Biomedical subjects

Shaker A Mousa

Publications and source records attributed to Shaker A Mousa.

At least 37 records · Page 2Linked to original sources

PubMed2005

Effect of resveratrol on angiogenesis and platelet/fibrin-accelerated tumor growth in the chick chorioallantoic membrane model.

We carried out this investigation to examine the effects on angiogenesis-mediated processes and to define anti-angiogenesis mechanisms for flavonoids. We examined the effects and mechanisms of the flavonoid resveratrol on angiogenesis and tumor growth using the chick chorioallantoic membrane (CAM) model of angiogenesis, the CAM tumor growth model, and the effect on p53 in fibroblast growth factor-2 (FGF2) stimulated human endothelial cells using immunoassay. Resveratrol demonstrated potent inhibition (effective dose50=0.7+/-0.1 microM) of FGF2-induced angiogenesis and tumor growth. Furthermore, resveratrol significantly (P<0.01) inhibited platelet/fibrin clot-promoted human colon and fibrosarcoma tumor growth in the CAM tumor model. Resveratrol in a concentration-dependent (1-3 microM) manner significantly promoted apoptosis in FGF2-stimulated endothelial cells by increasing p53 protein production. These data indicated potent anti-angiogenesis efficacy, inhibition of tumor growth, and clot-mediated enhanced tumor growth. These data suggest potential anticancer benefits as a chemopreventive and chemotherapeutic for the flavonoid resveratrol.

Angiogenesis Inhibitors↗

PubMed2005

Anti-angiogenesis efficacy of the garlic ingredient alliin and antioxidants: role of nitric oxide and p53.

Alliin, a compound derived from garlic, demonstrated dose-dependent inhibition of fibroblast growth factor-2 (FGF2)-induced human endothelial cell (EC) tube formation and angiogenesis in the chick chorioallantoic membrane (CAM) model. Additionally, alliin demonstrated potent inhibition of vascular endothelial growth factor (VEGF)-induced angiogenesis in the CAM model. The antioxidant vitamins C and E significantly (P < 0.001) enhanced the inhibitory efficacy of alliin on FGF2-induced EC tube formation and angiogenesis. Alliin significantly increased (P < 0.01) nitric oxide (NO) release into the CAM fluid, which was further enhanced by vitamins C and E. The NO synthesis inhibitor nitro-L-arginine methyl ester (L-NAME) reversed the anti-angiogenesis efficacy of alliin in the CAM model. Vitamins C and E significantly enhanced the anticancer efficacy of alliin in inhibiting colon and fibrosarcoma tumor growth. Alliin significantly inhibited both FGF2 and VEGF secretion from human fibrosarcoma cells in a concentration-dependent manner. Additionally, alliin up-regulated the p53 production in FGF2-stimulated EC. These data indicated a synergistic effect of antioxidants on the anti-angiogenesis and anticancer efficacy of alliin. These data also suggest the implication of cellular NO and p53 as mediators of anti-angiogenesis and anticancer effects of alliin.

Angiogenesis Inhibitors↗

PubMed2005

Anti-thrombotics in thrombosis and cancer.

Many cancer patients have a reportedly hypercoagulable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Studies have demonstrated that unfractionated heparin or its low-molecular-weight fractions interfere with various processes involved in tumor growth and metastasis. These include fibrin formation; binding of heparin to angiogenic growth factors, such as basic fibroblast growth factor and vascular endothelial growth factor; modulation of tissue factor; and perhaps other more important modulatory mechanisms, such as enhanced tissue factor pathway inhibitor (TFPI) release and inhibition of various matrix-degrading enzymes. Clinical trials have suggested a clinically relevant effect of low-molecular-weight heparin (LMWH), as compared with unfractionated heparin, on the survival of cancer patients with deep vein thrombosis. Similarly, the impact of warfarin on the survival of cancer patients with thromboembolic disorders was demonstrated. Studies from the author's laboratory demonstrated a significant role for LMWH, warfarin, anti-VIIa, and LMWH-releasable TFPI on the regulation of angiogenesis, tumor growth and tumor metastasis. Thus, modulation of tissue factor/VIIa noncoagulant activities by LMWH, warfarin, anti-VIIa, or TFPI may be a useful therapeutic method for the inhibition of angiogenesis associated with human tumor growth and metastasis. Additionally, antiplatelet drugs may have an impact on tumor metastasis, and the combination of antiplatelets and anticoagulants at adjusted doses may provide greater benefits to cancer patients.

