Enhancing RECK Expression Through miR-21 Inhibition: A Promising Strategy for Bladder Carcinoma Control.

Bladder carcinoma (BC) is the tenth most frequent malignancy worldwide, with high morbidity and mortality rates. Despite recent treatment advances, high-grade BC and muscle-invasive BC present with significant progression and recurrence rates, urging the need for alternative treatments. The microRNA-21 (miR-21) has superexpression in many malignancies and is associated with cellular invasion and progression. One of its mechanisms of action is the regulation of RECK, a tumor suppressor gene responsible for inhibiting metalloproteinases, including MMP9. In a high-grade urothelial cancer cell line, we aimed to assess if miR-21 downregulation would promote RECK expression and decrease MMP9 expression. We also evaluated cellular migration and proliferation potential by inhibition of this pathway. In a T24 cell line, we inhibited miR-21 expression by transfection of a specific microRNA inhibitor (anti-miR-21). There were also control and scramble groups, the last with a negative microRNA transfected. After the procedure, we performed a genetic expression analysis of miR-21, RECK, and MMP9 through qPCR. Migration, proliferation, and protein expression were evaluated via wound healing assay, colony formation assay, flow cytometry, and immunofluorescence.After anti-miR-21 transfection, miR-21 expression decreased with RECK upregulation and MMP9 downregulation. The immunofluorescence assay showed a significant increase in RECK protein expression (p < 0.0001) and a decrease in MMP9 protein expression (p = 0.0101). The anti-miR-21 transfection significantly reduced cellular migration in the wound healing assay (p < 0.0001). Furthermore, in the colony formation assay, the anti-miR-21 group demonstrated reduced cellular proliferation (p = 0.0008), also revealed in the cell cycle analysis by flow cytometry (p = 0.0038). Our results corroborate the hypothesis that miR-21 is associated with BC cellular migration and proliferation, revealing its potential as a new effective treatment for this pathology.

Microbial Metabolites Annotation by Mass Spectrometry-Based Metabolomics.

Since the discovery of penicillin, microbial metabolites have been extensively investigated for drug discovery purposes. In the last decades, microbial derived compounds have gained increasing attention in different fields from pharmacognosy to industry and agriculture. Microbial metabolites in microbiomes present specific functions and can be associated with the maintenance of the natural ecosystems. These metabolites may exhibit a broad range of biological activities of great interest to human purposes. Samples from either microbial isolated cultures or microbiomes consist of complex mixtures of metabolites and their analysis are not a simple process. Mass spectrometry-based metabolomics encompass a set of analytical methods that have brought several improvements to the microbial natural products field. This analytical tool allows the comprehensively detection of metabolites, and therefore, the access of the chemical profile from those biological samples. These analyses generate thousands of mass spectra which is challenging to analyse. In this context, bioinformatic metabolomics tools have been successfully employed to accelerate and facilitate the investigation of specialized microbial metabolites. Herein, we describe metabolomics tools used to provide chemical information for the metabolites, and furthermore, we discuss how they can improve investigation of microbial cultures and interactions.

Untargeted-based metabolomics analysis and in vitro/in silico antiviral activity of extracts from Phyllanthus brasiliensis (Aubl.) Poir.

