Regulation of the Hypoxia-Inducible Factor (HIF) by Pro-Inflammatory Cytokines.

Hypoxia and inflammation are frequently co-incidental features of the tissue microenvironment in a wide range of inflammatory diseases. While the impact of hypoxia on inflammatory pathways in immune cells has been well characterized, less is known about how inflammatory stimuli such as cytokines impact upon the canonical hypoxia-inducible factor (HIF) pathway, the master regulator of the cellular response to hypoxia. In this review, we discuss what is known about the impact of two major pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), on the regulation of HIF-dependent signaling at sites of inflammation. We report extensive evidence for these cytokines directly impacting upon HIF signaling through the regulation of HIF at transcriptional and post-translational levels. We conclude that multi-level crosstalk between inflammatory and hypoxic signaling pathways plays an important role in shaping the nature and degree of inflammation occurring at hypoxic sites.

Medication use and mammographic breast density.

PURPOSE: A dense breast on mammogram is a strong risk factor for breast cancer. Identifying factors that reduce mammographic breast density could thus provide insight into breast cancer prevention. Due to the limited number of studies and conflicting findings, we investigated the associations of medication use (specifically statins, aspirin, and ibuprofen) with mammographic breast density. METHODS: We evaluated these associations in 775 women who were recruited during an annual screening mammogram at Washington University School of Medicine, St. Louis. We measured mammographic breast density using Volpara. We used multivariable-adjusted linear regressions to determine the associations of medication use (statins, aspirin, and ibuprofen) with mammographic breast density. Least squared means were generated and back-transformed for easier interpretation. RESULTS: The mean age of study participants was 52.9 years. Statin use in the prior 12 months was not associated with volumetric percent density or dense volume, but was positively associated with non-dense volume. The mean volumetric percent density was 8.6% among statin non-users, 7.2% among women who used statins 1-3 days/week, and 7.3% among women who used statins ≥ 4 days/week (p trend = 0.07). The non-dense volume was 1297.1 cm3 among statin non-users, 1368.7 cm3 among women who used statins 1-3 days/week, and 1408.4 cm3 among those who used statins ≥ 4 days/week (p trend = 0.02). We did not observe statistically significant differences in mammographic breast density by aspirin or ibuprofen use. CONCLUSION: Statin, aspirin, and ibuprofen use was not associated with volumetric percent density and dense volume, but statin use was positively associated with non-dense volume. Any potential associations of these medications with breast cancer risk are unlikely to be mediated through an effect on volumetric percent density.

Paraoxonase activity in Greek migrants and Anglo-Celtic persons in the Melbourne Collaborative Cohort Study: relationship to dietary markers.

BACKGROUND: Greek migrants to Australia have low all-cause and cardiovascular disease (CVD) mortality. This may be partly due to maintenance of a traditional Mediterranean diet and its interaction with CVD risk factors. The enzyme paraoxonase-1 (PON1) is thought to contribute to the anti-atherogenic properties of high density lipoproteins (HDL) by metabolizing lipid peroxides. PON1 activity is subject to modulation by dietary and genetic factors. AIMS: To determine PON1 activity in Greek migrants and Anglo-Celtic subjects recruited from the Melbourne Collaborative Cohort Study, and its relationship to coronary risk factors and dietary markers. METHODS: Greek (n = 127) and Anglo-Celtic (n = 128) participants in the MCCS were recruited. By design, there were approximately equal numbers of men and women and of diabetic and non-diabetic subjects. Subjects were screened for glucose tolerance, dyslipidaemia, hypertension and coronary heart disease. Plasma markers of diet (carotenoids, retinol, tocopherol, homocysteine) and inflammation (C-reactive protein) were assessed. Serum PON1 activity was determined spectrophotometrically using two substrates: paraoxon (paraoxonase) and phenylacetate (arylesterase). RESULTS: PON1 activity was significantly higher in the presence of hyperlipidaemia but otherwise did not vary by ethnicity, presence of coronary heart disease, diabetes, hypertension or smoking. Among subjects with the high activity phenotype (defined by the ratio of paraoxonase:arylesterase activity), paraoxonase activity correlated directly with circulating diet-derived carotenoid concentrations for Greeks, and inversely with homocysteine and C-reactive protein for Anglo-Celtics. No such associations were seen among subjects with the low activity phenotype. CONCLUSIONS: The data suggest that dietary modulation of atherosclerotic risk may vary according to PON1 phenotype.

Paraoxonase and other coronary risk factors in a community-based cohort.

Oxidative damage to circulating lipids and vascular tissues contributes to the initiation and progression of atherosclerosis. High density lipoprotein provides protection from atherosclerosis and the enzyme paraoxonase may contribute to this effect. The aim of the present study was to examine the trends in paraoxonase activity during the course of a community-directed life-style intervention, and relationships of paraoxonase activity to other coronary heart disease risk factors, in a cohort of Australian Aboriginal people.