Contraction stimulates skeletal muscle glucose uptake predominantly through activation of AMP-activated protein kinase (AMPK) and Rac1. However, the molecular details of how contraction activates these signaling proteins are not clear. Recently, Axin1 has been shown to form a complex with AMPK and liver kinase B1 during glucose starvation-dependent activation of AMPK. Here, we demonstrate that electrical pulse-stimulated (EPS) contraction of C2C12 myotubes or treadmill exercise of C57BL/6 mice enhanced reciprocal coimmunoprecipitation of Axin1 and AMPK from myotube lysates or gastrocnemius muscle tissue. Interestingly, EPS or exercise upregulated total cellular Axin1 levels in an AMPK-dependent manner in C2C12 myotubes and gastrocnemius mouse muscle, respectively. Also, direct activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleotide treatment of C2C12 myotubes or gastrocnemius muscle elevated Axin1 protein levels. On the other hand, siRNA-mediated Axin1 knockdown lessened activation of AMPK in contracted myotubes. Further, AMPK inhibition with compound C or siRNA-mediated knockdown of AMPK or Axin1 blocked contraction-induced GTP loading of Rac1, p21-activated kinase phosphorylation, and contraction-stimulated glucose uptake. In summary, our results suggest that an AMPK/Axin1-Rac1 signaling pathway mediates contraction-stimulated skeletal muscle glucose uptake.

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Glioma is the most aggressive and malignant type of primary intracranial tumor. In recent decades, despite the rapid development of modern surgery and therapeutic strategies available for brain tumors, the prognosis of glioma remains poor and the median survival time is <15 months. In this study, we found that the levels of miRNA-320a were significantly decreased in patients with glioma, and that elevated miRNA-320a expression was associated with a better prognosis. In addition, aquaporin 4 (AQP4) was identified as a direct target of miRNA-320a. Overexpression of miRNA-320a led to the inhibition of cell invasion and migration via targeting of AQP4. Therefore, our results suggested that miRNA-320a could suppress the aggressive capacity of tumors by targeting AQP4, and that miRNA-320a could serve as a new effective therapeutic target for glioma surgical and therapeutic strategies.

Thrombosis and inflammation are two major factors underlying chronic thromboembolic pulmonary hypertension (CTEPH). Tissue factor (TF), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein 1 (MCP-1) may play critical roles in the process of CTEPH thrombosis and pulmonary vascular remodeling. Ten patients with a confirmed diagnosis of CTEPH, 20 patients with acute pulmonary thromboembolism and 15 patients with other types of pulmonary hypertension were enrolled in this study, along with 20 healthy subjects as the control group. The immunoturbidimetric method was used to determine the plasma content of CRP. The plasma levels of TNF-α, MCP-1, and TF antigen were measured by an enzyme-linked immunosorbent assay, and TF activity was measured by the chromogenic substrate method. Percoll density gradient centrifugation was used to separate peripheral blood mononuclear cells from plasma. The level of monocyte TF mRNA was examined by reverse transcriptase-polymerase chain reaction. The correlations between all indices described above were analyzed. In CTEPH patients, the expression of CRP, TNF-α, and MCP-1 was significantly higher than that in controls (P < 0.05). The levels of TF activity, TF antigen, and TF mRNA in monocyte cells were increased in CTEPH patients when compared with control subjects, but only the TF antigen and TF mRNA levels were significantly different (P < 0.05). In CTEPH patients, levels of CRP, MCP-1, and TNF-α significantly correlated with the level of TF antigen in plasma. TF gene expression was increased in patients with CTEPH, suggesting that blood-borne TF mainly comes from mononuclear cells. TF expression significantly correlated with levels of CRP, TNF-α and MCP-1. These factors may play an important role in the development of CTEPH via the inflammation–coagulation–thrombosis cycle.

BackgroundMyeloperoxidase (MPO) anti-neutrophil cytoplasm autoantibody (ANCA)-associated vasculitis commonly causes life-threatening pulmonary alveolar hemorrhage or fibrosis. Only a limited number of candidate gene variants have been explored, but hitherto, are not widely confirmed. In the present study, we investigated the importance of energy homeostasis associated gene (Enho) mutations and adropin deficiency in the development of MPO-ANCA associated lung injury.MethodsWe analyzed the peripheral blood mononuclear cells from 152 unrelated patients and 220 population-matched healthy individuals for genetic variations in Enho. Functional studies with adropin knockout (AdrKO) on C57BL/6J mice were also performed.FindingsSequencing revealed six patients with p.Ser43Thr and that five patients shared Cys56Trp amino acid substitution in Enho. Serum concentration of adropin was significantly lower in patients than that of the healthy subjects (P < 0.0001), especially those with Enho mutations. In vivo, homo- and heterozygous carriers of the null adropin allele exhibited MPO-ANCA associated pulmonary alveolar hemorrhage as compared to wild-type mice. AdrKO mice exhibit reduced eNOS (Ser1177) and Akt1 (Ser473) phosphorylation and loss of Treg cells.InterpretationOur findings indicate that the presence of Enho mutations or adropin-deficiency is a probable molecular basis for the initial events triggered in MPO-ANCA associated lung injury.

Ubiquinol cytochrome c reductase hinge (UQCRH) is a novel protein that localizes in the mitochondrial membrane and induces mitochondrial reactive oxygen species (ROS) generation. It had a high expression rate of 87.10% (108/124) in lung adenocarcinoma. Moreover, serum UQCRH level in patients with lung adenocarcinoma was significantly increased compared with that of pneumonia patients (p < 0.0001) and normal control subjects (p < 0.0001). Receiver operating characteristic curve analysis using an optimal cut-off value of 162.65 pg ml−1 revealed sensitivity and specificity for the diagnosis of lung adenocarcinoma of 88.7% and 85.7%, respectively, with an area under the curve of 0.927 (95% CI: 0.892 to 0.962, p < 0.0001). Serum UQCRH discriminates lung adenocarcinoma patients from the population without cancer with considerable sensitivity and specificity, but it does not distinguish between heavy smokers and lung adenocarcinoma patients. Serum UQCRH could be a potential diagnostic biomarker for lung adenocarcinoma.

Long noncoding RNA (lncRNA) maternal-expressed gene 3 (MEG3) is associated with proliferation of various tumor cells and has decreased expression in many types of cancers. In this study, we aimed at demonstrating the association between MEG3 polymorphisms and the risk of lung cancer in northeast China. There were 526 lung cancer patients and 526 healthy controls included in this hospital-based case-control study. The genotyping of two polymorphisms, rs7158663 G > A and rs4081134 G>A, was performed by the Taqman allelic discrimination method. We found that MEG3 rs4081134-AA may be associated with the risk of lung cancer (AA vs. GG: adjusted odds ratio [OR] = 0.487, confidence interval [95% CI] = 0.257-0.897, p = 0.030; AA vs. AG+GG: adjusted OR = 0.522, 95% CI = 0.274-0.992, p = 0.047). Similar associations in several subgroups were found in subsequent stratified analysis. Further, there were no statistically significant interactions of rs4081134 polymorphism and smoking to lung cancer susceptibility. In addition, the associations between the MEG3 rs7158663 polymorphism and lung cancer susceptibility were not found. These results indicate that the MEG3 rs4081134 polymorphism was significantly associated with lung cancer susceptibility in the Chinese population.

Artesunate has several mechanisms for augmenting the antitumor immune responses mediated by γδ T cells. These results suggested artesunate may be an efficacious agent in the treatment of hepatocellular carcinoma.