INTRODUCTION: This study describes the molecular profile and the potential antiviral activity of extracts from Phyllanthus brasiliensis, a plant widely found in the Brazilian Amazon. The research aims to shed light on the potential use of this species as a natural antiviral agent. METHODS: The extracts were analysed using liquid chromatography-mass spectrometry (LC-MS) system, a potent analytical technique to discover drug candidates. In the meantime, in vitro antiviral assays were performed against Mayaro, Oropouche, Chikungunya, and Zika viruses. In addition, the antiviral activity of annotated compounds was predicted by in silico methods. RESULTS: Overall, 44 compounds were annotated in this study. The results revealed that P. brasiliensis has a high content of fatty acids, flavones, flavan-3-ols, and lignans. Furthermore, in vitro assays revealed potent antiviral activity against different arboviruses, especially lignan-rich extracts against Zika virus (ZIKV), as follows: methanolic extract from bark (MEB) [effective concentration for 50% of the cells (EC50 ) = 0.80 µg/mL, selectivity index (SI) = 377.59], methanolic extract from the leaf (MEL) (EC50 = 0.84 µg/mL, SI = 297.62), and hydroalcoholic extract from the leaf (HEL) (EC50 = 1.36 µg/mL, SI = 735.29). These results were supported by interesting in silico prediction, where tuberculatin (a lignan) showed a high antiviral activity score. CONCLUSIONS: Phyllanthus brasiliensis extracts contain metabolites that could be a new kick-off point for the discovery of candidates for antiviral drug development, with lignans becoming a promising trend for further virology research.

Putative Identification of New Phragmaline-Type Limonoids from the Leaves of Swietenia macrophylla King: A Case Study Using Mass Spectrometry-Based Molecular Networking.

Swietenia macrophylla King is a plant commonly known as Brazilian mahogany. The wood from its stem is highly prized for its exceptional quality, while its leaves are valued for their high content of phragmalin-type limonoids, a subclass of compounds known for their significant biological activities, including antimalarial, antitumor, antiviral, and anti-inflammatory properties. In this context, twelve isolated limonoids from S. macrophylla leaves were employed as standards in mass spectrometry-based molecular networking to unveil new potential mass spectrometry signatures for phragmalin-type limonoids. Consequently, ultra-performance liquid chromatography coupled with high-resolution mass spectrometry was utilized for data acquisition. Subsequently, the obtained data were analyzed using the Global Natural Products Social Molecular Networking platform based on spectral similarity. In summary, this study identified 24 new putative phragmalin-type limonoids for the first time in S. macrophylla. These compounds may prove valuable in guiding future drug development efforts, leveraging the already established biological activities associated with limonoids.

Antiviral Plants from Marajó Island, Brazilian Amazon: A Narrative Review.

Diseases caused by viruses are a global threat, resulting in serious medical and social problems for humanity. They are the main contributors to many minor and major outbreaks, epidemics, and pandemics worldwide. Over the years, medicinal plants have been used as a complementary treatment in a range of diseases. In this sense, this review addresses promising antiviral plants from Marajó island, a part of the Amazon region, which is known to present a very wide biodiversity of medicinal plants. The present review has been limited to articles and abstracts available in Scopus, Web of Science, Science Direct, Scielo, PubMed, and Google Scholar, as well as the patent offices in Brazil (INPI), United States (USPTO), Europe (EPO) and World Intellectual Property Organization (WIPO). As a result, some plants from Marajó island were reported to have actions against HIV-1,2, HSV-1,2, SARS-CoV-2, HAV and HBV, Poliovirus, and influenza. Our major conclusion is that plants of the Marajó region show promising perspectives regarding pharmacological potential in combatting future viral diseases.

Chemical Composition of Leaves, Stem, and Roots of Peperomia pellucida (L.) Kunth.

Peperomia pellucida is a species known in the Amazon as "erva-de-jabuti" that has been used in several therapeutic applications based on folk medicine. Herein, we describe the classes, subclasses, and the main compounds of the leaves, stems, and roots from P. pellucida by ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry associated with molecular networks, mirror plot on the GNPS library, and machine learning. These data show compounds that were annotated for the first time in the Peperomia genus, such as 2',4',5'-trihydroxybutyrophenonevelutin, dehydroretrofractamide C, and retrofractamide B.

Does land use and land cover affect adult communities of Ephemeroptera, Plecoptera and Trichoptera (EPT)? A systematic review with meta-analysis.

