Establishment of a Systemic Inflammatory Response Syndrome Model and Evaluation of the Efficacy of Umbilical Cord Mesenchymal Stem Cell Transplantation.

Based on the characteristics of modern weapon injury, a repetitive model of traumatic systemic inflammatory response syndrome (SIRS) and an evaluation system were established. The models were treated with GFP-labeled tree shrew umbilical cord mesenchymal stem cells (UCMSCs). Forty out of 50 tree shrews were used to make a unilateral femoral comminuted fracture. Lipopolysaccharide was injected intravenously to create a traumatic SIRS model. The other 10 shrews were used as normal controls. After the model was established for 10 days, 20 tree shrews were injected intravenously with GFP-labeled UCMSCs, and 18 tree shrews were not injected as the model control group. The distribution of GFP-labeled cells in vivo was measured at 2 and 10 days after injection. Twenty days after treatment, the model group, the normal control group, and the treatment group were taken to observe the pathological changes in each tissue, and blood samples were taken for the changes in liver, renal, and heart function. Distribution of GFP-positive cells was observed in all tissues at 2 and 10 days after injection. After treatment, the HE staining results of the treatment group were close to those of the normal group, and the model group had a certain degree of lesions. The results of liver, renal, and heart function tests in the treatment group were returned to normal, and the results in the model group were abnormally increased. UCMSCs have a certain effect on the treatment of traumatic SIRS and provide a new technical solution for modern weapon trauma treatment.

MicroRNA-155 affects oxidative damage through regulating autophagy in endothelial cells.

MicroRNA-155 (miRNA-155) is a typical multifunctional miRNA, which serves a crucial role in the regulation of numerous vessel cells. However, its effects on dysfunctional endothelial cells have not been completely elucidated. In order to investigate the signaling pathway of miRNA-155-induced cell injury, H2O2 was used to establish an oxidative stress cell model, and miR-155 was transfected into H2O2-treated cells. The CCK8 assay was then employed to examine the effect of miR-155 on the cell proliferations of H2O2-treated cells, and the expressions of Microtubule Associated Protein 1 Light Chain 3 (LC3) and Sequestosome 1 (P62) were detected to examine the effect of miR-155 on the autophagy of Human umbilical vein endothelial cells, and then the formation of intracellular autophagosomes was observed. The results indicated that endothelial cell proliferation was promoted, and oxidant-induced injury was decreased when the expression of miR-155 was inhibited. In addition, the results also demonstrated that when the miR-155 inhibitor was used, the expression of LC3 was increased and the expression of P62 was decreased. This suggests that modulated miR-155 can prevent oxidative damage in endothelial cells, by regulating the level of autophagy. Furthermore, the present study also demonstrated that miR-155 regulated autophagy via promotion of the expression of the autophagy-related gene, Autophagy Related 5 (ATG5). In conclusion, the attenuated expression of miR-155 can decrease oxidant-induced injury and promote cell proliferation via upregulating autophagy, which subsequently affects the expression of ATG5. The present study provides a novel insight into microRNAs as potential therapeutics for the treatment of heart disease.

Efficacy and mechanisms underlying the effects of allogeneic umbilical cord mesenchymal stem cell transplantation on acute radiation injury in tree shrews.

Umbilical cord mesenchymal stem cells (UC-MSCs) exert strong immunomodulatory effects and can repair organs. However, their roles in radiation injury remain unclear. We show that in tree shrews with acute radiation injury, injected UC-MSCs significantly improved survival rates, reduced lung inflammation and apoptosis, prevented pulmonary fibrotic processes, recovered hematopoiesis, and increased blood counts. A protein microarray analysis showed that serum levels of the anti-inflammatory cytokines IL-10 and IL-13 and the growth factors BMP-5, BMP-7, HGF, insulin, NT-4, VEGFR3, and SCF were significantly higher, while those of the inflammatory cytokines IL-2, TIMP-2, TNF-α, IFN-γ, IL-1ra, and IL-8 and the fibrosis-related factors PDGF-BB, PDGF-AA, TGF-ß1, IGFBP-2, and IGFBP-4 were significantly lower in UC-MSC-injected animals. A transcriptome analysis of PBMCs showed that the mRNA expression of C1q was upregulated, while that of HLA-DP was downregulated after UC-MSC injection. These results confirm the immunohistochemistry results. eGFP-labeled UC-MSCs were traced in vivo and found in the heart, liver, spleen, lungs, kidneys, thymus, small intestine and bone marrow. Our findings suggest that UC-MSC transplantation may be a novel therapeutic approach for treating acute radiation injury.

