Stromal cell-derived factor-1 (SDF-1) enhances cells invasion by αvß6 integrin-mediated signaling in ovarian cancer.

Ovarian carcinoma is a common gynecological malignancy and a great threat to health as a result of metastasis. The chemokine stromal-derived factor (SDF-1) plays multiple roles in tumor pathogenesis. However, the precise molecular mechanism underlying SDF-1-induced ovarian cancer cell invasion is still undefined. αvß6 integrin is an important factor in tumor progression. Therefore, we speculate that SDF-1-enhanced ovarian cancer cell invasion is related to αvß6 integrin-mediated signaling. After culturing with SDF-1, an obvious time- and dose-dependent increase in αvß6 integrin was demonstrated. Furthermore, CXC receptor 4 (CXCR4) was responsible for SDF-1-induced αvß6 integrin expression. Simultaneously, SDF-1 was found to dramatically enhance extracellular matrix degradation via urokinase-type plasminogen activator (uPA) expression and cell invasion by αvß6 integrin expression; these reinforce failed to be increased when pretreatment was performed with the CXCR4 inhibitor AMD3100 or anti-αvß6 integrin antibody, respectively. In addition, αvß6 integrin induced the phosphorylation of p38 MAPK and PI3 K/Akt, contributing to the up-regulation of uPA, as treatment with the specific inhibitor for p38 mitogen-activated protein kinases (MAPK) (SB203580) or phosphatidylinositol 3-kinase (PI3 K)/Akt (LY294002) strikingly abrogated uPA expression. Taken together, these results demonstrated that SDF-1 enhanced ovarian cancer cell invasion through αvß6 integrin-mediated uPA expression via the p38 MAPK and PI3 K/Akt pathway. Consequently, our findings will provide a new explanation about how SDF-1 aggravates the pathogenesis of ovarian cancer.

DRD4 (Dopamine D4 Receptor) Mitigate Abdominal Aortic Aneurysm via Decreasing P38 MAPK (mitogen-activated protein kinase)/NOX4 (NADPH Oxidase 4) Axis-Associated Oxidative Stress.

[Figure: see text].

Tempol prevents isoprenaline-induced takotsubo syndrome via the reactive oxygen species/mitochondrial/anti-apoptosis /p38 MAPK pathway.

Takotsubo Syndrome (TS) is a kind of acute cardiac syndrome with a complex pathophysiological mechanism that remains to be elucidated. The relationship between TS and reactive oxygen species has received increasing attention over in recent years. Therefore, the relationship between TS and reactive oxygen species was investigated in vivo and in vitro. Isoprenaline (ISO) was used to induce TS and tempol (quercetin) was selected as a scavenger to eliminate reactive oxygen species in animal experiments, and echocardiography was used to determine the incidence of TS. The H9C2 cells were cultured with different reagents to investigate the detailed mechanism; Reactive oxygen species levels and mitochondrial function were evaluated. Cell apoptosis rate was analyzed by TUNEL staining and the proteins involved in the signaling pathways were examined by Western blotting. It was found that a high dose of tempol almost eliminated TS and protected the cardiac function. Moreover, tempol also decreased the reactive oxygen species levels and reduced lipid droplet deposition in myocardial tissue. In terms of the cultured cells, tempol preconditioning decreased reactive oxygen species production as well as lipid droplet deposition, and protected the mitochondrial function by reducing mitochondrial swelling, thereby maintaining the mitochondrial membrane potential (ΔΨm) at a level that was higher than that of controls. Furthermore, tempol could reduce cells apoptosis after ISO treatment and decrease the protein level of p38, which is a member of the MAPK family, which and thus plays an important role in regulating cells apoptosis. This antiapoptotic effect of tempol was similar to that of a control reagent, SB203580, which is a specific inhibitor of phospha-p38 (p-p38). This study demonstrated, for the first time, a sudden increase in reactive oxygen species and effects of the downstream cascades play core roles in the development of TS.

DRD4 Mitigates Myocardial Ischemia/Reperfusion Injury in Association With PI3K/AKT Mediated Glucose Metabolism.

