Metabolic reprogramming orchestrates cancer stem cell properties in nasopharyngeal carcinoma

Cancer stem cells (CSCs) represent a subpopulation of tumor cells endowed with self-renewal capacity and are considered as an underlying cause of tumor recurrence and metastasis. The metabolic signatures of CSCs and the mechanisms involved in the regulation of their stem cell-like properties still remain elusive. We utilized nasopharyngeal carcinoma (NPC) CSCs as a model to dissect their metabolic signatures and found that CSCs underwent metabolic shift and mitochondrial resetting distinguished from their differentiated counterparts. In metabolic shift, CSCs showed a greater reliance on glycolysis for energy supply compared with the parental cells. In mitochondrial resetting, the quantity and function of mitochondria of CSCs were modulated by the biogenesis of the organelles, and the round-shaped mitochondria were distributed in a peri-nuclear manner similar to those seen in the stem cells. In addition, we blocked the glycolytic pathway, increased the ROS levels, and depolarized mitochondrial membranes of CSCs, respectively, and examined the effects of these metabolic factors on CSC properties. Intriguingly, the properties of CSCs were curbed when we redirected the quintessential metabolic reprogramming, which indicates that the plasticity of energy metabolism regulated the balance between acquisition and loss of the stemness status. Taken together, we suggest that metabolic reprogramming is critical for CSCs to sustain self-renewal, deter from differentiation and enhance the antioxidant defense mechanism. Characterization of metabolic reprogramming governing CSC properties is paramount to the design of novel therapeutic strategies through metabolic intervention of CSCs.     

Carboxymethylated cyclodextrins and their complexes with Pr(III) and Yb(III) as water‐soluble chiral NMR solvating agents for cationic compounds

Cyclodextrins that are indiscriminately carboxymethylated at the 2‐, 3‐, and 6‐positions are used as chiral NMR solvating agents for cationic substrates with phenyl, naphthyl, pyridyl, indoline, and indole rings. Enantiodifferentiation with the α‐, β‐, and γ‐cyclodextrin derivatives is compared. The carboxymethylated derivatives are almost always more effective as chiral NMR solvating agents for cationic substrates than native cyclodextrins. The most effective carboxymethylated cyclodextrin varies for different substrates, and at times even different resonances of the substrate. Addition of paramagnetic praseodymium(III) or ytterbium(III) to mixtures of the carboxymethylated cyclodextrin and substrate often causes enhancements in enantiomeric discrimination and facilitates measurements of enantiomeric purity. The lanthanide ion bonds to the carboxymethyl groups and causes perturbations in the chemical shifts in the NMR spectra of substrate molecules in the cyclodextrin cavity. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Cyclic adenosine monophosphate induces plasminogen activator inhibitor-1 expression in human mast cells

Plaminogen activator inhibitor-1 (PAI-1), the key physiological inhibitor of the plasmin fibrinolytic system, plays important roles in the pathogenesis of asthma. Mast cells (MCs) are crucial effector cells and a major source of PAI-1 for asthma. Cyclic adenosine monophosphate (cAMP) is the important regulator of MCs; however, its effects on PAI-1 expression in MCs remain unknown. We reported cAMP/protein kinase A pathway positively regulates PAI-1 expression through cAMP-response element binding protein binding to hypoxia response element-1 at −158 to −153 bp of human PAI-1 promoter in human MCs. Moreover, cAMP synergistically augments PAI-1 expression with ionomycin- or IgE receptor cross-linking-mediated stimulation.     

Substrate recognition characteristics of human holocarboxylase synthetase for biotin ligation

Holocarboxylase synthetase (HCS) is an essential enzyme that catalyzes the incorporation of biotin into apo carboxylase and the biotinylation of the four biotin-dependent carboxylases in the human cell. Deficiency of HCS results in decreased activity of these carboxylases and affects various metabolic processes. Despite the importance of this enzyme, the recognition mechanism of the biotinoyl domain by human HCS (hHCS) has remained unclear. We have developed a method to express hHCS in the baculovirus system and used it to purify catalytically active, full-length hHCS. NMR experiments on the biotinoyl domains from acetyl-CoA carboxylase indicate that when hHCS is added, it recognizes the MKM motif in human and in Escherichia coli with a preference to the human biotinoyl domain. In addition, hHCS can biotinylate the biotinoyl domains from human and E. coli acetyl-CoA carboxylase at similar rates compared to the E. coli biotin protein ligase, BirA, which reacts very slowly with the human biotinoyl domain. We propose that the hHCS has greater substrate acceptability, while the BirA has higher substrate specificity. These results provide insights into substrate recognition by hHCS, which can be distinguished from BirA in this respect.     

Herbicides which inhibit photosystem II or produce chlorosis and their effect on production and transformation of pigments in etiolated radish seedlings (Raphanus sativus)

Abstract The herbicides DCMU, bentazon, amitrole, and SAN 6706 were tested for their ability to influence the carotenoid and pro-tochlorophyll(ide) composition as well as the protochloro-phyll(ide) phototransformation and the Shibata shift in dark-grown radish seedlings (Raphanus sativus L. cv. Saxa Treib). Bentazon enhanced the formation of lutein and carotenes, while SAN 6706 suppressed the biosynthesis of carotenoids. Amitrole led to a reduced accumulation of phototransformable pro-tochlorophyll(ide). The phototransformation of pro-tochlorophyll(ide) and the Shibata shift were not affected by any of the tested herbicides, irrespective of the presence or absence of activated phytochrome. From this we conclude that herbicides inhibiting photosystem II or producing chlorosis partly affect, but do not block, carotenoid and chlorophyll biosynthesis in dark-grown plants. The main herbicide effect becomes visible only after prolonged illumination.