 2672.50, 2067.5, and 3215 mg/mL, respectively. Moreover, seed extract presented significantly higher antifungal activity than peel and pulp (P < 0.001). Conclusions: Morinda citrifolia methanolic extract of peel, pulp, and seed showed fungistatic and fungicidal effect against Candida albicans, being this very sensitive to seed extract with a MIC of 1366.25 mg/mL and a MFC of 2672.5 mg/mL, which allows recommending the development of effective pharmacological formulations for the control of candidiasis.

Cross-Neutralizing Anti-Chikungunya and Anti-Dengue 2 IgG Antibodies from Patients and BALB/c Mice against Dengue and Chikungunya Viruses.

Dengue (DENV) and Chikungunya (CHIKV) viruses can be transmitted simultaneously by Aedes mosquitoes, and there may be co-infections in humans. However, how the adaptive immune response is modified in the host has yet to be known entirely. In this study, we analyzed the cross-reactivity and neutralizing activity of IgG antibodies against DENV and CHIKV in sera of patients from the Mexican Institute of Social Security in Veracruz, Mexico, collected in 2013 and 2015 and using IgG antibodies of BALB/c mice inoculated with DENV and/or CHIKV. Mice first inoculated with DENV and then with CHIKV produced IgG antibodies that neutralized both viruses. Mice were inoculated with CHIKV, and then with DENV; they had IgG antibodies with more significant anti-CHIKV IgG antibody neutralizing activity. However, the inoculation only with CHIKV resulted in better neutralization of DENV2. In sera obtained from patients in 2013, significant cross-reactivity and low anti-CHIKV IgG antibody neutralizing activity were observed. In CHIKV-positive 2015 sera, the anti-DENV IgG antibody neutralizing activity was high. These results suggest that CHIKV stimulates DENV2-induced memory responses and vice versa. Furthermore, cross-reactivity between the two viruses generated neutralizing antibodies, but exchanging CHIKV for DENV2 generated a better anti-CHIKV neutralizing response.

Gestational weight gain below recommendations and adverse maternal and child health outcomes for pregnancies with overweight or obesity: a United States cohort study.

BACKGROUND: The current Institute of Medicine (IOM) pregnancy weight gain guidelines were developed using the best available evidence but were limited by substantial knowledge gaps. Some have raised concern that the guidelines for individuals affected by overweight or obesity are too high and contribute to short- and long-term complications for the mother and child. OBJECTIVES: To determine the association between pregnancy weight gain below the lower limit of the current IOM recommendations and risk of 10 adverse maternal and child health outcomes among individuals with overweight and obesity. METHODS: We used data from a prospective cohort study of United States nulliparae with prepregnancy overweight (n = 955) or obesity (n = 897) followed from the first trimester to 2-7 y postpartum. We used multivariable Poisson regression to relate pregnancy weight gain z-scores with a severity-weighted composite outcome consisting of ≥1 of 10 adverse outcomes (gestational diabetes, preeclampsia, unplanned cesarean delivery, maternal postpartum weight increase >10 kg, maternal postpartum metabolic syndrome, infant death, stillbirth, preterm birth, small-for-gestational age birth, and childhood obesity). RESULTS: Pregnancy weight gain z-scores below, within, and above the IOM-recommended ranges occurred in 5%, 13%, and 80% of pregnancies with overweight and 17%, 13%, and 70% of pregnancies with obesity. There was a positive association between pregnancy weight gain z-scores and all adverse maternal outcomes, childhood obesity, and the composite outcome. Pregnancy weight gain z-scores below the lower limit of the recommended ranges (<6.8 kg for overweight, <5 kg for obesity) were not associated with the severity-weighted composite outcome. For example, compared with the lower limit, adjusted rate ratios (95% confidence interval) for z-scores of -2 standard deviations in pregnancies with overweight (equivalent to 3.6 kg at 40 wk) and obesity (-2.8 kg at 40 wk) were 0.99 (95% confidence interval [CI]: 0.91, 1.06) and 0.97 (95% CI: 0.87, 1.07). CONCLUSIONS: These findings support arguments to decrease the lower limit of recommended weight gain ranges in these prepregnancy body mass index groups.

Piperine, quercetin, and curcumin identified as promising natural products for topical treatment of cutaneous leishmaniasis.

