Small Molecules Target the Interaction between Tissue Transglutaminase and Fibronectin

Tissue transglutaminase (TG2) is a multi-functional protein, with enzymatic, GTP-ase and scaffold properties. TG2 interacts with fibronectin (FN) through its N-terminus domain, stabilizing integrin complexes, which regulate cell adhesion to the matrix. Through this mechanism, TG2 participates in key steps involved in metastasis in ovarian and other cancers. High throughput screening identified several small molecule inhibitors (SMIs) for the TG2/FN complex. Rational medicinal chemistry optimization of the hit compound (TG53) led to second generation analogues (MT1–6). ELISA demonstrated that these analogues blocked TG2/FN interaction and bio-layer interferometry (BLI) showed that the SMIs bound to TG2. The compounds also potently inhibited cancer cell adhesion to FN and decreased outside-in signaling mediated through the focal adhesion kinase (FAK). Blockade of TG2/FN interaction by the small molecules caused membrane ruffling, delaying the formation of stable focal contacts and mature adhesions points and disrupted organization of the actin cytoskeleton. In an in vivo model measuring intraperitoneal (ip) dissemination, MT4 and MT6 inhibited the adhesion of ovarian cancer (OC) cells to the peritoneum. Pre-treatment with MT4 also sensitized OC cells to paclitaxel. The data support continued optimization of the new class of SMIs that block the TG2/FN complex at the interface between cancer cells and the tumor niche

Musique et représentation romanesque de la métamorphose spatiale

Proposer d’écrire sur le rapport entre la musique et l’espace a de quoi surprendre vu que, habituellement, l’art des sons se définit comme déploiement dans le temps. Mais le temps en tant que tel est irreprésentable si ce n’est à travers son effet sur l’espace, sa manière d’affecter l’espace. La musique peut être présente dans le roman sous une multiplicité de formes, avec différentes fonctions dans la narration et dans l’agencement formel. Mais dès qu’on cherche à lui conférer une valeur sym..

The Mediterranean Diet: From an Environment-Driven Food Culture to an Emerging Medical Prescription

The Mediterranean diet originates in the food cultures of ancient civilizations which developed around the Mediterranean Basin and is based on the regular consumption of olive oil (as the main source of added fat), plant foods (cereals, fruits, vegetables, legumes, tree nuts, and seeds), the moderate consumption of fish, seafood, and dairy, and low-to-moderate alcohol (mostly red wine) intake, balanced by a comparatively limited use of red meat and other meat products. A few decades ago, the Mediterranean diet drew the attention of medical professionals by proving extended health benefits. The first reports ascertained cardiovascular protection, as multiple large-scale clinical studies, starting with Ancel Keys’ Seven Countries Study, showed a marked reduction of atherosclerotic clinical events in populations with a Mediterranean dietary pattern. Ensuing trials confirmed favorable influences on the risk for metabolic syndrome, obesity, type 2 diabetes mellitus, cancer, and neurodegenerative diseases. While its health benefits are universally recognized today by medical professionals, the present state of the Mediterranean diet is challenged by major difficulties in implementing this protective dietary pattern in other geographical and cultural areas and keeping it alive in traditional Mediterranean territories, also tainted by the unhealthy eating habits brought by worldwide acculturation

Determination of Apixaban Levels in Human Plasma by a High-Throughput Liquid Chromatographic Tandem Mass Spectrometry Assay / Determinarea rapidă a apixabanului în plasma umană prin cromatografie de lichide de înaltă performanță cuplată cu spectrometrie de masă în tandem

S-a elaborat și s-a validat o metodă de cromatografie de lichide de înaltă performanță cuplată cu spectrometrie de masă în tandem (LC-MS/MS) pentru cuantificarea apixabanului în plasma umană. Separarea s-a realizat pe o coloană Gemini-NX în condiții izocratice folosind un amestec de acetonitril și formiat de amoniu 1 mM în apă (33:67, v/v) la 40 ºC, cu un debit de 0,5 mL/min. Detecția apixabanului s-a realizat prin monitorizarea reacțiilor multiple (m/z 417,2 din m/z 460,2) cu ionizare pozitivă prin electrospray. Pentru pregătirea probelor de plasmă s-a folosit o singură etapă de precipitare a proteinelor cu metanol. Metoda s-a validat cu respectarea selectivității, linearității (r > 0,994), preciziei intrazilnice și interzilnice (CV < 14,4 %) și a acurateței (bias < 9.5 %) pe domeniul de concentrații 9,70 - 970,00 ng/mL plasmă. Cea mai mică limită de cuantificare (LLOQ) a fost de 9,70 ng/mL, iar randamentul de recuparare din plasmă a avut valori cuprinse între 97,4 - 104,5 %. Metoda este rapidă, eficientă, necesită prelucrarea unui volum mic de plasmă (50 μL), un timp de lucru scurt (1 min) pentru analiza cromatografică și o pregătire simplă și rapidă a probelor. Se pretează foarte bine pentru monitorizarea concentrațiilor apixabanului în timpul tratamentului clinic și pentru studii de farmacocinetică

