The Effect of Different Glucose Concentrations on the Antiproliferative Activity of Metformin in MCF-7 Breast Cancer Cells.

The glucose-lowering drug metformin has been reported to have anticancer properties through unknown mechanisms. Other unknown factors that may influence its anticancer potential include the glycemic status of the patient. Therefore, the objective of this study is to determine the effect of different glucose environments on the antiproliferative potency and the cellular mechanism of action of metformin.

Hyperglycaemia disrupts conducted vasodilation in the resistance vasculature of db/db mice.

Vascular dysfunction in small resistance arteries is observed during chronic elevations in blood glucose. Hyperglycaemia-associated effects on endothelium-dependent vasodilation have been well characterized, but effects on conducted vasodilation in the resistance vasculature are not known. Small mesenteric arteries were isolated from healthy and diabetic db/db mice, which were used as a model of chronic hyperglycaemia.

Challenges in the Biomedical Research Enterprise in the 21st century: Antecedents in the writings of David Triggle.

David Triggle's career as an educator, researcher, essayist and ethicist in many ways has paralleled the post WWII emergence of the "biomedical research ecosystem" that originated in the concept of the "Endless Frontier". In the ensuing 70 years biomedical research has irreparably changed the nature of society with vaccines, the birth control pill and new generations of drugs and biologics to treat infections, sexually transmitted diseases, psychiatric disorders and cardiovascular diseases. These have led to a shift in the population demographic to the elderly and the chronically sick leading to major issues in the provision of effective and affordable healthcare for much of the world's population.

Proteinase-activated receptors 1 and 2 and the regulation of porcine coronary artery contractility: a role for distinct tyrosine kinase pathways.

Background And Purpose: Because angiotensin-II-mediated porcine coronary artery (PCA) vasoconstriction is blocked by protein tyrosine kinase (PYK) inhibitors, we hypothesized that proteinase-activated receptors (PARs), known to regulate vascular tension, like angiotensin-II, would also cause PCA contractions via PYK-dependent signalling pathways.

Experimental Approach: Contractions of intact and endothelium-free isolated PCA rings, stimulated by PAR1 /PAR2 -activating peptides, angiotensin-II, PGF2α , EGF, PDGF and KCl, were monitored with/without multiple signalling pathway inhibitors, including AG-tyrphostins AG18 (non-specific PYKs), AG1478 (EGF-receptor kinase), AG1296 (PDGF receptor kinase), PP1 (Src kinase), U0126 and PD98059 (MEK/MAPKinase kinase), indomethacin/SC-560/NS-398 (COX-1/2) and L-NAME (NOS).

Key Results: AG18 inhibited the contractions induced by all the agonists except KCl, whereas U0126 attenuated contractions induced by PAR1 /PAR2 agonists, EGF and angiotensin-II, but not by PGF2α , the COX-produced metabolites of arachidonate and KCl.

Cytochrome P450 products and arachidonic acid-induced, non-store-operated, Ca2+ entry in cultured bovine endothelial cells.

Endothelial cells possess multiple mechanisms for the control of Ca2+ influx during agonist and mechanical stimulation. Increased intracellular Ca2+ during such events is important in the production of vasoactive substances including NO, prostacyclin, and, possibly, endothelium-derived hyperpolarizing factor(s). The present studies examined the effect of arachidonic acid on cellular Ca2+ entry and the underlying mechanisms by which this fatty acid regulates entry.

Endothelin blockade potentiates endothelial protective effects of ACE inhibitors in saphenous veins.

Background: Angiotensin II and endothelin-1 are potent endothelium-derived contracting factors. The effects of acute endothelin antagonism on endothelial function in saphenous vein from patients treated with and without angiotensin-converting enzyme inhibitors were compared.

Methods: Vascular segments of saphenous vein were obtained perioperatively from 14 patients on angiotensin-converting enzyme inhibitors and 29 controls.