Upregulated MMP28 in Hepatocellular Carcinoma Promotes Metastasis via Notch3 Signaling and Predicts Unfavorable Prognosis.

MMP28 belongs to the matrix metalloproteinases (MMPs) family and functions in tissue homeostasis and development. Although many other MMPs have been reported to regulate tumor progression, the roles of MMP28 in cancer remain largely elusive. In this study, we investigated the potential roles of MMP28 in hepatocellular carcinoma (HCC). The upregulation of MMP28 was first determined by the analysis on different public datasets. Further quantitative real-time PCR (qPCR) analysis, western blot (WB) assay and immunohistochemistry (IHC) assay on tumor and tumor-adjacent samples from HCC patients confirmed the aberrant elevation of MMP28 in HCC. Pathological analysis showed that increased MMP28 was associated with tumor size, vascular invasion, TNM stage and overall survival in HCC patients. Meanwhile, upregulated MMP28 was identified as an independent prognosis factor in multivariate analysis, and the incorporation of MMP28 expression with TNM staging system established a novel model to improve the accuracy of the predictions. In vivo and in vitro data revealed that MMP28 promoted migration and invasion of HCC cells, and enhanced epithelial-mesenchymal transition (EMT) via elevating zinc finger E-box binding homeobox (ZEB) homologues levels. Furthermore, we determined that Notch3 signaling was critical for the functions of MMP28 in HCC. In conclusion, upregulated MMP28 in HCC promoted migration and invasion and predicted poor prognosis for HCC patients, and the effects of MMP28 depended on Notch3 signaling.

Localized intrahepatic IgG4-related sclerosing cholangitis (IgG4-SC) as an additional type of IgG4-SC: a systematic analysis of 12 cases.

OBJECTIVES: IgG4-related sclerosing cholangitis (IgG4-SC), a recently defined disease entity, has been classified into four types based on the stricture regions revealed by cholangiography. However, localized intrahepatic IgG4-SC is not included into the classification. This study aimed to analyze and characterize localized intrahepatic IgG4-SC and justify the inclusion of this type into the classification. METHODS: PubMed and Embase were searched for studies published from March 2001 to June 2017 reporting localized intrahepatic IgG4-SC. Data were obtained and analyzed from the included articles. RESULTS: Twelve cases of localized intrahepatic IgG4-SC were included. All patients were adults with the median age of 73 years (range 46-78), and had a male preponderance (88.9%). The most common clinical presentation was obstructive jaundice (50%), abdominal pain (25%) and absence of symptoms (25%). On imaging and macroscopically, localized intrahepatic IgG4-SC presented with three subtypes, i.e., mass-forming (n = 6, 50%), stricture (n = 5, 41.7%) and periductal infiltrating (n = 1, 8.3%) subtypes. Among the eight cases with diagnoses reported, six patients were misdiagnosed as intrahepatic cholangiocarcinoma; one was diagnosed as hepatic mass and one as IgG4-SC before biopsy or operation. Information on treatment was available on 10 cases; eight underwent surgical resection, one received steroid treatment alone and one underwent endoscopic biliary drainage. No relapse was noted in patients with surgical resection during a period of followed up. CONCLUSIONS: The localized intrahepatic IgG4-SC presents with mass-forming, stricture and periductal infiltrating subtypes, and should be recognized as an additional type of IgG4-SC according to the cholangiographic classification or anatomic site.

Drug loaded nanoparticle coating on totally bioresorbable PLLA stents to prevent in-stent restenosis.

Biodegradable polymer poly (dl-lactide) (PDLLA) has been used as drug coating material for drug-eluting stents due to its excellent biocompatibility and sustained drug release ability. However, the uniform thin layer drug eluting coating on a stent not only inhibits the blood vessel's smooth muscle cell overgrowth but also delay the endotheliation process which is often associated with the occurrence of acute thrombosis. Therefore, in this study, we developed a novel coating method using PDLLA nanoparticles (NPs) as a coating to overcome this issue. The average 300 nm sized sirolimus-loaded PDLLA nanoparticles were prepared by a conventional emulsion solvent evaporation method. A low temperature plasma polymerization technology to graft hydrophilic polymers on to poly (l-lactide) stent was used to increase the surface coating efficiency of nanoparticles on the stent. Results showed that sirolimus-loaded nanoparticles can be successfully coated on to the stents with sustained drug release properties. In vitro cell culture study showed the drug loaded nanoparticle coating effectively inhibited the proliferation of smooth muscle cells while still allowed a faster proliferation of endothelial cells, suggesting that the new NP coated bioresorbable stents have the potential to reduce both the occurrence of in-stent restenosis and acute thrombosis. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 88-95, 2018.

Autophagy regulates proliferation and biliary differentiation of hepatic oval cells via the MAPK/ERK signaling pathway.

Hepatic oval cells (HOCs) are thought to possess self­renewal ability and a bipotential capacity for differentiation, which allows them to differentiate into hepatocytes and cholangiocytes. Autophagy serves an important role in self­renewal and differentiation of stem cells; however, how autophagy contributes to proliferation and differentiation of hepatic progenitor cells has yet to be elucidated. In the present study, autophagy was regulated by rapamycin (Rapa) and chloroquine (Chlo) administration. The results demonstrated that Chlo­treated HOCs exhibited decreased autophagic activity alongside a decreased tendency to proliferate, as determined by Cell Counting Kit­8. In addition, activation of autophagy by Rapa enhanced the biliary differentiation of HOCs. Furthermore, increased phosphorylated (p)­extracellular signal­regulated kinase (ERK)/p­p38 expression was observed following the induction of autophagy, thus indicating that the mitogen­activated protein kinase (MAPK)/ERK signaling pathway was activated by autophagy to exert effects on the stimulation of HOC proliferation and differentiation. In conclusion, the present study demonstrated that autophagy regulates proliferation and biliary differentiation of HOCs via the MAPK/ERK signaling pathway. These results suggest a role for autophagy in stimulating the proliferation and differentiation of HOCs.

Manufacture and property research of heparin grafted electrospinning PCU artificial vascular scaffolds.

PCU (polycarbonate polyurethane) is supposed to be an ideal elastomer for manufacturing artificial vessel scaffold with perfect mechanical strength and biocompatibility. Surface grafting by heparin sodium can increase its anticoagulant hemorrhagic, achieving a better application in artificial vessels. Artificial vessels were preliminarily prepared by electrostatic spinning, treated by NH3 plasma and cross-linked with the anticoagulant heparin sodium chemically. Performances of the PCU-Hep (heparin sodium grafted purethane artificial vessels) artificial vessel were calculated through the physical and chemical property tests, evaluation of blood and biocompatibility. Results manifested that heparin sodium was successfully grafted to the vascular surface, porosity, pore diameter and water permeability of the vascular prosthesis fitted the requirements of artificial vessels, the blood test results demonstrated that the vascular material had a low hemolysis, in vitro cytotoxicity experiment and animal experiments proved an excellent biocompatibility. Thus the heparin sodium grafted electrospinning vessels could reduce intravascular thrombus and had potential clinical application.