RESUMO

Glioblastoma (GBM) represents a formidable challenge in oncology, characterized by aggressive proliferation and poor prognosis. Iron metabolism plays a critical player in GBM progression, with dysregulated iron uptake and utilization contributing to tumor growth and therapeutic resistance. Iron's pivotal role in DNA synthesis, oxidative stress, and angiogenesis underscores its significance in GBM pathogenesis. Elevated expression of iron transporters, such as transferrin receptor 1 (TfR1), highlights the tumor's reliance on iron for survival. Innovative treatment strategies targeting iron dysregulation hold promise for overcoming therapeutic challenges in GBM management. Approaches such as iron chelation therapies, induction of ferroptosis to nanoparticle-based drug delivery systems exploit iron-dependent vulnerabilities, offering avenues for enhance treatment efficacy and improve patient outcomes. As research advances, understanding the complexities of iron-mediated carcinogenesis provides a foundation for developing precision medicine approaches tailored to combat GBM effectively. This review explores the intricate relationship between iron metabolism and GBM, elucidating its multifaceted implications and therapeutic opportunities. By consolidating the latest insights into iron metabolism in GBM, this review underscores its potential as a therapeutic target for improving patient care in combination with the standard of care approach.

Assuntos

Ferroptose , Glioblastoma , Ferro , Receptores da Transferrina , Humanos , Receptores da Transferrina/metabolismo , Ferro/metabolismo , Ferroptose/efeitos dos fármacos , Glioblastoma/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Antígenos CD/metabolismo , Antígenos CD/genética , Quelantes de Ferro/uso terapêutico , Quelantes de Ferro/farmacologia

RESUMO

The use of tyrosine kinase inhibitors (TKI) has been growing in veterinary oncology and in the past few years several TKI have been tested in dogs. However, different from human medicine, we lack strategies to select patients to be treated with each TKI. Therefore, this study aimed to screen different tumor subtypes regarding TKI target immunoexpression as a predictor strategy to personalize the canine cancer treatment. It included 18 prostatic carcinomas, 36 soft tissue sarcomas, 20 mammary gland tumors, 6 urothelial bladder carcinomas, and 7 tumors from the endocrine system. A total of 87 patients with paraffin blocks were used to perform immunohistochemistry (IHC) of human epidermal growth factor receptor 2 (HER-2), epidermal growth factor receptors 1 (EGFR1), vascular endothelial growth factor receptor 2 (VEGFR-2), platelet derived growth factor receptor beta (PDGFR-ß), c-KIT, and extracellular signal-regulated kinase 1/2 (ERK1/ERK2). The immunohistochemical screening revealed a heterogeneous protein expression among histological types with mesenchymal tumors showing the lowest expression level and carcinomas the highest expression. We have demonstrated by IHC screening that HER2, EGFR1, VEGFR-2, PDGFR-ß and ERK1/ERK2 are commonly overexpressed in dogs with different carcinomas, and KIT expression is considered relatively low in the analyzed samples.

Assuntos

Doenças do Cão , Imuno-Histoquímica , Cães , Animais , Doenças do Cão/metabolismo , Doenças do Cão/tratamento farmacológico , Doenças do Cão/patologia , Masculino , Feminino , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/veterinária , Neoplasias/patologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Biomarcadores Tumorais/metabolismo , Receptor ErbB-2/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores ErbB/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Humanos

RESUMO

Designing and developing inhibitors against the epigenetic target DNA methyltransferase (DNMT) is an attractive strategy in epigenetic drug discovery. DNMT1 is one of the epigenetic enzymes with significant clinical relevance. Structure-based de novo design is a drug discovery strategy that was used in combination with similarity searching to identify a novel DNMT inhibitor with a novel chemical scaffold and warrants further exploration. This study aimed to continue exploring the potential of de novo design to build epigenetic-focused libraries targeted toward DNMT1. Herein, we report the results of an in-depth and critical comparison of ligand- and structure-based de novo design of screening libraries focused on DNMT1. The newly designed chemical libraries focused on DNMT1 are freely available on GitHub.

