Syndecan-2 cytoplasmic domain regulates colon cancer cell migration via interaction with syntenin-1

The cell surface heparan sulfate proteoglycan, syndecan-2, is crucial for the tumorigenic activity of colon cancer cells. However, the role played by the cytoplasmic domain of the protein remains unclear. Using colon cancer cells transfected with various syndecan-2-encoding genes with deletions in the cytoplasmic domain, it was shown that syndecan-2-induced migration activity requires the EFYA sequence of the C-terminal region; deletion of these residues abolished the rise in cell migration seen when the wild-type gene was transfected and syndecan-2 interaction with syntenin-1, suggesting that syntenin-1 functioned as a cytosolic signal effector downstream from syndecan-2. Colon cancer cells transfected with the syntenin-1 gene showed increased migratory activity, whereas migration was decreased in cells in which syntenin-1 was knock-down using small inhibitory RNA. In addition, syntenin-1 expression potentiated colon cancer cell migration induced by syndecan-2, and syndecan-2-mediated cell migration was reduced when syntenin-1 expression diminished. However, syntenin-1-mediated migration enhancement was not noted in colon cancer cells transfected with a gene encoding a syndecan-2 mutant lacking the cytoplasmic domain. Furthermore, in line with the increase in cell migration, syntenin-1 mediated Rac activation stimulated by syndecan-2. Together, the data suggest that the cytoplasmic domain of syndecan-2 regulates colon cancer cell migration via interaction with syntenin-1.     

Evidences for correlation between the reduced VCAM-1 expression and hyaluronan synthesis during cellular senescence of human mesenchymal stem cells

Mesenchymal stem cells (MSCs) undergo cellular senescence during in vitro expansion culture, which accompanies the loss of migration and homing abilities. In this study, we analyzed expression levels of several surface markers of human MSCs at different passages of expansion culture. It has been shown that expression of vascular cell adhesion molecule-1 (VCAM-1) was most markedly decreased among the tested markers in the senescent MSCs. Interestingly the reduced VCAM-1 expression could be restored by applying hyaluronan, a major glycosaminoglycan ligand of CD44, to the culture. It was found that the hyaluronan level in extracellular and pericellular matrices was greatly reduced in the senescent MSCs, mainly due to the decreased expression of hyaluronan synthases, suggesting a correlation between the reduced VCAM-1 expression and hyaluronan synthesis. In fact, when hyaluronan synthases were knock-downed by siRNA transfection, the VCAM-1 expression was also reduced. Our results indicate that VCAM-1 expression in the senescent MSCs was down-regulated because of the reduced synthesis of hyaluronan. Thus, we suggest that hyaluronan supplementation in expansion culture of MSCs would compensate adverse effects induced by its decreased synthesis and subsequently enhance cell adhesion and migration abilities.     

Chiral lipidomics of E-series resolvins: aspirin and the biosynthesis of novel mediators

Control of the inflammatory response is of wide interest given its important role in many diseases. In recent years we identified novel mechanisms and lipid mediators that play an active role in stimulating the resolution of self-limited acute inflammation. These novel pro-resolving mediators include the essential fatty acid-derived lipoxins, resolvins, protectins and maresins. Members of each possess a unique pro-resolving mechanism of action; each limits neutrophilic infiltration, regulates local mediators (chemokines, cytokines) as well as stimulates macrophage-enhanced clearance of apoptotic PMN, cellular debris and microbes. Given this unique mechanism of action, resolvins have already been shown to play pivotal roles in regulating key events in a wide range of experimental inflammatory diseases. These pro-resolving mediators also provide a molecular link between omega-3 essential fatty acids (e.g. EPA, DHA) and the resolution process of inflammation and tissue homeostasis. Here, we review recent evidence obtained using chiral LC-MS-MS-based lipidomics to identify a novel 18S-series of resolvins derived from EPA. Resolvin E1 possesses potent actions in vivo and in vitro demonstrated now in many laboratories, and herein we review comparisons in E-series resolvin biosynthesis and action of 18S-resolvin E1 and 18S-resolvin E2. The biosynthesis and formation of both 18S and 18R-series are enhanced with aspirin treatment and involve the utilization of dietary EPA as well as recombinant human 5-lipoxygenase and LTA(4) hydrolase in their stereospecific biosynthesis. Herein we also demonstrate the utility of LC-MS-MS-based lipidomics in identifying resolvins, protectins and related products in marine organisms such as Engraulis (Peruvian anchovy). These new findings emphasize the utility of chiral LC-MS-MS lipidomics and the potential for identifying new resolution circuits with chiral LC-MS-MS-based lipidomics and metabolomics.     

