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Dynamics of epigenetic modifications such as acetylation and deacetylation of histone proteins have been shown to be crucial for the life cycle development and survival of Plasmodium falciparum, the deadliest malaria parasite. In this study, we present a novel series of peptoid-based histone deacetylase (HDAC) inhibitors incorporating nitrogen-containing bicyclic heteroaryl residues as a new generation of antiplasmodial peptoid-based HDAC inhibitors. We synthesized the HDAC inhibitors by an efficient multicomponent protocol based on the Ugi four-component reaction. The subsequent screening of 16 compounds from our mini-library identified 6i as the most promising candidate, demonstrating potent activity against asexual blood-stage parasites (IC 50 Pf3D7 = 30 nM; IC 50 PfDd2 = 98 nM), low submicromolar activity against liver-stage parasites (IC 50 PbEEF = 0.25 μM), excellent microsomal stability (t 1/2  > 60 min), and low cytotoxicity to HEK293 cells (IC 50  = 136 μM)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Ruthenium(II) tetraamine nitrosyl complexes with N-heterocyclic ligands are known for their potential as nitric oxide (NO • ) donors, capable of releasing NO • through either direct photodissociation or one-electron reduction of the Ru(II)NO + center. This study delivers a novel insight into the one-electron reduction mechanism for the model complex trans -[Ru II (NO)(NH 3 ) 4 (py)] 3+ (RuNOpy, py = pyridine) in phosphate buffer solution (pH 7.4). In situ FT-IR spectroelectrochemistry reveals that the pyridine ligand is readily released upon one-electron reduction of the nitrosyl complex, a finding supported by nuclear magnetic resonance spectroscopy ( 1 H NMR) and electrochemistry coupled to mass spectrometry (EC-MS), which detect free pyridine in solution. However, direct evidence of NO • release from RuNOpy as the primary step following reduction was not observed. Interestingly, FT-IR results indicate that the isomers of the nitrosyl complex, cis -[Ru(NO)(NH 3 ) 4 (OH)] + and trans -[Ru(NO)(NH 3 ) 4 (OH)] + , are formed following reduction and pyridine labilization, initiating an outer-sphere electron transfer process that triggers a chain electron transfer reaction. Finally, nitric oxide is liberated as an end product, arising from the reduction of the hydroxyl isomer complexes cis -[Ru(NO)(NH 3 ) 4 (OH)] 2+ and trans -[Ru(NO)(NH 3 ) 4 (OH)] 2+ . This study provides new insights into the reduction mechanism and transformation pathways of ruthenium nitrosyl complexes, contributing to our understanding of their potential as NO • donors.

Decision makers are often confronted with inadequate information to predict nutrient loads and yields in freshwater ecosystems at large spatial scales. We evaluate the potential of using data mapped at large spatial scales (regional to global) and often coarse resolution to predict nitrogen yields at varying smaller scales (e.g., at the catchment and stream reach level). We applied the SPAtially Referenced Regression On Watershed attributes (SPARROW) model in three regions: the Upper Midwest part of the United States, New Zealand, and the Grande River Basin in southeastern Brazil. For each region, we compared predictions of nitrogen delivery between models developed using novel large-scale datasets and those developed using local-scale datasets. Large-scale models tended to underperform the local-scale models in poorly monitored areas. Despite this, large-scale models are well suited to generate hypotheses about relative effects of different nutrient source categories (point and urban, agricultural, native vegetation) and to identify knowledge gaps across spatial scales when data are scarce. Regardless of the spatial resolution of the predictors used in the models, a representative network of water quality monitoring stations is key to improve the performance of large-scale models used to estimate loads and yields. We discuss avenues of research to understand how this large-scale modelling approach can improve decision making for managing catchments at local scales, particularly in data poor regions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Hybrid nanocomposites combining biopolymer fibers incorporated with nanoparticles (NPs) have received increasing attention due to their remarkable characteristics. Inorganic NPs are typically chosen for their properties, such as magnetism and thermal or electrical conductivity, for example. Meanwhile, the biopolymer fiber component is a backbone, and could act as a support structure for the NPs. This shift towards biopolymers over traditional synthetic polymers is motivated by their sustainability, compatibility with biological systems, non-toxic nature, and natural decomposition. This study employed the solution blow spinning (SBS) method to obtain a nanocomposite comprising poly(vinyl pyrrolidone), PVA, and gelatin biodegradable polymer fibers incorporated with magnetic iron oxide nanoparticles coated with poly(acrylic acid), PAA 2k , coded as γ-Fe 2 O 3 -NPs-PAA 2k . The fiber production process entailed a preliminary investigation to determine suitable solvents, polymer concentrations, and spinning parameters. γ-Fe 2 O 3 -NPs were synthesized via chemical co-precipitation as maghemite and coated with PAA 2k through the precipitation-redispersion protocol in order to prepare γ-Fe 2 O 3 -NPs-PAA 2k . Biopolymeric fibers containing coated NPs with sub-micrometer diameters were obtained, with NP concentrations ranging from 1.0 to 1.7% wt. The synthesized NPs underwent characterization via dynamic light scattering, zeta potential analysis, and infrared spectroscopy, while the biopolymer fibers were characterized through scanning electron microscopy, infrared spectroscopy, and thermogravimetric analysis. Overall, this study demonstrates the successful implementation of SBS for producing biopolymeric fibers incorporating iron oxide NPs, where the amalgamation of materials demonstrated superior thermal behavior to the plain polymers. The thorough characterization of the NPs and fibers provided valuable insights into their properties, paving the way for their potential applications in various fields such as biomedical engineering, environmental remediation, and functional materials.