Assuntos

DNA (Citosina-5-)-Metiltransferase 1 , Desenho de Fármacos , Inibidores Enzimáticos , Ligantes , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade

RESUMO

Synthetic organic chemicals, including pesticides, pharmaceuticals, and industrial compounds, pose a growing threat to marine ecosystems. Despite their potential impact, data on the co-occurrence of these contaminants in multiple compartments, including surface water, bottom water, porewater, and sediment in the marine environment remains limited. Such information is critical for assessing coastal chemical status, establishing environmental quality benchmarks, and conducting comprehensive environmental risk assessments. In this study, we describe a multifaceted monitoring campaign targeting pesticides, pharmaceuticals, surfactants, additives, and plasticizers among other synthetic chemicals in four sampling sites. One site was located in the small Coliumo bay affected by urban settlements and tourism in central-south and additionally, we sampled three sites, Caucahue Channel, affected by urban settlements and salmon farming in northern Patagonia in Chile. Surface water, bottom water, porewater, and adjacent sediment samples were collected for target screening analysis in LC- and GC-HRMS platforms. Our results show the detection of up to 83 chemicals in surface water, 71 in bottom water, 101 in porewater, and 244 in sediments. To enhance data utility and reuse potential, we provide valuable information on the mode of action and molecular targets of the identified chemicals. This comprehensive dataset contributes to defining pollution fingerprints in coastal areas of the Global South, including remote regions in Patagonia. It serves as a critical resource for future research including marine chemical risk assessment, policymaking, and the advancement of environmental protection in these regions.

RESUMO

BACKGROUND: Identifying individuals with depressive symptomatology (DS) promptly and effectively is of paramount importance for providing timely treatment. Machine learning models have shown promise in this area; however, studies often fall short in demonstrating the practical benefits of using these models and fail to provide tangible real-world applications. OBJECTIVE: This study aims to establish a novel methodology for identifying individuals likely to exhibit DS, identify the most influential features in a more explainable way via probabilistic measures, and propose tools that can be used in real-world applications. METHODS: The study used 3 data sets: PROACTIVE, the Brazilian National Health Survey (Pesquisa Nacional de Saúde [PNS]) 2013, and PNS 2019, comprising sociodemographic and health-related features. A Bayesian network was used for feature selection. Selected features were then used to train machine learning models to predict DS, operationalized as a score of ≥10 on the 9-item Patient Health Questionnaire. The study also analyzed the impact of varying sensitivity rates on the reduction of screening interviews compared to a random approach. RESULTS: The methodology allows the users to make an informed trade-off among sensitivity, specificity, and a reduction in the number of interviews. At the thresholds of 0.444, 0.412, and 0.472, determined by maximizing the Youden index, the models achieved sensitivities of 0.717, 0.741, and 0.718, and specificities of 0.644, 0.737, and 0.766 for PROACTIVE, PNS 2013, and PNS 2019, respectively. The area under the receiver operating characteristic curve was 0.736, 0.801, and 0.809 for these 3 data sets, respectively. For the PROACTIVE data set, the most influential features identified were postural balance, shortness of breath, and how old people feel they are. In the PNS 2013 data set, the features were the ability to do usual activities, chest pain, sleep problems, and chronic back problems. The PNS 2019 data set shared 3 of the most influential features with the PNS 2013 data set. However, the difference was the replacement of chronic back problems with verbal abuse. It is important to note that the features contained in the PNS data sets differ from those found in the PROACTIVE data set. An empirical analysis demonstrated that using the proposed model led to a potential reduction in screening interviews of up to 52% while maintaining a sensitivity of 0.80. CONCLUSIONS: This study developed a novel methodology for identifying individuals with DS, demonstrating the utility of using Bayesian networks to identify the most significant features. Moreover, this approach has the potential to substantially reduce the number of screening interviews while maintaining high sensitivity, thereby facilitating improved early identification and intervention strategies for individuals experiencing DS.

Assuntos

Algoritmos , Teorema de Bayes , Depressão , Humanos , Depressão/diagnóstico , Adulto , Feminino , Masculino , Brasil/epidemiologia , Pessoa de Meia-Idade , Aprendizado de Máquina , Programas de Rastreamento/métodos , Sensibilidade e Especificidade , Inquéritos Epidemiológicos

