RESUMEN
We investigated how human proislet peptide (HIP) regulates differentiation of human fetus-derived pancreatic progenitor cells (HFPPCs) and explored the potential link between HIP signaling and the menin pathway, which is key to regulating pancreatic islet differentiation. The data show that HIP promoted expression of proislet transcription factors (TFs), including PDX-1, MAFA, and NKX6.1, as well as other maturation markers of ß-cells, such as insulin, GLUT2, KIR6.2, SUR1, and VDCC. Moreover, HIP increased insulin content and promoted the ability of HFPPCs to normalize blood glucose in diabetic mice. HIP inhibited the TF FOXO1 by increasing AKT-mediated phosphorylation. HIP-induced repression of FOXO1 suppressed menin expression, leading to reducing menin binding to the promoter of the three key proislet TFs, decreasing recruitment of H3K9 methyltransferase SUV39H1, and thus reducing repressive H3K9me3 at the promoter. These coordinated actions lead to increased expression of the proislet TFs, resulting in induction of HFPPC differentiation. Consistently, constitutive activation of FOXO1 blocks HIP-induced transcription of these TFs. Together, these studies unravel the crucial role of the HIP/AKT/FOXO/menin axis in epigenetically controlling expression of proislet TFs, regulating the differentiation of HFPPCs, and normalizing blood glucose in diabetic mice.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Diabetes Mellitus Experimental/genética , Epigénesis Genética/efectos de los fármacos , Proteína Forkhead Box O1/genética , Péptidos/farmacología , Proteínas Proto-Oncogénicas/genética , Células Madre/efectos de los fármacos , Animales , Diferenciación Celular/genética , Células Cultivadas , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/terapia , Células HEK293 , Humanos , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/fisiología , Células Secretoras de Insulina/trasplante , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Páncreas/citología , Páncreas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Células Madre/fisiologíaRESUMEN
Single-walled carbon nanotube (SWCNT) random networks are easily fabricated on a wafer scale, which provides an attractive path to large-scale SWCNT-based thin-film transistor (TFT) manufacturing. However, the mixture of semiconducting SWCNTs and metallic SWCNTs (m-SWCNTs) in the networks significantly limits the TFT performance due to the m-SWCNTs dominating the charge transport. In this paper, we have achieved a uniform and high-density SWCNT network throughout a complete 3-in. Si/SiO2 wafer using a solution-based assembly method. We further utilized UV radiation to etch m-SWCNTs from the networks, and a remarkable increase in the channel current on/off ratio (Ion/Ioff) from 11 to 5.6 × 103 was observed. Furthermore, we used the SWCNT-TFTs as gas sensors to detect methyl methylphosphonate, a stimulant of benchmark threats. It was found that the SWCNT-TFT sensors treated with UV radiation show a much higher sensitivity and faster response to the analytes than those without treatment with UV radiation.