Leishmania braziliensis (L. braziliensis) causes cutaneous leishmaniasis (CL) in the New World. The costs and the side effects of current treatments render imperative the development of new therapies that are affordable and easy to administer. Topical treatment would be the ideal option for the treatment of CL. This underscores the urgent need for affordable and effective treatments, with natural compounds being explored as potential solutions. The alkaloid piperine (PIP), the polyphenol curcumin (CUR), and the flavonoid quercetin (QUE), known for their diverse biological properties, are promising candidates to address these parasitic diseases. Initially, the in vitro cytotoxicity activity of the compounds was evaluated using U-937 cells, followed by the assessment of the leishmanicidal activity of these compounds against amastigotes of L. braziliensis. Subsequently, a golden hamster model with stationary-phase L. braziliensis promastigote infections was employed. Once the ulcer appeared, hamsters were treated with QUE, PIP, or CUR formulations and compared to the control group treated with meglumine antimoniate administered intralesionally. We observed that the three organic compounds showed high in vitro leishmanicidal activity with effective concentrations of less than 50 mM, with PIP having the highest activity at a concentration of 8 mM. None of the compounds showed cytotoxic activity for U937 macrophages with values between 500 and 700 mM. In vivo, topical treatment with QUE daily for 15 days produced cured in 100% of hamsters while the effectiveness of CUR and PIP was 83% and 67%, respectively. No failures were observed with QUE. Collectively, our data suggest that topical formulations mainly for QUE but also for CUR and PIP could be a promising topical treatment for CL. Not only the ease of obtaining or synthesizing the organic compounds evaluated in this work but also their commercial availability eliminates one of the most important barriers or bottlenecks in drug development, thus facilitating the roadmap for the development of a topical drug for the management of CL caused by L. braziliensis.

3-styrylcoumarin scaffold-based derivatives as a new approach for leishmaniasis intervention: biological and molecular modeling studies.

Seven 3-styrylcoumarins were tested for antileishmanial activity against Leishmania (Viannia) panamensis amastigotes. Cytotoxic activity was also evaluated against mammalian U-937 cells. The 3-methoxy-4-hydroxy coumarin derivative 6 was the most active with an IC50 of 40.5 µM, and did not reveal any conspicuous toxicity toward mammalian U-937 cells. Therefore, it may have potential to be considered as candidate for antileishmanial drug development. Further, among several druggable Leishmania targets, molecular docking studies revealed that compound 6 had docking preference by the N-myristoyltransferase (Lp-NMT) of Leishmania panamensis, showing a higher docking score of - 10.1 kcal mol-1 than positive controls and making this protein as a presumably druggable target for this compound. On the other hand, molecular dynamics simulations affirm the docking hypothesis, showing a conformational stability of the 6/Lp-NMT complex throughout 100 ns simulation. Moreover, the molecular mechanics/Poisson-Boltzmann surface area method also support the docking findings, revealing a total free energy of binding of - 47.26 ± 0.08 kcal mol-1, and identifying through energy decomposition analysis that those key aminoacids are contributing strongly to ligand binding. Finally, an optimal pharmacokinetic profile was also estimated for 6. Altogether, coumarin 6 could be addressed as starting point for further pharmacological studies concerning the therapeutic leishmaniasis intervention.

Factors associated to mortality in children with critical COVID-19 and multisystem inflammatory syndrome in a resource-poor setting.

SARS-CoV-2 infection in children is usually asymptomatic/mild. However, some patients may develop critical forms. We aimed to describe characteristics and evaluate the factors associated to in-hospital mortality of patients with critical COVID-19/MIS-C in the Amazonian region. This multicenter prospective cohort included critically ill children (1 mo-18 years old), with confirmed COVID-19/MIS-C admitted to 3 tertiary Pediatric Intensive Care Units (PICU) in the Brazilian Amazon, between April/2020 and May/2023. The main outcome was in-hospital mortality and were evaluated using a multivariable Cox proportional regression. We adjusted the model for pediatric risk of mortality score version IV (PRISMIV) score and age/comorbidity. 266 patients were assessed with 187 in the severe COVID-19 group, 79 included in the MIS-C group. In the severe COVID-19 group 108 (57.8%) were male, median age was 23 months, 95 (50.8%) were up to 2 years of age. Forty-two (22.5%) patients in this group died during follow-up in a median time of 11 days (IQR, 2-28). In the MIS-C group, 56 (70.9%) were male, median age was 23 months and median follow-up was 162 days (range, 3-202). Death occurred in 17 (21.5%) patients with a median death time of 7 (IQR, 4-13) days. The mortality was associated with higher levels of Vasoactive Inotropic-Score (VIS), presence of acute respiratory distress syndrome (ARDS), higher levels of Erythrocyte Sedimentation Rate, (ESR) and thrombocytopenia. Critically ill patients with severe COVID-19 and MIS-C from the Brazilian Amazon showed a high mortality rate, within 12 days of hospitalization.

