Silibinin prevents prostate cancer cell-mediated differentiation of naïve fibroblasts into cancer-associated fibroblast phenotype by targeting TGF β2.

Tumor microenvironment (TM) is an essential element in prostate cancer (PCA), offering unique opportunities for its prevention. TM includes naïve fibroblasts that are recruited by nascent neoplastic lesion and altered into 'cancer-associated fibroblasts' (CAFs) that promote PCA. A better understanding and targeting of interaction between PCA cells and fibroblasts and inhibiting CAF phenotype through non-toxic agents are novel approaches to prevent PCA progression.

A novel antibody targeting the ligand binding domain of the thromboxane A₂ receptor exhibits antithrombotic properties in vivo.

In efforts to define new targets for antithrombotic purposes, there is interest in utilizing antibodies targeting ligand binding domains of platelet receptors. To this end, we have recently shown that an antibody (designated C-EL2Ab), which targets the C-terminus of the 2nd extracellular loop (C-EL2) of the thromboxane A(2) receptor (TPR), selectively blocks TPR-mediated platelet aggregation, under both in vitro and ex vivo experimental conditions. In the current studies we sought to determine whether C-EL2Ab exhibits in vivo antithrombotic activity, by employing a carotid artery injury thrombosis model.

Mouse transient receptor potential channel 6: role in hemostasis and thrombogenesis.

Although changes in the intracellular levels of calcium (Ca(2+)) are a central step in platelet activation, the underlying mechanism of Ca(2+) entry is still unclear. Previous studies have demonstrated that TRPC6, a member of the canonical transient receptor potential channel (TRPC) family is expressed in platelets in a significant amount, and is predominantly found on the plasma membrane. Based on these considerations, we hypothesized that TRPC6 plays a critical role in platelet function.

Characterization of the in vivo antiplatelet activity of the antihypertensive agent losartan.

Objective: The purpose of this study is to investigate the potential in vivo antiplatelet and thromboprotective properties of the antihypertensive drug losartan in mice.

Methods: Aggregometry studies were performed on platelets obtained from mice administered losartan for 5 days, via tail vein to examine the ex vivo effects (dose dependence) of this agent and to select an appropriate dose for the in vivo studies. Next, the tail bleeding time test and the time for occlusion in a carotid artery injury thrombosis model (ferric chloride) were also performed to assess the in vivo effects of losartan treatment.

Thromboxane A2 receptor: biology and function of a peculiar receptor that remains resistant for therapeutic targeting.

While blood platelets express several G-protein-coupled receptors (GPCRs) that play pivotal roles in their activation, several diseases, for example thrombotic disorders, may develop if these receptors are inappropriately activated. Thus, these receptors have been the subject of investigations to design therapeutic interventions for managing multiple thrombosis-based disease states. One such GPCR, the thromboxane A(2) receptor (TPR), remains resistant to such interventions.

The C-terminal segment of the second extracellular loop of the thromboxane A2 receptor plays an important role in platelet aggregation.

There is considerable interest in discovering novel antiplatelet approaches with an enhanced safety profile. To this end, in our efforts to define new targets for antithrombotic activity, we investigated the utility of antibodies which recognize the ligand binding domains of the platelet thromboxane A(2) receptor (TPR). We hypothesized that an antibody (abbreviated as C-EL2Ab), which interacts with the C-terminus of the second extracellular loop (C-EL2; i.

Glybenclamide: an antidiabetic with in vivo antithrombotic activity.

While proper platelet function is a vital component of hemostasis, their inappropriate activation contributes to thrombotic disorders. One pathway for platelet activation involves their synthesis of the lipid mediator thromboxane A₂ (TXA₂). Although TXA₂ acts by binding to a seven-transmembrane receptor (i.

Platelet function and Isoprostane biology. Should isoprostanes be the newest member of the orphan-ligand family?

While there have been many reports investigating the biological activity and signaling mechanisms of isoprostanes, their role in biology, particularly in platelets, appears to still be underestimated. Moreover, whether these lipids have their own receptors is still debated, despite multiple reports that discrete receptors for isoprostane do exist on platelets, vascular tissues, amongst others. This paper provides a review of the important literature of isoprostanes and provides reasoning that isoprostanes should be classified as orphan ligands until their receptor(s) is/are identified.

Repurposing an old drug for a new use: glybenclamide exerts antiplatelet activity by interacting with the thromboxane A(2) receptor.

Aim: To investigate the potential antagonistic activity of the antidiabetic agent glybenclamide for the human platelet thromboxane A(2) receptor (abbreviated as TPR).

Methods: Platelets were obtained from healthy donors. Aggregation studies were performed in a model 700 aggregometry system.

Spatial regulation of inflammation by human aortic endothelial cells in a linear gradient of shear stress.

Objective: Atherosclerosis is a focal disease that develops at sites of low and oscillatory shear stress in arteries. This study aimed to understand how endothelial cells sense a gradient of fluid shear stress and transduce signals that regulate membrane expression of cell adhesion molecules and monocyte recruitment.

Methods: Human aortic endothelial cells were stimulated with TNF-alpha and simultaneously exposed to a linear gradient of shear stress that increased from 0 to 16 dyne/cm2.

CD11c/CD18: novel ligands and a role in delayed-type hypersensitivity.

CD11c, a member of the leukointegrin family, is expressed prominently on tissue macrophages and dendritic cells and binds to complement fragment (iC3b), provisional matrix molecules (fibrinogen), and the Ig superfamily cell adhesion molecule, ICAM-1. CD11c has been proposed to function in phagocytosis, cell migration, and cytokine production by monocytes/macrophages as well as induction of T cell proliferation by Langerhans cells. Using assays to quantify CD11c-mediated cell adhesion, we demonstrate that CD11c recognizes ICAM-2 and VCAM-1.

Triglyceride-rich lipoproteins prime aortic endothelium for an enhanced inflammatory response to tumor necrosis factor-alpha.

High levels of triglyceride-rich lipoproteins (TGRLs) in blood are linked to development of atherosclerosis, yet the mechanisms by which these particles initiate inflammation of endothelium are unknown. TGRL isolated from human plasma during the postprandial state was examined for its capacity to bind to cultured human aortic endothelial cells (HAECs) and alter the acute inflammatory response to tumor necrosis factor-alpha. HAECs were repetitively incubated with dietary levels of freshly isolated TGRL for 2 hours per day for 1 to 3 days to mimic postprandial lipidemia.