RESUMO

BACKGROUND: Biomarkers for colorectal cancer (CRC) can complement population screening methods, but so far, few plasma proteins have been identified as biomarkers for CRC. This study aims to identify potential protein biomarkers and therapeutic targets for CRC within the proteome range. METHODS: We extracted summary-level data of circulating protein from 7 published genome-wide association studies (GWASs) of plasma proteome for Mendelian randomization (MR), summary-data-based MR (SMR), and co-localization analyses to screen and validate proteins with causal effects in CRC. In addition, we further conducted druggability evaluation, prognosis analysis at the transcriptional level, and enrichment expression at the single-cell level, highlighting the important role of these plasma protein biomarkers in CRC. RESULTS: We identified 117 plasma protein biomarkers associated with CRC risk, with 9 proteins showing stronger genetic correlations in Bayesian co-localization (PP.H4 > 0.70). Further, we found 26 protein-coding genes already used in targeted drug development and may potentially become therapeutic targets for CRC. In prognosis analysis, the encoding genes of plasma proteins exhibited consistent effects with MR analysis and can serve as prognostic biomarkers for CRC. Additionally, we also found that the differentially expressed proteins are mainly expressed in fibroblasts, endothelial cells, macrophages, and T cells. CONCLUSION: Our study has identified plasma protein biomarkers associated with CRC risk, which may complement population screening methods for CRC and achieve more precise treatment for patients.

RESUMO

The Continuous Visual Attention Test (CVAT) is a test that detects visuomotor reaction time (RT, alertness), variability of reaction time (VRT, sustained attention), omission errors (OE, focused attention), and commission errors (CE, response inhibition). The standard test takes 15 min, while the ultrafast version only 90 s. Besides overall task length, the two versions differ by target probability (20% and 80% in the 15-min vs. only 80% in the 90-s test) and stimulus-onset asynchrony (SOA) (1, 2, and 4 s in the 15-min vs. only 1 s in the 90-s test. We aimed to analyze the effect of target probability, SOA, and time length on the CVAT variables across the 15-min task and to verify correlations and agreements between the 15-min and the 90-s CVATs. 205 healthy participants performed the two CVATs on the same day. Considering the 15-min task, RT and CE were strongly affected by target probability. Conversely, VRT was not affected. When the 15-min task was compared to the 90-s task, we found no significant difference in the VRT variable. Additionally, a significant agreement between the two tasks was found for the VRT variable. We concluded that sustained attention can be measured with the 90-s CVAT.

Assuntos

Atenção , Tempo de Reação , Humanos , Atenção/fisiologia , Tempo de Reação/fisiologia , Masculino , Feminino , Adulto , Adulto Jovem , Desempenho Psicomotor/fisiologia , Testes Neuropsicológicos , Adolescente , Pessoa de Meia-Idade , Percepção Visual/fisiologia , Estimulação Luminosa

RESUMO

Apocrine gland anal sac adenocarcinoma is an aggressive neoplasm, and surgery remains the treatment of choice, although it is controversial in advanced cases. The prognostic factors are not well established. Human Epidermal Growth Factor Receptor 2 (HER2) is a membrane protein related to tumorigenesis, whereas Ki67 is a nuclear protein related to cell proliferation. Both are potential prognostic markers and therapeutic targets. This study aimed to evaluate the expression of HER2 and Ki67 markers in canine apocrine gland anal sac adenocarcinoma. The tumor samples were divided into four groups: largest tumor diameter less than 2.5 cm, largest tumor diameter greater than 2.5 cm, metastatic lymph nodes, and control group of non-neoplastic anal sacs. Each contained 10 samples. Immunohistochemistry was performed to verify the expression of HER2 and Ki67 markers. Positive HER2 staining was observed in 45% of the neoplastic cases and negative HER2 staining in 100% of the control group. The Ki67 expression had a median of 25% in all groups, except for the control group, which had a median of 8%. The HER2 and Ki67 expression was present in apocrine gland anal sac adenocarcinoma, making them potential therapeutic targets. However, it was not possible to determine the clinical value of either marker.