Mortality Risks Over 20 Years in Men With Stage I to III Hormone Receptor-Positive Breast Cancer.

Importance: In women with hormone receptor-positive (HR+) breast cancer, the risk of distant recurrence and death persists for at least 20 years from diagnosis. The risk of late mortality in men with HR+ breast cancer has not been reported. Objective: To report 20-year risks of breast cancer-specific mortality (BCSM) and non-BCSM in men with stage I to III HR+ breast cancer and identify factors associated with late BCSM. Design, Setting, and Participants: An observational cohort study was conducted of men diagnosed with HR+ breast cancer from 1990 to 2008, using population-based data from the Surveillance, Epidemiology, and End Results program. Men diagnosed with stage I to III HR+ breast cancer were included in the analysis. Cumulative incidence function was used to estimate the outcomes of baseline clinicopathologic variables regarding cumulative risk of BCSM and non-BCSM since diagnosis. Smoothed hazard estimates over time were plotted for BCSM. Fine and Gray multivariable regression evaluated the association of preselected variables with BCSM, conditional on having survived 5 years. Main Outcome Measure: BCSM. Results: A total of 2836 men with stage I to III HR+ breast cancer were included, with a median follow-up of 15.41 (IQR, 12.08-18.67) years. Median age at diagnosis was 67 (IQR, 57-76) years. The cumulative 20-year risk of BCSM was 12.4% for stage I, 26.2% for stage II, and 46.0% for stage III. Smoothed annual hazard estimates for BCSM revealed an increase in late hazard rates with each incremental node category, reaching a bimodal distribution in N3 and stage III, with each having peaks in hazard rates at 4 and 11 years. Among patients who survived 5 years from diagnosis, the adjusted BCSM risk was higher for those younger than 50 years vs older than 64 years, those with grade II or III/IV vs grade I tumors, and stage II or III vs stage I disease. Conclusions and Relevance: The findings of this study suggest that, in men with stage I to III HR+ breast cancer, the risk of BCSM persists for at least 20 years and depends on traditional clinicopathologic factors, such as age, tumor stage, and tumor grade. Among men with higher stages of disease, the kinetics of the BCSM risk appear different from the risk that has been reported in women.

Immune response to SARS-CoV-2 variants after immunization with different vaccines in Mexico.

There is limited information on the antibody responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in subjects from developing countries with populations having a high incidence of co-morbidities. Here, we analysed the immunogenicity of homologous schemes using the ChAdOx1-S, Sputnik V, or BNT162b2 vaccines and the effect of a booster dose with ChAdOx1-S in middle-aged adults who were seropositive or seronegative to the SARS-CoV-2 spike protein before vaccination. The study was conducted post-vaccination with a follow-up of 4 months for antibody titre using enzyme-linked immunosorbent assay (ELISA) and pseudovirus (PV) neutralization assays (PNAs). All three vaccines elicited a superior IgG anti-receptor-binding domain (RBD) and neutralization response against the Alpha and Delta variants when administered to individuals with a previous infection by SARS-CoV-2. The booster dose spiked the neutralization activity among individuals with and without a prior SARS-CoV-2 infection. The ChAdOx1-S vaccine induced weaker antibody responses in infection-naive subjects. A follow-up of 4 months post-vaccination showed a drop in antibody titre, with about 20% of the infection-naive and 100% of SARS-CoV-2 pre-exposed participants with detectable neutralization capacity against Alpha pseudovirus (Alpha-PV) and Delta PV (Delta-PV). Our observations support the use of different vaccines in a country with high seroprevalence at the vaccination time.

Do current pregnancy weight gain guidelines balance risks of adverse maternal and child health in a United States cohort?

