RESUMEN
Neuraminidases catalyze the desialylation of cell-surface glycoconjugates and play crucial roles in the development and function of tissues and organs. In both physiological and pathophysiological contexts, neuraminidases mediate diverse biological activities via the catalytic hydrolysis of terminal neuraminic, or sialic acid residues in glycolipid and glycoprotein substrates. The selective modulation of neuraminidase activity constitutes a promising strategy for treating a broad spectrum of human pathologies, including sialidosis and galactosialidosis, neurodegenerative disorders, cancer, cardiovascular diseases, diabetes, and pulmonary disorders. Structurally distinct as a large family of mammalian proteins, neuraminidases (NEU1 through NEU4) possess dissimilar yet overlapping profiles of tissue expression, cellular/subcellular localization, and substrate specificity. NEU1 is well characterized for its lysosomal catabolic functions, with ubiquitous and abundant expression across such tissues as the kidney, pancreas, skeletal muscle, liver, lungs, placenta, and brain. NEU1 also exhibits a broad substrate range on the cell surface, where it plays hitherto underappreciated roles in modulating the structure and function of cellular receptors, providing a basis for it to be a potential drug target in various human diseases. This review seeks to summarize the recent progress in the research on NEU1-associated diseases and highlight the mechanistic implications of NEU1 in disease pathogenesis. An improved understanding of NEU1-associated diseases should help accelerate translational initiatives to develop novel or better therapeutics.
RESUMEN
Myocardial ischemia/reperfusion injury (MIRI) is a significant challenge in the management of myocardial ischemic disease. Extensive evidence suggests that the macrophagemediated inflammatory response may play a vital role in MIRI. Mesenchymal stem cells and, in particular, exosomes derived from these cells, may be key mediators of myocardial injury and repair. However, whether exosomes protect the heart by regulating the polarization of macrophages and the exact mechanisms involved are poorly understood. The present study aimed to determine whether exosomes secreted by bone marrow mesenchymal stem cells (BMSCExo) harboring miR253p can alter the phenotype of macrophages by affecting the JAK2/STAT3 signaling pathway, which reduces the inflammatory response and protects against MIRI. An in vivo MIRI model was established in rats by ligating the anterior descending region of the left coronary artery for 30 min followed by reperfusion for 120 min, and BMSCExo carrying miR253p (BMSCExo253p) were administered through tail vein injection. A hypoxiareoxygenation model of H9C2 cells was established, and the cells were cocultured with BMSCExo253p in vitro. The results of the present study demonstrated that BMSCExo or BMSCExo253p could be taken up by cardiomyocytes in vivo and H9C2 cells in vitro. BMSCExo253p demonstrated powerful cardioprotective effects by decreasing the cardiac infarct size, reducing the incidence of malignant arrhythmias and attenuating myocardial enzyme activity, as indicated by lactate dehydrogenase and creatine kinase levels. It induced M1like macrophage polarization after myocardial ischemia/reperfusion (I/R), as evidenced by the increase in iNOS expression through immunofluorescence staining and upregulation of proinflammatory cytokines through RTqPCR, such as interleukin1ß (IL1ß) and interleukin6 (IL6). As hypothesized, BMSCExo253p inhibited M1like macrophage polarization and proinflammatory cytokine expression while promoting M2like macrophage polarization. Mechanistically, the JAK2/STAT3 signaling pathway was activated after I/R in vivo and in LPSstimulated macrophages in vitro, and BMSCExo253p pretreatment inhibited this activation. The results of the present study indicate that the attenuation of MIRI by BMSCExo253p may be related to JAK2/STAT3 signaling pathway inactivation and subsequent inhibition of M1like macrophage polarization.