We conducted a systematic review to better understand this gap and analyzed i) in which global regions are studies usually conducted, ii) the taxon studied, iii) sampling methods and iv) how authors collaborated in these studies. We also tested the relationship between different types of land use and land cover and adult EPT communities using a meta-analysis. We searched for relevant articles on the website Web of Science, using specific words related to the subject. We found 454 papers and selected 31 of them for the scientometric analysis, as they were in accordance with our objectives, and eight for the meta-analysis. Among this subset, we observed that study areas and collaborations among authors were largely restricted to a few countries in Europe and North America. Most studies used the group Trichoptera, probably due to its diversity and the longevity of the adults compared to other groups. Light traps were the most common sampling method, most likely due to their efficiency in capturing flying insects with nocturnal habits. The greatest differences in adult EPT communities were found between open areas (moorland and prairie) and forest areas. This result indicated that the conversion of forest habitats into open areas negatively impacts adult EPT communities. Our systematic review can be an important tool to help researchers choose appropriate collection methods and taxonomic groups to work with in studies on impacts of land use change on adult EPT communities.

The Antimicrobial Peptide MK58911-NH2 Acts on Planktonic, Biofilm, and Intramacrophage Cells of Cryptococcus neoformans.

Cryptococcosis is associated with high rates of morbidity and mortality, especially in AIDS patients. Its treatment is carried out by combining amphotericin B and azoles or flucytosine, which causes unavoidable toxicity issues in the host. Thus, the urgency in obtaining new antifungals drives the search for antimicrobial peptides (AMPs). This study aimed to extend the understanding of the mechanism of action of an AMP analog from wasp peptide toxins, MK58911-NH2, on Cryptococcus neoformans. We also evaluated if MK58911-NH2 can act on cryptococcal cells in macrophages, biofilms, and an immersion zebrafish model of infection. Finally, we investigated the structure-antifungal action and the toxicity relationship of MK58911-NH2 fragments and a derivative of this peptide (MH58911-NH2). The results demonstrated that MK58911-NH2 did not alter the fluorescence intensity of the cell wall-binding dye calcofluor white or the capsule-binding dye 18b7 antibody-fluorescein isothiocyanate (FITC) in C. neoformans but rather reduced the number and size of fungal cells. This activity reduced the fungal burden of C. neoformans in both macrophages and zebrafish embryos as well as within biofilms. Three fragments of the MK58911-NH2 peptide showed no activity against Cryptococcus and not toxicity in lung cells. The derivative peptide MH58911-NH2, in which the lysine residues of MK58911-NH2 were replaced by histidines, reduced the activity against extracellular and intracellular C. neoformans. On the other hand, it was active against biofilms and showed reduced toxicity. In summary, these results showed that peptide MK58911-NH2 could be a promising agent against cryptococcosis. This work also opens a perspective for the verification of the antifungal activity of other derivatives.

Ventricular pre-excitation in primary care patients: Evaluation of the risk of mortality.

BACKGROUND: Ventricular pre-excitation is characterized by the presence of atrioventricular accessory pathways, predisposing to arrhythmias. Although it is well established that risk stratification in symptomatic patients should be invasive, there is a lack of evidence of the benefit in asymptomatic. OBJECTIVE: Evaluate ventricular pre-excitation in the electrocardiogram (ECG) as a risk factor for overall mortality in patients of Telehealth Network of Minas Gerais (TNMG), Brazil. METHODS: This observational study was developed with the database of digital ECGs (2010-2017) from TNMG. The electronic cohort was obtained by linking data from ECG exams and those from the national mortality information system. Only the first ECG was considered. Clinical data were self-reported, and ECGs were interpreted manually by cardiologists and automatically by the Glasgow University Interpreter software. Hazard ratio (HR) for mortality was estimated using weighted Cox regression. RESULTS: Nearly 1 665 667 patients were included (median age: 50 [Q1: 34; Q3: 63] years; 41.4% were male). In a mean follow-up of 3.7 years, the overall mortality rate was 3.1%. The prevalence of ventricular pre-excitation was 0.07%. In multivariate analysis, adjusting for sex and age, ventricular pre-excitation was not associated with an increased risk of mortality (HR: 1.41; 95% confidence interval [CI]: 0.56-3.57; p = .47) when compared to the whole sample or to patients with normal ECG (HR: 1.41; 95% CI: 0.53-4.36; p = .43). In a subanalysis on accessory pathway location, there was no evidence of a higher risk of death related to any location. CONCLUSION: Ventricular pre-excitation was not associated with an increased risk of mortality in a primary care cohort.

