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1.
Mol Biochem Parasitol ; 259: 111629, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38750697

RESUMEN

Leishmaniases comprise a group of infectious parasitic diseases caused by various species of Leishmania and are considered a significant public health problem worldwide. Only a few medications, including miltefosine, amphotericin B, and meglumine antimonate, are used in current therapy. These medications are associated with severe side effects, low efficacy, high cost, and the need for hospital support. Additionally, there have been occurrences of drug resistance. Additionally, only a limited number of drugs, such as meglumine antimonate, amphotericin B, and miltefosine, are available, all of which are associated with severe side effects. In this context, the need for new effective drugs with fewer adverse effects is evident. Therefore, this study investigated the anti-Leishmania activity of a dichloromethane fraction (DCMF) extracted from Arrabidaea brachypoda roots. This fraction inhibited the viability of L. infantum, L. braziliensis, and L. Mexicana promastigotes, with IC50 values of 10.13, 11.44, and 11.16 µg/mL, respectively, and against L. infantum amastigotes (IC50 = 4.81 µg/mL). Moreover, the DCMF exhibited moderate cytotoxicity (CC50 = 25.15) towards RAW264.7 macrophages, with a selectivity index (SI) of 5.2. Notably, the DCMF caused damage to the macrophage genome only at 40 µg/mL, which is greater than the IC50 found for all Leishmania species. The results suggest that DCMF demonstrates similar antileishmanial effectiveness to isolated brachydin B, without causing genotoxic effects on mammalian cells. This finding is crucial because the isolation of the compounds relies on several steps and is very costly while obtaining the DCMF fraction is a simple and cost-effective process. Furthermore, In addition, the potential mechanisms of action of brachydins were also investigated. The computational analysis indicates that brachydin compounds bind to the Triosephosphate isomerase (TIM) enzyme via two main mechanisms: destabilizing the interface between the homodimers and interacting with catalytic residues situated at the site of binding. Based on all the results, DCMF exhibits promise as a therapeutic agent for leishmaniasis due to its significantly reduced toxicity in comparison to the adverse effects associated with current reference treatments.


Asunto(s)
Antiprotozoarios , Bignoniaceae , Flavonoides , Leishmania , Simulación del Acoplamiento Molecular , Extractos Vegetales , Bignoniaceae/química , Antiprotozoarios/farmacología , Antiprotozoarios/química , Antiprotozoarios/aislamiento & purificación , Flavonoides/farmacología , Flavonoides/química , Animales , Leishmania/efectos de los fármacos , Leishmania/genética , Extractos Vegetales/farmacología , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Ratones , Concentración 50 Inhibidora , Macrófagos/efectos de los fármacos , Macrófagos/parasitología , Células RAW 264.7
2.
Clin Exp Nephrol ; 2024 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-38678166

RESUMEN

Cisplatin (CP) is a chemotherapy drug widely prescribed to treat various neoplasms. Although fundamental for the therapeutic action of the drug, its cytotoxic mechanisms trigger adverse effects in several tissues, such as the kidney, liver, and heart, which limit its clinical use. In this sense, studies point to an essential role of damage to nuclear and mitochondrial DNA associated with oxidative stress, inflammation, and apoptosis in the pathophysiology of tissue injuries. Due to the limitation of effective preventive and therapeutic measures against CP-induced toxicity, new strategies with potential cytoprotective effects have been studied. Therefore, this article is timely in reviewing the characteristics and main molecular mechanisms common to renal, hepatic, and cardiac toxicity previously described, in addition to addressing the main validated strategies for the current management of these adverse events in clinical practice. We also handle the main promising antioxidant substances recently presented in the literature to encourage the development of new research that consolidates their potential preventive and therapeutic effects against CP-induced cytotoxicity.

3.
Life Sci Alliance ; 7(5)2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38453365

RESUMEN

KRAS is a proto-oncogene encoding a small GTPase. Mutations contribute to ∼30% of human solid tumours, including lung adenocarcinoma, pancreatic, and colorectal carcinomas. Most KRAS activating mutations interfere with GTP hydrolysis, essential for its role as a molecular switch, leading to alterations in their molecular environment and oncogenic signalling. However, the precise signalling cascades these mutations affect are poorly understood. Here, APEX2 proximity labelling was used to profile the molecular environment of WT, G12D, G13D, and Q61H-activating KRAS mutants under starvation and stimulation conditions. Through quantitative proteomics, we demonstrate the presence of known KRAS interactors, including ARAF and LZTR1, which are differentially captured by WT and KRAS mutants. Notably, the KRAS mutations G12D, G13D, and Q61H abrogate their association with LZTR1, thereby affecting turnover. Elucidating the implications of LZTR1-mediated regulation of KRAS protein levels in cancer may offer insights into therapeutic strategies targeting KRAS-driven malignancies.


