64Cu-CTS: A Promising Radiopharmaceutical for the Identification of Low-Grade Cardiac Hypoxia by PET.

Unlabelled: The subtle hypoxia underlying chronic cardiovascular disease is an attractive target for PET imaging, but the lead hypoxia imaging agents (64)Cu-2,3-butanedione bis(N4-methylthiosemicarbazone) (ATSM) and (18)F-fluoromisonidazole are trapped only at extreme levels of hypoxia and hence are insufficiently sensitive for this purpose. We have therefore sought an analog of (64)Cu-ATSM better suited to identify compromised but salvageable myocardium, and we validated it using parallel biomarkers of cardiac energetics comparable to those observed in chronic cardiac ischemic syndromes.

Methods: Rat hearts were perfused with aerobic buffer for 20 min, followed by a range of hypoxic buffers (using a computer-controlled gas mixer) for 45 min.

2-methoxyestradiol and disorders of female reproductive tissues.

2-Methoxyestradiol (2ME) is an endogenous metabolite of 17β-estradiol. Once thought of as a mere degradation product, 2ME has gained attention as an important component of reproductive physiology and as a therapeutic agent in reproductive pathologies such as preeclampsia, endometriosis, infertility, and cancer. In this review, we discuss the involvement of 2ME in reproductive pathophysiology and summarize its known mechanisms of action: microtubule disruption, inhibition of angiogenesis and stimulation of apoptosis.

Cardiac hypoxia imaging: second-generation analogues of 64Cu-ATSM.

Unlabelled: Myocardial hypoxia is an attractive target for diagnostic and prognostic imaging, but current approaches are insufficiently sensitive for clinical use. The PET tracer copper(II)-diacetyl-bis(N4-methylthiosemicarbazone) ((64)Cu-ATSM) has promise, but its selectivity and sensitivity could be improved by structural modification. We have therefore evaluated a range of (64)Cu-ATSM analogs for imaging hypoxic myocardium.

Assessing radiotracer kinetics in the Langendorff perfused heart.

Background: The Langendorff perfused heart is a physiologically relevant and controllable model with potential for assessing the pharmacokinetics of new radiotracers under a range of pathophysiological conditions.. We assess the feasibility of extending the methods validated for in vivo PET data analysis to the characterisation of PET tracer kinetics applied to Langendorff perfused hearts.

Trapped platelets activated in ischemia initiate ventricular fibrillation.

Background: We tested the hypothesis that ischemia-induced ventricular fibrillation (VF) is facilitated by platelets, trapped regionally in the ischemic zone and activated to release arrhythmogenic secretome.

Methods And Results: In a randomized study in blood-free, buffer-perfused isolated rat hearts, ischemic zone territory (34±1% of left ventricle) was selected so that ischemia evoked VF in only 42% of controls. VF incidence was increased to 91% (P<0.

Demonstration of the retention of 64Cu-ATSM in cardiac myocytes using a novel incubation chamber for screening hypoxia-dependent radiotracers.

Objective: We have designed a low-cost, reusable incubation system that allows cells to be cultured in either plated or suspension culture under complete atmospheric control for radiotracer characterization. We demonstrate its utility here in the first quantification of the hypoxia-dependent accumulation of Cu-diacetyl bis(N4-methylthiosemicarbazone) (Cu-ATSM) in adult rat ventricular myocytes (ARVMs).

Materials And Methods: ARVMs were allowed to adhere overnight in 9 cm culture plates (2×10 cells/dish) or were used in suspension culture, placed inside the chamber and equilibrated with either oxic (95 or 21% O₂/5% CO₂) or anoxic gas (95% N₂/5% CO₂).

Insulin regulates GLUT1-mediated glucose transport in MG-63 human osteosarcoma cells.

Osteosarcoma is the most common type of malignant bone cancer, accounting for 35% of primary bone malignancies. Because cancer cells utilize glucose as their primary energy substrate, the expression and regulation of glucose transporters (GLUT) may be important in tumor development and progression. GLUT expression has not been studied previously in human osteosarcoma cell lines.

Glucose transporters in sex steroid hormone related cancer.

Cancer cells, as with most mammalian cells, depend on a continuous supply of glucose; not only as a precursor of glycoproteins, triglycerides and glycogen, but also as an important source of energy. This review concentrates on GLUT transporter expression in both normal and cancerous classical sex-steroid hormone tissues (i.e.