BACKGROUND: The Institute of Medicine pregnancy weight gain guidelines were developed without evidence linking high weight gain to maternal cardiometabolic disease and child obesity. The upper limit of current recommendations may be too high for the health of the pregnant individual and child. OBJECTIVES: The aim of this study was to identify the range of pregnancy weight gain for pregnancies within a normal body mass index (BMI) range that balances the risks of high and low weight gain by simultaneously considering 10 different health conditions. METHODS: We used data from an United States prospective cohort study of nulliparae followed until 2 to 7 y postpartum (N = 2344 participants with a normal BMI). Pregnancy weight gain z-score was the main exposure. The outcome was a composite consisting of the occurrence of ≥1 of 10 adverse health conditions that were weighted for their seriousness. We used multivariable Poisson regression to relate weight gain z-scores with the weighted composite outcome. RESULTS: The lowest risk of the composite outcome was at a pregnancy weight gain z-score of -0.6 SD (standard deviation) (equivalent to 13.1 kg at 40 wk). The weight gain ranges associated with no more than 5%, 10%, and 20% increase in risks were -1.0 to -0.2 SD (11.2-15.3 kg), -1.4 to 0 SD (9.4-16.4 kg), and -2.0 to 0.4 SD (7.0-18.9 kg). When we used a lower threshold to define postpartum weight increase in the composite outcome (>5 kg compared with >10 kg), the ranges were 1.6 to -0.7 SD (8.9-12.6 kg), -2.2 to -0.3 SD (6.3-14.7 kg), and ≤0.2 SD (≤17.6 kg). Compared with the ranges of the current weight gain guidelines (-0.9 to -0.1 SD, 11.5-16 kg), the lower limits from our data tended to be lower while upper limits were similar or lower. CONCLUSIONS: If replicated, our results suggest that policy makers should revisit the recommended pregnancy weight gain range for individuals within a normal BMI range.

First report of a member of the family Mermithidae parasitizing the sandhopper Orchestoidea tuberculata (Amphipoda, Talitridae) in Chile.

Specimens of the sandhopper Orchestoidea tuberculata (Amphipoda; Talitridae) collected from sandy beaches in south-central Chile, were found to be parasitized by juvenile mermithids, constituting the first record of a mermithid infecting a marine amphipod in Chile. A morphological description of juveniles is provided. Sequence analyses based on mitochondrial COI and nuclear 18S rDNA of the mermithids showed extremely low genetic variation. Phylogenetic analyses indicate that the mermithid is more closely related to Hexamermis agrotis, which parasitize Coleoptera, than to Thaumamermis zealandica, which parasitizes New Zealand confamilial talitrid amphipods.

Review of the concept of Profilicollis Meyer, 1931 with a description of Profilicollis rancoensis n. sp. (Acanthocephala: Polymorphidae) from the freshwater crab, Aegla abtao Schmitt, 1942 (Decapoda: Anomura) in Chile, with a key to congeneric species.

Profilicollis rancoensis n. sp. is the tenth species of Profilicollis Meyer, 1931 which includes 9 other species mostly known from marine decapod crabs and shore birds. Cystacanths of P. rancoensis are described from the dominant freshwater crab Aegla abtao in Ranco Lake, Chile and are morphologically distinguished from cystacanths of the 9 other species based on a combination of 4 characters. These are body size, number of proboscis hook rows, number of hooks per row, and length of the largest anterior 2-4 hooks. Male and female cystacanths of P. rancoensis are 2.10-3.33 mm long having an ovoid proboscis with 14 rows of 6-7 hooks per row, with the largest anterior 2-4 hooks being 105-110 micrometers long; the anterior trunk has many small spines in 70-80 concentric rings, each with 50-60 spines around them; hook roots are simple, directed posteriorly, about as long as the blades anteriorly with unremarkable anterior manubria; the cephalic ganglion are in mid-receptacle just anterior to the level of the anterior trunk; the lemnisci are long and slender; the testes are in the anterior trunk, posterior trunk, or one in each; the primordia of 2 tubular cement glands are evident; strong bundles of fibers link the anterior and posterior trunk; and the posterior trunk has a corrugated surface cuticula. Molecular analysis (COI and 18S) sequences coincided with the morphology and support its taxonomy. The phylogenetic profile revealed that P. rancoensis n. sp. fell into the Profilicollis clade. Both sequences showed low genetic variation, and three different haplotypes were found. The new species was more closely related to P. botulus (Van Cleave, 1916) Witenberg, 1932 than to other Profilicollis species.

