Targeted Metabolomics Identifies Glucuronides of Dietary Phytoestrogens as a Major Class of MRP3 Substrates In Vivo

2009 ◽  
Vol 137 (5) ◽  
pp. 1725-1735 ◽  
Author(s):  
Koen van de Wetering ◽  
Wouter Feddema ◽  
J. Bernd Helms ◽  
Jos F. Brouwers ◽  
Piet Borst
Keyword(s):  
Targeted Metabolomics ◽  
Major Class

Genetic Modifiers of Tauopathy in Drosophila

Genetics ◽  
2003 ◽  
Vol 165 (3) ◽  
pp. 1233-1242
Author(s):  
Joshua M Shulman ◽  
Mel B Feany
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Genetic Modifier ◽  
Genetic Modifiers ◽  
Protein Tau ◽  
Major Class ◽  
Drosophila Model ◽  
Tau Kinases

Abstract In Alzheimer's disease and related disorders, the microtubule-associated protein Tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles. Mutations in the tau gene cause familial frontotemporal dementia. To investigate the molecular mechanisms responsible for Tau-induced neurodegeneration, we conducted a genetic modifier screen in a Drosophila model of tauopathy. Kinases and phosphatases comprised the major class of modifiers recovered, and several candidate Tau kinases were similarly shown to enhance Tau toxicity in vivo. Despite some clinical and pathological similarities among neurodegenerative disorders, a direct comparison of modifiers between different Drosophila disease models revealed that the genetic pathways controlling Tau and polyglutamine toxicity are largely distinct. Our results demonstrate that kinases and phosphatases control Tau-induced neurodegeneration and have important implications for the development of therapies in Alzheimer's disease and related disorders.

scholarly journals Leishmania mexicana Mutants Lacking Glycosylphosphatidylinositol (GPI):Protein Transamidase Provide Insights into the Biosynthesis and Functions of GPI-anchored Proteins

2000 ◽  
Vol 11 (4) ◽  
pp. 1183-1195 ◽  
Author(s):  
James D. Hilley ◽  
Jody L. Zawadzki ◽  
Malcolm J. McConville ◽  
Graham H. Coombs ◽  
Jeremy C. Mottram
Keyword(s):  
Normal Growth ◽  
Surface Proteins ◽  
Host Cells ◽  
Mammalian Host ◽  
Putative Protein ◽  
Major Class ◽  
Major Surface Proteins ◽  
Major Surface

The major surface proteins of the parasitic protozoonLeishmania mexicana are anchored to the plasma membrane by glycosylphosphatidylinositol (GPI) anchors. We have cloned the L. mexicana GPI8 gene that encodes the catalytic component of the GPI:protein transamidase complex that adds GPI anchors to nascent cell surface proteins in the endoplasmic reticulum. Mutants lacking GPI8 (ΔGPI8) do not express detectable levels of GPI-anchored proteins and accumulate two putative protein–anchor precursors. However, the synthesis and cellular levels of other non–protein-linked GPIs, including lipophosphoglycan and a major class of free GPIs, are not affected in the ΔGPI8 mutant. Significantly, the ΔGPI8 mutant displays normal growth in liquid culture, is capable of differentiating into replicating amastigotes within macrophages in vitro, and is infective to mice. These data suggest that GPI-anchored surface proteins are not essential to L. mexicana for its entry into and survival within mammalian host cells in vitro or in vivo and provide further support for the notion that free GPIs are essential for parasite growth.

scholarly journals Effects of the kinase inhibitor sorafenib on heart, muscle, liver and plasma metabolism in vivo using non-targeted metabolomics analysis

2017 ◽  
Vol 174 (24) ◽  
pp. 4797-4811 ◽  
Author(s):  
Brian C Jensen ◽  
Traci L Parry ◽  
Wei Huang ◽  
Ju Youn Beak ◽  
Amro Ilaiwy ◽  
...  
Keyword(s):  
Heart Muscle ◽  
Kinase Inhibitor ◽  
Targeted Metabolomics ◽  
Metabolomics Analysis

Gene expression in Brassica tissues and species following heat shock

1988 ◽  
Vol 66 (12) ◽  
pp. 1303-1311 ◽  
Author(s):  
Chris L. Baszczynski
Keyword(s):  
Molecular Weight ◽  
Heat Shock ◽  
General Pattern ◽  
Brassica Species ◽  
Low Molecular Weight ◽  
Major Class ◽  
Polypeptide Synthesis ◽  
Small Hsps

Several tissues from the three oilseed Brassica species have been analyzed for polypeptides synthesized in vivo and in vitro under control (23 °C) and heat-shock conditions. The various tissues have characteristically unique patterns of polypeptide synthesis, the general pattern being maintained following heat shock. In addition, all tissues exhibit synthesis of a set of qualitatively similar heat shock protein (HSP) that differ, however, in relative intensity among tissues. Synthesis of control polypeptides as well as high molecular-weight HSP is similar in hypocotyls of the three genomically interrelated species B. napus, B. campestris, and B. juncea; however, the three species exhibit variation in in vivo and in vitro synthesized polypeptides in the 18 000–27 000 molecular-weight region, with several prominent differences in the number and distribution of the major class of low molecular-weight (20 000) HSP. Several of the HSP appear to be unique to B. juncea and one is unique to B. napus. Immunochemical studies of in vitro synthesized Brassica polypeptides using antisera to maize HSP of molecular weight 18 000 substantiate the observed differences in synthesis of various members of the 20 000 molecular-weight HSP family among the three species, and indicate that the Brassica low molecular-weight HSP are immunologically similar to the small HSPs of other plants including maize, soybean, pea, and Arabidopsis.

