17 research outputs found
Ligand-Substitution Reactions of the Tellurium Compound AS-101 in Physiological Aqueous and Alcoholic Solutions
Since its first crystallization,
the aqueous structure of the tellurium-containing experimental drug
AS-101 has never been studied. We show that, under the aqueous conditions
in which it is administered, AS-101 is subjected to an immediate ligand-substitution
reaction with water, yielding a stable hydrolyzed oxide anion product
that is identified, for the first time, to be TeOCl<sub>3</sub><sup>–</sup>. Studying the structure of AS-101 in propylene glycol
(PG), an alcoholic solvent often used for the topical and oral administration
of AS-101, revealed the same phenomenon of ligand-substitution reaction
between the alcoholic ligands. Upon exposure to water, the PG-substituted
product is also hydrolyzed to the same telluriumÂ(IV) oxide form, TeOCl<sub>3</sub><sup>–</sup>
Biodegradable, Biocompatible, and Implantable Multifunctional Sensing Platform for Cardiac Monitoring.
Cardiac monitoring after heart surgeries is crucial for health maintenance and detecting postoperative complications early. However, current methods like rigid implants have limitations, as they require performing second complex surgeries for removal, increasing infection and inflammation risks, thus prompting research for improved sensing monitoring technologies. Herein, we introduce a nanosensor platform that is biodegradable, biocompatible, and integrated with multifunctions, suitable for use as implants for cardiac monitoring. The device has two electrochemical biosensors for sensing lactic acid and pH as well as a pressure sensor and a chemiresistor array for detecting volatile organic compounds. Its biocompatibility with myocytes has been tested in vitro, and its biodegradability and sensing function have been proven with ex vivo experiments using a three-dimensional (3D)-printed heart model and 3D-printed cardiac tissue patches. Moreover, an artificial intelligence-based predictive model was designed to fuse sensor data for more precise health assessment, making it a suitable candidate for clinical use. This sensing platform promises impactful applications in the realm of cardiac patient care, laying the foundation for advanced life-saving developments
The mitochondrial carrier Citrin plays a role in regulating cellular energy during carcinogenesis
International audienceCitrin, encoded by SLC25A13 gene, is an inner mitochondrial transporter that is part of the malate–aspartate shuttle, which regulates the NAD+/NADH ratio between the cytosol and mitochondria. Citrullinemia type II (CTLN-II) is an inherited disorder caused by germline mutations in SLC25A13, manifesting clinically in growth failure that can be alleviated by dietary restriction of carbohydrates. The association of citrin with glycolysis and NAD+/NADH ratio led us to hypothesize that it may play a role in carcinogenesis. Indeed, we find that citrin is upregulated in multiple cancer types and is essential for supplementing NAD+ for glycolysis and NADH for oxidative phosphorylation. Consequently, citrin deficiency associates with autophagy, whereas its overexpression in cancer cells increases energy production and cancer invasion. Furthermore, based on the human deleterious mutations in citrin, we found a potential inhibitor of citrin that restricts cancerous phenotypes in cells. Collectively, our findings suggest that targeting citrin may be of benefit for cancer therapy
Induction of Nitric-Oxide Metabolism in Enterocytes Alleviates Colitis and Inflammation-Associated Colon Cancer
Nitric oxide (NO) plays an established role in numerous physiological and pathological processes, but the specific cellular sources of NO in disease pathogenesis remain unclear, preventing the implementation of NO-related therapy. Argininosuccinate lyase (ASL) is the only enzyme able to produce arginine, the substrate for NO generation by nitric oxide synthase (NOS) isoforms. Here, we generated cell-specific conditional ASL knockout mice in combination with genetic and chemical colitis models. We demonstrate that NO derived from enterocytes alleviates colitis by decreasing macrophage infiltration and tissue damage, whereas immune cell-derived NO is associated with macrophage activation, resulting in increased severity of inflammation. We find that induction of endogenous NO production by enterocytes with supplements that upregulate ASL expression and complement its substrates results in improved epithelial integrity and alleviation of colitis and of inflammation-associated colon cance
Acid-Induced Downregulation of ASS1 Contributes to the Maintenance of Intracellular pH in Cancer
The histone deacetylase SIRT6 is a novel tumor suppressor that controls cancer metabolism
Reprogramming of cellular metabolism is a key event during tumorigenesis. Despite being known for decades (Warburg effect), the molecular mechanisms regulating this switch remained unexplored. Here, we identify SIRT6 as a tumor suppressor that regulates aerobic glycolysis in cancer cells. Importantly, loss of SIRT6 leads to tumor formation without activation of known oncogenes, whereas transformed SIRT6-deficient cells display increased glycolysis and tumor growth, suggesting that SIRT6 plays a role in both establishment and maintenance of cancer. By using a conditional SIRT6 allele, we show that SIRT6 deletion in vivo increases the number, size, and aggressiveness of tumors. SIRT6 also functions as a regulator of ribosome metabolism by corepressing MYC transcriptional activity. Lastly, Sirt6 is selectively downregulated in several human cancers, and expression levels of SIRT6 predict prognosis and tumor-free survival rates, highlighting SIRT6 as a critical modulator of cancer metabolism. Our studies reveal SIRT6 to be a potent tumor suppressor acting to suppress cancer metabolism
The mitochondrial carrier Citrin plays a role in regulating cellular energy during carcinogenesis
A Transgenic Rat for Investigating the Anatomy and Function of Corticotrophin Releasing Factor Circuits
Chronic CRH depletion from GABAergic, long-range projection neurons in the extended amygdala reduces dopamine release and increases anxiety.
The interplay between corticotropin-releasing hormone (CRH) and the dopaminergic system has predominantly been studied in addiction and reward, while CRH-dopamine interactions in anxiety are scarcely understood. We describe a new population of CRH-expressing, GABAergic, long-range-projecting neurons in the extended amygdala that innervate the ventral tegmental area and alter anxiety following chronic CRH depletion. These neurons are part of a distinct CRH circuit that acts anxiolytically by positively modulating dopamine release