ABSTRACT
A family of combined Kojic acid and polyamine derivatives has been synthesized as phosphate anion and metal ion ligands. The stoichiometry, stability and structure of the ion/ligand adducts were determined by 1H NMR spectroscopy, potentiometry, EXAFS and DFT calculations. The presented dual ligands bind effectively both phosphate anions and metal ions and could be used as effective ion receptors in challenging water conditions in the broad pH range. A careful analysis of the heatmaps of the stability constants allows to choose the most appropriate ligand for the ion for qualitative and/or quantitative analysis in water, without analyte pre-treatment. Extremely high-water solubility (>0.6 M) and ion(s)/ligand stability of the adducts in the pH 3-11 are the greatest advantages of the presented here molecules over other known ion sensors. The presented here molecules represent an innovative class of dual metal/anion ligands, with perspective of medical and environmental use.
Subject(s)
Chelating Agents/chemistry , Coordination Complexes/chemistry , Diamines/chemistry , Metals/chemistry , Phosphates/chemistry , Pyrones/chemistry , Density Functional Theory , Hydrogen-Ion Concentration , Ligands , Models, ChemicalABSTRACT
In photodynamic therapy (PDT), photosensitizer (PS) molecules are irradiated by light to generate reactive oxygen species (ROS), the presence of which subsequently leads to cell death. At present, the modality is limited to the treatment of skin diseases because of the low tissue penetration of visible or ultraviolet light required for producing ROS. To increase tissue penetration and extend the therapeutic possibilities of PDT to the treatment of deep-seated cancer, rare-earth doped nanoparticles capable of up-converting infrared to visible light are investigated. These up-converting nanoparticles (UCNPs) are conjugated with PS molecules to efficiently generate ROS. In this work, we employ hexagonal ß-NaYF4:Yb3 + ,Er3 + as UCNPs and Rose Bengal (RB) as PS molecules and demonstrate efficient in vitro PDT using this nanoformulation. Covalent bonding of the RB molecules is accomplished without their functionalization-an approach which is expected to increase the efficiency of ROS generation by 30%. Spectroscopic studies reveal that our approach results in UCNP surface fully covered with RB molecules. The energy transfer from UCNPs to RB is predominantly non-radiative as evidenced by luminescence lifetime measurements. As a result, ROS are generated as efficiently as under visible light illumination. The in vitro PDT is tested on murine breast 4T1 cancer cells incubated with 250 µg ml-1 of the nanoparticles and irradiated with NIR light under power density of 2 W cm-2 for 10 minutes. After 24 hours, the cell viability decreased to 33% demonstrating a very good treatment efficiency. These results are expected to simplify the protocols for preparation of the PDT agents and lead to improved therapeutic effects.
Subject(s)
Erbium/pharmacology , Fluorides/pharmacology , Photosensitizing Agents/pharmacology , Rose Bengal/pharmacology , Ytterbium/pharmacology , Yttrium/pharmacology , Animals , Cell Line, Tumor , Erbium/chemistry , Female , Fluorides/chemistry , Mammary Neoplasms, Animal/drug therapy , Mammary Neoplasms, Experimental/drug therapy , Mice , Nanoparticles/chemistry , Photochemotherapy , Photosensitizing Agents/chemistry , Rose Bengal/chemistry , Ytterbium/chemistry , Yttrium/chemistryABSTRACT
The liver is a key regulator of systemic energy homeostasis whose proper function is dependent on the circadian clock. Here, we show that livers deficient in the oscillator component JARID1a exhibit a dysregulation of genes involved in energy metabolism. Importantly, we find that mice that lack hepatic JARID1a have decreased lean body mass, decreased respiratory exchange ratios, faster production of ketones, and increased glucose production in response to fasting. Finally, we find that JARID1a loss compromises the response of the hepatic transcriptome to nutrient availability. In all, ablation of hepatic JARID1a disrupts the coordination of hepatic metabolic programs with whole-body consequences.
Subject(s)
DNA-Binding Proteins/metabolism , Feeding Behavior/physiology , Jumonji Domain-Containing Histone Demethylases/metabolism , Liver/metabolism , Adaptation, Physiological , Animals , Circadian Rhythm/physiology , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , Humans , Jumonji Domain-Containing Histone Demethylases/deficiency , Jumonji Domain-Containing Histone Demethylases/genetics , Mice , Mice, KnockoutABSTRACT
[This corrects the article DOI: 10.1371/journal.pbio.2006145.].
ABSTRACT
The circadian oscillator is a molecular feedback circuit whose orchestration involves posttranslational control of the activity and protein levels of its components. Although controlled proteolysis of circadian proteins is critical for oscillator function, our understanding of the underlying mechanisms remains incomplete. Here, we report that JmjC domain-containing protein 5 (JMJD5) interacts with CRYPTOCHROME 1 (CRY1) in an F-box/leucine-rich repeat protein 3 (FBXL3)-dependent manner and facilitates targeting of CRY1 to the proteasome. Genetic deletion of JMJD5 results in greater CRY1 stability, reduced CRY1 association with the proteasome, and disruption of circadian gene expression. We also report that in the absence of JMJD5, AMP-regulated protein kinase (AMPK)-induced CRY1 degradation is impaired, establishing JMJD5 as a key player in this mechanism. JMJD5 cooperates with CRY1 to repress circadian locomotor output cycles protein kaput (CLOCK)-brain and muscle ARNT-like protein 1 (BMAL1), thus linking CRY1 destabilization to repressive function. Finally, we find that ablation of JMJD5 impacts FBXL3- and CRY1-related functions beyond the oscillator.