Assuntos

Adenocarcinoma , Sacos Anais , Glândulas Apócrinas , Biomarcadores Tumorais , Imuno-Histoquímica , Antígeno Ki-67 , Receptor ErbB-2 , Antígeno Ki-67/metabolismo , Antígeno Ki-67/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Receptor ErbB-2/metabolismo , Glândulas Apócrinas/metabolismo , Glândulas Apócrinas/patologia , Humanos , Biomarcadores Tumorais/metabolismo , Animais , Sacos Anais/metabolismo , Sacos Anais/patologia , Cães , Feminino , Masculino , Neoplasias das Glândulas Anais/metabolismo , Neoplasias das Glândulas Anais/patologia

RESUMO

This study aimed to isolate and identify pathogenic bacteria in the intestinal tract, skin, and muscles of Sciades herzbergii; detect histopathological changes in the gill and liver; and use these biomarkers for the assessment of potential risks to human health. Fish were sampled during the rainy and dry seasons at two points in São Marcos Bay, Maranhão, Brazil: Ilha dos Caranguejos (IC) and Porto Grande (PG). Isolation and quantification were carried out using COLItest®. Colonies were subjected to identification and phenotypic investigation of antimicrobial resistance using Vitek®. Gill and liver samples were subjected to routine histological examination. The results indicated the presence of Klebsiella pneumoniae and Escherichia coli, the latter of which showed phenotypic resistance to norfloxacin and gentamicin. Fish caught at PG exhibited more extensive gill and liver damage than fish caught at IC. The findings suggest that histological changes in target organs of S. herzbergii may be influenced by infection with pathogenic bacteria.

Assuntos

Monitoramento Ambiental , Estuários , Brânquias , Animais , Brasil , Brânquias/microbiologia , Brânquias/patologia , Humanos , Biomarcadores , Fígado/patologia , Peixes/microbiologia , Escherichia coli/isolamento & purificação , Klebsiella pneumoniae/isolamento & purificação

RESUMO

Schizophrenia (SCZ) is a severe psychiatric disorder with unclear pathophysiology. Moreover, there is no specific biological marker to help clinicians to define a diagnosis, and medication is decided according to the psychiatrist's experience. In this scenario, microRNAs (miRNAs), which are small noncoding RNA molecules that regulate several genes, emerge as potential peripheral biomarkers to help not only the evaluation of the disease state but also the treatment response. Here, we systematically reviewed indexed literature and evaluated follow-up studies investigating the changes in miRNA expression due to antipsychotic treatment. We also assessed target genes and performed pathway enrichment analysis of miRNAs listed in this systematic review. A total of 11 studies were selected according to research criteria, and we observed that 28 miRNAs play a relevant role in schizophrenia pathogenesis or response to antipsychotic treatment, seven of those of extreme interest as possible biomarkers either for condition or treatment. Predicted targets of the miRNAs reviewed here were previously associated with schizophrenia in genome-wide studies, and pathway analysis showed enrichment for genes related to neural processes. With this review, we expect to highlight the importance of miRNAs in schizophrenia pathogenesis and its treatment and point out interesting miRNAs to future studies.

Assuntos

Antipsicóticos , MicroRNAs , Esquizofrenia , Humanos , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , MicroRNAs/genética , Antipsicóticos/farmacologia

RESUMO

Epilepsy is a neurological disease with no defined cause, characterized by recurrent epileptic seizures. These occur due to the dysregulation of excitatory and inhibitory neurotransmitters in the central nervous system (CNS). Psychopharmaceuticals have undesirable side effects; many patients require more than one pharmacotherapy to control crises. With this in mind, this work emphasizes the discovery of new substances from natural products that can combat epileptic seizures. Using in silico techniques, this review aims to evaluate the antiepileptic and multi-target activity of phenylpropanoid derivatives. Initially, ligand-based virtual screening models (LBVS) were performed with 468 phenylpropanoid compounds to predict biological activities. The LBVS were developed for the targets alpha- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), voltage-gated calcium channel Ttype (CaV), gamma-aminobutyric acid A (GABAA), gamma-aminobutyric acid transporter type 1 (GAT-1), voltage-gated potassium channel of the Q family (KCNQ), voltage-gated sodium channel (NaV), and N-methyl D-aspartate (NMDA). The compounds that had good results in the LBVS were analyzed for the absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters, and later, the best molecules were evaluated in the molecular docking consensus. The TR430 compound showed the best results in pharmacokinetic parameters; its oral absorption was 99.03%, it did not violate any Lipinski rule, it showed good bioavailability, and no cytotoxicity was observed either from the molecule or from the metabolites in the evaluated parameters. TR430 was able to bind with GABAA (activation) and AMPA (inhibition) targets and demonstrated good binding energy and significant interactions with both targets. The studied compound showed to be a promising molecule with a possible multi-target activity in both fundamental pharmacological targets for the treatment of epilepsy.

