Galectin 3 enhances platelet aggregation and thrombosis via Dectin-1 activation: a translational study.

AIMS: Galectin-3, a ß-galactoside-binding lectin, is abnormally increased in cardiovascular disease. Plasma Galectin-3 receives a Class II recommendation for heart failure management and has been extensively studied for multiple cellular functions. The direct effects of Galectin-3 on platelet activation remain unclear. This study explores the direct effects of Galectin-3 on platelet activation and thrombosis. METHODS AND RESULTS: A strong positive correlation between plasma Galectin-3 concentration and platelet aggregation or whole blood thrombus formation was observed in patients with coronary artery disease (CAD). Multiple platelet function studies demonstrated that Galectin-3 directly potentiated platelet activation and in vivo thrombosis. Mechanistic studies using the Dectin-1 inhibitor, laminarin, and Dectin-1-/- mice revealed that Galectin-3 bound to and activated Dectin-1, a receptor not previously reported in platelets, to phosphorylate spleen tyrosine kinase and thus increased Ca2+ influx, protein kinase C activation, and reactive oxygen species production to regulate platelet hyperreactivity. TD139, a Galectin-3 inhibitor in a Phase II clinical trial, concentration dependently suppressed Galectin-3-potentiated platelet activation and inhibited occlusive thrombosis without exacerbating haemorrhage in ApoE-/- mice, which spontaneously developed increased plasma Galectin-3 levels. TD139 also suppressed microvascular thrombosis to protect the heart from myocardial ischaemia-reperfusion injury in ApoE-/- mice. CONCLUSION: Galectin-3 is a novel positive regulator of platelet hyperreactivity and thrombus formation in CAD. As TD139 has potent antithrombotic effects without bleeding risk, Galectin-3 inhibitors may have therapeutic advantages as potential antiplatelet drugs for patients with high plasma Galectin-3 levels.

New Means to Control Molecular Assembly.

While self-assembly of molecules is relatively well-known and frequently utilized in chemical synthesis and material science, controlled assembly of molecules represents a new concept and approach. The present work demonstrates the concept of controlled molecular assembly using a non-spherical biomolecule, heparosan tetrasaccharide (MW = 1.099 kD). The key to controlled assembly is the fact that ultra-small solution droplets exhibit different evaporation dynamics from those of larger ones. Using an independently controlled microfluidic probe in an atomic force microscope, sub-femtoliter aqueous droplets containing designed molecules produce well-defined features with dimensions as small as tens of nanometers. The initial shape of the droplet and the concentration of solute within the droplet dictate the final assembly of molecules due to the ultrafast evaporation rate and dynamic spatial confinement of the droplets. The level of control demonstrated in this work brings us closer to programmable synthesis for chemistry and materials science which can be used to develop vehicles for drug delivery three-dimensional nanoprinting in additive manufacturing.

NUDT15 and TPMT Genetic Polymorphisms Are Related to Azathioprine Intolerance in Chinese Patients with Rheumatic Diseases.

Aims: Azathioprine (AZA) is commonly used to treat autoimmune diseases, but its applications have been limited due to significant adverse effects, particularly leukopenia. The aim of this study was to investigate the associations of NUDT15, TPMT, and inosine triphosphatase (ITPA) polymorphisms with AZA-induced toxicity. Materials and Methods: A total of 86 Chinese patients with autoimmune diseases were recruited, and the NUDT15*2-*6, TPMT*3C, and ITPA rs7270101 genotypes of these patients were characterized by Sanger sequencing. Sociodemographic data and clinical records over a period of 6 months were also collected. Results: The TPMT*3C and NUDT15*3 genotypes were significantly associated with AZA-induced leukopenia (p = 0.007 and 4.475 × 10-6, respectively). The p-value for the correlation between ITPA rs7270101 and leukopenia was 0.059. In addition, NUDT15*3 was significantly associated with gastrointestinal effects, erythropenia, hypochromia, and thrombocytopenia [p = 0.002, 1.109 × 10-5, 1.653 × 10-7, and 9.110 × 10-6, respectively; allelic odds ratio (95% confidence interval): 5.714 (1.56-20.95), 9.333 (2.96-29.47), 13.18 (4.15-41.87), and 20.13 (3.40-119.18), respectively]. The TPMT*3C genotypes were also significantly associated with gastrointestinal discomfort [p = 0.028, 12.08 (0.71-204.49)], alopecia [p = 2.864 × 10-4, 33 (1.80-606.47)], and hypochromia [p = 0.045, 10.33 (0.61-173.66)]. Conclusion: This study demonstrated that NUDT15*3 and TPMT*3C are both highly predictive genetic markers for AZA-induced toxicity in Chinese populations with rheumatic diseases.