Genome sequence of strain IMCC3088, a proteorhodopsin-containing marine bacterium belonging to the OM60/NOR5 clade

Strain IMCC3088, cultivated from the Yellow Sea, is a novel isolate belonging to the OM60/NOR5 clade and is closely related to clone OM241, Congregibacter litoralis, and strain HTCC2080. Here, the genome sequence of strain IMCC3088 is presented, showing the absence of photosynthetic gene clusters and the presence of proteorhodopsin.     

Whole-genome sequence of the xylanase-producing Mesoflavibacter zeaxanthinifaciens strain S86

We isolated Mesoflavibacter zeaxanthinifaciens S86 as xylanase-producing bacteria from seawater sampled in Micronesia. Analysis of the M. zeaxanthinifaciens genome revealed that it contains a single circular chromosome of 3,704,661 bp with 3,249 putative open reading frames.     

Cigarette smoke induces Akt protein degradation by the ubiquitin-proteasome system

Emphysema is one of the characteristic features of chronic obstructive pulmonary disease, which is caused mainly by cigarette smoking. Recent data have suggested that apoptosis and cell cycle arrest may contribute to the development of emphysema. In this study, we addressed the question of whether and how cigarette smoke affected Akt, which plays a critical role in cell survival and proliferation. In normal human lung fibroblasts, cigarette smoke extract (CSE) caused cell death, accompanying degradation of total and phosphorylated Akt (p-Akt), which was inhibited by MG132. CSE exposure resulted in preferential ubiquitination of the active Akt (myristoylated), rather than the inactive (T308A/S473A double mutant) Akt. Consistent with cytotoxicity, CSE induced a progressive decrease of phosphorylated human homolog of mouse double minute homolog 2 (p-HDM2) and phosphorylated apoptosis signal regulating kinase 1 (p-ASK1) with concomitant elevation of p53, p21, and phosphorylated p38 MAPK. Forced expression of the active Akt reduced both CSE-induced cytotoxicity and alteration in HDM2/p53/p21 and ASK1/p38 MAPK, compared with the inactive Akt. Of note, CSE induced expression of the tetratrico-peptide repeat domain 3 (TTC3), known as a ubiquitin ligase for active Akt. TTC3 siRNAs suppressed not only CSE-induced Akt degradation but also CSE-induced cytotoxicity. Accordingly, rat lungs exposed to cigarette smoke for 3 months showed elevated TTC3 expression and reduced Akt and p-Akt. Taken together, these data suggest that cigarette smoke induces cytotoxicity, partly through Akt degradation via the ubiquitin-proteasome system, in which TTC3 acts as a ubiquitin ligase for active Akt.     

HZE ⁵⁶Fe-ion irradiation induces endothelial dysfunction in rat aorta: role of xanthine oxidase

Ionizing radiation has been implicated in the development of significant cardiovascular complications. Since radiation exposure is associated with space exploration, astronauts are potentially at increased risk of accelerated cardiovascular disease. This study investigated the effect of high atomic number, high-energy (HZE) iron-ion radiation on vascular and endothelial function as a model of space radiation. Rats were exposed to a single whole-body dose of iron-ion radiation at doses of 0, 0.5 or 1 Gy. In vivo aortic stiffness and ex vivo aortic tension responses were measured 6 and 8 months after exposure as indicators of chronic vascular injury. Rats exposed to 1 Gy iron ions demonstrated significantly increased aortic stiffness, as measured by pulse wave velocity. Aortic rings from irradiated rats exhibited impaired endothelial-dependent relaxation consistent with endothelial dysfunction. Acute xanthine oxidase (XO) inhibition or reactive oxygen species (ROS) scavenging restored endothelial-dependent responses to normal. In addition, XO activity was significantly elevated in rat aorta 4 months after whole-body irradiation. Furthermore, XO inhibition, initiated immediately after radiation exposure and continued until euthanasia, completely inhibited radiation-dependent XO activation. ROS production was elevated after 1 Gy irradiation while production of nitric oxide (NO) was significantly impaired. XO inhibition restored NO and ROS production. Finally, dietary XO inhibition preserved normal endothelial function and vascular stiffness after radiation exposure. These results demonstrate that radiation induced XO-dependent ROS production and nitroso-redox imbalance, leading to chronic vascular dysfunction. As a result, XO is a potential target for radioprotection. Enhancing the understanding of vascular radiation injury could lead to the development of effective methods to ameliorate radiation-induced vascular damage.