Assuntos

Anticonvulsivantes , Epilepsia , Humanos , Epilepsia/tratamento farmacológico , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/química , Simulação de Acoplamento Molecular

RESUMO

The nervous system is rich in miRNAs, indicating an important role of these molecules in regulating processes associated with cognition, memory, and others. Therefore, qualitative and quantitative imbalances involving such miRNAs may be involved in dementia contexts, including Late-Onset Alzheimer's Disease (LOAD). To test the viability of circulating miRNAs (c-miRNAs) as biomarkers for LOAD, we proceed accordingly to the following reasoning. The first stage was to discover and identify profile of c-miRNAs by RNA sequencing (RNA-Seq). For this purpose, blood serum samples were used from LOAD patients (n = 5) and cognitively healthy elderly control group (CTRL_CH) (n = 5), all over 70 years old. We identified seven c-miRNAs differentially expressed (p ≤ 0.05) in the serum of LOAD patients compared to CTRL_CH (miR-10a-5p; miR-29b-2-5p; miR-125a-5p; miR-342-3p, miR-708-5p, miR-380-5p and miR-340-3p). Of these, five (p ≤ 0.01) were selected for in silico analysis (miR-10a-5p; miR-29b-2-5p; miR-125a-5p; miR-342-3p, miR-708-5p), for which 44 relevant target genes were found regulated by these c-miRNAs and related to LOAD. Through the analysis of these target genes in databases, it was possible to observe that they have functions related to the development and progress of LOAD, directly or indirectly connecting the different Alzheimer's pathways. Thus, this work found five promising serum c-miRNAs as options for biomarkers contributing to LOAD diagnosis. Our study shows the complex network between these molecules and LOAD, supporting the relevance of studies using c-miRNAs in dementia contexts.

Assuntos

Doença de Alzheimer , Biomarcadores , MicroRNAs , Humanos , Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Doença de Alzheimer/diagnóstico , MicroRNAs/sangue , MicroRNAs/genética , Masculino , Idoso , Biomarcadores/sangue , Feminino , Idoso de 80 Anos ou mais

RESUMO

Multi-target drug treatment has become popular as a substitute for traditional monotherapy. Monotherapy can lead to resistance and side effects. Multi-target drug discovery is gaining importance as data on bioactivity becomes more abundant. The design of multi-target drugs is expected to be an important development in the pharmaceutical industry in the near future. This review presents multi-target compounds against trypanosomatid parasites (Trypanosoma cruzi, T. brucei, and Leishmania sp.) and tuberculosis (Mycobacterium tuberculosis), which mainly affect populations in socioeconomically unfavorable conditions. The article analyzes the studies, including their chemical structures, viral strains, and molecular docking studies, when available. The objective of this review is to establish a foundation for designing new multi-target inhibitors for these diseases.

Assuntos

Antituberculosos , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis , Mycobacterium tuberculosis/efeitos dos fármacos , Humanos , Antituberculosos/farmacologia , Antituberculosos/química , Antituberculosos/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Animais , Descoberta de Drogas , Leishmania/efeitos dos fármacos , Desenho de Fármacos , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Tripanossomicidas/química

RESUMO

T-2 toxin, a hazardous mycotoxin often present in cereals and products based on cereals, poses a substantial risk to humans and animals due to its high toxicity. The development of uncomplicated, quick and highly sensitive methods for detecting T-2 toxin is imperative. In this work, a portable sensing system was constructed using water column height as a readout device in combination with a controlled release system, which allows for an accurate quantitative analysis of T-2 toxin without the need for expensive instrumentation or skilled technicians. Hyaluronic acid (HA) hydrogel was constructed by double cross-linked DNA/aptamer hybrids with polyethyleneimine (PEI) and embedded with platinum nanoparticles (Pt NPs). The aptamer specifically bound to T-2 toxin in its presence, resulting in the disruption of the hydrogel and subsequent release of the Pt NPs. These Pt NPs were later mixed with a solution of H2O2 in a confined reaction flask, leading to the decomposition of H2O2 into O2. A glass capillary tube containing a column of red water had been inserted into the cap of the reaction flask, and the low solubility of O2 led to an increase in pressure within the reaction unit, causing the red water column to rise. There is a good linear correlation between the height of the capillary liquid level and the T-2 toxin concentration in the range of 20 ng/mL to 6 µg/mL. The system has been successfully used to detect T-2 toxin in samples of barley tea and corn.

