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Leibundgut G.,University of California at San Diego | Leibundgut G.,University of Basel | Scipione C.,University of Windsor | Yin H.,Institute for Nutritional science | And 8 more authors.
Journal of Lipid Research

Oxidized phospholipids (OxPLs) are present on apolipoprotein (a) [apo(a)] and lipoprotein (a) [Lp(a)] but the determinants influencing their binding are not known. The presence of OxPLs on apo(a)/Lp(a) was evaluated in plasma from healthy humans, apes, monkeys, apo(a)/Lp(a) transgenic mice, lysine binding site (LBS) mutant apo(a)/ Lp(a) mice with Asp55/57 → Ala 55/57 substitution of kringle (K) IV10)], and a variety of recombinant apo(a) [r-apo(a)] constructs. Using antibody E06, which binds the phosphocholine (PC) headgroup of OxPLs, Western and ELISA formats revealed that OxPLs were only present in apo(a) with an intact KIV10 LBS. Lipid extracts of purified human Lp(a) contained both E06- and nonE06-detectable OxPLs by tandem liquid chromatography-mass spectrometry (LC-MS/MS). Trypsin digestion of 17K r-apo(a) showed PC-containing OxPLs covalently bound to apo(a) fragments by LC-MS/MS that could be saponified by ammonium hydroxide. Interestingly, PCcontaining OxPLs were also present in 17K r-apo(a) with Asp57 → Ala57 substitution in KIV10 that lacked E06 immunoreactivity. In conclusion, E06- and nonE06-detectable OxPLs are present in the lipid phase of Lp(a) and covalently bound to apo(a). E06 immunoreactivity, reflecting pro-inflammatory OxPLs accessible to the immune system, is strongly influenced by KIV10 LBS and is unique to human apo(a), which may explain Lp(a)'s pro-atherogenic potential. Copyright © 2013 by the American Society for Biochemistry and Molecular Biology, Inc. Source

Papakostas S.,University of Turku | Vollestad L.A.,University of Oslo | Bruneaux M.,University of Turku | Aykanat T.,University of Turku | And 5 more authors.
Nature Communications

Understanding the factors that shape the evolution of gene expression is a central goal in biology, but the molecular mechanisms behind this remain controversial. A related major goal is ascertaining how such factors may affect the adaptive potential of a species or population. Here we demonstrate that temperature-driven gene expression changes in fish adapted to differing thermal environments are constrained by the level of gene pleiotropy estimated by either the number of protein interactions or gene biological processes. Genes with low pleiotropy levels were the main drivers of both plastic and evolutionary global expression profile changes, while highly pleiotropic genes had limited expression response to temperature treatment. Our study provides critical insights into the molecular mechanisms by which natural populations can adapt to changing environments. In addition to having important implications for climate change adaptation, these results suggest that gene pleiotropy should be considered more carefully when interpreting expression profiling data. © 2014 Macmillan Publishers Limited. All rights reserved. Source

Zhang Y.,Institute for Nutritional science | Gan Z.,Institute for Nutritional science | Gan Z.,Sanford Burnham Institute for Medical Research | Huang P.,Institute for Nutritional science | And 11 more authors.
Journal of Biological Chemistry

Background: PIAS proteins are implicated in the regulation of many transcription factors through distinct mechanisms. It remains largely unknown whether PIAS proteins exert metabolic actions. Results: PIAS1 repressed LXR-dependent up-regulation of lipogenic genes in a SUMOylation-independent manner. Conclusion: PIAS1 could act as a lipogenic regulator by negatively modulating LXRs. Significance: These findings reveal a regulatory role for PIAS proteins in lipid metabolism. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Yong Y.,Institute for Nutritional science | Ding H.,Institute for Nutritional science | Fan Z.,Institute for Nutritional science | Luo J.,Institute for Nutritional science | And 2 more authors.
Neurochemical Research

Lithium has been used for the treatment of bipolar mood disorder and is shown to have neuroprotective properties. Since lithium inhibits the activity of glycogen synthase kinase 3 (GSK3) which is implicated in various human diseases, particularly neurodegenerative diseases, the therapeutic potential of lithium receives great attention. Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by the pathological loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Intranigral injection of the catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) causes selective and progressive degeneration of dopaminergic neurons in SNpc, and is a commonly used animal model of PD. The current study was designated to determine whether lithium is effective in alleviating 6-OHDA-induced neurodegeneration in the SNpc of rats. We demonstrated that chronic subcutaneous administration of lithium inhibited GSK3 activity in the SNpc, which was evident by an increase in phosphorylation of GSK3β at serine 9, cyclin D1 expression, and a decrease in tau phosphorylation. 6-OHDA did not affect GSK3 activity in the SNpc. Moreover, lithium was unable to alleviate 6-OHDA-induced degeneration of SNpc dopaminergic neurons. The results suggest that GSK3 is minimally involved in the neurodegeneration in the rat 6-OHDA model of PD. © Springer Science+Business Media, LLC 2010. Source

Mu M.,Institute for Nutritional science | Mu M.,Zhejiang University | Wu A.,Zhejiang University | An P.,Institute for Nutritional science | And 6 more authors.
British Journal of Nutrition

Hepcidin, a key regulator of Fe homeostasis, is an ideal drug target for treating patients with Fe disorders such as haemochromatosis, anaemia of chronic inflammation and Fe-deficiency anaemia. However, whether (and how) traditional Chinese black foods (e.g. black soyabeans) target hepcidin and improve Fe-deficiency anaemia remains unclear. Herein, we report that black soyabean seed coat extract (BSSCE) can potently inhibit the in vitro and in vivo expression of hepcidin. In the present study, in cells treated with 200 μg/ml BSSCE, hepcidin expression was found to be reduced to only 6 % of the control levels (P< 0.01). An AIN-76A diet containing 2 % BSSCE was fed to 8-week-old male C57BL/6 mice for 0, 1, 7, 15 or 30 d; importantly, compared with the day 0 group, the day 7 group exhibited nearly a 50 % decrease in hepatic hepcidin expression (P< 0.01), a 35 % decrease in splenic Fe concentrations (P< 0.05) and a 135 % increase in serum Fe concentrations (P< 0.05). Mechanistically, the effect of BSSCE on hepcidin expression was mediated via a reduction in the phosphorylation levels of mothers against decapentaplegic homolog proteins (Smad)1/5/8. Consequently, the mice in the day 30 group exhibited large increases in erythrocyte counts (111 % v. day 0, P< 0.01), Hb concentrations (109 %, P< 0.01) and haematocrit values (108 %, P< 0.01). In conclusion, these results indicate that black soyabean extract regulates Fe metabolism by inhibiting the expression of hepcidin. This finding can be used to optimise the intervention of patients with hepcidin-related diseases, including Fe-deficiency anaemia. © The Authors 2013. Source

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