Title: Révision du concept de Profilicollis Meyer, 1931 avec la description de Profilicollis rancoensis n. sp. (Acanthocephala, Polymorphidae) du crabe d'eau douce Aegla abtao Schmitt, 1942 (Decapoda, Anomura) au Chili, avec une clé des espèces congénères. Abstract: Profilicollis rancoensis n. sp. est la dixième espèce de Profilicollis Meyer, 1931 qui comprend neuf autres espèces principalement connues de crabes décapodes marins et d'oiseaux de rivage. Les cystacanthes de P. rancoensis sont décrits chez le crabe d'eau douce dominant Aegla abtao dans le lac Ranco, au Chili et se distinguent morphologiquement des cystacanthes des neuf autres espèces sur la base d'une combinaison de quatre caractères. Il s'agit de la taille du corps, du nombre de rangées de crochets du proboscis, du nombre de crochets par rangée et de la longueur des 2 à 4 crochets antérieurs les plus grands. Les cystacanthes mâles et femelles de P. rancoensis mesurent de 2,10 à 3,33 mm de long et ont une trompe ovoïde avec 14 rangées de 6 à 7 crochets par rangée, les 2 à 4 crochets antérieurs les plus grands mesurant 105 à 110 micromètres de long ; le tronc antérieur a de nombreuses petites épines en 70-80 anneaux concentriques chacun avec 50-60 épines ; les racines des crochets sont simples, dirigées vers l'arrière, à peu près aussi longues que les lames vers l'avant avec une manubrie antérieure sans particularité ; les ganglions céphaliques sont au milieu du réceptacle juste en avant du niveau du tronc antérieur ; les lemnisques sont longs et minces ; les testicules sont dans le tronc antérieur, le tronc postérieur ou un dans chacun ; les ébauches des 2 glandes cémentaires tubulaires sont évidentes ; de solides faisceaux de fibres relient le tronc antérieur et postérieur ; le tronc postérieur a une cuticule à surface ondulée. Les séquences d'analyse moléculaire (COI et 18S) coïncidaient avec la morphologie et confirmaient sa taxonomie. Le profil phylogénétique a révélé que P. rancoensis n. sp. appartient au clade Profilicollis. Les deux séquences ont montré une faible variation génétique et trois haplotypes différents ont été trouvés. La nouvelle espèce était plus proche de P. botulus (Van Cleave, 1916) Witenberg, 1932 que des autres espèces de Profilicollis.

Screening of the antileishmanial and antiplasmodial potential of synthetic 2-arylquinoline analogs.

In this study, six analogs of 2-arylquinoline were synthesized and evaluated for their in vitro and in vivo antiplasmodial and leishmanicidal activity. At a later stage, hemolytic activity and druggability were tested in vitro and in silico, respectively, observing as a result: firstly, compounds showed half-maximal effective concentration (EC50) values between 3.6 and 19.3 µM. Likewise, a treatment using the compounds 4a-f caused improvement in most of the treated hamsters and cured some of them. Regarding the antiplasmodial activity, the compounds showed moderate to high activity, although they did not show hemolytic activity. Furthermore, 4e and 4f compounds were not able to control P. berghei infection when administered to animal models. Molecular dynamic simulations, molecular docking and ligand binding affinity indicate good characteristics of the studied compounds, which are expected to be active. And lastly, the compounds are absorbable at the hematoencephalic barrier but not in the gastrointestinal tract. In summary, ADMET properties suggest that these molecules may be used as a safe treatment against Leishmania.

Assessment of the electromagnetic field exposure due to wireless communication technologies in two university campuses of medellin, Colombia.

Exposure to radiofrequency electromagnetic fields (RF-EMFs) is considered an area of significant importance in the medical and scientific community. However, the availability of exposure data for indoor and outdoor locations in universities is limited and currently inconsiderate in Latin America. The aim of this work was to evaluate the electric field levels due to mobile telecommunication technologies and Wi-Fi to which students and faculty staff from two campuses of a higher education institution are exposed. Using a portable spectrum analyzer, we carried out 516 short-term measurements in the 800-3000 MHz frequency range at both indoor and outdoor locations. These locations were chosen to cover all areas of the assessed buildings. The electric field differences between floors and buildings are discussed. Finally, we compared the electric field levels with exposure limits. The highest electric field level measured was 13.97 V/m at the 850 MHz band. However, the average electric field values were below 2 V/m. The greatest contribution to the total electric field was due to sources using the 850 MHz and 1900 MHz bands (98%), while the contribution of the Wi-Fi network was low (1.0%). The results show that all the electric field levels measured were lower than the ICNIRP reference levels for radio-frequency exposure.

