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Promotion of Cellular NAD+ Anabolism: Therapeutic Potential for Oxidative Stress in Ageing and Alzheimer's Disease(2008) Braidy, Nady; Guillemin, Gilles; Grant, RossJournal ArticleOxidative imbalance is a prominent feature in Alzheimer's disease and ageing. Increased levels of reactive oxygen species (ROS) can result in disordered cellular metabolism due to lipid peroxidation, protein-cross linking, DNA damage and the depletion of nicotinamide adenine dinucleotide (NAD+). NAD+ is a ubiquitous pyridine nucleotide that plays an essential role in important biological reactions, from ATP production and secondary messenger signalling, to transcriptional regulation and DNA repair. Chronic oxidative stress may be associated with NAD+ depletion and a subsequent decrease in metabolic regulation and cell viability. Hence, therapies targeted toward maintaining intracellular NAD+ pools may prove efficacious in the protection of age-dependent cellular damage, in general, and neurodegeneration in chronic central nervous system inflammatory diseases such as Alzheimer's disease, in particular.
(2009) Shen, Bojiang; Bhargav, Divya; Wei, Ai-Qun; Williams, Lisa; Diwan, AshishJournal ArticleBone morphogenetic protein-13 (BMP-13) plays an important role in skeletal development. In the light of a recent report that mutations in the BMP-13 gene are associated with spine vertebral fusion in Klippel-Feil syndrome, we hypothesized that BMP-13 signaling is crucial for regulating embryonic endochondral ossification. In this study, we found that BMP-13 inhibited the osteogenic differentiation of human bone marrow multipotent mesenchymal stromal cells (BM MSCs) in vitro. The endogenous BMP-13 gene expression in MSCs was examined under expansion conditions. The MSCs were then induced to differentiate into osteoblasts in osteo-inductive medium containing exogenous BMP-13. Gene expression was analysed by real-time PCR. Alkaline phosphatase (ALP) expression and activity, proteoglycan (PG) synthesis and matrix mineralization were assessed by cytological staining or ALP assay. Results showed that endogenous BMP-13 mRNA expression was higher than BMP-2 or -7 during MSC growth. BMP-13 supplementation strongly inhibited matrix mineralization and ALP activity of osteogenic differentiated MSCs, yet increased PG synthesis under the same conditions. In conclusion, BMP-13 inhibited osteogenic differentiation of MSCs, implying that functional mutations or deficiency of BMP-13 may allow excess bone formation. Our finding provides an insight into the molecular mechanisms and the therapeutic potential of BMP-13 in restricting pathological bone formation.
(2005) Stephenson, Niamh; Webb, Cammi; Carman, MarinaReportThis monograph outlines some contemporary explorations of the promises and challenges of approaching HIV through the framework of human rights. It includes an introduction and six chapters: • A public health dilemma: the vexed question of Voluntary Counselling and Testing (by Susan Kippax) • HIV testing and human rights in the era of scaling up access to treatments (by David Buchanan) • Ethical issues in trials of HIV prevention (by John Kaldor and Iona Millwood) • Power, prejudice and prevention: can research advance social justice? (by Bridge Haire) • Re-thinking human rights and the HIV epidemic: a reflection on power and goodness (by Elizabeth Reid) • HIV and human rights: through an East African prism (Michael Burke)
(2001) O'Sullivan, Anthony; Martin, Allison; Brown, MarkJournal ArticleThere is a sexual dimorphism in body fat in humans. Adipose tissue increases with puberty and early pregnancy in women, suggesting gonadal steroids can influence body fat. Previously, we have observed that oral estrogen, compared with transdermal estrogen, reduced postprandial lipid oxidation and increased body fat, possibly due to suppressed hepatic lipid oxidation. If estrogen effects lipid oxidation, we predicted that subjects with significantly different endogenous estrogen production would oxidize lipids at different rates. The aim of this study was to compare energy metabolism in 12 pregnant (19 wk gestation, 29 ± 1 yr, 1.66 ± 0.02 m, 73.5 ± 2.4 kg), 11 nonpregnant premenopausal (29 ± 2 yr, 1.68 ± 0.02 m, 63.1 ± 1.8 kg), and 28 postmenopausal (58 ± 1 yr, 1.62 ± 0.01 m, 69.9 ± 1.0 kg) women who were not receiving estrogen, and to relate these findings to endogenous estrogen concentrations. All women underwent indirect calorimetry under identical situations in the basal and postprandial state following a standard mixed meal. Basal (5998 ± 184 vs. 5712 ± 184 vs. 5800 ± 121 kJ·24 h, respectively) and postprandial energy expenditure (7172 ± 239 vs. 6964 ± 210 vs. 6955 ± 147 kJ·24 h) was similar among groups. However, basal lipid oxidation was reduced in pregnant (45.3 ± 6.1 mg/min, P < 0.05) and nonpregnant women (44.5 ± 6.3 mg/min, P < 0.05) compared with postmenopausal women (58.4 ± 2.9 mg/min). Postprandial lipid oxidation differed among groups, being least in pregnant women (8.8 ± 6.2 mg/min) compared with nonpregnant (28.9 ± 6.4 mg/min, P < 0.04) and postmenopausal (48.1 ± 4.0 mg/min, P = 0.0001) women. There was a significant reciprocal increase in postprandial carbohydrate oxidation. Mean postprandial glucose levels were slightly but nonsignificantly higher in pregnant women. Insulin levels were significantly higher in postmenopausal compared nonpregnant, but not pregnant, women. In a multiple regression analysis, serum estradiol (log transformed) correlated negatively with postprandial lipid oxidation (r = -0.66, P = 0.0001) and positively with postprandial nonesterified free fatty acid levels, whereas no correlation was found with postprandial insulin, glucose, fat free mass, and fat mass. In summary, postprandial lipid oxidation is reduced in pregnancy compared with that in healthy nonpregnant women, who in turn have lower postprandial lipid oxidation than postmenopausal women. This implies that the premenopausal years and early pregnancy are states of efficient fat storage, possibly mediated through reduced lipid oxidation due to estrogen, therefore increasing body fat for reproduction, thus supporting the notion that fat mass can be regulated.