Assuntos

Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , Nanopartículas Metálicas , Platina , Toxina T-2 , Toxina T-2/análise , Técnicas Biossensoriais/métodos , Aptâmeros de Nucleotídeos/química , Nanopartículas Metálicas/química , Platina/química , Água/química , DNA/química , DNA/análise , Hidrogéis/química , Limite de Detecção , Ácido Hialurônico/química , Polietilenoimina/química

RESUMO

BACKGROUND: Preservation of organ function and viability is a crucial factor for survival in cardiogenic shock (CS) patients. There is not information enough on cytoprotective substances that may delay organs damage in CS. We hypothesize that cytidine-5-diphosphocholine (CDP-choline) can act as a cytoprotective pharmacological measure that diminishes the target organ damage. So, we aimed to perform a review of works carried out in our institution to evaluate the effect of therapeutic cytoprotection of the CDP-choline. SUMMARY: CDP-choline is an intermediate metabolite in the synthesis of phosphatidylcholine. It is also a useful drug for the treatment of acute ischaemic stroke, traumatic brain injury, and neurodegenerative diseases and has shown an excellent pharmacological safety profile as well. We review our institution's work and described the cytoprotective effects of CDP-choline in experimental models of heart, liver, and kidney acute damage, where this compound was shown to diminish reperfusion-induced ventricular arrhythmias, oxidative stress, apoptotic cell death, inflammation, lactic acid levels and to preserve mitochondrial function. KEY MESSAGES: We propose that additional research is needed to evaluate the impact of cytoprotective therapy adjuvant to mitigate target organ damage in patients with CS.

Assuntos

Citidina Difosfato Colina , Citoproteção , Estresse Oxidativo , Choque Cardiogênico , Citidina Difosfato Colina/farmacologia , Citidina Difosfato Colina/uso terapêutico , Humanos , Animais , Choque Cardiogênico/tratamento farmacológico , Choque Cardiogênico/metabolismo , Choque Cardiogênico/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Miocárdio/metabolismo , Miocárdio/patologia

RESUMO

Leishmaniasis is a neglected tropical disease; there is currently no vaccine and treatment is reliant upon a handful of drugs suffering from multiple issues including toxicity and resistance. There is a critical need for development of new fit-for-purpose therapeutics, with reduced toxicity and targeting new mechanisms to overcome resistance. One enzyme meriting investigation as a potential drug target in Leishmania is M17 leucyl-aminopeptidase (LAP). Here, we aimed to chemically validate LAP as a drug target in L. major through identification of potent and selective inhibitors. Using RapidFire mass spectrometry, the compounds DDD00057570 and DDD00097924 were identified as selective inhibitors of recombinant Leishmania major LAP activity. Both compounds inhibited in vitro growth of L. major and L. donovani intracellular amastigotes, and overexpression of LmLAP in L. major led to reduced susceptibility to DDD00057570 and DDD00097924, suggesting that these compounds specifically target LmLAP. Thermal proteome profiling revealed that these inhibitors thermally stabilized two M17 LAPs, indicating that these compounds selectively bind to enzymes of this class. Additionally, the selectivity of the inhibitors to act on LmLAP and not against the human ortholog was demonstrated, despite the high sequence similarities LAPs of this family share. Collectively, these data confirm LmLAP as a promising therapeutic target for Leishmania spp. that can be selectively inhibited by drug-like small molecules.

Assuntos

Antiprotozoários , Leishmania major , Proteínas de Protozoários , Animais , Humanos , Antiprotozoários/farmacologia , Antiprotozoários/química , Leishmania donovani/enzimologia , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/genética , Leishmania major/enzimologia , Leishmania major/efeitos dos fármacos , Leishmania major/genética , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo

RESUMO

This study investigated lead (Pb) and cadmium (Cd) transfer in three dairy farming areas in the Mantaro river headwaters in the central Peruvian Andes and at varying distances from the mining complex at La Oroya. At each of these sites, the transfer of trace metals from the soil to raw milk was estimated, and a hazard assessment for lead and cadmium was carried out in scenarios of minimum, average, and maximum milk consumption in a Peruvian population aged 2-85. Pb and Cd were quantified by flame atomic absorption spectrometry. Significantly, the concentrations of lead and cadmium were found to exceed the maximum limits recommended by the World Health Organization, with a positive geospatial trend correlated with the distance from mining activity. Both Pb and Cd were found to be transferred through the soil-pasture-milk pathway, with the primary source of Cd being phosphate-based fertilizers used in pasture improvement. Pb was found to be the most significant contributor to the Hazard Index (HI) with those under 19 years of age and over 60 recording an HI of >1, with infants being the most vulnerable group due to their greater milk consumption in relation to their body weight. A marginal increase in contamination was observed in the dry season, indicating the need for studies to be expanded over several annual cycles.