Asunto(s)
Neoplasias Colorrectales , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Proteínas Proto-Oncogénicas p21(ras)/genética , Transducción de Señal/genética , Mutación , Ubiquitina-Proteína Ligasas , Proteínas Cullin/genética , Factores de Transcripción
4.
Psychiatr Serv ; 74(5): 463-471, 2023 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-36377367

RESUMEN

OBJECTIVE: The purpose of this study was to examine the efficacy of the Nutrition and Exercise for Wellness and Recovery (NEW-R) intervention for improving competency and behaviors related to diet, physical activity, and weight management. METHODS: Participants with psychiatric disabilities were recruited from four community mental health agencies and a hospital-based psychiatric outpatient clinic and randomly assigned to the NEW-R intervention (N=55) or control condition (N=58). Outcome measures included the Perceived Competence Scale, Health-Promoting Lifestyle Profile (HPLP), and weight change; random-effects regression models were used. A follow-up analysis examined the interactions of group, time, and site. RESULTS: Fifty of the 55 intervention participants and 57 of the 58 control participants completed the study. The two groups did not differ significantly on any measured baseline characteristic. The intervention group had statistically significant improvements, compared with the control group, in perceived competence for exercise and healthy eating, total HPLP score, and scores on two HPLP subscales (nutrition and spiritual growth). No significant difference between groups was found for weight loss. A study condition × time × site effect was observed: at the three sites where mean weight loss occurred, NEW-R participants lost significantly more weight than did control participants. CONCLUSIONS: NEW-R offers promise as an intervention that can initiate the change to healthy lifestyle behaviors and boost perceived competence in a healthy lifestyle. It may also be effective for weight loss when administered in supportive settings.


Asunto(s)
Ejercicio Físico , Estilo de Vida , Humanos , Pérdida de Peso
5.
J Chem Inf Model ; 62(17): 4083-4094, 2022 09 12.
Artículo en Inglés | MEDLINE | ID: mdl-36044342

RESUMEN

We have used molecular dynamics (MD) simulations with hybrid quantum mechanics/molecular mechanics (QM/MM) potentials to investigate the reaction mechanism for covalent inhibition of cathepsin K and assess the reversibility of inhibition. The computed free energy profiles suggest that a nucleophilic attack by the catalytic cysteine on the inhibitor warhead and proton transfer from the catalytic histidine occur in a concerted manner. The results indicate that the reaction is more strongly exergonic for the alkyne-based inhibitors, which bind irreversibly to cathepsin K, than for the nitrile-based inhibitor odanacatib, which binds reversibly. Gas-phase energies were also calculated for the addition of methanethiol to structural prototypes for a number of warheads of interest in cysteine protease inhibitor design in order to assess electrophilicity. The approaches presented in this study are particularly applicable to assessment of novel warheads, and computed transition state geometries can be incorporated into molecular models for covalent docking.


Asunto(s)
Inhibidores de Cisteína Proteinasa , Simulación de Dinámica Molecular , Catálisis , Catepsina K/metabolismo , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Proteasas , Teoría Cuántica
6.
Nat Med ; 28(6): 1277-1287, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35654907