The precise mode of action of ganaplacide (KAF156), a phase III antimalarial candidate, remains elusive. Here we employ omics-based methods with the closely related chemical analog, GNF179, to search for potential Plasmodium targets. Ranking potential targets derived from chemical genetics and proteomic affinity chromatography methodologies identifies SEY1 , or Synthetic Enhancement of YOP1, which is predicted to encode an essential dynamin-like GTPase implicated in homotypic fusion of endoplasmic reticulum (ER) membranes. We demonstrate that GNF179 decreases Plasmodium SEY1 melting temperature. We further show that GNF179 binds to recombinant Plasmodium SEY1 and subsequently inhibits its GTPase activity, which is required for maintaining ER architecture. Using ultrastructure expansion microscopy, we find GNF179 treatment changes parasite ER and Golgi morphology. We also confirm that SEY1 is an essential gene in P. falciparum . These data suggest that SEY1 may contribute to the mechanism of action of imidazolopiperazines and is a new and attractive druggable target.

This study shows the development of a software for calculating the number of nursing team members required for providing care during the coronavirus disease 2019 pandemic. Study about the development of a technology based on the literature about data and indicators. The indicators were systematized in the following dimensions: institutional, professional, and occupational structure, all with a focus on coronavirus disease 2019. The software was created to be used on the Web, client-server, in browsers such as Internet Chrome, Explorer, and/or Mozilla Firefox, accessing via an Internet address and also allowing access by Windows, Android, and Linux operating systems, with MySQL database used for data storage. The data and indicators related to the institutional structure for coronavirus disease 2019 were systematized with 10 dimensions and indicators, and the professional and occupational structure, with 14 dimensions and indicators. The construction of computer requirements followed the precepts of software engineering, with theoretical support from the area. In the evaluation of the software, data simulation revealed points that had to be adjusted to ensure security, data confidentiality, and easy handling. The software provides to calculate the size and quality of the team, nursing sizing required due to the needs generated by the coronavirus disease 2019 pandemic., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc.)

Background: Acute pancreatitis following surgical or endoscopic procedures on the pancreas can compromise the outcome and lead to severe complications and even death. The aim of this study was to determine whether prolonged fasting affects the severity of acute pancreatitis (AP)., Methods: Male mice were divided into 4 groups: Group CF (n=5) control animals that fasted for 24 hours; Group CNF (n=5) control animals that did not fast; Group APF (n=7) that fasted for 24 hours and underwent induction of acute pancreatitis (AP) and Group APNF (n=7) that did not fast and underwent AP. Eight hours after AP blood was collected for evaluation of cytokines: IL-1β, IL-6, IL-10, TNF-α and MCP-1. Liver tissue was collected for determination of Malondialdehyde, pancreatic tissue for determination of enzyme content and lung tissue for determination of myeloperoxidase., Results: Significant increase in pancreatic amylase content was observed in group CF and increased serum levels of IL -6, Il-10 and MCP-1 were in group APF. Liver malondialdehyde was also increased in APF animals. APF group showed much more necrosis of the pancreatic acinar cells., Conclusion: In the present study, we observed an increase in the severity of acute pancreatitis with prolonged fasting in a severe acute pancreatitis model. These results suggest that in clinical practice, the preoperative fasting time should be shortened before pancreatic procedures.

