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Biomedical subjects

Maria A O'Connell

Publications and source records attributed to Maria A O'Connell.

7 recordsLinked to original sources
PubMed2006

Seasonal childhood anaemia in West Africa is associated with the haptoglobin 2-2 genotype.

BACKGROUND: Anaemia is a major cause of morbidity and mortality for children in Africa. The plasma protein haptoglobin (Hp) binds avidly to free haemoglobin released following malaria-induced haemolysis. Haptoglobin polymorphisms result in proteins with altered haemoglobin-binding capacity and different antioxidant, iron-recycling, and immune functions. Previous studies examined the importance of haptoglobin polymorphism in malaria and iron homeostasis, but it is unknown whether haptoglobin genotype might be a risk factor for anaemia in children in a malaria-endemic area. METHODS AND FINDINGS: A cohort of 780 rural Gambian children aged 2-6 y was surveyed at the start and end of the malaria season. Samples were taken to assess haemoglobin (Hb) concentration, iron status (ferritin, zinc protoporphyrin, transferrin saturation, and soluble transferrin receptor concentration), haptoglobin concentration, alpha-1-antichymotrypsin (a measure of inflammation), and malaria parasites on blood film. We extracted DNA and genotyped for haptoglobin, sickle cell, and glucose-6-phosphate (G6PD) deficiency. Mean Hb levels fell over the malaria season. Children with the haptoglobin 2-2 genotype (17%) had a greater mean drop in Hb level over the malaria season (an 8.9 g/l drop; confidence interval [CI] 5.7, 12.1) compared to other children (a 5.1 g/l drop; CI 3.8, 6.4). In multivariate regression analysis, controlling for baseline Hb level, age group, village, malaria parasites on blood film, iron status, haptoglobin concentration, and G6PD deficiency, haptoglobin genotype predicted Hb level at the end of the malaria season (p = 0.0009, coefficient = -4.2). Iron status was not influenced by haptoglobin genotype. CONCLUSIONS: The finding that haptoglobin 2-2 genotype is a risk factor for anaemia in children in a malaria-endemic area may reflect the reduced ability of the Hp2-2 polymer to scavenge free haemoglobin-iron following malaria-induced haemolysis. The magnitude of the effect of haptoglobin genotype (4 g/l Hb difference, p = 0.0009) was comparable to that of G6PD deficiency or HbAS (3 g/l difference, p = 0.03; and 2 g/l difference, p = 0.68, respectively).

Anemia↗
PubMed2006

Role of protein kinase C delta in curcumin-induced antioxidant response element-mediated gene expression in human monocytes.

The Nrf2/antioxidant response element (ARE) signaling pathway plays a key role in activating cellular antioxidants, including heme oxygenase-1 (HO-1), NADPH quinone oxidoreductase-1 (NQO1), and glutathione. Protein kinase C (PKC) may also regulate these antioxidants, as PKC phosphorylates Nrf2 in vitro. This study examined the role of PKC in ARE-mediated gene regulation in human monocytes by curcumin, a potent inducer of the Nrf2/ARE pathway. Curcumin increased HO-1 and glutamyl cysteine ligase modulator (GCLM) expression and stimulated Nrf2 binding to the ARE. Curcumin also rapidly stimulated PKC phosphorylation and Ro-31-8220, a pan-PKC inhibitor, decreased curcumin-induced GCLM and HO-1 mRNA expression and ARE binding. Rottlerin (a PKC delta inhibitor) and PKC delta antisense oligonucleotides significantly inhibited curcumin-induced GCLM and HO-1 mRNA expression and ARE binding. Furthermore, a p38 MAP kinase inhibitor reduced GCLM and HO-1 expression and rottlerin inhibited curcumin-induced p38 phosphorylation. In summary, curcumin activates ARE-mediated gene expression in human monocytes via PKC delta, upstream of p38 and Nrf2.

Acetophenones↗
PubMed2006

Fruit and vegetable intakes and bone mineral status: a cross sectional study in 5 age and sex cohorts.

BACKGROUND: Evidence is increasing for positive effects of fruit and vegetable intakes on bone health. However, most of the studies to date were conducted in adults, and few reports included adolescents. OBJECTIVE: We explored the association between bone mineral status and fruit and vegetable intakes in adolescent boys and girls (aged 16-18 y), young women (aged 23-37 y), and older men and women (aged 60-83 y). DESIGN: Bone mineral measurements of the whole body, hip, and spine were made in all subjects by using dual-energy X-ray absorptiometry. Information on health and lifestyle and physical activity was obtained by questionnaire. Fruit, vegetable, and nutrient intakes were ascertained from 7-d food diaries. RESULTS: In adolescent boys and girls and older women, significant positive associations were observed between spine size-adjusted bone mineral content (SA-BMC) and fruit intake. In boys only, femoral neck SA-BMC was also significantly and positively associated with the intakes of both fruit and dietary vitamin C. No significant associations were found in the young women or older men, or between bone measurements and intake of vegetables alone (after adjustments) in any of the groups. CONCLUSIONS: Higher fruit and vegetable intakes may have positive effects on bone mineral status in both younger and older age groups, especially at the spine and femoral neck. The specific mechanisms remain to be ascertained, but vitamin C, other fruit-specific antioxidants, and lifestyle may play a role.