RESUMEN

Alcohol-related liver disease (ALD) is a major cause of liver-related death worldwide, yet understanding of the three key pathological features of the disease-fibrosis, inflammation and steatosis-remains incomplete. Here, we present a paired liver-plasma proteomics approach to infer molecular pathophysiology and to explore the diagnostic and prognostic capability of plasma proteomics in 596 individuals (137 controls and 459 individuals with ALD), 360 of whom had biopsy-based histological assessment. We analyzed all plasma samples and 79 liver biopsies using a mass spectrometry (MS)-based proteomics workflow with short gradient times and an enhanced, data-independent acquisition scheme in only 3 weeks of measurement time. In plasma and liver biopsy tissues, metabolic functions were downregulated whereas fibrosis-associated signaling and immune responses were upregulated. Machine learning models identified proteomics biomarker panels that detected significant fibrosis (receiver operating characteristic-area under the curve (ROC-AUC), 0.92, accuracy, 0.82) and mild inflammation (ROC-AUC, 0.87, accuracy, 0.79) more accurately than existing clinical assays (DeLong's test, P < 0.05). These biomarker panels were found to be accurate in prediction of future liver-related events and all-cause mortality, with a Harrell's C-index of 0.90 and 0.79, respectively. An independent validation cohort reproduced the diagnostic model performance, laying the foundation for routine MS-based liver disease testing.


Asunto(s)
Hepatopatías , Proteómica , Biomarcadores/metabolismo , Biopsia , Humanos , Inflamación/patología , Hígado/metabolismo , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/patología , Hepatopatías/metabolismo
7.
Nat Biotechnol ; 40(8): 1231-1240, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35590073

RESUMEN

Despite the availabilty of imaging-based and mass-spectrometry-based methods for spatial proteomics, a key challenge remains connecting images with single-cell-resolution protein abundance measurements. Here, we introduce Deep Visual Proteomics (DVP), which combines artificial-intelligence-driven image analysis of cellular phenotypes with automated single-cell or single-nucleus laser microdissection and ultra-high-sensitivity mass spectrometry. DVP links protein abundance to complex cellular or subcellular phenotypes while preserving spatial context. By individually excising nuclei from cell culture, we classified distinct cell states with proteomic profiles defined by known and uncharacterized proteins. In an archived primary melanoma tissue, DVP identified spatially resolved proteome changes as normal melanocytes transition to fully invasive melanoma, revealing pathways that change in a spatial manner as cancer progresses, such as mRNA splicing dysregulation in metastatic vertical growth that coincides with reduced interferon signaling and antigen presentation. The ability of DVP to retain precise spatial proteomic information in the tissue context has implications for the molecular profiling of clinical samples.


Asunto(s)
Melanoma , Proteómica , Humanos , Captura por Microdisección con Láser/métodos , Espectrometría de Masas/métodos , Melanoma/genética , Proteoma/química , Proteómica/métodos
8.
Proteins ; 89(10): 1340-1352, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34075621

RESUMEN

Recently, a bacterium strain of Ideonella sakaiensis was identified with the uncommon ability to degrade the poly(ethylene terephthalate) (PET). The PETase from I. sakaiensis strain 201-F6 (IsPETase) catalyzes the hydrolysis of PET converting it to mono(2-hydroxyethyl) terephthalic acid (MHET), bis(2-hydroxyethyl)-TPA (BHET), and terephthalic acid (TPA). Despite the potential of this enzyme for mitigation or elimination of environmental contaminants, one of the limitations of the use of IsPETase for PET degradation is the fact that it acts only at moderate temperature due to its low thermal stability. Besides, molecular details of the main interactions of PET in the active site of IsPETase remain unclear. Herein, molecular docking and molecular dynamics (MD) simulations were applied to analyze structural changes of IsPETase induced by PET binding. Results from the essential dynamics revealed that the ß1-ß2 connecting loop is very flexible. This loop is located far from the active site of IsPETase and we suggest that it can be considered for mutagenesis to increase the thermal stability of IsPETase. The free energy landscape (FEL) demonstrates that the main change in the transition between the unbound to the bound state is associated with the ß7-α5 connecting loop, where the catalytic residue Asp206 is located. Overall, the present study provides insights into the molecular binding mechanism of PET into the IsPETase structure and a computational strategy for mapping flexible regions of this enzyme, which can be useful for the engineering of more efficient enzymes for recycling plastic polymers using biological systems.