Synthesis of Novel Heterocyclic Ferrocenyl Chalcones and Their Biological Evaluation.

Breast cancer is currently the most commonly diagnosed cancer, with 287,850 new cases estimated for 2022 as reported by the American Cancer Society. Therefore, finding an effective treatment for this disease is imperative. Chalcones are α,ß-unsaturated systems found in nature. These compounds have shown a wide array of biological activities, making them popular synthetic targets. Chalcones consist of two aromatic substituents connected by an enone bridge; this arrangement allows for a large number of derivatives. Given the biological relevance of these compounds, novel ferrocene-heterocycle-containing chalcones were synthesized and characterized based on a hybrid drug design approach. These heterocycles included thiophene, pyrimidine, thiazolyl, and indole groups. Fourteen novel heterocyclic ferrocenyl chalcones were synthesized and characterized. Herein, we also report their cytotoxicity against triple-negative breast cancer cell lines MDA-MB-231 and 4T1 and the noncancer lung cell line MRC-5. System 3 ferrocenyl chalcones displayed superior anticancer properties compared to their system 1 analogues. System 3 chalcones bearing five-membered heterocyclic substituents (thiophene, pyrazole, pyrrole, and pyrimidine) were the most active toward the MDA-MB-231 cancer cell line with IC50 values from 6.59 to 12.51 µM. Cytotoxicity of the evaluated compounds in the 4T1 cell line exhibited IC50 values from 13.23 to 213.7 µM. System 3 pyrazole chalcone had consistent toxicity toward both cell lines (IC50 ∼ 13 µM) as well as promising selectivity relative to the noncancer MRC-5 control. Antioxidant activity was also evaluated, where, contrary to anticancer capabilities, system 1 ferrocenyl chalcones were superior to their system 3 analogues. Antioxidant activity comparable to that of ascorbic acid was observed for thiophene-bearing ferrocenyl chalcone with EC50 = 31 µM.

Biological response of degradation products of PEO-modified magnesium on vascular tissue cells, hemocompatibility and its influence on the inflammatory response.

Cardiovascular stenting is the most widely used therapy to treat coronary artery disease caused by partial or total obstruction of the artery due to atherosclerotic plaque formation, with potentially fatal effects. There are different types of stents: bare metal stents, drug-eluting stents, bioabsorbable stents and dual therapy stents. However, they can lead to long-term complications, such as in-stent restenosis and late thrombosis. To reduce these adverse effects, research has focused on biodegradable metallic stents, since they retain the mechanical properties necessary to contain the injured artery while it is being repaired and, once their function has been fulfilled, the stent degrades without altering the system or compromising the patient's health. In this work we have evaluated the biological response of the degradation products of a bare Mg based biomaterial surface-modified by the plasma electrolytic oxidation (PEO) method on vascular tissue cells, hemocompatibility and inflammatory response. The results obtained are compatible with a biosafe material for future use as a cardiovascular implant, but it is necessary to continue with in vivo and mechanical properties tests to ensure and guarantee its use. SIGNIFICANCE STATEMENT: The development of fully bioresorbable stents is a promising alternative for the management of coronary artery disease without causing long-term problems at the implantation site. In this work, the hematological and immunological biocompatibility of bare Mg modified superficially by plasma electrolytic oxidation (PEO-Mg) was evaluated by in vitro and ex vivo assays. PEO-Mg was found to be compatible with blood and immune components surrounding the implantation site with no signs of toxicity to endothelial cells, macrophages, and arterial tissue. In addition, degradation products of PEO-Mg are eliminated by phagocytosis. However, an in-depth study of the physical and mechanical properties and in vivo biocompatibility must be carried out for its future use as a biomedical implant.

Reversing the biofilm-inducing effect of two xanthones from Garcinia mangostana by 3-methyl-2(5H)-furanone and N-butyryl-D-L homoserine lactone.

