Exosome-mediated transfer of miR-1260b promotes cell invasion through Wnt/ß-catenin signaling pathway in lung adenocarcinoma.

Increasing evidence confirms that exosome-mediated transfer of microRNAs can influence cancer progression including tumor cell invasion, cell proliferation, and drug resistance via cell-cell communication. However, the potential role of exosomal-miR-1260b in lung adenocarcinoma (LAC) remains poorly understood. Thus, this study focused on investigating the function of exosomal-miR-1260b on cell invasion. Exosomal-miR-1260b was found to be higher in plasma of patients with LAC than that of healthy persons via quantitative real-time polymerase chain reaction assay. The sensitivity and specificity of exosomal-miR-1260b (cutoff point: 2.027) were 72% and 86%, and area under the curve of 0.845 (95% CI = 0.772-0.922). Elevated expression of miR-1260b in LAC tissues was positively correlated with exosomal-miR-1260b in plasma (r = .642, p < .05). Furthermore, ceramide biosynthesis regulated exosomal-miR-1260b secretion. Exosome-mediated transfer of miR-1260b promoted A549 cell invasion and was still functional inside A549 cells. Moreover, exosomal-miR-1260b regulated Wnt/ß-catenin signaling pathway by inhibiting sFRP1 and Smad4. This study identified a new regulation mechanism involving in cell invasion by exosome-mediated tumor-cell-to-tumor-cell communication. Targeting exosome-microRNAs may provide new insights into the diagnosis and treatment of LAC.

S100A8 contributes to postoperative cognitive dysfunction in mice undergoing tibial fracture surgery by activating the TLR4/MyD88 pathway.

Neuro-inflammation plays a key role in the occurrence and development of postoperative cognitive dysfunction (POCD). Although S100A8 and Toll-like receptor 4 (TLR4) have been increasingly recognized to contribute to neuro-inflammation, little is known about the interaction between S100A8 and TLR4/MyD88 signaling in the process of systemic inflammation that leads to neuro-inflammation. Firstly, we demonstrated that C57BL/6 wide-type mice exhibit cognitive deficit 24h after the tibial fracture surgery. Subsequently, increased S100A8 and S100A9 expression was found in the peripheral blood mononuclear cells (PBMCs), spleen, and hippocampus of C57BL/6 wide-type mice within 48h after the surgery. Pre-operative administration of S100A8 antibody significantly inhibited hippocampal microgliosis and improved cognitive function 24h after the surgery. Secondly, we also observed TLR4/MyD88 activation in the PBMCs, spleen, and hippocampus after the surgery. Compared with those in their corresponding wide-type mice, TLR4(-/-) and MyD88(-/-) mice showed lower immunoreactive area of microglia in the hippocampal CA3 region after operation. TLR4 deficiency also led to reduction of CD45(hi)CD11b(+) cells in the brain and better performance in both Y maze and open field test after surgery, suggesting a new regulatory mechanism of TLR4-dependent POCD. At last, the co-location of S100A8 and TLR4 expression in spleen after operation suggested a close relationship between them. On the one hand, S100A8 could induce TLR4 activation of CD11b(+) cells in the blood and hippocampus via intraperitoneal or intracerebroventricular injection. On the other hand, TLR4 deficiency conversely alleviated S100A8 protein-induced hippocampal microgliosis. Furthermore, the increased expression of S100A8 protein in the hippocampus induced by surgery sharply decreased in both TLR4 and MyD88 genetically deficient mice. Taken together, these data suggest that S100A8 exerts pro-inflammatory effect on the occurrence and development of neuro-inflammation and POCD by activating TLR4/MyD88 signaling in the early pathological process of the postoperative stage.

Propofol attenuation of hydrogen peroxide-induced injury in human umbilical vein endothelial cells involves aldose reductase.

Propofol is a widely used intravenous anesthetic agent with antioxidant/antiapoptotic properties. Aldose reductase (AR) has been implicated in oxidative stress and apoptosis in endothelial cells. AR inhibition may protect cells from cardiovascular injury. Although the cytoprotective effect of propofol against hydrogen peroxide (H2O2)-induced injury has been widely studied, there is no information about the effects of propofol on AR. We therefore investigated the effect of propofol on H2O2-mediated injury and on aldose reductase expression. We found that propofol protected HUVECs against H2O2-induced damage and apoptosis and ameliorated AR expression induced by H2O2. Propofol also inhibited H2O2-induced p38 MAPK, JNK and Akt phosphorylation. Epalrestat (an AR inhibitor) or ablation of AR siRNA had a similar effect to propofol. The results suggest that propofol may be a preemptive anesthetic in patients with cardiovascular disease and inhibition of AR might be a new cytoprotective pathway for propofol.

Correction: miR-1260b, mediated by YY1, activates KIT signaling by targeting SOCS6 to regulate cell proliferation and apoptosis in NSCLC.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

miR-1260b, mediated by YY1, activates KIT signaling by targeting SOCS6 to regulate cell proliferation and apoptosis in NSCLC.