RESUMO

Aims: We adopted a modeling approach to predict the likely future prevalence of type 2 diabetes, taking into account demographic changes and trends in obesity and smoking in Brazil. We then used the model to estimate the likely future impact of different policy scenarios, such as policies to reduce obesity. Methods: The IMPACT TYPE 2 DIABETES model uses a Markov approach to integrate population, obesity, and smoking trends to estimate future type 2 diabetes prevalence. We developed a model for the Brazilian population from 2006 to 2036. Data on the Brazilian population in relation to sex and age were collected from the Brazilian Institute of Geography and Statistics, and data on the prevalence of type 2 diabetes, obesity, and smoking were collected from the Surveillance of Risk and Protection Factors for Chronic Diseases by Telephone Survey (VIGITEL). Results: The observed prevalence of type 2 diabetes among Brazilians aged over 25 years was 10.8% (5.2-14.3%) in 2006, increasing to 13.7% (6.9-18.4%) in 2020. Between 2006 and 2020, the observed prevalence in men increased from 11.0 to 19.1% and women from 10.6 to 21.3%. The model forecasts a dramatic rise in prevalence by 2036 (27.0% overall, 17.1% in men and 35.9% in women). However, if obesity prevalence declines by 1% per year from 2020 to 2036 (Scenario 1), the prevalence of diabetes decreases from 26.3 to 23.7, which represents approximately a 10.0% drop in 16 years. If obesity declined by 5% per year in 16 years as an optimistic target (Scenario 2), the prevalence of diabetes decreased from 26.3 to 21.2, representing a 19.4% drop in diabetes prevalence. Conclusion: The model predicts an increase in the prevalence of type 2 diabetes in Brazil. Even with ambitious targets to reduce obesity prevalence, type 2 diabetes in Brazil will continue to have a large impact on Brazilian public health.

Assuntos

Diabetes Mellitus Tipo 2 , Obesidade , Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Brasil/epidemiologia , Masculino , Feminino , Prevalência , Adulto , Pessoa de Meia-Idade , Obesidade/epidemiologia , Idoso , Fumar/epidemiologia , Previsões , Cadeias de Markov , Fatores de Risco

RESUMO

The γ-aminobutyric acid (GABA) receptors play pivotal roles in the transmission of neuronal information in the nervous system of insects, which has led these proteins to be targeted by synthetic and natural products. Here, we assessed the insecticidal potential of the essential oil of Pectis brevipedunculata (Gardner) Sch. Bip., a neotropical Asteraceae plant used in traditional medicine, for controlling Drosophila suzukii (Matsumura) adults by feeding exposure. By using in silico approaches, we disentangle the contribution of GABA receptors and other potential neuronal targets (e.g., acetylcholinesterase, glutathione-S-transferases) in insects that may explain the essential oil differential activities against D. suzukii and two essential pollinator bees (Apis mellifera Linnaeus and Partamona helleri Friese). Neral (26.7%) and geranial (33.9%) were the main essential oil components which killed D. suzukii with an estimated median lethal concentration (LC50) of 2.25 µL/mL. Both pollinator forager bee species, which would likely contact this compound in the field, were more tolerant to the essential oil and did not have their diet consumptions affected by the essential oil. Based on the molecular predictions for the three potential targets and the essential oil main components, a higher affinity of interaction with the GABA receptors of D. suzukii (geranial -6.2 kcal/mol; neral -5.8 kcal/mol) in relation to A. mellifera (geranial -5.2 kcal/mol; neral -4.9 kcal/mol) would contribute to explaining the difference in toxicities observed in the bioassays. Collectively, our findings indicated the involvement of GABA receptors in the potential of P. brevipedunculata essential oil as an alternative tool for controlling D. suzukii.