Renal alterations caused by ligature-induced periodontitis persist after ligature removal in rats.

BACKGROUND AND OBJECTIVE: Periodontitis may crosstalk with renal diseases, yet that remains unclear. We investigated whether the renal alterations caused by induced periodontitis are reversible after removal of the ligatures in experimental ligature-induced periodontitis. MATERIAL AND METHODS: Twenty-four female rats were divided into three groups: control (without periodontitis), periodontitis (20 days of ligature-induced periodontitis), and P20-20 (20 days of ligature-induced periodontitis and 20 days after ligature removal). The following periodontal parameters were assessed: gingival bleeding index, probing pocket depth, myeloperoxidase activity, and alveolar bone height. For renal tissues, histopathology, malonaldehyde (MDA) levels, glutathione (GSH) content, and renal weight were evaluated. In the blood, creatinine, uric acid, albumin, total cholesterol, total protein, and glucose levels were assessed. Total protein and creatinine levels in urine were also investigated. RESULTS: Rat renal tissues did not demonstrate reversal of periodontitis-related changes in the P20-20 group in terms of MDA, GSH, and histopathological evaluations when compared to the periodontitis group. Accordingly, only total cholesterol levels were reversible in the P20-20. CONCLUSION: Renal alterations caused by ligature-induced periodontitis persisted even after removal of ligatures in rats.

Automated method to determine pharmaceutical compounds in wastewater using on-line solid-phase extraction coupled to LC-MS/MS.

An automated method was developed using on-line solid-phase extraction (SPE) as a sample preparation step, coupled to liquid chromatography-tandem mass spectrometry (LC-MS/MS), for determination of pharmaceutical compounds in wastewater samples at nanograms per liter to micrograms per liter concentration levels. This method is suitable for use in routine analysis, especially in environmental applications, avoiding cross-contamination and requiring minimal sample handling. Results can be obtained rapidly, with a chromatographic run time of only 24 min (including sample preparation and chromatographic analysis). Using a 50 µL injection volume, the method was validated according to international guidelines, considering parameters included in terms of method detection (MDL) and quantification limit (MQL), linearity, inter-day and intra-day precisions, and matrix effects. Assessment of chromatographic efficiency considered peak resolution and asymmetry, and carryover was evaluated to ensure analytical reliability and the ability to reuse the SPE cartridge. The intra- and inter-day precisions were lower than 10 and 17%, respectively. The MDL values ranged from 1×10-6 to 1 µg L-1, while the MQL values were from 0.001 to 3 µg L-1. Matrix effects were minimized by isotope dilution calibration. Application of the method to 20 wastewater samples showed that caffeine was the most frequently detected compound, with the highest concentration of 715 µg L-1, while other pharmaceutical compounds were detected in fewer samples and at lower concentrations (up to 8.51 µg L-1).

Can increased expression of miR-Let-7c reduce the transition potential of high-grade urothelial carcinoma?

