No abstract

3D cell printing using pdECM bioink can recapitulate pancreatic tissue specific microenvironmental niche that can induce higher insulins production by islets.

Human epidermal growth factor receptor 2 (HER2)-directed treatment using trastuzumab has shown clinical benefit in HER2-positive gastric cancer. Clinical trials using lapatinib in HER2-positive gastric cancer are also currently underway. As with other molecularly targeted agents, the emergence of acquired resistance to HER2-directed treatment is an imminent therapeutic problem for HER2-positive gastric cancer. In order to investigate the mechanisms of acquired resistance to HER2-directed treatment in gastric cancer, we generated lapatinib-resistant gastric cancer cell lines (SNU216 LR) in vitro by chronic exposure of a HER2-positive gastric cancer cell line (SNU216) to lapatinib. The resultant SNU216 LR cells were also resistant to gefitinib, cetuximab, trastuzumab, afatinib and dacomitinib. Interestingly, SNU216 LR cells displayed an epithelial-mesenchymal transition (EMT) phenotype and maintained the activation of MET, HER3, Stat3, Akt and mitogen-activated protein kinase signaling in the presence of lapatinib. Using gene expression arrays, we identified the upregulation of a variety of EMT-related genes and extracellular matrix molecules, such as Testican-1, in SNU216 LR cells. We showed that the inhibition of Testican-1 by small interfering RNA decreased Testican-1-induced, MET-dependent, downstream signaling, and restored sensitivity to lapatinib in these cells. Furthermore, treatment with XAV939 selectively inhibited β-catenin-mediated transcription and Testican-1-induced EMT signaling, leading to G1 arrest. Taken together, these data support the potential role of EMT in acquired resistance to HER2-directed treatment in HER2-positive gastric cancer, and provide insights into strategies for preventing and/or overcoming this resistance in patients.

No abstract

Sodium-dependent vitamin C transporters (SVCTs) is known to transport the reduced form of ascorbic acid into the cell, whereas the oxidized form of vitamin C (VC) is moved through a facilitative sugar transporter, such as glucose transporter (GLUT). With regard to the distribution of SVCT1 and -2 within the various organs, they were reported to be expressed in different types of cells. Especially in the central nervous system, only SVCT2 mRNA was expressed mainly in neurons and some types of neuroglial cells. However, data on the expression of SVCT proteins in the brain are scant. Therefore, we tried to develop comprehensive data on the distribution of SVCT proteins in adult rat brain by using immunohistochemical techniques for the first time. In our study, SVCT2 immunoreactivities (IRs) were intensely localized in the neurons of cerebral cortex, hippocampus, and Purkinje cells of cerebellum, and much weaker SVCT2 IRs were found in the other brain regions. Judging from double-immunohistochemical data, most of the cells expressing SVCT2 IRs were likely to be neurons or microglia, even though the cells in choroids plexus or ependymal cells around the ventricles also exhibited SVCT2 IRs. Complete mapping of the distribution of SVCT2 IRs was available by using a semiquantitative method. The subcellular localization of SVCT proteins is necessary for understanding the exact role of the protein, so the current overall mapping of SVCT IRs in the rat brain could be the basis for further studies on related subjects.

Small ubiquitin-like modifier (SUMO)-specific proteases (SENPs) that reverse protein modification by SUMO are involved in the control of numerous cellular processes, including transcription, cell division, and cancer development. However, the physiological function of SENPs in energy metabolism remains unclear. Here, we investigated the role of SENP2 in fatty acid metabolism in C2C12 myotubes and in vivo. In C2C12 myotubes, treatment with saturated fatty acids, like palmitate, led to nuclear factor-κB–mediated increase in the expression of SENP2. This increase promoted the recruitment of peroxisome proliferator–activated receptor (PPAR)δ and PPARγ, through desumoylation of PPARs, to the promoters of the genes involved in fatty acid oxidation (FAO), such as carnitine-palmitoyl transferase-1 (CPT1b) and long-chain acyl-CoA synthetase 1 (ACSL1). In addition, SENP2 overexpression substantially increased FAO in C2C12 myotubes. Consistent with the cell culture system, muscle-specific SENP2 overexpression led to a marked increase in the mRNA levels of CPT1b and ACSL1 and thereby in FAO in the skeletal muscle, which ultimately alleviated high-fat diet–induced obesity and insulin resistance. Collectively, these data identify SENP2 as an important regulator of fatty acid metabolism in skeletal muscle and further implicate that muscle SENP2 could be a novel therapeutic target for the treatment of obesity-linked metabolic disorders.

Environmental and health concerns force the search for sustainable super engineering plastics (SEPs) that utilise bio-derived cyclic monomers, e.g. isosorbide instead of restricted petrochemicals. However, previously reported bio-derived thermosets or thermoplastics rarely offer thermal/mechanical properties, scalability, or recycling that match those of petrochemical SEPs. Here we use a phase transfer catalyst to synthesise an isosorbide-based polymer with a high molecular weight >100 kg mol −1 , which is reproducible at a 1-kg-scale production. It is transparent and solvent/melt-processible for recycling, with a glass transition temperature of 212 °C, a tensile strength of 78 MPa, and a thermal expansion coefficient of 23.8 ppm K −1 . Such a performance combination has not been reported before for bio-based thermoplastics, petrochemical SEPs, or thermosets. Interestingly, quantum chemical simulations show the alicyclic bicyclic ring structure of isosorbide imposes stronger geometric restraint to polymer chain than the aromatic group of bisphenol-A.

As a new class of materials, implantable flexible electrical conductors have recently been developed and applied to bioelectronics. An ideal electrical conductor requires high conductivity, tissue‐like mechanical properties, low toxicity, reliable adhesion to biological tissues, and the ability to maintain its shape in wet physiological environments. Despite significant advances, electrical conductors that satisfy all these requirements are insufficient. Herein, a facile method for manufacturing a new conductive hydrogels through the simultaneous exfoliation of graphite and polymerization of zwitterionic monomers triggered by microwave irradiation is introduced. The mechanical properties of the obtained conductive hydrogel are similar to those of living tissue, which is ideal as a bionic adhesive for minimizing contact damage due to mechanical mismatches between hard electronics and soft tissues. Furthermore, it exhibits excellent adhesion performance, electrical conductivity, non‐swelling, and high conformability in water. Excellent biocompatibility of the hydrogel is confirmed through a cytotoxicity test using C2C12 cells, a biocompatibility test on rat tissues, and their histological analysis. The hydrogel is then implanted into the sciatic nerve of a rat and neuromodulation is demonstrated through low‐current electrical stimulation. This hydrogel demonstrates a tissue‐like extraneuronal electrode, which possesses high conformability to improve the tissue–electronics interfaces, promising next‐generation bioelectronics applications.