Ischemia-reperfusion (I/R) could cause heart irreversible damage, which is tightly combined with glucose metabolism disorder. It is demonstrated that GLUT4 (glucose transporter 4) translocation is critical for glucose metabolism in the cardiomyocytes under I/R injury. Moreover, DRD4 (dopamine receptor D4) modulate glucose metabolism, and protect neurocytes from anoxia/reoxygenation (A/R) injury. Thus, DRD4 might regulate myocardial I/R injury in association with GLUT4-mediated glucose metabolism. However, the effects and mechanisms are largely unknown. In the present study, the effect of DRD4 in heart I/R injury were studied ex vivo and in vitro. For I/R injury ex vivo, DRD4 agonist (PD168077) was perfused by Langendorff system in the isolated rat heart. DRD4 activated by PD168077 improved cardiac function in the I/R-injured heart as determined by the left ventricular developed pressure (LVDP), +dp/dt, and left ventricular end diastolic pressure (LVEDP), and reduced heart damage evidenced by infarct size, the release of troponin T (TNT) and lactate dehydrogenase (LDH). DRD4 activation diminished I/R injury induced apoptosis and enhanced cell viability impaired by I/R injury in cardiomyocyte, showed by TUNEL staining, flow cytometer and CCK8 assay. Furthermore, DRD4 activation did not change total GULT4 protein expression level but increased the membrane GULT4 localization determined by western blot. In terms of mechanism, DRD4 activation increased pPI3K/p-AKT but not the total PI3K/AKT during anoxia/reoxygenation (A/R) injury in vitro. Interestingly, PI3K inhibitor, Wortmannin, blocked PI3K/AKT pathway and depleted the membrane GULT4, and further promoted apoptosis showed by TUNEL staining, flow cytometer, western blot of cleaved caspase 3, BAX and BCL2 expression. Thus, DRD4 activation exerted a protective effect against I/R injury by promoting GLUT4 translocation depended on PI3K/AKT pathway, which enhanced the ability of glucose uptake, and ultimately reduced the apoptosis in cardiomyocytes.

The cardioprotective effects of icariin on the isoprenaline-induced takotsubo-like rat model: Involvement of reactive oxygen species and the TLR4/NF-κB signaling pathway.

INTRODUCTION: Takotsubo syndrome (TS) is an acute cardiac syndrome that mimics acute coronary syndrome (ACS) but lacks coronary obstruction and is associated with sudden physical or psychiatric episodes. Several hypotheses have been proposed for the TS mechanism, but the precise cause of this syndrome remains poorly known. Recent studies noted TS patients with acute endogenous catecholamine discharge, which could trigger an oxidative stress response and inflammatory action. METHODS: A single dose of the selective ß-adrenergic agonist isoprenaline (ISO) was used to induce a takotsubo-like (TS-like) model. Different icariin or metoprolol doses were supplied as cardioprotective agents by intragastric administration (IG), and lipopolysaccharides (LPS) were assessed to investigate the possible mechanism of action of icariin. Transthoracic echocardiography was used to study cardiac function and morphology. The amounts of intracellular lipids and myocardial fibrosis, which represent the degree of cardiac impairment, were assessed by histological analysis. Real-time polymerase chain reaction (RT-PCR) was performed to analyze a variety of anti-oxidant elements and inflammatory factors, and Western blotting was conducted to analyze the expression of signaling pathway proteins involved in the development of TS. RESULTS: The TS-like incidence in rats was lowest with icariin precondition at 2-h post-ISO administration, and both the left ventricular ejection fraction (LVEF) and ejection volume per minute were higher than those of the other groups. However, LPS administration increased the incidence of TS and aggravated cardiac impairment. Moreover, ISO significantly increased the levels of both reactive oxygen species (ROS) and TLR4/NF-κB signaling pathway proteins compared to those of the Sha-group, whereas icariin remarkably decreased the ROS levels and increased anti-oxidant element expression while reducing pro-inflammatory factor secretion and suppressing TLR4/NF-κB signaling pathway protein expression. However, the cardioprotective effect of icariin was significantly weakened by combining treatment with LPS. CONCLUSION: Icariin prevented ISO-induced TS-like cardiac dysfunction in rats. The effects were induced mainly through maintenance of the dynamic balance of the ROS system, promotion of anti-oxidant element activity, and suppression of TLR4/NF-κB signaling pathway protein expression. Furthermore, the ability of icariin to increase anti-inflammatory and reduce pro-inflammatory factor secretion may be involved in the protective process.