Biomedical subjects

Sara J Israels

Publications and source records attributed to Sara J Israels.

3 recordsLinked to original sources

PubMed2003

BNIP3 plays a role in hypoxic cell death in human epithelial cells that is inhibited by growth factors EGF and IGF.

Hypoxic regions within solid tumors are often resistant to chemotherapy and radiation. BNIP3 (Bcl-2/E1B 19 kDa interacting protein) is a proapoptotic member of the Bcl-2 family that is expressed in hypoxic regions of tumors. During hypoxia, BNIP3 expression is increased in many cell types and upon forced overexpression BNIP3 induces cell death. Herein, we have demonstrated that blockage of hypoxia-induced BNIP3 expression using antisense oligonucleotides against BNIP3 or blockage of BNIP3 function through expression of a mutant form of BNIP3 inhibits hypoxia-induced cell death in human embryonic kidney 293 cells. We have also determined that hypoxia-mediated BNIP3 expression is regulated by the transcription factor, hypoxia-inducible factor-1alpha (HIF-1alpha) in human epithelial cell lines. Furthermore, HIF-1alpha directly binds to a consensus HIF-1alpha-responsive element (HRE) in the human BNIP3 promoter that upon mutation of this HRE site eliminates the hypoxic responsiveness of the promoter. Since BNIP3 is expressed in hypoxic regions of tumors but fails to induce cell death, we determined whether growth factors block BNIP3-induced cell death. Treatment of the breast cancer cell line MCF-7 cells with epidermal growth factor (EGF) or insulin-like growth factor effectively protected these cells from BNIP3-induced cell death. Furthermore, inhibiting EGF receptor signaling using antibodies against ErbB2 (Herceptin) resulted in increased hypoxia-induced cell death in MCF-7 cells. Taken together, BNIP3 plays a role in hypoxia-induced cell death in human epithelial cells that could be circumvented by growth factor signaling.

Acridine Orange↗

PubMed2003

Neonatal platelet function.

Healthy newborns maintain normal circulating platelet counts, with a platelet ultrastructure that does not differ from adults. In vitro assessments of intrinsic platelet function, however, have demonstrated transient hyporesponsiveness that is most marked in platelets from preterm infants. Decreased responses were originally considered to be the result of platelet activation and degranulation during labor and delivery, but more recent studies of platelet activation markers have not supported this theory. Decreased activation responses are due to relative deficiencies of phospholipid metabolism, calcium mobilization, granule secretion, and aggregation. These result in turn from differences in intrinsic signal transduction in the neonatal platelet compared with the adult. In contrast, there is enhanced platelet adhesion due to the presence in neonatal plasma of larger, more functionally potent von Willebrand factor multimers. These ultralarge multimers may result from decreased activity of von Willebrand factor-cleaving protease in neonatal plasma and are associated with shorter bleeding times and Platelet Function Analyser-100 closure times in neonates. In the immediate newborn period, this enhanced platelet adhesion may compensate for the decreased intrinsic platelet activation in healthy neonates, but may leave sick neonates at increased risk of bleeding.

Blood Platelet Disorders↗

PubMed2003

Platelets and anti-platelet therapy.

Platelets play a central role in the hemostatic process and consequently are similarly involved in the pathological counterpart, thrombosis. They adhere to various subendothelial proteins, exposed either by injury or disease, and subsequently become activated by the thrombogenic surface or locally produced agonists. These activated platelets aggregate to form a platelet plug, release agonists which recruit more platelets to the growing thrombus, and provide a catalytic surface for thrombin generation and fibrin formation. These platelet-rich thrombi are responsible for the acute occlusion of stenotic vessels and ischemic injury to heart and brain. A range of anti-platelet drugs are currently used, both prophylactically and therapeutically, in regimens to manage thrombo-embolic disorders. These include inhibitors of the generation, or effects, of locally produced agonists; several large clinical trials have supported roles for cyclooxygenase inhibitors, which prevent thromboxane generation, and thienopyridine derivatives, which antagonize ADP receptors. Similarly intravenous alpha IIb beta 3 antagonists have been shown to be effective anti-thrombotics, albeit in highly selective situations; in contrast, to date studies with their oral counterparts have been disappointing. Recent advances in understanding of platelet physiology have suggested several novel, if yet untested, targets for anti-platelet therapy. These include the thrombin receptor, the serotonin handling system, and the leptin receptor.

Animals↗