Apical and basolateral localisation of GLUT2 transporters in human lung epithelial cells.

Glucose concentrations of normal human airway surface liquid are approximately 12.5 times lower than blood glucose concentrations indicating that glucose uptake by epithelial cells may play a role in maintaining lung glucose homeostasis. We have therefore investigated potential glucose uptake mechanisms in non-polarised and polarised H441 human airway epithelial cells and bronchial biopsies.

Regulation of GLUT3 and glucose uptake by the cAMP signalling pathway in the breast cancer cell line ZR-75.

Increased glucose uptake as a principal energy source is a requirement for the continued survival of tumour cells. Facilitative glucose transporter-1 (GLUT1) and -3 (GLUT3) have been previously shown to be present and regulated in breast cancer cells and are associated with poor patient prognosis. In cancer cells, the cAMP secondary messenger pathway is known to potentiate described glucose transporter activators and regulate cell fate.

Differential subcellular distribution of glucose transporters GLUT1-6 and GLUT9 in human cancer: ultrastructural localization of GLUT1 and GLUT5 in breast tumor tissues.

It has been proposed that the enhanced metabolic activity of tumor cells is accompanied by an increased expression of facilitative hexose transporters (GLUTs). However, a previous immunohistochemical analysis of GLUT1 expression in 154 malignant human neoplasms failed to detect the GLUT1 isoform in 87 tumors. We used 146 normal human tissues and 215 tumor samples to reassess GLUT1 expression.

Differential regulation of glucose transporter expression by estrogen and progesterone in Ishikawa endometrial cancer cells.

Estrogen replacement therapy and other unopposed estrogen treatments increase the incidence of endometrial abnormalities, including cancer. However, this effect is counteracted by the co-administration of progesterone. In the endometrium, glucose transporter (GLUT) expression and glucose transport are known to fluctuate throughout the menstrual cycle.

Tissue-specific differences in 2-fluoro-2-deoxyglucose metabolism beyond FDG-6-P: a 19F NMR spectroscopy study in the rat.

2-Fluoro-[(18)F]-2-deoxy-glucose (FDG) is a positron-emitting analogue of glucose used clinically in positron emission tomography (PET) to assess glucose utilization in diseased and healthy tissue. Originally developed to measure local cerebral glucose utilization rates, it has now found applications in tumour diagnosis and in the study of myocardial glucose uptake. Once taken up into the cell, FDG is phosphorylated to FDG-6-phosphate (FDG-6-P) by hexokinase and was originally believed to be trapped as a terminal metabolite.

The action of ovarian hormones in cardiovascular disease.

The incidence of cardiovascular disease (CAD) differs between men and women, in part because of differences in risk factors and hormones. This sexual dimorphism means a lower incidence in atherosclerotic diseases in premenopausal women, which subsequently rises in postmenopausal women to eventually equal that of men. These observations point towards estrogen and progesterone playing a lifetime protective role against CAD in women.

Estrogen and progesterone up-regulate glucose transporter expression in ZR-75-1 human breast cancer cells.

Breast cancer incidence increases in women receiving combined estrogen and progesterone therapy. Breast tumors show increased expression of the glucose transporter GLUT1. We determined the effect of these hormones on GLUT1-4 expression and deoxyglucose transport in ZR-75-1 breast cancer cells.

Glucose transporters: expression, regulation and cancer.

Mammalian cells depend on glucose as a major substrate for energy production. Glucose is transported into the cell via facilitative glucose transporters (GLUT) present in all cell types. Many GLUT isoforms have been described and their expression is cell-specific and subject to hormonal and environmental control.

Lactate-induced translocation of GLUT1 and GLUT4 is not mediated by the phosphatidyl-inositol-3-kinase pathway in the rat heart.

We have determined the effect of lactate on the translocation of GLUT1 and GLUT4 and on the myocardial uptake and phosphorylation of the glucose analogues 2-deoxy-D-glucose (DG) and 2-18F-fluoro-2-deoxy-D-glucose (18FDG). The involvement of phosphatidyl-inositol-3-kinase (PI3K) in this translocation was determined using wortmannin. Hearts from fed and fasted male Wistar rats were perfused in the presence of 11 mM glucose +/- 10 mM lactate for two hours and the distribution of glucose transporters was determined using Western blot techniques.