Anticoagulants↗

PubMed2004

Fluid shear regulates the kinetics and receptor specificity of Staphylococcus aureus binding to activated platelets.

The interaction between surface components on the invading pathogen and host cells such as platelets plays a key role in the regulation of endovascular infections. However, the mechanisms mediating Staphylococcus aureus binding to platelets under shear remain largely unknown. This study was designed to investigate the kinetics and molecular requirements of platelet-S. aureus interactions in bulk suspensions subjected to a uniform shear field. Hydrodynamic shear-induced collisions augment platelet-S. aureus binding, which is further potentiated by platelet activation with stromal derived factor-1beta. Peak adhesion efficiency occurs at low shear (100 s(-1)) and decreases with increasing shear. The molecular interaction of platelet alpha(IIb)beta(3) with bacterial clumping factor A through fibrinogen bridging is necessary for stable bacterial binding to activated platelets under shear. Although this pathway is sufficient at low shear (</=400 s(-1)), the involvement of platelet gpIb and staphylococcal protein A through von Willebrand factor bridging is essential for optimal recruitment of S. aureus cells by platelets in the high shear regime. IgG plays an inhibitory role in the adhesion process, presumably by interfering with the binding of von Willebrand factor to staphylococcal protein A. This study demonstrates that platelet activation and a fluid-mechanical environment representative of the vasculature affect platelet-S. aureus cell-adhesive interactions pertinent to the process of S. aureus-induced bloodstream infections.

Blood Platelets↗

PubMed2004

Proangiogenic action of thyroid hormone is fibroblast growth factor-dependent and is initiated at the cell surface.

The effects of thyroid hormone analogues on modulation of angiogenesis have been studied in the chick chorioallantoic membrane model. Generation of new blood vessels from existing vessels was increased 3-fold by either l-thyroxine (T4; 10(-7) mol/L) or 3,5,3'-triiodo-l-thyronine (10(-9) mol/L). T4-agarose reproduced the effects of T4, and tetraiodothyroacetic acid (tetrac) inhibited the effects of both T4 and T4-agarose. Tetrac itself was inactive and is known to block actions of T4 on signal transduction that are initiated at the plasma membrane. T4 and basic fibroblast growth factor (FGF2) were comparably effective as inducers of angiogenesis. Low concentrations of FGF2 combined with submaximal concentrations of T4 produced an additive angiogenic response. Anti-FGF2 inhibited the angiogenic effect of T4. The proangiogenic effects of T4 and FGF2 were blocked by PD 98059, a mitogen-activated protein kinase (MAPK) pathway inhibitor. Endothelial cells (ECV304) treated with T4 or FGF2 for 15 minutes demonstrated activation of MAPK, an effect inhibited by PD 98059 and the protein kinase C inhibitor CGP41251. Reverse transcription-polymerase chain reaction of RNA extracted from endothelial cells treated with T4 revealed increased abundance of FGF2 transcript at 6 to 48 hours, and after 72 hours, the medium of treated cells showed increased FGF2 content, an effect inhibited by PD 98059. Thus, thyroid hormone is shown to be a proangiogenic factor. This action, initiated at the plasma membrane, is MAPK dependent and mediated by FGF2.

Animals↗

PubMed2004

Synthesis and biological evaluation of nonpeptide integrin antagonists containing spirocyclic scaffolds.

Analogues of isoxazoline alpha(v)beta(3) antagonist 1 designed to further restrict the four carbon alkyl tether were prepared by incorporating two spirocyclic scaffolds, 1-oxa-2-azaspiro[4,5]dec-2-ene and 1-oxa-2,7-diazaspiro[4,4]non-2-ene. Additional optimization provided potent antagonists of both alpha(v)beta(3) and alpha(5)beta(1) which are selective over GPIIb/IIIa.

Binding Sites↗

PubMed2004

Low-molecular-weight heparin in thrombosis and cancer.