BACKGROUND: Bladder cancer is the leading transitional cell carcinoma affecting men and women with high morbidity and mortality rates, justifying the need to develop new molecular target therapies using microRNAs. This study aimed to evaluate the behavior of the T24 cell line after transfection with miR-Let-7c precursor mimic through invasion, migration, apoptosis, and cell cycle assays. METHODS AND RESULTS: T24 cell was transfected with the Let-7c mimic and its respective control and evaluated after 24 h. The expression levels of miR-Let-7c were analyzed by qPCR. We performed wound healing, Matrigel and flow cytometry, apoptosis, and cell cycle assays to determine its effect on cellular processes. Cells transfected with miR-Let-7c showed increased apoptosis rates (p = 0.019), decreased migration 24 h (p = 0.031) and 48 h (p = 0.0006), invasion potential (p = 0.0007), and cell proliferation (p = 0.002). CONCLUSIONS: Our results demonstrate that miR-Let-7c can act in different pathways of the carcinogenic cellular processes of muscle-invasive urothelial carcinoma cells, inhibiting cell proliferation and increasing apoptosis levels, consequently limiting their invasion potential. However, further studies should be carried out better to elucidate this microRNA's role in high-grade urothelial carcinomas and unveil which targets this microRNA may present, which are intrinsically related to the cancer survival pathways.

Prevalence of major and minor electrocardiographic abnormalities in one million primary care Latinos.

This study aims to assess the prevalence of electrocardiographic abnormalities based on the Minnesota code from a large sample of 1.01 m adult Brazilian primary care patients and to evaluate its association with age, sex, and cardiovascular risk factors. A large electrocardiogram (ECG) database of such patients aged ≥18 years (mean age 52 ± 17 years-old with 60.2% female). was analyzed and the results were stratified by sex and age. The prevalence of abnormalities was more common in men and the elderly population. Major electrocardiographic abnormalities were observed in 20.2% of adults and 43.1% of elderly patients, and minor abnormalities were found in 46.0% 39.4%, respectively. For adult patients, the number and percentage of major abnormalities rise depending on the number of cardiovascular risk factors. For elderly patients, the correlation between these variables is not clear, and the percentage of major abnormalities remains stable independently of the number of risk factors.

Composition and structure of the bryophyte community of Park Savanna in Marajó Island, Pará, Brazil.

Aiming to enrich the knowledge about the flora of savannas, this paper studied the composition and structure of the bryophyte community of Park Savanna areas in Marajó Island - PA. Biological material was collected within 60 100-m2 plots equally distributed in the dry season of 2016 and the rainy season of 2017 in five Park Savanna areas (SP-I to SP-V). The composition, density, richness and diversity of species and presence of indicator species were compared between the sampled areas and seasons. The species were classified according to the substrates colonized and ecological groups of light tolerance. Significant differences in SP-V indicated that the area was the main factor influencing the composition of bryophytes (p: 0.0001), with five indicator species. There were also significant differences in density (p = 0.0001168) and richness (p = 0.0001317) of bryophytes between seasons (p-value = 0.3393; p-value = 0.04065; p: 0.1081). There was a predominance of generalist (25 spp.) and corticolous (728 individuals) species, which were widely distributed in the sampled areas. Therefore, the structure of the bryophyte communities was not influenced by seasonality, and this indicates that these plants are adapted to the environmental conditions.

Label-Free Ultrasensitive and Environment-Friendly Immunosensor Based on a Silica Optical Fiber for the Determination of Ciprofloxacin in Wastewater Samples.

Emerging contaminants, including pharmaceutical compounds, are receiving research attention as a result of their widespread presence in effluents and wastewater treatment plants (WWTPs). The antibiotic ciprofloxacin (CIP) is extensively employed to treat infections in animal and human medicine. Both CIP and its metabolites are common contaminants found in WWTPs. In this study, a label-free ultrasensitive U-bent optical fiber-based immunosensor for the determination of CIP in wastewater samples was developed using the properties of the conducting polymer polyaniline (PANI). The anti-CIP immunoglobulin G (IgG) was deposited on a silica optical fiber surface previously functionalized with PANI. Scanning electron microscopy and micro-Raman spectroscopy were used to investigate the surface of the immunosensor. The analysis of CIP in wastewater was performed without the use of an organic solvent or sample preparation steps, with only the sample dilution in saline buffer (pH = 7.4). The linear range for CIP was from 0.01 to 10,000 ng L-1. The detection limit was 3.30 × 10-3 ng L-1 and the quantification limit was 0.01 ng L-1. The immunosensor provided a high average recovery of 91% after spiking wastewater samples with CIP at a concentration of 9,100 ng L-1. The method was applied in triplicate to wastewater samples from Quebec (Canada), obtaining concentrations of 549 and 267 ng L-1. A comparison with a reference method showed no significant difference (t-test at 95% confidence). The new technique developed is selective, allowing a quantitative analysis of CIP in wastewater.