BACKGROUND: According to the WHO, 12 bacteria cause numerous human infections, including Enterobacteriaceae Klebsiella pneumoniae, and thus represent a public health problem. Microbial resistance is associated with biofilm formation; therefore, it is critical to know the biofilm-inducing potential of various compounds of everyday life. Likewise, the reversibility of biofilms and the modulation of persister cells are important for controlling microbial pathogens. In this work, we investigated the biofilm-inducing effects of xanthones from Garcinia mangostana on Klebsiella pneumoniae. Furthermore, we investigated the reversal effect of 3-methyl-2(5H)-furanone and the formation of persister cells induced by xanthones and their role in modulating the biofilm to the antibiotic gentamicin. METHODS: To analyze the biofilm-inducing role of xanthones from Garcinia mangostana, cultures of K. pneumoniae containing duodenal probe pieces were treated with 0.1-0.001 µM α- and γ-mangostin, and the biofilm levels were measured using spectrophotometry. To determine biofilm reversion, cultures treated with xanthones, or gentamicin were mixed with 3-methyl-2(5H)-furanone or N-butyryl-DL-homoserine lactone. The presence of K. pneumoniae persister cells was determined by applying the compounds to the mature biofilm, and the number of colony-forming units was counted. RESULTS: The xanthones α- and γ-mangostin increased K. pneumoniae biofilm production by 40% with duodenal probes. However, 3-methyl-2(5H)-furanone at 0.001 µΜ reversed biofilm formation by up to 60%. Moreover, adding the same to a culture treated with gentamicin reduced the biofilm by 80.5%. This effect was highlighted when 3-methyl-2(5H)-furanone was administered 6 h later than xanthones. At high concentrations of α-mangostin, persister K. pneumoniae cells in the biofilm were about 5 - 10 times more abundant than cells, whereas, with γ-mangostin, they were about 100 times more. CONCLUSION: Two xanthones, α- and γ-mangostin from G. mangostana, induced biofilm formation in K. pneumoniae and promoted persister cells. However, the biofilm formation was reversed by adding 3-methyl-2(5H)-furanone, and even this effect was achieved with gentamicin. In addition, this compound controlled the persister K. pneumoniae cells promoted by α-mangostin. Thus, synthetic, and natural biofilm-inducing compounds could harm human health. Therefore, avoiding these substances and looking for biofilm inhibitors would be a strategy to overcome microbial resistance and recover antibiotics that are no longer used.

Phytosterols reverse antiretroviral-induced hearing loss, with potential implications for cochlear aging.

Cholesterol contributes to neuronal membrane integrity, supports membrane protein clustering and function, and facilitates proper signal transduction. Extensive evidence has shown that cholesterol imbalances in the central nervous system occur in aging and in the development of neurodegenerative diseases. In this work, we characterize cholesterol homeostasis in the inner ear of young and aged mice as a new unexplored possibility for the prevention and treatment of hearing loss. Our results show that cholesterol levels in the inner ear are reduced during aging, an effect that is associated with an increased expression of the cholesterol 24-hydroxylase (CYP46A1), the main enzyme responsible for cholesterol turnover in the brain. In addition, we show that pharmacological activation of CYP46A1 with the antiretroviral drug efavirenz reduces the cholesterol content in outer hair cells (OHCs), leading to a decrease in prestin immunolabeling and resulting in an increase in the distortion product otoacoustic emissions (DPOAEs) thresholds. Moreover, dietary supplementation with phytosterols, plant sterols with structure and function similar to cholesterol, was able to rescue the effect of efavirenz administration on the auditory function. Altogether, our findings point towards the importance of cholesterol homeostasis in the inner ear as an innovative therapeutic strategy in preventing and/or delaying hearing loss.

Tumor Mutational Burden in Breast Cancer: Current Evidence, Challenges, and Opportunities.

Tumor mutational burden (TMB) correlates with tumor neoantigen burden, T cell infiltration, and response to immune checkpoint inhibitors in many solid tumor types. Based on data from the phase II KEYNOTE-158 study, the anti-PD-1 antibody pembrolizumab was granted approval for treating patients with advanced solid tumors and TMB ≥ 10 mutations per megabase. However, this trial did not include any patients with metastatic breast cancer; thus, several questions remain unanswered about the true role of TMB as a predictive biomarker of benefit to immune checkpoint inhibitor therapy in breast cancer. In this review, we will discuss the challenges and opportunities in establishing TMB as a predictive biomarker of benefit to immunotherapy in metastatic breast cancer.