Asunto(s)
Proteínas Bacterianas/metabolismo , Burkholderiales/metabolismo , Hidrolasas/metabolismo , Tereftalatos Polietilenos/metabolismo , Biocatálisis , Hidrólisis
9.
Interface Focus ; 11(4): 20200072, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34123356

RESUMEN

Glioblastoma (GBM) is the most aggressive and common brain cancer in adults with the lowest life expectancy. The current neuro-oncology practice has incorporated genes involved in key molecular events that drive GBM tumorigenesis as biomarkers to guide diagnosis and design treatment. This study summarizes findings describing the significant heterogeneity of GBM at the transcriptional and genomic levels, emphasizing 18 driver genes with clinical relevance. A pattern was identified fitting the stem cell model for GBM ontogenesis, with an upregulation profile for MGMT and downregulation for ATRX, H3F3A, TP53 and EGFR in the mesenchymal subtype. We also detected overexpression of EGFR, NES, VIM and TP53 in the classical subtype and of MKi67 and OLIG2 genes in the proneural subtype. Furthermore, we found a combination of the four biomarkers EGFR, NES, OLIG2 and VIM with a remarkable differential expression pattern which confers them a strong potential to determine the GBM molecular subtype. A unique distribution of somatic mutations was found for the young and adult population, particularly for genes related to DNA repair and chromatin remodelling, highlighting ATRX, MGMT and IDH1. Our results also revealed that highly lesioned genes undergo differential regulation with particular biological pathways for young patients. This multi-omic analysis will help delineate future strategies related to the use of these molecular markers for clinical decision-making in the medical routine.

10.
Mol Metab ; 42: 101080, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32937194

RESUMEN

OBJECTIVE: Glucagon is well known to regulate blood glucose but may be equally important for amino acid metabolism. Plasma levels of amino acids are regulated by glucagon-dependent mechanism(s), while amino acids stimulate glucagon secretion from alpha cells, completing the recently described liver-alpha cell axis. The mechanisms underlying the cycle and the possible impact of hepatic steatosis are unclear. METHODS: We assessed amino acid clearance in vivo in mice treated with a glucagon receptor antagonist (GRA), transgenic mice with 95% reduction in alpha cells, and mice with hepatic steatosis. In addition, we evaluated urea formation in primary hepatocytes from ob/ob mice and humans, and we studied acute metabolic effects of glucagon in perfused rat livers. We also performed RNA sequencing on livers from glucagon receptor knock-out mice and mice with hepatic steatosis. Finally, we measured individual plasma amino acids and glucagon in healthy controls and in two independent cohorts of patients with biopsy-verified non-alcoholic fatty liver disease (NAFLD). RESULTS: Amino acid clearance was reduced in mice treated with GRA and mice lacking endogenous glucagon (loss of alpha cells) concomitantly with reduced production of urea. Glucagon administration markedly changed the secretion of rat liver metabolites and within minutes increased urea formation in mice, in perfused rat liver, and in primary human hepatocytes. Transcriptomic analyses revealed that three genes responsible for amino acid catabolism (Cps1, Slc7a2, and Slc38a2) were downregulated both in mice with hepatic steatosis and in mice with deletion of the glucagon receptor. Cultured ob/ob hepatocytes produced less urea upon stimulation with mixed amino acids, and amino acid clearance was lower in mice with hepatic steatosis. Glucagon-induced ureagenesis was impaired in perfused rat livers with hepatic steatosis. Patients with NAFLD had hyperglucagonemia and increased levels of glucagonotropic amino acids, including alanine in particular. Both glucagon and alanine levels were reduced after diet-induced reduction in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR, a marker of hepatic steatosis). CONCLUSIONS: Glucagon regulates amino acid metabolism both non-transcriptionally and transcriptionally. Hepatic steatosis may impair glucagon-dependent enhancement of amino acid catabolism.


Asunto(s)
Aminoácidos/metabolismo , Hígado Graso/fisiopatología , Glucagón/metabolismo , Adulto , Animales , Glucemia/metabolismo , Hígado Graso/metabolismo , Femenino , Glucagón/fisiología , Células Secretoras de Glucagón/metabolismo , Glucosa/metabolismo , Hepatocitos/metabolismo , Humanos , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Ratas , Ratas Wistar , Receptores de Glucagón/antagonistas & inhibidores , Receptores de Glucagón/metabolismo , Urea/metabolismo
11.
Nature ; 582(7813): 592-596, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32555458

