RESUMEN
Brain-derived neurotrophic factor (BDNF) is a pleiotropic neuronal growth and survival factor that is indispensable in the brain, as well as in multiple other tissues and organs, including the cardiovascular system. In approximately 30% of the general population, BDNF harbors a nonsynonymous single nucleotide polymorphism that may be associated with cardiometabolic disorders, coronary artery disease, and Duchenne muscular dystrophy cardiomyopathy. We recently showed that transgenic mice with the human BDNF rs6265 polymorphism (Val66Met) exhibit altered cardiac function, and that cardiomyocytes isolated from these mice are also less contractile. To identify the underlying mechanisms involved, we compared cardiac function by echocardiography and performed deep sequencing of RNA extracted from whole hearts of all three genotypes (Val/Val, Val/Met, and Met/Met) of both male and female Val66Met mice. We found female-specific cardiac alterations in both heterozygous and homozygous carriers, including increased systolic (26.8%, p = 0.047) and diastolic diameters (14.9%, p = 0.022), increased systolic (57.9%, p = 0.039) and diastolic volumes (32.7%, p = 0.026), and increased stroke volume (25.9%, p = 0.033), with preserved ejection fraction and fractional shortening. Both males and females exhibited lower heart rates, but this change was more pronounced in female mice than in males. Consistent with phenotypic observations, the gene encoding SERCA2 (Atp2a2) was reduced in homozygous Met/Met mice but more profoundly in females compared to males. Enriched functions in females with the Met allele included cardiac hypertrophy in response to stress, with down-regulation of the gene encoding titin (Tcap) and upregulation of BNP (Nppb), in line with altered cardiac functional parameters. Homozygous male mice on the other hand exhibited an inflammatory profile characterized by interferon-γ (IFN-γ)-mediated Th1 immune responses. These results provide evidence for sex-based differences in how the BDNF polymorphism modifies cardiac physiology, including female-specific alterations of cardiac-specific transcripts and male-specific activation of inflammatory targets.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/genética , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Sustitución de Aminoácidos , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Femenino , Expresión Génica , Masculino , Metionina/genética , Ratones , Ratones Transgénicos , Mutación Missense , Polimorfismo de Nucleótido Simple , Caracteres Sexuales , Valina/genética , Función Ventricular/genética , Función Ventricular/fisiologíaRESUMEN
The detection of early-stage cancer offers patients the best chance of treatment and could help reduce cancer mortality rates. However, cancer cells or biomarkers are present in extremely small amounts in the early stages of cancer, requiring high-precision quantitative approaches with high sensitivity for accurate detection. With the advantages of simplicity, rapid response, reusability, and a low cost, aptamer-based electrochemical biosensors have received considerable attention as a promising approach for the clinical diagnosis of early-stage cancer. Various methods for developing highly sensitive aptasensors for the early detection of cancers in clinical samples are in progress. In this article, we discuss recent advances in the development of electrochemical aptasensors for the early detection of different cancer biomarkers and cells based on different detection strategies. Clinical applications of the aptasensors and future perspectives are also discussed.