Non-small cell lung cancer (NSCLC) is one of the most common aggressive malignancies. miRNAs have been identified as important biomarkers and regulators of NSCLC. However, the functional contributions of miR-1260b to NSCLC cell proliferation and apoptosis have not been studied. In this study, miR-1260b was upregulated in NSCLC plasma, tissues, and cell lines, and its high expression was correlated with tumor size and progression. Functionally, miR-1260b overexpression promoted cell proliferation and cell cycle, conversely inhibited cell apoptosis and senescence. Mechanically, miR-1260b negatively regulated SOCS6 by directly binding to its 3'-UTR. Furthermore, miR-1260b-mediated suppression of SOCS6 activated KIT signaling. Moreover, YY1 was an upstream regulator of miR-1260b. This study is the first to illustrate that miR-1260b, mediated by YY1, activates KIT signaling by targeting SOCS6 to regulate NSCLC cell proliferation and apoptosis, and is a potential biomarker and therapeutic target for NSCLC. In sum, our work provides new insights into the molecular mechanisms of NSCLC involved in cell proliferation and apoptosis.

Propofol attenuates hydrogenperoxide-induced apoptosis in human umbilical vein endothelial cells via multiple signaling pathways.

BACKGROUND: Propofol has been reported to protect vascular endothelial cells against oxidative stress. In this study we investigated its effect on hydrogen peroxide (H2O2)-induced apoptosis of human umbilical vein endothelial cells (HUVECs) and examined the possible signaling pathways. METHODS: HUVECs were pretreated with propofol (1, 5, 25, and 50 µM) for 30 min and then co-incubated with 0.4 mM H2O2 for 4 h. Cell viability was assessed using a Cell Counting Kit-8. Cell apoptosis was analyzed using flow cytometry with annexin V/propidium iodide staining, and evaluated by quantifying caspase-3, Bax, and Bcl-2 expression levels. The expression levels of p38 mitogen activated protein kinase (MAPK), phosphorylated (p)-p38 MAPK, cJun-N-terminal kinases (JNK), phosphorylated (p)-JNK, Akt and phosphorylated Akt [(p)-Akt] (Ser473) were measured by western blotting. RESULTS: H2O2 treatment induced the activation of caspase-3, downregulated Bcl-2 expression, and up-regulated Bax expression, all of which were dose-dependently attenuated by propofol pretreatment. Furthermore, propofol significantly ameliorated H2O2-induced phosphorylation of p38 MAPK, JNK, and Akt in HUVECs. CONCLUSIONS: Propofol can protect HUVECs against H2O2-induced apoptosis via a mechanism that may involve p38 MAPK, JNK, and Akt signaling pathways.

Prophylactic lithium alleviates splenectomy-induced cognitive dysfunction possibly by inhibiting hippocampal TLR4 activation in aged rats.

Though the pathogenesis of postoperative cognitive dysfunction (POCD) remains unclear, evidence is accumulating for a pivotal role of neuroinflammation in the disease process. Advanced age and severe surgical trauma are two main risk factors for POCD. Lithium, a neuroprotective agent, can alleviate peripheral surgery-induced memory impairment in aged rats. The results of in vivo and in vitro experiments also showed that toll like receptor 4 (TLR4) was associated with the occurrence and development of neuroinflammation and POCD. So we hypothesized that inhibition of TLR4 signaling in the hippocampus maybe involved in the protective effects of prophylactic lithium on the occurrence of inflammation and POCD. In the present study, we incubated BV-2 microglia with 1µg/ml lipopolysaccharide (LPS) to mimic neuroinflammation in vitro. We found that pretreatment with 10mM of lithium or 100nM of TLR4 siRNA could inhibit the tumor necrosis factor (TNF)-α and TLR4 mRNA expression induced by LPS in BV-2 microglia. Furthermore, combination of prophylactic lithium and TLR4 siRNA even decreased their mRNA expression to the baseline levels, which showed that TLR4 signaling may be vital in protective effects of prophylactic lithium on neuroinflammation. So we further undergone the in vivo experiment. Then, we firstly demonstrated that prophylactic 2mM/kg of lithium alleviated splenectomy-induced cognitive impairments, decreased splenectomy-associated systemic, central, and hippocampal TNF-α and interleukin (IL)-1ß expression and reduced the increase of CD11b(+) area in hippocampal CA1 region caused by the surgery. Then, we also found that splenectomy merely increased hippocampal TLR2 and TLR4 mRNA levels in aged rats. At last, we confirmed that prophylactic lithium reduced the increased levels of hippocampal TLR4/NF-κB induced by splenectomy. Taken together, these results demonstrate that TLR4 signaling inactivation may contribute to the protective effects of prophylactic lithium on the occurrence of POCD by inhibiting systemic inflammation and especially neuroinflammation.