RESUMEN

Proteins carry out the vast majority of functions in all biological domains, but for technological reasons their large-scale investigation has lagged behind the study of genomes. Since the first essentially complete eukaryotic proteome was reported1, advances in mass-spectrometry-based proteomics2 have enabled increasingly comprehensive identification and quantification of the human proteome3-6. However, there have been few comparisons across species7,8, in stark contrast with genomics initiatives9. Here we use an advanced proteomics workflow-in which the peptide separation step is performed by a microstructured and extremely reproducible chromatographic system-for the in-depth study of 100 taxonomically diverse organisms. With two million peptide and 340,000 stringent protein identifications obtained in a standardized manner, we double the number of proteins with solid experimental evidence known to the scientific community. The data also provide a large-scale case study for sequence-based machine learning, as we demonstrate by experimentally confirming the predicted properties of peptides from Bacteroides uniformis. Our results offer a comparative view of the functional organization of organisms across the entire evolutionary range. A remarkably high fraction of the total proteome mass in all kingdoms is dedicated to protein homeostasis and folding, highlighting the biological challenge of maintaining protein structure in all branches of life. Likewise, a universally high fraction is involved in supplying energy resources, although these pathways range from photosynthesis through iron sulfur metabolism to carbohydrate metabolism. Generally, however, proteins and proteomes are remarkably diverse between organisms, and they can readily be explored and functionally compared at www.proteomesoflife.org.


Asunto(s)
Clasificación , Aprendizaje Profundo , Péptidos/química , Péptidos/aislamiento & purificación , Proteoma/química , Proteoma/aislamiento & purificación , Proteómica/métodos , Animales , Bacteroides/química , Bacteroides/clasificación , Metabolismo de los Hidratos de Carbono , Cromatografía , Glucólisis , Homeostasis , Transporte Iónico , Proteínas Hierro-Azufre/metabolismo , Oxidación-Reducción , Fotosíntesis , Biosíntesis de Proteínas , Pliegue de Proteína , Proteolisis , Especificidad de la Especie
12.
J Chem Inf Model ; 60(2): 880-889, 2020 02 24.
Artículo en Inglés | MEDLINE | ID: mdl-31944110

RESUMEN

One tactic for cysteine protease inhibition is to form a covalent bond between an electrophilic atom of the inhibitor and the thiol of the catalytic cysteine. In this study, we evaluate the reaction free energy obtained from a hybrid quantum mechanical/molecular mechanical (QM/MM) free energy profile as a predictor of affinity for reversible, covalent inhibitors of rhodesain. We demonstrate that the reaction free energy calculated with the PM6/MM potential is in agreement with the experimental data and suggest that the free energy profile for covalent bond formation in a protein environment may be a useful tool for the inhibitor design.


Asunto(s)
Proteasas de Cisteína/metabolismo , Inhibidores de Cisteína Proteinasa/metabolismo , Teoría Cuántica , Proteasas de Cisteína/química , Ligandos , Modelos Moleculares , Conformación Proteica , Termodinámica
13.
Curr Comput Aided Drug Des ; 16(5): 605-617, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31654518

RESUMEN

BACKGROUND: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) is an enzyme that isomerizes phosphorylated serine or threonine motifs adjacent to proline residues. Pin1 has important roles in several cellular signaling pathways, consequently impacting the development of multiple types of cancers. METHODS: Based on the previously reported inhibitory activity of pentacyclic triterpenoids isolated from the gum resin of Boswellia genus against Pin1, we designed a computational experiment using molecular docking, pharmacophore filtering, and structural clustering allied to molecular dynamics (MD) simulations and binding free energy calculations to explore the inhibitory activity of new triterpenoids against Pin1 structure. RESULTS: Here, we report different computational evidence that triterpenoids from neem (Azadirachta indica A. Juss), such as 6-deacetylnimbinene, 6-Oacetylnimbandiol, and nimbolide, replicate the binding mode of the Pin1 substrate peptide, interacting with high affinity with the binding site and thus destabilizing the Pin1 structure. CONCLUSIONS: Our results are supported by experimental data, and provide interesting structural insights into their molecular mechanism of action, indicating that their structural scaffolds could be used as a start point to develop new inhibitors against Pin1.


