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31.
Sreepradha Eswaran Anshu Babbar Hannah K. Drescher Thomas C. A. Hitch Thomas Clavel Moritz Muschaweck Thomas Ritz Daniela C. Kroy Christian Trautwein Norbert Wagner Angela Schippers 《International journal of molecular sciences》2021,22(14)
(1) Background: Non-alcoholic fatty liver disease (NAFLD) is a growing global health problem. NAFLD progression involves a complex interplay of imbalanced inflammatory cell populations and inflammatory signals such as reactive oxygen species and cytokines. These signals can derive from the liver itself but also from adipose tissue or be mediated via changes in the gut microbiome. We analyzed the effects of a simultaneous migration blockade caused by L-selectin-deficiency and an enhancement of the anti-oxidative stress response triggered by hepatocytic Kelch-like ECH-associated protein 1 (Keap1) deletion on NAFLD progression. (2) Methods: L-selectin-deficient mice (Lsel−/−Keap1flx/flx) and littermates with selective hepatic Keap1 deletion (Lsel−/−Keap1Δhepa) were compared in a 24-week Western-style diet (WD) model. (3) Results: Lsel−/−Keap1Δhepa mice exhibited increased expression of erythroid 2-related factor 2 (Nrf2) target genes in the liver, decreased body weight, reduced epidydimal white adipose tissue with decreased immune cell frequencies, and improved glucose response when compared to their Lsel−/−Keap1flx/flx littermates. Although WD feeding caused drastic changes in fecal microbiota profiles with decreased microbial diversity, no genotype-dependent shifts were observed. (4) Conclusions: Upregulation of the anti-oxidative stress response improves metabolic changes in L-selectin-deficient mice but does not prevent NAFLD progression and shifts in the gut microbiota. 相似文献
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George M. Burslem Hannah F. Kyle Dr. Alexander L. Breeze Dr. Thomas A. Edwards Prof. Adam Nelson Dr. Stuart L. Warriner Prof. Andrew J. Wilson 《Chembiochem : a European journal of chemical biology》2014,15(8):1083-1087
The therapeutically relevant hypoxia inducible factor HIF‐1α–p300 protein–protein interaction can be orthosterically inhibited with α‐helix mimetics based on an oligoamide scaffold that recapitulates essential features of the C‐terminal helix of the HIF‐1α C‐TAD (C‐terminal transactivation domain). Preliminary SAR studies demonstrated the important role of side‐chain size and hydrophobicity/hydrophilicity in determining potency. These small molecules represent the first biophysically characterised HIF‐1α–p300 PPI inhibitors and the first examples of small‐molecule aromatic oligoamide helix mimetics to be shown to have a selective binding profile. Although the compounds were less potent than HIF‐1α, the result is still remarkable in that the mimetic reproduces only three residues from the 42‐residue HIF‐1α C‐TAD from which it is derived. 相似文献
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One Question,Multiple Answers: Biochemical and Biophysical Screening Methods Retrieve Deviating Fragment Hit Lists 下载免费PDF全文
Dr. Johannes Schiebel Nedyalka Radeva Dr. Helene Köster Dr. Alexander Metz Timo Krotzky Dr. Maren Kuhnert Prof. Wibke E. Diederich Prof. Andreas Heine Dr. Lars Neumann Dr. Cedric Atmanene Dominique Roecklin Dr. Valérie Vivat‐Hannah Dr. Jean‐Paul Renaud Dr. Robert Meinecke Dr. Nina Schlinck Dr. Astrid Sitte Franziska Popp Dr. Markus Zeeb Prof. Gerhard Klebe 《ChemMedChem》2015,10(9):1511-1521
Fragment‐based lead discovery is gaining momentum in drug development. Typically, a hierarchical cascade of several screening techniques is consulted to identify fragment hits which are then analyzed by crystallography. Because crystal structures with bound fragments are essential for the subsequent hit‐to‐lead‐to‐drug optimization, the screening process should distinguish reliably between binders and non‐binders. We therefore investigated whether different screening methods would reveal similar collections of putative binders. First we used a biochemical assay to identify fragments that bind to endothiapepsin, a surrogate for disease‐relevant aspartic proteases. In a comprehensive screening approach, we then evaluated our 361‐entry library by using a reporter‐displacement assay, saturation‐transfer difference NMR, native mass spectrometry, thermophoresis, and a thermal shift assay. While the combined results of these screening methods retrieve 10 of the 11 crystal structures originally predicted by the biochemical assay, the mutual overlap of individual hit lists is surprisingly low, highlighting that each technique operates on different biophysical principles and conditions. 相似文献
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The analysis of almost 200 Scottish Sphagnum moss samples collected over the past 170 years has revealed trends in the isotopic composition of lead similar to those previously established for dated Scottish lake sediments and peat bogs, lending credibility to these proxy records of atmospheric lead contamination and deposition. The effect of temporal variations in contributions from sources such as smelting of indigenous lead ores (206Pb/207Pb approximately 1.16-1.18), coal combustion (206Pb/207Pb approximately 1.17-1.19), and the use of imported Australian lead (206Pb/207Pb approximately 1.04) was clearly seen in the Scottish moss 206Pb/207Pb record. This showed some differences from the corresponding archival herbage record for the south of England, where the initial influence of Australian lead occurred earlier, at the end of the 19th century. A significant decline from a 206Pb/ 207Pb value of approximately 1.17 in the Scottish moss record began in the 1920s and continued until the 1980s (206Pb/207Pb approximately 1.12). The success of measures to reduce lead emissions to the atmosphere over the past 20 years in the U.K., in particular from petrol-engined vehicles using alkyl lead additives manufactured primarily from Australian lead, is evident in both the increasing 206Pb/207Pb ratio and falling lead concentration data for Scottish moss. 相似文献
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JG Mercer N Hoggard LM Williams CB Lawrence LT Hannah PJ Morgan P Trayhurn 《Canadian Metallurgical Quarterly》1996,8(10):733-735
Leptin, the protein product of the adipose tissue-specific ob (obese) gene (1), reduces the body weight, adiposity and food intake of obese ob/ob mice on peripheral or central injection (2, 3, 4). [125I]leptin binding has been detected in mouse choroid plexus (5), from which a leptin receptor gene was expression cloned (5). The gene has at least 6 splice variants (6, 7). Leptin receptor mRNA was localized in the hypothalamus by in situ hybridization being particularly abundantly expressed in the arcuate nucleus (8). There is evidence linking the physiological effects of injected leptin with hypothalamic neuropeptide Y (9, 10) (NPY), which has potent central effects on food intake and energy balance (11), and is also expressed in the arcuate nucleus. Here we report dual in situ hybridization studies for leptin receptor and NPY gene expression in the mouse arcuate nucleus, where the majority of cells examined expressed both genes. This provides the first direct evidence that leptin acts on cells that express NPY mRNA. 相似文献
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Mounting media for examining rubber reinforced copolymers using the phase microscope are described. The mounting media are based on cinnamaldehyde as the basic solvent with suitable adjustments made depending upon the copolymer under examination. 相似文献