Background: Neglected Tropical Diseases (NTD) are chronic infectious conditions that primarily affect marginalized populations. The chemotherapeutic arsenal available for treating NTD is limited and outdated, which poses a challenge in controlling and eradicating these diseases. This is exacerbated by the pharmaceutical industry's lack of interest in funding the development of new therapeutic alternatives. In addition, a considerable number of drugs used in NTD therapy have low aqueous solubility. To address this issue, solubility enhancement strategies, such as the use of inclusion complexes with cyclodextrins (CD) can be employed., Objective: Therefore, this systematic review aims to present the application of CD in complexing with drugs and chemotherapeutic compounds used in the therapy of some of the most prevalent NTD worldwide and how these complexes can enhance the treatment of these diseases., Methods: Two bibliographic databases, Science Direct and PubMed, were used to conduct the search. The selection of studies and the writing of this systematic review followed the criteria outlined by the PRISMA guidelines., Results: From a total of 978 articles, 23 were selected after applying the exclusion criteria. All the studies selected were consistent with the use of CD as a strategy to increase the solubility of therapeutic agents used in NTD., Conclusion: The results indicate that CD can enhance the solubility of chemotherapeutic agents for the treatment of Neglected Tropical Diseases (NTD). This review presents data that clearly highlights the potential use of CD in the development of new treatments for neglected tropical diseases. It can assist in the formulation of future treatments that are more effective and safer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Benznidazole, the drug of choice for treating Chagas Disease (CD), has significant limitations, such as poor cure efficacy, mainly in the chronic phase of CD, association with side effects, and parasite resistance. Understanding parasite resistance to benznidazole is crucial for developing new drugs to treat CD., Areas Covered: Here, the authors review the current understanding of the molecular basis of benznidazole resistance. Furthermore, they discuss the state-of-the-art methods and critical outcomes employed to evaluate the efficacy of potential drugs against T. cruzi , aiming to select better compounds likely to succeed in the clinic. Finally, the authors describe the different strategies employed to overcome resistance to benznidazole and find effective new treatments for CD., Expert Opinion: Resistance to benznidazole is a complex phenomenon that occurs naturally among T. cruzi strains. The combination of compounds that inhibit different metabolic pathways of the parasite is an important strategy for developing a new chemotherapeutic protocol.

Controlling malaria requires new drugs against Plasmodium falciparum . The P. falciparum cGMP-dependent protein kinase (PfPKG) is a validated target whose inhibitors could block multiple steps of the parasite's life cycle. We defined the structure-activity relationship (SAR) of a pyrrole series for PfPKG inhibition. Key pharmacophores were modified to enable full exploration of chemical diversity and to gain knowledge about an ideal core scaffold. In vitro potency against recombinant PfPKG and human PKG were used to determine compound selectivity for the parasite enzyme. P. berghei sporozoites and P. falciparum asexual blood stages were used to assay multistage antiparasitic activity. Cellular specificity of compounds was evaluated using transgenic parasites expressing PfPKG carrying a substituted "gatekeeper" residue. The structure of PfPKG bound to an inhibitor was solved, and modeling using this structure together with computational tools was utilized to understand SAR and establish a rational strategy for subsequent lead optimization.

The diagnosis of attention-deficit hyperactivity disorder (ADHD) is based on the health history and on the evaluation of questionnaires to identify symptoms. This evaluation can be subjective and lengthy, especially in children. Therefore, a biomarker would be of great value to assist mental health professionals in the process of diagnosing ADHD. Event-related potential (ERP) is one of the most informative and dynamic methods of monitoring cognitive processes. Previous works suggested that specific sets of ERP-microstates are selectively affected by ADHD. This paper proposes a new methodology for the ERP-microstate analysis and identification of ADHD patients based on complex networks to model the microstate topographic maps. The analysis of global and local features of ERP-microstate networks revealed topological differences between ADHD and healthy control. The classification using a neural network with a single hidden layer resulted in an average accuracy of 99.72% in binary classification and 99.31% in the classification of ADHD subtypes. The results were compared to the power band spectral densities and the energy of wavelet coefficients. The temporal features of ERP-microstates, such as frequency of occurrence, duration, coverage, and transition probabilities, were also evaluated for comparison proposes. Overall, the selected topological features of ERP-microstate networks derived from the proposed method performed significantly better classification results. The results suggest that topological features of ERP-microstate networks are promising to identify ADHD and its subtypes with a neural network model compared to power band spectrum density, wavelet transform, and temporal features of ERP-microstates., (© 2023. International Federation for Medical and Biological Engineering.)