Venous thromboembolism (VTE) is a recognized complication of malignant disease and multiple risk factors contribute to the hypercoagulability that commonly accompanies malignancy. Thromboprophylaxis with antithrombotic drugs such as the low-molecular-weight heparins (LMWHs) can be used to control the hypercoagulable state and to reduce the incidence of VTE in patients with cancer. Clinical and biochemical data suggest that LMWHs may also inhibit tumor growth, leading to a survival benefit in these patients. Many cancer patients reportedly have a hypercoaguable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Studies have demonstrated that unfractionated heparin (UFH) or its low-molecular-weight fractions interfere with various processes involved in tumor growth and metastasis. Clinical trials in cancer patients with thromboembolic disorders have suggested a clinically relevant effect of LMWHs (as compared with UFH) on the survival of cancer patients with deep vein thrombosis. Similarly, the impact of warfarin on the survival of cancer patients with thromboembolic disorders was demonstrated in certain tumor types. Studies from our laboratory demonstrated a significant role for LMWH, warfarin, anti-VIIa, and LMWH releasable tissue factor pathway inhibitor on the regulation of angiogenesis, tumor growth, and tumor metastasis. However, a direct anticancer effect for heparin in cancer patients without thrombosis still remains to be clinically documented.

Hemostasis↗

PubMed2004

Low-molecular-weight heparins in thrombosis and cancer: emerging links.

Heparin as well as low-molecular-weight heparins (LMWHs) have polypharmacological actions at various levels. Earlier studies focused on the plasma anti-Xa and anti-IIa pharmacodynamics (PD) for the different LMWHs. Other important PD parameters for heparin and LMWHs might explain the diverse clinical impacts of this class of agents in thrombosis and beyond: the release of the vascular tissue factor pathway inhibitor (TFPI), inhibition of key matrix-degrading enzymes, and other mechanisms. There is much evidence for the key role of LMWHs in hypercoagulation in thrombosis and cancer, angiogenesis, and inflammatory disorders. Many cancer patients reportedly have a hypercoaguable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Studies have demonstrated that unfractionated heparin (UFH) or its low molecular weight fractions interfere with various processes involved in tumor growth and metastasis. Clinical trials have suggested a clinically relevant and improved efficacy of LMWHs, as compared to UFH, on the survival of cancer patients with deep vein thrombosis. Our laboratory has demonstrated a significant role for LMWHs and for LMWH-releasable TFPI on the regulation of angiogenesis, tumor growth, and tumor metastasis; we have also seen potent inhibition of matrix-degrading enzymes by LMWHs but not by TFPI. The antiangiogenesis effect of LMWHs or non-anticoagulant LMWH derivatives was shown to be reversed by anti-TFPI. Thus, modulation of tissue factor/VIIa noncoagulant activities by LMWH-releasable TFPI and the inhibitory effects on matrix-degrading enzymes beside the anticoagulant efficacy have provided an expanded clinical utility for LMWHs in angiogenesis-associated disorders, including human tumor growth and metastasis.

Anticoagulants↗

PubMed2004

Inhibition of endothelial cell tube formation by the low molecular weight heparin, tinzaparin, is mediated by tissue factor pathway inhibitor.

Heparin and low molecular weight heparins (LMWHs) have both antithrombotic and anti-angiogenic activities. The anti-angiogenic activity of LMWH may be associated with the release of endothelial tissue factor pathway inhibitor (TFPI), an important endogenous inhibitor of tissue factor/Factor VIIa (TF/fVIIa). To evaluate the effects of LMWH, tinzaparin, and TFPI in a model of angiogenesis-mediated processes, we compared the effects of tinzaparin, and recombinant TFPI in inhibiting either basic fibroblast growth factor-2 (FGF2)- or TF/fVIIa-induced endothelial cell tube formation in human umbilical vein endothelial cells (HUVEC). Our results show that tinzaparin and recombinant TFPI both blocked endothelial tube formation induced by either FGF2 or TF/fVIIa, in a concentration-dependent manner. Endothelial tube formation was only marginally inhibited by a potent and specific anti-Factor Xa, recombinant tick anticoagulant protein (rTAP). A monoclonal anti-TFPI anti-body reversed the inhibitory effects of either tinzaparin or recombinant-TFPI on HUVEC tube formation. Tinzaparin fractions in the range of 8,000 to 12,600 Da were most effective in stimulating the release of TFPI from HUVEC. These results suggest that the inhibitory effect of the LMWH tinzaparin on endothelial tube formation is associated with stimulation of the release of TFPI, but not to anti-Factor Xa activity.

Cells, Cultured↗

PubMed2004