Phase diagrams of the Ziff-Gulari-Barshad model on random networks.

In this study, we revisited the Ziff-Gulari-Barshad (ZGB) model in order to study the behavior of its phase diagram when two well-known random networks play the role of the catalytic surfaces: the random geometric graph and the Erdös-Rényi network. The connectivity and, therefore, the average number of neighbors of the nodes of these networks can vary according to their control parameters, the neighborhood radius α, and the linking probability p, respectively. In addition, the catalytic reactions of the ZGB model are governed by the parameter y, the adsorption rate of carbon monoxide molecules on the catalytic surface. So, to study the phase diagrams of the model on both random networks, we carried out extensive steady-state Monte Carlo simulations in the space parameters (y, α) and (y, p) and showed that the continuous phase transition is greatly affected by the topological features of the networks while the discontinuous one remains present in the diagram throughout the interval of study.

Secure and Sustainable Sourcing of Plant Tissues for the Exhaustive Exploration of Their Chemodiversity.

The main challenge of plant chemical diversity exploration is how to develop tools to study exhaustively plant tissues. Their sustainable sourcing is a limitation as bioguided strategies and dereplication need quite large amounts of plant material. We examine if alternative solutions could overcome these difficulties by obtaining a secure, sustainable, and scalable source of tissues able to biosynthesize an array of metabolites. As this approach would be as independent of the botanical origin as possible, we chose eight plant species from different families. We applied a four steps culture establishment procedure, monitoring targeted compounds through mass spectrometry-based analytical methods. We also characterized the capacities of leaf explants in culture to produce diverse secondary metabolites. In vitro cultures were successfully established for six species with leaf explants still producing a diversity of compounds after the culture establishment procedure. Furthermore, explants from leaves of axenic plantlets were also analyzed. The detection of marker compounds was confirmed after six days in culture for all tested species. Our results show that the first stage of this approach aiming at easing exploration of plant chemodiversity was completed, and leaf tissues could offer an interesting alternative providing a constant source of natural compounds.

Tele-electrocardiography and bigdata: The CODE (Clinical Outcomes in Digital Electrocardiography) study.

Digital electrocardiographs are now widely available and a large number of digital electrocardiograms (ECGs) have been recorded and stored. The present study describes the development and clinical applications of a large database of such digital ECGs, namely the CODE (Clinical Outcomes in Digital Electrocardiology) study. ECGs obtained by the Telehealth Network of Minas Gerais, Brazil, from 2010 to 17, were organized in a structured database. A hierarchical free-text machine learning algorithm recognized specific ECG diagnoses from cardiologist reports. The Glasgow ECG Analysis Program provided Minnesota Codes and automatic diagnostic statements. The presence of a specific ECG abnormality was considered when both automatic and medical diagnosis were concordant; cases of discordance were decided using heuristisc rules and manual review. The ECG database was linked to the national mortality information system using probabilistic linkage methods. From 2,470,424 ECGs, 1,773,689 patients were identified. After excluding the ECGs with technical problems and patients <16 years-old, 1,558,415 patients were studied. High performance measures were obtained using an end-to-end deep neural network trained to detect 6 types of ECG abnormalities, with F1 scores >80% and specificity >99% in an independent test dataset. We also evaluated the risk of mortality associated with the presence of atrial fibrillation (AF), which showed that AF was a strong predictor of cardiovascular mortality and mortality for all causes, with increased risk in women. In conclusion, a large database that comprises all ECGs performed by a large telehealth network can be useful for further developments in the field of digital electrocardiography, clinical cardiology and cardiovascular epidemiology.