Adolescent↗
PubMed2005

Lipopolysaccharide-induced heme oxygenase-1 expression in human monocytic cells is mediated via Nrf2 and protein kinase C.

Monocytes play a key role in mobilization of the immune response during sepsis. In response to LPS, monocytes produce both proinflammatory mediators and regulatory proteins that counteract the inflammation and oxidative stress. In murine macrophages, LPS stimulates expression of heme oxygenase 1 (HO-1), a cytoprotective enzyme that catalyzes the degradation of heme. The HO-1 5'-untranslated region, similarly to other cytoprotective genes, contains antioxidant-response elements (AREs) that can bind the transcription factor NF-E2-related factor 2 (Nrf2). At present, the role of Nrf2 in LPS-induced HO-1 expression in monocytic cells has not been investigated. In this study, LPS induced HO-1 mRNA and protein expression in human monocytes and THP-1 cells. Nrf2 translocated from the cytosol to the nucleus in response to LPS and bound to the ARE site in the human HO-1 promoter. In addition, a dominant negative Nrf2 mutant inhibited LPS-induced HO-1 mRNA expression but not TNF-alpha mRNA expression in THP-1 cells. Ro-31-8220, a pan-protein kinase C (PKC) inhibitor, and Go6976, a classical PKC inhibitor, blunted LPS-induced HO-1 mRNA expression in monocytes and THP-1 cells. Both PKC inhibitors also blocked LPS-induced Nrf2 binding to the ARE. These results indicate that LPS-induced HO-1 expression in human monocytic cells requires Nrf2 and PKC.

Active Transport, Cell Nucleus↗
PubMed2005

Alpha-lipoic acid-induced heme oxygenase-1 expression is mediated by nuclear factor erythroid 2-related factor 2 and p38 mitogen-activated protein kinase in human monocytic cells.

OBJECTIVE: Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, plays a protective role in the vascular system. HO-1 induction inhibits cytokine production in macrophages. Antioxidants induce HO-1 expression in various cell types. Alpha-lipoic acid (ALA), a thiol-containing dietary antioxidant, exhibits protective effects in vascular disease and induces anti-inflammatory effects in monocytes. This study examined the effects of ALA on HO-1 expression in human monocytic cells. METHODS AND RESULTS: ALA time and dose-dependently induced HO-1 mRNA expression in THP-1 cells, with peak expression at 4 hours and returning to baseline by 24 hours. This correlated with an increase in HO-1 protein expression. ALA stimulated translocation of the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) into the nucleus and binding to a human HO-1 antioxidant response element (ARE) by 30 minutes. A dominant-negative Nrf2 inhibitor reduced ALA-induced HO-1 mRNA expression by 66%. Pretreatment with SB203580, a p38 mitogen-activated protein kinase inhibitor, reduced ALA-induced HO-1 mRNA expression by 75% and inhibited ALA-induced Nrf2 binding to the HO-1 ARE. CONCLUSIONS: These results demonstrate that ALA induces HO-1 expression in THP-1 monocytic cells via Nrf2 and p38. Further studies are required to investigate whether the protective effects of ALA in monocytes are mediated by HO-1.

Active Transport, Cell Nucleus↗
PubMed2003

Micronutrient deficiencies. Hohenheim Consensus Conference.

OBJECTIVE: The aim of this study was to consider the risk of micronutrient deficiencies and approaches for intervention, and to summarize existing knowledge and identify areas of ignorance. DESIGN: Experts from a range of relevant disciplines received and considered a series of questions related to aspects of the topic. INTERVENTION: The experts met and discussed the questions and arrived at a consensus. CONCLUSION: Though healthy balanced diet is available for the general European population, a few defined groups are at risk of micronutrient deficiencies. In addition, the intake of specific micronutrients such as iron, folic acid, vitamin D and vitamin B12 are often marginal. To overcome these deficiencies, either selected micronutrients or a mixture of different micronutrients might be recommended. However, to define and detect micronutrient deficiencies, specific biomarkers are only available for a few micronutrients (e. g. vitamin D, folic acid, vitamin C, iron). The definition of a risk group, based on scientific data, might be an appropriate way to justify intervention with supplements.

Aging↗