Asunto(s)
Antineoplásicos/química , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Sitios de Unión , Diseño de Fármacos , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Triterpenos
14.
Cell Syst ; 7(6): 601-612.e3, 2018 12 26.
Artículo en Inglés | MEDLINE | ID: mdl-30528273

RESUMEN

Obesity-related diseases affect half of the global population, and bariatric surgery is one of the few interventions with long-lasting weight loss and cardio-metabolic effects. Here, we investigated the effect of Roux-en-Y gastric bypass surgery on the plasma proteome, hypothesizing that specific proteins or protein patterns may serve as key mediators and markers of the metabolic response. We performed mass spectrometry (MS)-based proteomics on two longitudinal studies encompassing 47 morbidly obese patients, generating quantitative information on more than 1,700 proteins. A global correlation matrix incorporating about 200,000 relationships revealed functional connections between proteins and assigned them to physiological processes. The main classes of significantly altered proteins were markers of systemic inflammation and those involved in lipid metabolism. Our data highlight robust correlative and anti-correlative behaviors of circulating proteins to each other and to clinical parameters. A group of inflammation-related proteins showed distinct inverse relationships to proteins consistently associated with insulin sensitivity.


Asunto(s)
Proteínas Sanguíneas/metabolismo , Derivación Gástrica , Metabolismo de los Lípidos , Obesidad Mórbida/sangre , Obesidad Mórbida/cirugía , Mapas de Interacción de Proteínas , Adulto , Biomarcadores/sangre , Biomarcadores/metabolismo , Femenino , Derivación Gástrica/métodos , Humanos , Inflamación/sangre , Inflamación/metabolismo , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Obesidad Mórbida/metabolismo , Proteoma/metabolismo , Proteómica
15.
Phys Chem Chem Phys ; 20(37): 24317-24328, 2018 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-30211406

RESUMEN

Chagas disease affects millions of people in Latin America. This disease is caused by the protozoan parasite Trypanossoma cruzi. The cysteine protease cruzain is a key enzyme for the survival and propagation of this parasite lifecycle. Nitrile-based inhibitors are efficient inhibitors of cruzain that bind by forming a covalent bond with this enzyme. Here, three nitrile-based inhibitors dubbed Neq0409, Neq0410 and Neq0570 were synthesized, and the thermodynamic profile of the bimolecular interaction with cruzain was determined using isothermal titration calorimetry (ITC). The result suggests the inhibition process is enthalpy driven, with a detrimental contribution of entropy. In addition, we have used hybrid Quantum Mechanical/Molecular Mechanical (QM/MM) and Molecular Dynamics (MD) simulations to investigate the reaction mechanism of reversible covalent modification of cruzain by Neq0409, Neq0410 and Neq0570. The computed free energy profile shows that the nucleophilic attack of Cys25 on the carbon C1 of inhibitiors and the proton transfer from His162 to N1 of the dipeptidyl nitrile inhibitor take place in a single step. The calculated free energy of the inhibiton reaction is in agreement with covalent experimental binding. Altogether, the results reported here suggests that nitrile-based inhibitors are good candidates for the development of reversible covalent inhibitors of cruzain and other cysteine proteases.


Asunto(s)
Cisteína Endopeptidasas/química , Proteasas de Cisteína/química , Inhibidores de Cisteína Proteinasa/química , Nitrilos/síntesis química , Proteínas Protozoarias/química , Tripanocidas/química , Trypanosoma cruzi/enzimología , Diseño de Fármacos , Simulación de Dinámica Molecular , Unión Proteica , Teoría Cuántica , Termodinámica
16.
Clin Cancer Res ; 24(21): 5433-5444, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30042207

RESUMEN

Purpose: Bone is the most predominant site of distant metastasis in prostate cancer, and patients have limited therapeutic options at this stage.Experimental Design: We performed a system-wide quantitative proteomic analysis of bone metastatic prostate tumors from 22 patients operated to relieve spinal cord compression. At the time of surgery, most patients had relapsed after androgen-deprivation therapy, while 5 were previously untreated. An extended cohort of prostate cancer bone metastases (n = 65) was used for immunohistochemical validation.Results: On average, 5,067 proteins were identified and quantified per tumor. Compared with primary tumors (n = 26), bone metastases were more heterogeneous and showed increased levels of proteins involved in cell-cycle progression, DNA damage response, RNA processing, and fatty acid ß-oxidation; and reduced levels of proteins were related to cell adhesion and carbohydrate metabolism. Within bone metastases, we identified two phenotypic subgroups: BM1, expressing higher levels of AR canonical targets, and mitochondrial and Golgi apparatus resident proteins; and BM2, with increased expression of proliferation and DNA repair-related proteins. The two subgroups, validated by the inverse correlation between MCM3 and prostate specific antigen immunoreactivity, were related to disease prognosis, suggesting that this molecular heterogeneity should be considered when developing personalized therapies.Conclusions: This work is the first system-wide quantitative characterization of the proteome of prostate cancer bone metastases and a valuable resource for understanding the etiology of prostate cancer progression. Clin Cancer Res; 24(21); 5433-44. ©2018 AACR.


