A Rac1–Aurora A–MCAK signaling pathway mediates endothelial cell polarization and directional migration by promoting regional differences in microtubule dynamics in the leading and trailing cell edges.
The nitrogen isotope composition (δ¹⁵N) of different amino acids carries different dietary information. We hypothesized that transamination and de novo synthesis create three groups that largely explain their dietary information. Rats were fed with ¹⁵N-labeled amino acids. The redistribution of the dietary ¹⁵N labels among the muscular amino acids was analyzed. Subsequently, the labeling was changed and the nitrogen isotope turnover was analyzed. The amino acids had a common nitrogen half-life of ∼20 d, but differed in δ¹⁵N. Nontransaminating and essential amino acids largely conserved the δ¹⁵N of the source and, hence, trace the origin in heterogeneous diets. Nonessential and nontransaminating amino acids showed a nitrogen isotope composition between their dietary composition and that of their de novo synthesis pool, likely indicating their fraction of de novo synthesis. The bulk of amino acids, which are transaminating, derived their N from a common N pool and hence their δ¹⁵N was similar.
The synthesis of a series of platinum complexes containing cyclooctadiene ligands with the general structure PtMeL(R-cod) (where L = Cl, I, nC 3 F 7 , iC 3 F 7 , nC 8 F 17 , Me, aryl, alkynyl and R = H, Me, Et, iPr, nBu, iBu, nHex, Ph) is presented. All complexes are remarkably stable and were obtained in excellent yields. Their structure in both solution and the solid state were explored by crystal structures and multinuclear ( 1 H, 13 C, 19 F, 195 Pt) NMR spectroscopy. Cytotoxicity experiments with selected complexes in HeLa cells revealed higher toxicity in comparison to that of cisplatin for most of the structures.
ObjectiveThe metabolic role of d-serine, a non-proteinogenic NMDA receptor co-agonist, is poorly understood. Conversely, inhibition of pancreatic NMDA receptors as well as loss of the d-serine producing enzyme serine racemase have been shown to modulate insulin secretion. Thus, we aim to study the impact of chronic and acute d-serine supplementation on insulin secretion and other parameters of glucose homeostasis.MethodsWe apply MALDI FT-ICR mass spectrometry imaging, NMR based metabolomics, 16s rRNA gene sequencing of gut microbiota in combination with a detailed physiological characterization to unravel the metabolic action of d-serine in mice acutely and chronically treated with 1% d-serine in drinking water in combination with either chow or high fat diet feeding. Moreover, we identify SNPs in SRR, the enzyme converting L-to d-serine and two subunits of the NMDA receptor to associate with insulin secretion in humans, based on the analysis of 2760 non-diabetic Caucasian individuals.ResultsWe show that chronic elevation of d-serine results in reduced high fat diet intake. In addition, d-serine leads to diet-independent hyperglycemia due to blunted insulin secretion from pancreatic beta cells. Inhibition of alpha 2-adrenergic receptors rapidly restores glycemia and glucose tolerance in d-serine supplemented mice. Moreover, we show that single nucleotide polymorphisms (SNPs) in SRR as well as in individual NMDAR subunits are associated with insulin secretion in humans.ConclusionThus, we identify a novel role of d-serine in regulating systemic glucose metabolism through modulating insulin secretion.
Aminolevulinic acid (ALA) is a prodrug that is metabolized in the heme biosynthesis pathway to produce protoporphyrin IX (PpIX) for tumor fluorescence detection and photodynamic therapy (PDT). The iron chelator deferoxamine (DFO) has been widely used to enhance PpIX accumulation by inhibiting the iron-dependent bioconversion of PpIX to heme, a reaction catalyzed by ferrochelatase (FECH). Tumor response to DFO treatment is known to be highly variable, and some tumors even show no response. Given the fact that tumors often exhibit reduced FECH expression/enzymatic activity, we examined how reducing FECH level affected the DFO enhancement effect. Our results showed that reducing FECH level by silencing FECH in SkBr3 breast cancer cells completely abrogated the enhancement effect of DFO. Although DFO enhanced ALA-PpIX fluorescence and PDT response in SkBr3 vector control cells, it caused a similar increase in MCF10A breast epithelial cells, resulting in no net gain in the selectivity toward tumor cells. We also found that DFO treatment induced less increase in ALA-PpIX fluorescence in tumor cells with lower FECH activity (MDA-MB-231, Hs 578T) than in tumor cells with higher FECH activity (MDA-MB-453). Our study demonstrates that FECH activity is an important determinant of tumor response to DFO treatment.
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