CYP3A5 Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Regulating mTORC2/Akt Signaling.

CYP3A5 is a cytochrome P450 protein that functions in the liver metabolism of many carcinogens and cancer drugs. However, it has not been thought to directly affect cancer progression. In this study, we challenge this perspective by demonstrating that CYP3A5 is downregulated in many hepatocellular carcinomas (HCC), where it has an important role as a tumor suppressor that antagonizes the malignant phenotype. CYP3A5 was downregulated in multiple cohorts of human HCC examined. Lower CYP3A5 levels were associated with more aggressive vascular invasion, poor differentiation, shorter time to disease recurrence after treatment, and worse overall patient survival. Mechanistic investigations showed that CYP3A5 overexpression limited MMP2/9 function and suppressed HCC migration and invasion in vitro and in vivo by inhibiting AKT signaling. Notably, AKT phosphorylation at Ser473 was inhibited in CYP3A5-overexpressing HCC cells, an event requiring mTORC2 but not Rictor/mTOR complex formation. CYP3A5-induced ROS accumulation was found to be a critical upstream regulator of mTORC2 activity, consistent with evidence of reduced GSH redox activity in most clinical HCC specimens with reduced metastatic capacity. Taken together, our results defined CYP3A5 as a suppressor of HCC pathogenesis and metastasis with potential utility a prognostic biomarker.

MUC15 inhibits dimerization of EGFR and PI3K-AKT signaling and is associated with aggressive hepatocellular carcinomas in patients.

BACKGROUND & AIMS: Aberrant expression of MUC15 correlates with development of colorectal adenocarcinoma, and MUC15 has been reported to prevent trophoblast invasion of human placenta. However, little is known about the role of MUC15 in pathogenesis of hepatocellular carcinoma (HCC). METHODS: We analyzed HCC samples and matched nontumor liver tissues (controls) collected from 313 patients who underwent hepatectomy in Shanghai, China, from January 2006 through September 2009. Levels of messenger RNAs and proteins were determined by immunohistochemical, quantitative reverse transcription polymerase chain reaction, and immunoblot analyses. Statistical analyses were used to associate levels of MUC15 with tumor features and patient outcomes. RESULTS: Levels of MUC15 messenger RNA and protein were reduced in a greater percentage of HCC samples than control tissues. Tumors with reduced levels of MUC15 were more likely to have aggressive characteristics (eg, high levels of α-fetoprotein, vascular invasion, lack of encapsulation, and poor differentiation) than those with low levels. Patients whose tumors had reduced levels of MUC15 had shorter overall survival times (24 months vs 46 months for patients with tumors with high levels of MUC15) and time to disease recurrence. Stable expression of MUC15 in HCC cell lines (SMMC-7721 and HCC-LM3) reduced their proliferation and invasive features in vitro, and ability to form metastatic tumors in mice. MUC15 reduced transcription of the matrix metalloproteinases 2 and 7 increased expression of tissue inhibitor of metalloproteinase-2, which required phosphoinositide 3-kinase-v-akt murine thymoma viral oncogene homolog signaling. Physical interaction between MUC15 and epidermal growth factor receptor led to its relocation and degradation within early endosomes and was required for inactivation of phosphoinositide 3-kinase-v-akt murine thymoma viral oncogene homolog signaling. CONCLUSIONS: Reduced levels of MUC15 in HCCs are associated with shorter survival times of patients and reduced time to disease recurrence. Expression of MUC15 in HCC cells reduces their aggressive behavior in vitro and in mice by inducing dimerization of epidermal growth factor receptor and decreasing phosphoinositide 3-kinase signaling via v-akt murine thymoma viral oncogene homolog.