Background: Chagas disease is caused by the parasite Trypanosoma cruzi , and the lack of effective and safe treatments makes identifying new classes of compounds with anti- T. cruzi activity of paramount importance. Methods: Hit-to-lead exploration of a metabolically stable N -imidazoylpiperazine was performed. Results: Compound 2 , a piperazine derivative active against T. cruzi , was selected to perform the hit-to-lead exploration, which involved the design, synthesis and biological evaluation of 39 new derivatives. Conclusion: Compounds 6e and 10a were identified as optimized compounds with low micromolar in vitro activity, low cytotoxicity and suitable preliminary absorption, distribution, metabolism and excretion and physicochemical properties. Both compounds reduced parasitemia in mouse models of Chagas disease, providing a promising opportunity for further exploration of new antichagasic compounds.

This study investigates the interaction between sakuranetin, a versatile pharmaceutical flavonoid, and monolayers composed of unsaturated phospholipids, serving as a surrogate for cell membranes. The phospholipids were 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE). We conducted a series of experiments to comprehensively investigate this interaction, including surface pressure assessments, Brewster angle microscopy (BAM), and polarization-modulated infrared reflection-absorption spectroscopy (PM-IRRAS). Our findings unequivocally demonstrate that sakuranetin interacts with these phospholipids, expanding the monomolecular films. Notably, regarding POPC, the presence of sakuranetin led to a reduction in stability and a decline in surface elasticity, which can likely be attributed to intricate molecular rearrangements at the interface. The visual evidence of aggregations in BAM images reinforces the interactions substantiated by PM-IRRAS, highlighting sakuranetin's interaction with the polar and nonpolar regions of POPC. However, it is worth noting that these aggregations do not appear to contribute significantly to the viscosity of the mixed film, and our investigations did not reveal any substantial hysteresis. In contrast, when examining POPE, we observed a minor reduction in thermodynamic stability, indicative of fewer rearrangements within the monolayer. This notion was further reinforced by the limited presence of aggregations in the BAM images. Sakuranetin also increased the rigidity of the lipid monolayer; nevertheless, the monolayer remained predominantly elastic, facilitating easy re-spreading on the surface, especially for the first lipid. PM-IRRAS analysis unveiled interactions between sakuranetin and POPE's polar and nonpolar segments, compellingly explaining the observed monolayer expansion. Taken together, our data suggest that sakuranetin was more effectively incorporated into the monomolecular layer of POPE, indicating that membranes comprised of POPC might exhibit a greater degree of interaction in the presence of this pharmacologically active compound., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism., (© 2024. The Author(s).)

Background: Morus nigra L. is a plant with significant potential for drug development due to the presence of numerous bioactive compounds in its various parts., Objectives: This article aims to compile the technological perspectives of Morus nigra L. towards drug development and therapeutic indications based on registered patents in databases., Methods: The study analyzed patents published within the last five years, focusing on products derived from different parts of the Morus nigra L. plant. Patent databases such as the European Patent Office (EPO), the United States Patent and Trademark Office (USPTO), the World Intellectual Property Organization (WIPO), and the National Institute of Industrial Property Databases (INPI) were examined., Results: A total of 45 patents were categorized by country of origin, type of applicant, extraction method, and therapeutic indications. China had the highest number of patent filings (43.48%), and private companies were the primary technology patent holders (38.64%). Noteworthy extraction methods included ultrasound-assisted extraction, decoction, infusion, and maceration. The most utilized plant parts were leaves (44.44%), followed by fruits (35.56%), root bark (15.56%), and stems (4.44%). The main therapeutic indications identified were the treatment of hyperglycemia and dyslipidemia (43.33%), along with digestive problems, cosmetics, nutrition, and cleaning applications., Conclusion: The study of patents covers discoveries and advancements often absent in scientific articles, making a review focused on this advanced information crucial for expanding existing scientific knowledge. Even if some therapies have been explored previously, patents can reveal innovative approaches and fresh perspectives that contribute to sustained scientific progress., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)