RESUMO
Aims: To investigate the correlations between meeting the muscle-strengthening activities guideline, body fat %, and mortality for individuals living with obesity and to explore if these correlations are moderated by sex. Methods: Data from 3915 adults (51.9% women; 48.1% men ) living with obesity (body fat % ≥25 for men and ≥35 for women) from two cycles of the National Health and Nutrition Examination Survey (NHANES 2003-04/2005-06) were analyzed. Muscle-strengthening activities were self-reported via a questionnaire, body fat % was measured via Dual Energy X-ray, and mortality was obtained via administrative data for an average of 10 years. Results: 18.7% of men and 15.2% of women living with obesity met the muscle-strengthening activities guideline (p = 0.021) . Sex was correlated with body fat %; (ß (SE)= 11.34 (0.18); p ≤ 0.001) and risk of mortality (hazard ratio (95% confidence interval) = 0.36 (0.24-0.54); p ≤ 0.001), once adjusted for confounders (weekly aerobic activities, ethnicity, education, household income, smoking, and the sum of chronic conditions). The interaction between sex and meeting the muscle-strengthening activities guideline was not significantly correlated with the studied outcomes. Conclusion: Performing muscle-strengthening activities a minimum of two times per week does not impact body fat % or risk of mortality (over 10 years) differently in men or women living with obesity.
RESUMO
Prostate-specific membrane antigen (PSMA) is highly overexpressed in most prostate cancers and is clinically visualized using PSMA-specific probes incorporating glutamate-ureido-lysine (GUL). PSMA is effectively absent from certain high-mortality, treatment-resistant subsets of prostate cancers, such as neuroendocrine prostate cancer (NEPC); however, GUL-based PSMA tracers are still reported to have the potential to identify NEPC metastatic tumors. These probes may bind unknown proteins associated with PSMA-suppressed cancers. We have identified the up-regulation of PSMA-like aminopeptidase NAALADaseL and the metabotropic glutamate receptors (mGluRs) in PSMA-suppressed prostate cancers and find that their expression levels inversely correlate with PSMA expression and are associated with GUL-based radiotracer uptake. Furthermore, we identify that NAALADaseL and mGluR expression correlates with a unique cell cycle signature. This provides an opportunity for the future study of the biology of NEPC and potential therapeutic directions. Computationally predicting that GUL-based probes bind well to these targets, we designed and synthesized a fluorescent PSMA tracer to investigate these proteins in vitro, where it shows excellent affinity for PSMA, NAALADaseL, and specific mGluRs associated with poor prognosis.
Assuntos
Antígenos de Superfície/metabolismo , Glutamato Carboxipeptidase II/metabolismo , Glutamatos , Lisina , Sondas Moleculares , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/metabolismo , Ureia , Animais , Antígenos de Superfície/química , Sítios de Ligação , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Imunofluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Expressão Gênica , Glutamato Carboxipeptidase II/química , Glutamatos/química , Humanos , Imuno-Histoquímica , Lisina/química , Masculino , Camundongos , Modelos Moleculares , Conformação Molecular , Imagem Molecular/métodos , Sondas Moleculares/química , Neoplasias da Próstata/genética , Ligação Proteica , Receptores de Ácido Caínico/genética , Receptores de Ácido Caínico/metabolismo , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/químicaRESUMO
(S)-2,4-Diaminobutanoic acid (DABA) is a noncanonical amino acid often co-produced by cyanobacteria along with ß-N-methylamino-l-alanine (BMAA) in algal blooms. Although BMAA is a well-established neurotoxin, the toxicity of DABA remains unclear. As part of our development of biocompatible materials, we wish to make use of DABA as both a building block and as the end-product of enzymatically induced depolymerization; however, if it is toxic at very low concentrations, this would not be possible. We examined the toxicity of DABA using both in vivo embryonic and adult zebrafish models. At higher sublethal concentrations (700 µm), the fish demonstrated early signs of cardiotoxicity. Adolescent zebrafish were able to tolerate a higher concentration. Post-mortem histological analysis of juvenile zebrafish showed no liver or brain abnormalities associated with hepato- or neurotoxicity. Combined, these results show that DABA exhibits no overt toxicity at concentrations (100-300 µm) within an order of magnitude of those envisioned for its application. This study further highlights the low cost and ease of using zebrafish as an early-stage toxicological screening tool.