VEGF-Modified PVA/Silicone Nanofibers Enhance Islet Function Transplanted in Subcutaneous Site Followed by Device-Less Procedure.

INTRODUCTION: As heterologous islets or islet-like stem cells become optional sources for islet transplantation, the subcutaneous site appears to be an acceptable replacement of the intrahepatic site due to its graft retrievability. The device-less (DL) procedure improves the feasibility; however, some limitations such as fibrotic overgrowth or immunodeficiency still exist. Nanofibers could mimic the extracellular matrix to improve the vitality of transplanted islets. Therefore, we designed a vascular endothelial growth factor (VEGF)-modified polyvinyl alcohol (PVA)/silicone nanofiber (SiO2-VEGF) to optimize the DL procedure. METHODS: SiO2-VEGF nanofibers were designed by nano-spinning and characterized the physical-chemical properties before subcutaneous islet transplantation. Cell viability, vessel formation, and glucose-stimulated insulin secretion were tested in vitro to ensure biocompatibility; and blood glucose level (BGL), transplanted islet function, and epithelial-mesenchymal transition (EMT)-related biomarker expression were analyzed in vivo. RESULTS: The intensity of inflammatory reaction induced by SiO2 nanofibers was between nylon and silicone, which did not bring out excessive fibrosis. The vascularization could be enhanced by VEGF functionalization both in vitro and in vivo. The BGL control was better in the DL combined with SiO2-VEGF group. The percentage of recipients that achieved normoglycemia was higher and earlier (71% at day 57), and the intraperitoneal glucose tolerance test (IPGTT) also confirmed better islet function. The expressions of vimentin, α-SMA, and twist-1 were upregulated, which indicated that SiO2-VEGF nanofibers might promote islet function by regulating the EMT pathway. DISCUSSION: In summary, our new SiO2-VEGF combined with DL procedure might improve the feasibility of subcutaneous islet transplantation for clinical application.

A New Fusion Peptide Targeting Pancreatic Cancer and Inhibiting Tumor Growth.

BACKGROUND: Pancreatic cancer is a highly malignant tumor of the digestive system. Early pancreatic cancer is often difficult to diagnosis due to its atypical clinical symptoms. Patients with pancreatic cancer have a very poor prognosis because they have lost the opportunity for radical surgical tumor resection and they are less sensitive to the clinically used radiotherapy and chemotherapy. METHODS: In this study, a peptide targeting pancreatic cancer cells was screened by phage display technology, and its targeting property was evaluated in vitro using PANC1 cells by fluorescence imaging and flow cytometry. Furthermore, the targeting peptide was conjugated to the pro-apoptotic KLAKLAKKLAKLAK (KLA), the fusion peptide and its targeting ability that allowing KLA to specifically enter pancreatic tumor cells in vitro and in vivo was confirmed by fluorescence imaging and in vivo imaging system (IVIS). Its mechanism was determined using flow cytometry, mitochondrial membrane potential evaluation and Western blot. The inhibitory effect on pancreatic tumor growth and toxic effects were evaluated by animal experiment. RESULTS: Due to the internalization facilitated by the targeting mechanism of the targeting peptide, KLA specifically entered pancreatic cancer cells, destroyed mitochondria and induced apoptosis. The fusion peptide and its targeting ability that allowing KLA to specifically enter pancreatic tumor cells and exert a significant inhibitory effect on pancreatic tumor growth with reduced toxic effects. CONCLUSION: This approach possesses potential advantages in the clinical diagnosis and treatment of pancreatic cancer.

FHL3 promotes pancreatic cancer invasion and metastasis through preventing the ubiquitination degradation of EMT associated transcription factors.

Pancreatic ductal adenocarcinoma (PDAC) is intractable due to its strong invasiveness and metastatic ability. Epithelial-mesenchymal transition (EMT) is the pivotal driver of tumor invasion and metastasis. The four-and-a-half LIM domain (FHL) family is involved in regulating transforming growth factor (TGF)-ß and Ras signaling, which might control the EMT process. In this study, we found that higher expression of four-and-a-half LIM domains 3 (FHL3) predicted poor prognosis in PDAC. The decreasing of FHL3 changed the EMT phenotype by blocking the TGFß/Atk/GSK3ß/ubiquitin pathways. Interestingly, the GSK3ß inhibitor could abrogate the role of FHL3 in the regulation of snail1 and twist1 expression, which implied that GSK3ß plays a pivotal role in the FHL3-mediated EMT process. Furthermore, we found that FHL3 can directly bind to GSK3ß, which weakened the interaction between GSK3ß and snail1/twist1. We also found that the LIM-3 domain of FHL3 was required for the binding of FHL3 to GSK3ß. Collectively, our study implied that FHL3, as a binding partner of GSK3ß, promoted tumor metastasis in PDAC through inhibiting the ubiquitin-degradation of snail1 and twist1.