Asunto(s)
Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Proteoma , Proteómica , Anciano , Biomarcadores de Tumor , Biopsia , Neoplasias Óseas/mortalidad , Neoplasias Óseas/terapia , Terapia Combinada , Biología Computacional/métodos , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Clasificación del Tumor , Pronóstico , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/terapia , Proteómica/métodos , Transcriptoma
17.
Mol Oncol ; 12(8): 1296-1307, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29901861

RESUMEN

Recent advances in mass spectrometry (MS)-based technologies are now set to transform translational cancer proteomics from an idea to a practice. Here, we present a robust proteomic workflow for the analysis of clinically relevant human cancer tissues that allows quantitation of thousands of tumor proteins in several hours of measuring time and a total turnaround of a few days. We applied it to a chemorefractory metastatic case of the extremely rare urachal carcinoma. Quantitative comparison of lung metastases and surrounding tissue revealed several significantly upregulated proteins, among them lysine-specific histone demethylase 1 (LSD1/KDM1A). LSD1 is an epigenetic regulator and the target of active development efforts in oncology. Thus, clinical cancer proteomics can rapidly and efficiently identify actionable therapeutic options. While currently described for a single case study, we envision that it can be applied broadly to other patients in a similar condition.


Asunto(s)
Histona Demetilasas/genética , Proteómica , Regulación hacia Arriba , Neoplasias de la Vejiga Urinaria/genética , Secuenciación de Nucleótidos de Alto Rendimiento/economía , Histona Demetilasas/análisis , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Espectrometría de Masas/economía , Terapia Molecular Dirigida/economía , Medicina de Precisión/economía , Proteómica/economía , Factores de Tiempo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Flujo de Trabajo
18.
Psicol. rev ; 27(n.esp): 469-496, 2018. ilus, tab
Artículo en Portugués | LILACS | ID: biblio-1007164

RESUMEN

A psicologia do esporte é uma área em expansão e é instada a participar da preparação de atletas, iniciando seu trabalho no Brasil a partir do futebol. O objetivo deste trabalho foi caracterizar publicações em periódicos científicos com textos completos em português, disponíveis on-line e com acesso livre, nos portais de busca CAPES, LILACS, PEPsic e SciELO, com foco na psicologia do esporte e futebol. Foram analisados 18 trabalhos publicados em revistas da área da Psicologia e da Educação Física. Os artigos se distribuem entre 2003 e 2017 e a metade foi publicada nos anos de grandes eventos esportivos. Quinze artigos são pesquisas não-experimentais descritivas e correlacionais estudando atletas e treinadores, ex-atletas e psicólogo do esporte. Fenômenos que a Psicologia tem tratado especialmente foram, ainda, objetos de estudo: fatores emocionais, estresse, julgamento moral, atitudes agressivas, estilos de liderança e sentidos de celebrização de atleta notável; e a relação entre ansiedade e pensamentos automáticos em jogadores, e entre insatisfação e comportamento alimentar inadequado em jovens futebolistas. Embora fique evidente que grande parte dos esforços são voltados para o alto rendimento, deve-se salientar que a psicologia do esporte se dedica, primariamente, à promoção de saúde no âmbito do esporte.


Sport psychology is an increasingly popular field that participates in the preparation of athletes. In Brazil, this science was firstly introduced in the work with soccer players. The objective of this paper was to characterize publications in scientific journals with full texts in Portuguese, available online and with free access, in the search portals CAPES, LILACS, PEPsic and SciELO, focused on Sport Psychology and Soccer. Eighteen papers published in journals in the area of Psychology and Physical Education were selected and analyzed. The articles ranged from between 2003 and 2017, and half of them were published in the years of major sporting events. Fourteen articles are non-experimental and correlational researches centered on the verbal reports of the athletes, coaches and sport psychologists. The issues dealt with included housing, professionalization and career projects. This paper also aimed to study psychological phenomena such as emotional factors, stress, moral judgment, aggressive attitudes, leadership styles and how athletes celebrate their victories and face their losses; anxiety and automatic thoughts in players, dissatisfaction and inappropriate eating behavior in young soccer players. Although it is evident that a great deal of effort is focused on high performance, it should be pointed out that sport psychology is primarily devoted to fostering health in the sports field.


