RESUMEN
Mesenchymal stem cells have neuroprotective effects that limit damage to the retina and photoreceptors, and which may be mediated by extracellular vesicles (or exosomes) released by mesenchymal stem cells. To investigate the neuroprotective effect of extracellular vesicles derived from umbilical cord mesenchymal stem cells on glaucoma, we established rat models of chronic ocular hypertension by injecting conjunctival fibroblasts into the anterior chamber to mimic optic nerve injury caused by glaucoma. One week after injury, extracellular vesicles derived from umbilical cord-derived mesenchymal stem cells were injected into the vitreous cavity. We found that extracellular vesicles derived from mesenchymal stem cells substantially reduced retinal damage, increased the number of retinal ganglion cells, and inhibited the activation of caspase-3. These findings suggest that mesenchymal stem cell-derived extracellular vesicles can help alleviate optic nerve injury caused by chronic ocular hypertension, and this effect is achieved by inhibiting cell apoptosis.
RESUMEN
Reprogrammed glucose metabolism is essential for tumor initiation and development, especially for pancreatic ductal adenocarcinoma (PDAC). Most cancer cells rely on aerobic glycolysis, a phenomenon termed "the Warburg effect", to support uncontrolled proliferation and evade apoptosis. However, the direct regulators of the Warburg effect remain areas of active investigation. In this study, we found that the highly conserved transcription factor, TWIST1, is a crucial regulator of aerobic glycolysis in PDAC. Genetic silencing of TWIST1 significantly inhibited the glycolytic phenotypes of PDAC cells as revealed by reduced glucose uptake, lactate production, and extracellular acidification rate, which can be restored by re-expression of siRNA-resistant TWIST1. Moreover, tamoxifen-inducible expression of TWIST1 promoted the Warburg metabolism of PDAC cells. Mechanistically, by luciferase reporter assay and chromatin immunoprecipitation experiment, we showed that TWIST1 can directly increase the expression of several glycolytic genes, including SLC2A1, HK2, ENO1, and PKM2. Of note, the transcriptional regulation by TWIST1 was not dependent on HIF1α or c-Myc. In The Cancer Genome Atlas and Gene Expression Omnibus accession GSE15471, we confirmed that TWIST1 was closely associated with the glycolysis pathway. Collectively, our findings indicate that TWIST1 is likely to act as important regulator of the Warburg effect in PDAC.
Asunto(s)
Adenocarcinoma/metabolismo , Regulación Neoplásica de la Expresión Génica , Glucólisis , Proteínas Nucleares/genética , Neoplasias Pancreáticas/metabolismo , Proteína 1 Relacionada con Twist/genética , Adenocarcinoma/genética , Adenocarcinoma/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 1/metabolismo , Hexoquinasa/genética , Hexoquinasa/metabolismo , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Fosfopiruvato Hidratasa/genética , Fosfopiruvato Hidratasa/metabolismo , Hormonas Tiroideas/genética , Hormonas Tiroideas/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Proteínas de Unión a Hormona TiroideRESUMEN
A practical Fe-catalyzed decarbonylative cascade reaction of N-aryl cinnamamides with aliphatic aldehydes to provide C3 alkylated 3,4-dihydroquinolin-2(1H)-ones is developed. Aliphatic aldehydes were oxidatively decarbonylated into 1°, 2° and 3° alkyl radicals conveniently, allowing for the subsequent cascade construction of C(sp3)-C(sp3) and C(sp3)-C(sp2) bonds via radical addition and HAS-type cyclization. The importance of the amide linkage and the selectivity of the 6-endo-trig over 5-exo-trig cyclization pathway were elucidated by experimental results and DFT calculations.
