Negative regulation of AMPK signaling by high glucose via E3 ubiquitin ligase MG53.

As a master regulator of metabolism, AMP-activated protein kinase (AMPK) is activated upon energy and glucose shortage but suppressed upon overnutrition. Exaggerated negative regulation of AMPK signaling by nutrient overload plays a crucial role in metabolic diseases. However, the mechanism underlying the negative regulation is poorly understood. Here, we demonstrate that high glucose represses AMPK signaling via MG53 (also called TRIM72) E3-ubiquitin-ligase-mediated AMPKα degradation and deactivation. Specifically, high-glucose-stimulated reactive oxygen species (ROS) signals AKT to phosphorylate AMPKα at S485/491, which facilitates the recruitment of MG53 and the subsequent ubiquitination and degradation of AMPKα. In addition, high glucose deactivates AMPK by ROS-dependent suppression of phosphorylation of AMPKα at T172. These findings not only delineate the mechanism underlying the impairment of AMPK signaling in overnutrition-related diseases but also highlight the significance of keeping the yin-yang balance of AMPK signaling in the maintenance of metabolic homeostasis.

Diazo-carboxyl Click Derivatization Enables Sensitive Analysis of Carboxylic Acid Metabolites in Biosamples.

Carboxylic acids are central metabolites in bioenergetics, signal transduction, and post-translation protein regulation. However, the quantitative analysis of carboxylic acids as an indispensable part of metabolomics is prohibitively challenging, particularly in trace amounts of biosamples. Here we report a diazo-carboxyl/hydroxylamine-ketone double click derivatization method for the sensitive analysis of hydrophilic, low-molecular-weight carboxylic acids. In general, our method renders a 5- to 2000-fold higher response in mass spectrometry along with improved chromatographic separation. With this method, we presented the near-single-cell analysis of carboxylic acid metabolites in 10 mouse egg cells before and after fertilization. Malate, fumarate, and ß-hydroxybutyrate were found to decrease after fertilization. We also monitored the isotope labeling kinetics of carboxylic acids inside adherent cells cultured in 96-well plates during drug treatment. Finally, we applied this method to plasma or serum samples (5 µL) collected from mice and humans under pathological and physiological conditions. The double click derivatization method paves a way toward single-cell metabolomics and bedside diagnostics.

Fluorescigenic Magnetofluids Based on Gadolinium, Terbium, and Dysprosium-Containing Imidazolium Salts.

Multistimuli responsive soft materials are urgently needed in many different fields, such as anticounterfeiting technology and microdroplet manipulation. Herein, the straightforward preparation of fluorescigenic magnetofluids by the introduction of the paramagnetic metal ions Gd3+, Tb3+, and Dy3+ into alkylimidazolium-based ionic liquids (ILs) is reported. Bright visible fluorescence was observed under UV irradiation for Tb- and Dy-containing ILs. Either pure samples or papers coated with these ILs exhibited pronounced magnetic responses. Consistent and stable structures of these salts were confirmed by systematical characterizations. Because of the competition of nitrate ligands, structural water in the precursors was eliminated easily under a vacuum. For Tb- and Dy-containing ILs, featured electronic transitions were observed and were assigned in the fluorescence spectra. The long lifetimes of these transitions were also confirmed. The field-cooling experiments showed that all of these ILs display paramagnetism at room temperature. At low temperature, small deviations from the Curie Law indicate the occurrence of antiferromagnetic coupling and spin canting in these ILs. Temperature-induced differences in magnetic properties were further verified by field-dependent magnetic susceptibility measurements carried out at 5 and 300 K.

Low-melting multicharge ionic liquids with [Ln(NO3)5]2- (Ln = Ho-Lu): structural, electrostatic, thermochemical, and fluorescence properties.

A series of green and safe heavy-rare-earth ionic liquids were obtained using a straightforward method. The stable structures of these ionic liquids, characterized by high-coordinating anions, were confirmed by nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy, and single crystal X-ray diffraction (XRD). These ionic liquids exhibited wide liquid phase intervals and excellent thermal stability. The bidentate nitrato ligands occupied a sufficient number of coordination sites on the lanthanide ions, resulting in the formation of water-free 10-coordination structures. To explain the anomalous melting points observed in these multi-charged ionic liquids, a combination of experimental data and theoretical studies was employed to investigate the relationship between the electrostatic properties and the melting point. The electrostatic potential density per unit ion surface and volume were proposed and utilized for melting point prediction, demonstrating good linearity. Furthermore, the coordinating spheres of the lanthanide ions in these ionic liquids were devoid of luminescence quenchers such as O-H and N-H groups. Notably, the ionic liquids containing Ho3+, Er3+, and Tm3+ exhibited long lifetime near-infrared (NIR) and blue emissions, respectively. The UV-vis-NIR spectra revealed numerous electronic transitions of the lanthanide ions, which were attributed to their unique optical properties.

Manganese regulation of COPII condensation controls circulating lipid homeostasis.

Precise control of circulating lipids is instrumental in health and disease. Bulk lipids, carried by specialized lipoproteins, are secreted into the circulation, initially via the coat protein complex II (COPII). How the universal COPII machinery accommodates the abundant yet unconventional lipoproteins remains unclear, let alone its therapeutic translation. Here we report that COPII uses manganese-tuning, self-constrained condensation to selectively drive lipoprotein delivery and set lipid homeostasis in vivo. Serendipitously, adenovirus hijacks the condensation-based transport mechanism, thus enabling the identification of cytosolic manganese as an unexpected control signal. Manganese directly binds the inner COPII coat and enhances its condensation, thereby shifting the assembly-versus-dynamics balance of the transport machinery. Manganese can be mobilized from mitochondria stores to signal COPII, and selectively controls lipoprotein secretion with a distinctive, bell-shaped function. Consequently, dietary titration of manganese enables tailored lipid management that counters pathological dyslipidaemia and atherosclerosis, implicating a condensation-targeting strategy with broad therapeutic potential for cardio-metabolic health.