La psicología del deporte es un área creciente la cual es solicitada a participar en la preparación de deportistas, y el inicio de su actuación en Brasil comenzó a partir del fútbol. El objetivo de este estudio fue identificar publicaciones en revistas con texto completo en portugués, disponible online y gratis, en los portales de búsqueda CAPES, LILACS, PEPsic Y SciELO, centrándose en la psicología del deporte y el fútbol. Fueron analizados 18 artículos publicados en revistas en el área de Psicología y educación física. Los artículos se distribuyeron entre 2003 y 2017 y la mitad fue publicado en los años en que acontecieron grandes eventos deportivos. Quince artículos son investigaciones descriptivas no experimentales y correlacionales, estudiando atletas y entrenadores; ex atletas y el psicólogo del deporte. Fenómenos que la psicología ha investigado, también fueron objetos de estudio: factores emocionales, estrés, juicio moral, actitudes agresivas, estilos de liderazgo, el sentido del atleta notable tornarse célebre; y la relación entre ansiedad y pensamientos automáticos en jugadores, y entre insatisfacción y la conducta alimentar inadecuada en jóvenes futbolistas. Aunque es evidente que gran parte de los esfuerzos están direccionados para el alto rendimiento, se debe señalar que la psicología del deporte se dedica, principalmente a la promoción de la salud en el ámbito deportivo.


Asunto(s)
Humanos , Masculino , Fútbol , Revisión , Psicología del Deporte
19.
Eur Arch Otorhinolaryngol ; 274(4): 1933-1938, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28213779

RESUMEN

Adenoids play a key role in both respiratory and ear infection in children. It has also been shown that adenoidectomy improves these symptoms in this population. The main goal of the present study was to evaluate adenoid bacterial colonization and document a possible relation with infectious respiratory disease. A prospective observational study was designed to evaluate the proposed hypothesis in a paediatric population submitted to adenoidectomy by either infectious or non-infectious indications and compare these two cohorts. A total of 62 patients with ages ranging from 1 to 12 years old were enrolled in the study. Adenoid surface, adenoid core and middle meatus microbiota were compared. A close association between adenoid colonization and nasal infection was found, supporting that adenoids may function as bacterial reservoir for upper airway infection. The obtained results also contribute to explain the success of adenoidectomy in patients with infectious indications.


Asunto(s)
Tonsila Faríngea/microbiología , Infecciones del Sistema Respiratorio/microbiología , Adenoidectomía , Tonsila Faríngea/cirugía , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Estudios Prospectivos , Infecciones del Sistema Respiratorio/prevención & control
20.
Psychiatr Serv ; 67(11): 1269-1271, 2016 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-27301761

RESUMEN

OBJECTIVE: This study examined the prevalence and correlates of co-occurring obesity and diabetes among community mental health program members. METHODS: Medical screenings of 457 adults with serious mental illnesses were conducted by researchers and peer wellness specialists in four U.S. states. Body mass index was measured directly. Diabetes was assessed via glycosylated hemoglobin and interview self-report. Multivariable logistic regression analysis examined associations with known predictors. RESULTS: In the sample, 59% were obese, 25% had diabetes, and 19% had both conditions. When gender, diagnosis, and site were controlled, co-occurring diabetes and obesity was almost three times as likely among African Americans (OR=2.93) as among participants from other racial groups and half as likely among smokers as among nonsmokers (OR=.58). Older persons and those with poorer self-rated physical health also were more likely to have these co-occurring conditions. CONCLUSIONS: Results support the need for culturally competent treatment and for smoking cessation options with sensitivity to the potential for weight gain.


Asunto(s)
Servicios Comunitarios de Salud Mental/estadística & datos numéricos , Diabetes Mellitus/epidemiología , Trastornos Mentales/epidemiología , Obesidad/epidemiología , Adulto , Comorbilidad , Diabetes Mellitus/etnología , Femenino , Humanos , Masculino , Trastornos Mentales/etnología , Persona de Mediana Edad , Obesidad/etnología , Estados Unidos/epidemiología
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