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IntroductionAngiogenesis, the formation of new blood vessels from a preexisting vascular bed, is a pivotal process not only in embryonic development but also in the progression of a variety of pathologic conditions. 1 A large number of molecules, which are composed of growth factors, cytokines, and lipid metabolites, are shown to be involved in pathophysiologic neovascularization by stimulating endothelial cells (ECs) directly or indirectly. 2 Some of these factors, including VEGF, often possess their abilities to increase vascular permeability and thus contribute to deteriorating tissue damage.Receptor activator of nuclear factor (NF)-B ligand (RANKL), also known as ODF, TRANCE, and OPGL, has well-understood roles in the skeletal and immune systems in which it induces osteoclast differentiation from hematopoietic precursors and regulates the function and survival of dendritic cells. 3 Recently, interest has grown in its physiologic and pathologic relevance to vascular biology. 4 Mounting evidence suggests that RANKL and its decoy receptor, osteoprotegrin (OPG), participate in multiple aspects of vascular calcification; for example, mice lacking OPG suffer late medial calcification of the renal and aortic arteries in addition to early onset osteoporosis. [5][6][7] Moreover, a role for the OPG/RANKL/ RANK axis in atherogenesis and plaque destabilization has been recently reported. 8 OPG inactivation accelerates advanced atherosclerotic lesion progression and calcification in older ApoE Ϫ/Ϫ mice. 9 TRANCE is strongly expressed in vascular cells in vitro, as well as in vivo. OPG and it are induced by inflammatory cytokines in human ECs, although with different temporal profiles. 10 In vivo, RANKL is present in the small blood vessels of the skin and in arterial smooth muscle cells, 11 and it appears to be up-regulated in atherosclerotic lesions, calcified vessels, and valves. 4,6,9 Moreover, the RANKL receptor, RANK, is also expressed in ECs of the rat coronary artery and developing blood vessels of the rat embryo in vivo, as well as in freshly isolated human umbilical vein ECs (HUVECs). 12 In agreement with these patterns of expression, RANKL stimulates the survival of cultured ECs and their production of inflammatory cell adhesion molecules; it also promotes in vitro angiogenesis by the ECs and elicits neoangiogenesis in animal models. 13 Moreover, VEGF increases RANK mRNA and protein in ECs, augmenting their angiogenic response to RANKL. 12 Therefore, the RANKL/RANK/OPG system is believed to be an important link between the vascular, skeletal, and immune systems.Endothelium-derived nitric oxide (NO), originally identified as endothelium-derived relaxing factor, promotes angiogenesis and plays an important role in vascular remodeling and the maintenance of vascular integrity. 14,15 In ECs, NO is a product of the An Inside Blood analysis of this article appears at the front of this issue.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact,...

Glioblastomas (GBMs) are very aggressive tumors with low chemosensitivity. The DNA-alkylating agent temozolomide (TMZ) is currently the most efficient chemotoxic drug for GBM therapy; however, many patients develop resistance to TMZ. Combining TMZ with another agent could present an improved treatment option if it could overcome TMZ resistance and avoid side effects. Sphingosine kinase inhibitors (SKIs) have emerged as anticancer agents. Sphingosine kinases are often overexpressed in tumors where their activity of phosphorylating sphingosine (Sph) contributes to tumor growth and migration. They control the levels of the pro-apoptotic ceramide (Cer) and Sph and of the pro-survival sphingosine-1 phosphate. In the present work, TMZ was combined with a specific SKI, and the cytotoxic effect of each drug alone or in combination was tested on GBM cell lines. The combination of sublethal doses of both agents resulted in the cell death potentiation of GBM cell lines without affecting astrocyte viability. It triggered a caspase-3-dependent cell death that was preceded by accumulation of dihydrosphingosine (dhSph) and dihydroceramide (dhCer), oxidative stress, endoplasmic reticulum stress, and autophagy. Autophagy was identified as the crucial switch that facilitated induction of this cell death potentiation. The sublethal dose of the inhibitor induced these stress events, whereas that of TMZ induced the destructive autophagy switch. Remarkably, neither Cer nor Sph, but rather the Cer intermediates, dhSph and dhCer, was involved in the cytotoxicity from the combination. Cell lines sensitive to the combination expressed low levels of the antioxidant enzyme glutathione peroxidase-1, indicating this enzyme as a potential marker of sensitivity to such treatment. This work shows for the first time a strong interaction between a SKI and TMZ, leading to a tumor cell-specific death induction. It further demonstrates the biological relevance of dihydrosphingolipids in cell death mechanisms and emphasizes the potential of drugs that affect sphingolipid metabolism for cancer therapy.

The reliable predictions of liquid holdup and pressure drop are essential for pipeline design in oil and gas industry. In this study, the drift-flux approach is utilized to calculate liquid holdups. This approach has been widely used in formulation of the basic equations for multiphase flow in pipelines. Most of the drift-flux models have been developed on an empirical basis from the experimental data. Even though, previous studies showed that these models can be applied to different flow pattern and pipe inclination, when the distribution parameter is flow pattern dependent. They are limited to a set of fluid properties, pipe geometries and operational conditions. The objective of this study is to develop a new drift-flux closure relationship for prediction of liquid holdups in pipes that can be easily applied to a wide range of flow conditions. The developed correlation is compared with nine available correlations from literatures, and validated using the TUFFP (Fluid Flow Projects of University of Tulsa) experimental datasets and OLGA (OiL and GAs simulator supplied by SPTgroup) steady-state synthetic data generated by OLGA Multiphase Toolkit. The developed correlation performs better in predicting liquid holdups than the available correlations for a wide range of flow conditions.

Ischemia-reperfusion injury is a phenomenon that occurs when tissues are subjected to ischemia for a variable period of time, and then reperfused. Inflammatory reaction has been implicated as one of the most important mechanism of ischemia-reperfusion injury. The purpose of this study was to evaluate the anti-inflammatory effects of anthocyanins from black soybean seed coat on keratinocytes in vitro and ischemia-reperfusion injury in vivo. We investigated the inhibition, by anthocyanins, of the expression of various inflammatory genes associated with ischemia-reperfusion injury in the tumor necrosis factor-alpha-treated (TNF-α) immortalized epidermal keratinocyte cell line (HaCaT). We also investigated the effects of anthocyanins on the survival of skin flaps after ischemia-reperfusion injury in the rats. According to Western blot analysis and a luciferase activity assay, anthocyanins inhibited TNF-α-induced intercellular adhesion molecule-1 and cyclooxygenase-2 (COX-2) levels through the NF-κB-dependent pathway. Administration of anthocyanins (50 and 100 mg/kg) significantly improved the flap area survival in the 10-hour ischemic model from 62% to 74.5% and 83%, respectively (P = 0.001). The related cytokines in skin flap also changed as the same pattern as in vitro. Our results indicate that anthocyanins from black soybean seed coat had anti-inflammatory effects on the HaCaT cell line and increase the survival of skin flaps through anti-inflammatory properties against ischemia-reperfusion injury.

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Therapeutic, IV.

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