Search

Angiogenesis is a normal physiological process that also contributes to diabetic retinopathy-related complications and facilitates tumor metastasis by promoting the hematogenic dissemination of malignant cells from solid tumors. Here, we investigated the in vitro, ex vivo, and in vivo anti-angiogenic activity of phloridzin docosahexaenoate (PZ-DHA), a novel ω-3 fatty acid ester of a flavonoid precursor. Human umbilical vein endothelial cells (HUVEC) and human dermal microvascular endothelial cells (HMVEC) treated with a sub-cytotoxic concentration of PZ-DHA to assess in vitro anti-angiogenic activity showed impaired tubule formation on a Matrigel matrix. Ex vivo angiogenesis was measured using rat thoracic aortas, which exhibited reduced vessel sprouting and tubule formation in the presence of PZ-DHA. Female BALB/c mice bearing VEGF165- and basic fibroblast growth factor-containing Matrigel plugs showed a significant reduction in blood vessel development following PZ-DHA treatment. PZ-DHA inhibited HUVEC and HMVEC proliferation, as well as the migration of HUVECs in gap closure and trans-well cell migration assays. PZ-DHA inhibited upstream and downstream components of the Akt pathway and vascular endothelial growth factor (VEGF165)-induced overexpression of small molecular Rho GTPases in HUVECs, suggesting a decrease in actin cytoskeletal-mediated stress fiber formation and migration. Taken together, these findings reveal the potential of combined food biomolecules in PZ-DHA to inhibit angiogenesis. [ABSTRACT FROM AUTHOR]

ABSTRACT Background: Many plant-derived chemicals have been studied for their potential benefits in ailments including inflammation, cancer, neurodegeneration, and cardiovascular disease. The health benefits of phytochemicals are often attributed to [...]

Purpose: Iron is an essential trace element for the inflammatory response to infection. In this study, we determined the effect of the recently developed iron-binding polymer DIBI on the synthesis of inflammatory mediators by RAW 264.7 macrophages and bone marrow-derived macrophages (BMDMs) in response to lipopolysaccharide (LPS) stimulation. Methods: Flow cytometry was used to determine the intracellular labile iron pool, reactive oxygen species production, and cell viability. Cytokine production was measured by quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Nitric oxide synthesis was determined by the Griess assay. Western blotting was used to assess signal transducer and activator of transcription (STAT) phosphorylation. Results: Macrophages cultured in the presence of DIBI exhibited a rapid and significant reduction in their intracellular labile iron pool. DIBI-treated macrophages showed reduced expression of proinflammatory cytokines interferon-β, interleukin (IL)-1β, and IL-6 in response to LPS. In contrast, exposure to DIBI did not affect LPS-induced expression of tumor necrosis factor-α (TNF-α). The inhibitory effect of DIBI on IL-6 synthesis by LPS-stimulated macrophages was lost when exogenous iron in the form of ferric citrate was added to culture, confirming the selectivity of DIBI for iron. DIBI-treated macrophages showed reduced production of reactive oxygen species and nitric oxide following LPS stimulation. DIBI-treated macrophages also showed a reduction in cytokine-induced activation of STAT 1 and 3, which potentiate LPS-induced inflammatory responses. Conclusion: DIBI-mediated iron withdrawal may be able to blunt the excessive inflammatory response by macrophages in conditions such as systemic inflammatory syndrome. [ABSTRACT FROM AUTHOR]

The multifunctional cell-surface protein dipeptidyl peptidase IV (DPPIV/CD26) is aberrantly expressed in many cancers and plays a key role in tumorigenesis and metastasis. Its diverse cellular roles include modulation of chemokine activity by cleaving dipeptides from the chemokine N[H.sub.2]-terminus, perturbation of extracellular nucleoside metabolism by binding the ecto-enzyme adenosine deaminase, and interaction with the extracellular matrix by binding proteins such as collagen and fibronectin. We have recently shown that DPPIV can be downregulated from the cell surface of HT-29 colorectal carcinoma cells by adenosine, which is a metabolite that becomes concentrated in the extracellular fluid of hypoxic solid tumors. Most of the known responses to adenosine are mediated through four different subtypes of G protein-coupled adenosine receptors: [A.sub.1], [A.sub.2A], [A.sub.2B], and [A.sub.3]. We report here that adenosine downregulation of DPPIV from the surface of HT-29 cells occurs independently of these classic receptor subtypes, and is mediated by a novel cell-surface mechanism that induces an increase in protein tyrosine phosphatase activity. The increase in protein tyrosine phosphatase activity leads to a decrease in the tyrosine phosphorylation of ERK1/2 MAP kinase that in turn links to the decline in DPPIV mRNA and protein. The downregulation of DPPIV occurs independently of changes in the activities of protein kinases A or C, phosphatidylinositol 3-kinase, other serine/threonine phosphatases, or the p38 or JNK MAP kinases. This novel action of adenosine has implications for our ability to manipulate adenosine-dependent events within the solid tumor microenvironment. CD26; deaminase binding protein; mitogen-activated protein kinases; nucleosides; tumor microenvironment doi:10.1152/ajpcell.00238.2005.