scholarly journals Histidine triad nucleotide-binding protein 2 protects cardiomyocytes via maintaining NAD homeostasis in virto and in vivo

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
F Mengkang ◽  
Y.I.N Huang ◽  
J Qian
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Molecular Docking ◽  
Nucleotide Binding ◽  
Metabolic Status ◽  
Funding Source ◽  
Targeted Metabolomics ◽  
Pet Ct

Abstract Background Heart failure (HF) is the end-stage of most heart diseases with poor clinical outcomes. The mitochondrial dysfunction is a critical therapeutic target in HF, and the histidine triad nucleotide-binding (HINT2) protein has been shown to enhance energy metabolism in liver. However, the role of HINT2 in HF remains unclear. Purpose To explore the role of the histidine triad nucleotide-binding 2 (HINT2) protein in heart failure. Methods Neonatal mouse ventricle myocytes (NMVMs) and myocardial infarction-induced heart failure mice were used for in vitro or in vivo experiments. Adenovirus (ADV) and adeno-associated virus serum type 9 (AAV9) vectors were used to regulate HINT2 expression. The expression of HINT2 was determined by quantifying the mRNA and protein levels. Cell survival was analysed using the CCK-8 kit and TUNEL staining. Mitochondrial function was determined by the mitochondrial membrane potential and oxygen consumption rates. AAV9-HINT2 was injected 24 h post myocardial infarction following which transthoracic echocardiography and histological analyses were performed after 4 weeks. Positron emission tomography tomography-computed tomography (PET/CT) and targeted metabolomics analyses were used to explore the metabolic status in vivo. NAD levels were measured using a colorimetric kit. Computer-simulated rigid body molecular docking was performed using AUTODOCK4. Molecule binding kinetics assays were performed using biolayer interferometry. Results After 12 hours hypoxia stimuli, HINT2 was down regulated. ADV-HINT2 induced HINT2 overexpression improved NMVMs survival and reduced apoptosis after hypoxia. MMP was reduced in ADV-shHINT2 group and was preserved in ADV-HINT2 group under hypoxia. HINT2 overexpressed NMVMs showed less reduction in basal, ATP-linked and maximum OCR after hypoxia stimuli. In vivo experiment, showed that cardiac function and metabolic status was preserved by HINT2 overexpression. PET/CT displayed glucose uptake ability was significantly reduced in in failing heart, which was preserved by overexpression of HINT2. Targeted metabolomics analysis showed that nicotinate and nicotinamide metabolism pathway was regulated by HINT2, in which oxidized state NAD (NAD+) and redox state NAD (NADH) was increased in AAV9-HINT2 group. NAD concentration was detected in NMVMs. HINT2 can improve total NAD level rather than ratio of NAD+/NADH, and its effect was limited into mitochondria.HINT2 overexpression restored mitochondrial NAD levels; this was dependent on nicotinamide mononucleotide (NMN). Using computer-simulated molecular docking analysis and biolayer interferometry, we observed that HINT2 potentially binds and associates with NMN. Conclusion In summary, these findings demonstrate that the HINT2 is beneficial to preserve the heart function and metabolism in the HF murine model after acute MI, and this positive effect may due to the maintenance of mitochondrial NAD homeostasis. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Natural Science Foundation of China (Grant Nos: 81970295, 81870267)

scholarly journals Processing of the asparagine-linked oligosaccharides of secreted and intracellular forms of the vesicular stomatitis virus G protein: in vivo evidence of Golgi apparatus compartmentalization.

1985 ◽  
Vol 101 (2) ◽  
pp. 460-469 ◽  
Author(s):  
C A Gabel ◽  
J E Bergmann
Keyword(s):  
Sialic Acid ◽  
Golgi Apparatus ◽  
G Protein ◽  
Vesicular Stomatitis Virus ◽  
Vesicular Stomatitis Virus Glycoprotein ◽  
Complex Type ◽  
Major Class ◽  
Vesicular Stomatitis ◽  
High Mannose

The structures of the asparagine-linked oligosaccharides of several variant forms of the vesicular stomatitis virus glycoprotein transiently expressed from cloned cDNAs have been determined. Glycopeptides isolated from forms of the G protein that reach the cell surface or that are secreted into the medium are virtually identical; they contain complex-type oligosaccharides whose nonreducing ends terminate in galactose and sialic acid residues. In contrast, forms of the G protein that remain intracellular possess oligosaccharides at intermediate stages in the processing pathway. One deletion mutant, delta 1473, codes for a protein that remains in the rough endoplasmic reticulum (Rose, J. K., and J. E. Bergmann, 1982, Cell, 30:753-762) and contains only high mannose-type oligosaccharides. Another mutant, delta 1554, codes for a glycoprotein that contains oligosaccharides of primarily two classes. One class is of the high mannose type and is similar to those found on the protein coded for by delta 1473. However, the major class contains biantennary and more highly branched complex-type oligosaccharides that terminate in N-acetylglucosamine rather than galactose or sialic acid residues. These data suggest that the protein coded for by delta 1554 migrates to the Golgi apparatus, but does not enter the more distal compartment(s) of the organelle which contains galactosyl- and sialyltransferases.

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