Protective Effects of Ischemic Postconditioning on Livers in Rats with Limb Ischemia-Reperfusion via Glycogen Synthase Kinase 3 beta (GSK-3ß)/Fyn/Nuclear Receptor-Erythroid-2-Related Factor (Nrf2) Pathway.

BACKGROUND Ischemia/reperfusion (I/R) injury not only exists in ischemic tissues and organs, but also can cause damage to distant tissues and organs. As the largest metabolic organ of the human body, the liver is very vulnerable to injury after limb I/R. However, the mechanism of liver injury caused by limb I/R injury has not been fully elucidated. This study investigated the effect and mechanism of ischemic postconditioning (IPO) on the liver after hindlimb I/R in rats. MATERIAL AND METHODS A rat model of hindlimb I/R was established and treated by IPO. Liver function, changes of oxidative stress index and inflammation, Bcl-2 and Bax proteins, and apoptosis were assessed. The structural changes were observed by electron microscopy. GSK-3ß/Fyn/Nrf2 levels were detected by quantitative PCR and Western blot. RESULTS IPO significantly reduced serum AST, ALP, LDH, and ALT levels induced by I/R. Compared with the I/R group, the levels of SOD, GSH-Px, and CAT in the IPO group were significantly increased, while the levels of MDA, MPO, and ROS were significantly decreased. The IPO group had significantly higher Bcl-2 level and significantly lower Bax level compared to the I/R group. Consistently, IPO decreased the apoptosis rate induced by I/R. Furthermore, IPO lowered the levels of TNF-alpha, IL-1ß, IL-10, and INF-γ and alleviated the ultrastructural changes of hepatocytes. Finally, Nrf2, Fyn, and GSK-3ß mRNA and protein levels in the IPO group were significantly higher than in the I/R group. CONCLUSIONS IPO protects against liver injury caused by I/R injury of the hindlimb, possibly via the GSK-3ß/Fyn/Nrf2 pathway.

A novel DNA methylation-based model that effectively predicts prognosis in hepatocellular carcinoma.

PURPOSE: To build a novel predictive model for hepatocellular carcinoma (HCC) patients based on DNA methylation data. METHODS: Four independent DNA methylation datasets for HCC were used to screen for common differentially methylated genes (CDMGs). Gene Ontology (GO) enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to explore the biological roles of CDMGs in HCC. Univariate Cox analysis and least absolute shrinkage and selection operator (LASSO) Cox analysis were performed to identify survival-related CDMGs (SR-CDMGs) and to build a predictive model. The importance of this model was assessed using Cox regression analysis, propensity score-matched (PSM) analysis and stratification analysis. A validation group from the Cancer Genome Atlas (TCGA) was constructed to further validate the model. RESULTS: Four SR-CDMGs were identified and used to build the predictive model. The risk score of this model was calculated as follows: risk score = (0.01489826 × methylation level of WDR69) + (0.15868618 × methylation level of HOXB4) + (0.16674959 × methylation level of CDKL2) + (0.16689301 × methylation level of HOXA10). Kaplan-Meier analysis demonstrated that patients in the low-risk group had a significantly longer overall survival (OS; log-rank P-value =0.00071). The Cox model multivariate analysis and PSM analysis identified the risk score as an independent prognostic factor (P<0.05). Stratified analysis results further confirmed this model performed well. By analyzing the validation group, the results of receiver operating characteristic (ROC) curve analysis and survival analysis further validated this model. CONCLUSION: Our DNA methylation-based prognosis predictive model is effective and reliable in predicting prognosis for patients with HCC.

Optimization schemes for endovascular repair with parallel technique based on hemodynamic analyses.

Endovascular repair with parallel stent-grafts (SG) is a challenging technique that reconstructs the luminal flow pathways by implanting parallel-placed SGs into the vessel. After treatment, occlusion and shifting of the parallel SGs are sometimes reported, which could be fatal and difficult to be re-operated. These issues are highly related to the local hemodynamic conditions in the stented region. In this study, a patient case treated by the octopus endograft technique (a head-SG with three limb-SGs) and experienced limb-SG occlusion is studied. 3-D models are established based on computed tomography (CT) angiography datasets pretreatment and posttreatment as well as during follow-ups. Hemodynamic quantities such as pressure drop, wall shear stress-related parameters, and flow division in limb-SGs and visceral arteries are quantitatively investigated. Optimizations on the length of the head-SG and diameter of the limb-SGs are analyzed based on various scenarios. The results indicate that when reconstructing the flow pathways via octopus stenting, it is important to ensure the flow distribution as physiologically required with this new morphology. Position (or length) of the head-SG and diameter of the limb-SGs play an important role in controlling flow division, and high time average wall shear stress (TAWSS) around the head-SG acts as a main factor for graft immigration. This study, by proposing optimization suggestions with hemodynamic analyses for a specific case, implicates that pretreatment SG scenarios may assist in wise selection and placement of the device and thus may improve long-term effectiveness of this kind of challenging endovascular repair techniques.