Evaluation of mortality in bundle branch block patients from an electronic cohort: Clinical Outcomes in Digital Electrocardiography (CODE) study.

BACKGROUND: Left bundle branch block is recognized as a marker of higher risk of death, but the prognostic value of the right bundle branch block in the general population is still controversial. Our aim is to evaluate the risk of overall and cardiovascular mortality in patients with right (RBBB) and left bundle branch block (LBBB) in a large electronic cohort of Brazilian patients. METHODS: This observational retrospective study was developed with the database of digital ECGs from Telehealth Network of Minas Gerais, Brazil (TNMG). All ECGs performed from 2010 to 2017 in primary care patients over 16 years old were assessed. The electronic cohort was obtained by linking data from ECG exams (name, sex, date of birth, city of residence) and those from national mortality information system, using standard probabilistic linkage methods (FRIL: Fine-grained record linkage software, v.2.1.5, Atlanta, GA). Only the first ECG of each patient was considered. Clinical data were self-reported, and ECGs were interpreted manually by cardiologists and automatically by the Glasgow University Interpreter software. Hazard ratio (HR) for mortality was estimated using Cox regression. RESULTS: From a dataset of 1,773,689 patients, 1,558,421 primary care patients over 16 years old underwent a valid ECG recording during 2010 to 2017. We excluded 17,359 patients that didn't have a valid QRS measure from the Glasgow program and 11,091 patients from the control group that had QRS equal or above 120 ms and were not RBBB or LBBB. Therefore, 1,529,971 were included (median age 52 [Q1:38; Q3:65] years; 40.2% were male). In a mean follow-up of 3.7 years, the overall mortality rate was 3.34%. RBBB was more frequent (2.42%) than LBBB (1.32%). In multivariate analysis, adjusting for sex, age and comorbidities, both patients with RBBB (HR 1.32; CI 95% 1.27-1.37) and LBBB (HR 1.69; CI 95% 1.62-1.76) had higher risk of overall mortality. Women with RBBB had an increased risk of all-cause death compared to men (p < 0.001). Cardiovascular mortality was higher in patients with LBBB (HR 1.77; CI 95% 1.55-2.01), but not for RBBB. CONCLUSIONS: Patients with RBBB and LBBB had higher risk of overall mortality. Women with RBBB had more risk of all-cause death than men. LBBB was associated with higher risk of cardiovascular mortality.

Phthalimido-thiazole as privileged scaffold: activity against immature and adult worms of Schistosoma mansoni.

Phthalimide, 1,3-thiazole, and thiazolidinone cores are considered privileged scaffolds and represent an attractive starting point to design new bioactive compounds for neglected tropical disease (NTD). Schistosomiasis is a NTD, caused by Schistosoma worms which praziquantel (PZQ) is the only drug used to treat humans, but the decrease in the effect after treatment has been reported. Recently, some phthalimide-thiazole derivatives exhibited in vitro antischistosomal activity against adult worms with significant ultrastructural changes and a lower cytotoxic effect on splenocytes. This new biological phthalimido-thiazole profile has motivated us to evaluate a new generation of such molecules in immature and adult worms. Thus, a phthalimido-thiazolidinone derivative, (3c), and three phthalimido-thiazoles (6c, 7a, and 7h) were evaluated concerning their in vitro activity on schistosomulae and adult worms. The results showed that these compounds brought a significant reduction on the mortality, inhibited oviposition, and then induced mortality in immature and adult worms alike. According to scanning electron microscopy, the tegument was the principal target for 7a and 7h and revealed gradual damage to the tegument surface, inducing destruction and decomposition of the tegument in the same areas and exposition of subtegumental tissue and of muscle tissue. Furthermore, they caused less toxicity in splenocytes than PZQ. Compounds 7a and 7h revealed to possess promising activity against larval forms. According to the present study, the privileged structure phthalimido-thiazoles act as a molecular framework that has antischistosomal activity and most form the basis to the next pre-clinical tests. Graphical abstract.