Institute for Nutritional science
Institute for Nutritional science
Feng Y.,Institute for Nutritional science |
Feng Y.,University of Chinese Academy of Sciences |
Yan T.,Institute for Nutritional science |
Yan T.,University of Chinese Academy of Sciences |
And 14 more authors.
Journal of Neuroscience Research | Year: 2010
Axon degeneration is supposed to be a therapeutic target for treating neurodegenerative diseases. Mauthner cells (M-cells) are ideal for studying axons in vivo because of their limited numbers, large size, and long axons. In this study, we labeled M-cells by single-cell electroporation with plasmids expressing DsRed2 or EGFP. Injury-induced axon degeneration in labeled Mcell was imaged under a confocal microscope, and we found that the Mauthner axons started to degenerate about 24 hr after lesion. The WldS protein containing full-length Nmnat1 is well-known for its axon-protective function in many systems. Overexpression of WldS in M-cells also greatly delayed axon degeneration in live zebrafish. Nmnat2 is the only Nmnat highly expressed in brain. Here we demonstrated that overexpression of Nmnat2 in M-cells significantly delayed axon degeneration in vivo, and disruption of the NAD synthesis activity of Nmnat2 markedly attenuated its axon-protective function. All these data show that injury-induced axon degeneration of M-cell has a mechanism similar to that in mammalians and would be a valuable model for studying axon degeneration in vivo. © 2010 Wiley-Liss, Inc.
Deng J.,Institute for Nutritional science |
Yuan F.,Institute for Nutritional science |
Guo Y.,Institute for Nutritional science |
Xiao Y.,Institute for Nutritional science |
And 6 more authors.
Diabetes | Year: 2017
Although many functions of activating transcription factor 4 (ATF4) are identified, a role of ATF4 in the hypothalamus in regulating energy homeostasis is unknown. Here, we generated adult-onset agouti-related peptide neuron-specific ATF4 knockout (AgRP-ATF4 KO) mice and found that these mice were lean, with improved insulin and leptin sensitivity and decreased hepatic lipid accumulation. Furthermore, AgRP-ATF4 KO mice showed reduced food intake and increased energy expenditure, mainly because of enhanced thermogenesis in brown adipose tissue. Moreover, AgRPATF4 KO mice were resistant to high-fat diet-induced obesity, insulin resistance, and liver steatosis and maintained at a higher body temperature under cold stress. Interestingly, the expression of FOXO1 was directly regulated by ATF4 via binding to the cAMP-responsive element site on its promoter in hypothalamic GT1-7 cells. Finally, Foxo1 expression was reduced in the arcuate nucleus (ARC) of the hypothalamus of AgRPATF4 KO mice, and adenovirus-mediated overexpression of FOXO1 in ARC increased the fat mass in AgRP-ATF4 KO mice. Collectively, our data demonstrate a novel function of ATF4 in AgRP neurons of the hypothalamus in energy balance and lipid metabolism and suggest hypothalamic ATF4 as a potential drug target for treating obesity and its related metabolic disorders. © 2017 by the American Diabetes Association.
Wu Y.,University of California at Riverside |
Wu Y.,University of Medicine and Science |
Lee S.,University of California at Riverside |
Bobadilla S.,University of California at Riverside |
And 3 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2017
High levels of glucose (HG) induce reactive oxygen species-mediated oxidative stress in endothelial cells (ECs), which leads to endothelial dysfunction and tissue damage. However, the molecular mechanisms involved in HG-induced endothelial oxidative stress and damage remain elusive. Here we show that cellular ATP level-modulated p53 Thr55 phosphorylation plays a critical role in the process. Upon HG exposure, the elevated ATP levels induced the kinase activity of TAF1 (TBP-associated factor 1), which leads to p53 Thr55 phosphorylation. The phosphorylation dissociates p53 from the glutathione peroxidase 1 (GPX1) promoter and results in reduction of GPX1 expression. Inhibition of TAF1-mediated p53 Thr55 phosphorylation abolished those events, supporting the role of TAF1 in sensing cellular ATP elevation and in regulating GPX1 expression under the HG condition. Importantly, treating cells with HG increased intracellular H2O2 and cell apoptosis, as well as suppressed nitric oxide (NO) bioavailability and tube network formation. These effects were also remarkably reversed by inhibition of TAF1 and p53 Thr55 phosphorylation. We conclude that HG leads to endothelial dysfunction via TAF1-mediated p53 Thr55 phosphorylation and subsequent GPX1 inactivation. Our study thus revealed a novel mechanism by which HG induces endothelial oxidative stress and damage and possibly provided an avenue for targeted therapy for diabetes-associated cardiovascular diseases. © 2017 Elsevier B.V.
Liu H.,Institute for Nutritional science |
Yu J.,Institute for Nutritional science |
Xia T.,Institute for Nutritional science |
Xiao Y.,Institute for Nutritional science |
And 7 more authors.
Biochemical Journal | Year: 2014
Insulin resistance is a major hallmark of metabolic syndromes, including Type 2 diabetes. Although numerous functions of SGK1 (serum- and glucocorticoid-regulated kinase 1) have been identified, a direct effect of SGK1 on insulin sensitivity has not been previously reported. In the present study, we generated liver-specific SGK1-knockout mice and found that these mice developed glucose intolerance and insulin resistance. We also found that insulin signalling is enhanced or impaired in Hep1-6 cells infected with adenoviruses expressing SGK1 (Ad-SGK1) or shRNA directed against the coding region of SGK1 (Ad-shSGK1) respectively. In addition, we determined that SGK1 inhibits ERK1/2 (extracellular-signal-regulated kinase 1/2) activity in liver and Ad-shERK1/2-mediated inhibition of ERK1/2 reverses the attenuated insulin sensitivity in Ad-shSGK1 mice. Finally, we found that SGK1 functions are compromised under insulinresistant conditions and overexpression of SGK1 by Ad-SGK1 significantly ameliorates insulin resistance in both glucosaminetreated HepG2 cells and livers of db/db mice, a genetic model of insulin resistance. © 2014 Biochemical Society.
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 | Year: 2013
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.
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 | Year: 2014
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.
PubMed | Zhejiang Agriculture And forestry University, CAS Shanghai Institutes for Biological Sciences and Institute for Nutritional science
Type: | Journal: Cancer research | Year: 2017
Aberrant RNA splicing is recognized to contribute to cancer pathogenesis but the underlying mechanisms remain mainly obscure. Here we report that the splicing factor SRSF2 is upregulated frequently in human hepatocellular carcinoma (HCC) where this event is associated with poor prognosis in patients. RNA-seq and other molecular analyses were used to identify SRSF2-regulated alternative splicing events. SRSF2 binding within an alternative exon was associated with its inclusion in the RNA, whereas SRSF2 binding in a flanking constitutive exon was associated with exclusion of the alternative exon. Notably, cancer-associated splice variants upregulated by SRSF2 in clinical specimens of HCC were found to be crucial for pathogenesis and progression in hepatoma cells, where SRSF2 expression increased cell proliferation and tumorigenic potential by controlling expression of these variants. Our findings identify SRSF2 as a key regulator of RNA splicing dysregulation in cancer, with possible clinical implications as a candidate prognostic factor in HCC patients.
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 | Year: 2011
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.
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 | Year: 2014
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.