Keap-NRF2 signaling contributes to the Notch1 protected heart against ischemic reperfusion injury via regulating mitochondrial ROS generation and bioenergetics.

Myocardial ischemia/reperfusion (I/R) injury is recognized as the leading cause of death worldwide. However, the molecular mechanisms involved in this process are still not fully understood. We previously reported that the combined action of Notch1 and Keap1-NRF2 signaling pathway can significantly increase the activity of cardiomyocytes, inhibit the apoptosis of cardiomyocytes, reduce the formation of reactive oxygen species, and improve the antioxidant activity in neonate rat myocardial cells. However, the regulatory mechanism of Notch1 signaling pathway on the NRF2 signaling pathway and its actual role on I/R injury are still unclear. Herein, we found that Keap-NRF2 signaling is activated by Notch1 in RBP-Jκ dependent manner, thus protects the heart against I/R injury via inhibiting the mitochondrial ROS generation and improves the mitochondrial bioenergetics in vitro and in vivo. These results suggest that Keap-NRF2 signaling might become a promising therapeutic strategy for treating myocardial I/R injury.

Chromosome 8 gain is associated with high-grade transformation in MPNST.

One of the most common malignancies affecting adults with Neurofibromatosis type 1 (NF1) is the malignant peripheral nerve sheath tumor (MPNST), an aggressive and often fatal sarcoma that commonly arises from benign plexiform neurofibromas. Despite advances in our understanding of MPNST pathobiology, there are few effective therapeutic options, and no investigational agents have proven successful in clinical trials. To further understand the genomic heterogeneity of MPNST, and to generate a preclinical platform that encompasses this heterogeneity, we developed a collection of NF1-MPNST patient-derived xenografts (PDX). These PDX were compared with the primary tumors from which they were derived using copy number analysis, whole exome sequencing, and RNA sequencing. We identified chromosome 8 gain as a recurrent genomic event in MPNST and validated its occurrence by FISH in the PDX and parental tumors, in a validation cohort, and by single-cell sequencing in the PDX. Finally, we show that chromosome 8 gain is associated with inferior overall survival in soft-tissue sarcomas. These data suggest that chromosome 8 gain is a critical event in MPNST pathogenesis and may account for the aggressive nature and poor outcomes in this sarcoma subtype.

Enhanced Poly(propylene carbonate) with Thermoplastic Networks: A Cross-Linking Role of Maleic Anhydride Oligomer in CO2/PO Copolymerization.

Cross-linking is an effective way to enhance biodegradable poly(propylene carbonate) (PPC) from CO2 and propylene oxide (PO). Cross-linked PPC can be prepared by one-step terpolymerization of multifunctional third monomers with CO2 and PO. However, few such third monomers are available. Each molecule of maleic anhydride oligomer (MAO) contains more than two cyclic anhydride groups. Here, we use it to synthesize PPC with cross-linked networks by adding a small quantity of MAO (0.625-5 wt% of PO) in CO2/PO copolymerization that was catalyzed by zinc glutarate. The formation of networks in the prepared copolymers was confirmed by the presence of gel in copolymers combined Fourier transform infrared spectroscopy (FT-IR), 1H NMR, and the improved mechanical properties. The 5% weight-loss degradation temperatures and maximum weight-loss degradation temperatures greatly increase up to 289.8 °C and 308.8 °C, respectively, which are remarkably high when compared to those of PPC. The minimum permanent deformation of the copolymers closes to 0, while that of PPC is 173%. The maximum tensile strength of the copolymers is 25.5 MPa higher than that of PPC, reaching 38.4 MPa, and it still has some toughness with the elongation at break of 25%. The above phenomena indicate that MAO that was inserted in PPC chains play a cross-linking role, which results in enhanced thermal stability, dimensional stability, and mechanical strength, comprehensively.

A Novel One-Pot Synthesis of Poly(Propylene Carbonate) Containing Cross-Linked Networks by Copolymerization of Carbon Dioxide, Propylene Oxide, Maleic Anhydride, and Furfuryl Glycidyl Ether.

The thermoplastic poly(propylene carbonate) (PPC) containing cross-linked networks was one-pot synthesized by copolymerization of carbon dioxide, propylene oxide (PO), maleic anhydride (MA), and furfuryl glycidyl ether (FGE). The copolymers were characterized by Fourier transform infrared spectroscopy (FT-IR), gel permeation chromatography (GPC), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) measurements. The thermal and dimensional stability of the copolymers were improved. When the MA and FGE load increased from 1 mol% to 4 mol% of PO, the copolymers contained the gel contents of 11.0%-26.1% and their yields were about double that of the PPC. The 5% weight-loss degradation temperatures (Td,-5%) and the maximum weight-loss degradation temperatures (Td,max) increased from 149.7-271.3 °C and from 282.6-288.6 °C, respectively, corresponding to 217.1 °C and 239.0 °C of PPC. Additionally, the hot-set elongation tests showed that the copolymers exhibited elasticity and dimensional stability with the minimum permanent deformation of 6.5% which was far less than that of PPC of 157.2%, while the tensile strengths were a little lower than that of PPC because of the following two conflicting factors, cross-links and flexibility of the units formed by the introduced third monomers, MA and FGE. In brief, we provide a novel method of one-pot synthesis of PPC containing cross-linked networks. According to this idea, the properties would be more extensively regulated by changing the cross-linkable monomers.