New Insights into Non-Alcoholic Fatty Liver Disease and Coronary Artery Disease: The Liver-Heart Axis

Non-alcoholic fatty liver disease (NAFLD) represents the hepatic expression of the metabolic syndrome and is the most prevalent liver disease. NAFLD is associated with liver-related and extrahepatic morbi-mortality. Among extrahepatic complications, cardiovascular disease (CVD) is the primary cause of mortality in patients with NAFLD. The most frequent clinical expression of CVD is the coronary artery disease (CAD). Epidemiological data support a link between CAD and NAFLD, underlain by pathogenic factors, such as the exacerbation of insulin resistance, genetic phenotype, oxidative stress, atherogenic dyslipidemia, pro-inflammatory mediators, and gut microbiota. A thorough assessment of cardiovascular risk and identification of all forms of CVD, especially CAD, are needed in all patients with NAFLD regardless of their metabolic status. Therefore, this narrative review aims to examine the available data on CAD seen in patients with NAFLD, to outline the main directions undertaken by the CVD risk assessment and the multiple putative underlying mechanisms implicated in the relationship between CAD and NAFLD, and to raise awareness about this underestimated association between two major, frequent and severe diseases

Association of Antihyperglycemic Therapy with Risk of Atrial Fibrillation and Stroke in Diabetic Patients

Type 2 diabetes mellitus (DM) is associated with an increased risk of cardiovascular disease (CVD). Atrial fibrillation (AF) and stroke are both forms of CVD that have major consequences in terms of disabilities and death among patients with diabetes; however, they are less present in the preoccupations of scientific researchers as a primary endpoint of clinical trials. Several publications have found DM to be associated with a higher risk for both AF and stroke; some of the main drugs used for glycemic control have been found to carry either increased, or decreased risks for AF or for stroke in DM patients. Given the risk for thromboembolic cerebrovascular events seen in AF patients, the question arises as to whether stroke and AF occurring with modified incidences in diabetic individuals under therapy with various classes of antihyperglycemic medications are interrelated and should be considered as a whole. At present, the medical literature lacks studies specifically designed to investigate a cause&ndash;effect relationship between the incidences of AF and stroke driven by different antidiabetic agents. In default of such proof, we reviewed the existing evidence correlating the major classes of glucose-controlling drugs with their associated risks for AF and stroke; however, supplementary proof is needed to explore a hypothetically causal relationship between these two, both of which display peculiar features in the setting of specific drug therapies for glycemic control

Bidirectional Relationship between Gastric Emptying and Plasma Glucose Control in Normoglycemic Individuals and Diabetic Patients

Gastric emptying and glycemic control pathways are closely interrelated processes. Gastric chyme is transferred into the duodenum with velocities depending on its solid or liquid state, as well as on its caloric and nutritional composition. Once nutrients enter the intestine, the secretion of incretins (hormonal products of intestinal cells) is stimulated. Among incretins, glucagon-like peptide-1 (GLP-1) has multiple glycemic-regulatory effects that include delayed gastric emptying, thus triggering a feedback loop lowering postprandial serum glucose levels. Glycemic values also influence gastric emptying; hyperglycemia slows it down, and hypoglycemia accelerates it, both limiting glycemic fluctuations. Disordered gastric emptying in diabetes mellitus is understood today as a complex pathophysiological condition, with both irreversible and reversible components and high intra- and interindividual variability of time span and clinical features. While limited delays may be useful for reducing postprandial hyperglycemias, severely hindered gastric emptying may be associated with higher glycemic variability and worsened long-term glycemic control. Therapeutic approaches for both gastric emptying and glycemic control include dietary modifications of meal structure or content and drugs acting as GLP-1 receptor agonists. In the foreseeable future, we will probably witness a wider range of dietary interventions and more incretin-based medications used for restoring both gastric emptying and glycemic levels to nearly physiological levels