Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous group of monogenic endocrine disorders that is characterised by autosomal dominant inheritance and pancreatic β-cell dysfunction. These patients are commonly misdiagnosed with type 1 or type 2 diabetes, as the clinical symptoms largely overlap. Even though several biomarkers have been tested none of which could be used as single clinical discriminator. The correct diagnosis for individuals with MODY is of utmost importance, as the applied treatment depends on the gene mutation or is subtype-specific. Moreover, in patients with HNF1A-MODY, additional clinical monitoring can be included due to the high incidence of vascular complications observed in these patients. Finally, stratification of MODY patients will enable better and newer treatment options for MODY patients, once the disease pathology for each patient group is better understood. In the current review the clinical characteristics and the known disease-related abnormalities of the most common MODY subtypes are discussed, together with the up-to-date applied diagnostic criteria and treatment options. Additionally, the usage of pluripotent stem cells together with CRISPR/Cas9 gene editing for disease modelling with the possibility to reveal new pathophysiological mechanisms in MODY is discussed.
Cardiovascular diseases are the major cause of morbidity and mortality in both men and women in industrially developed countries. These disorders may result from impaired angiogenesis, particularly in response to hypoxia. Despite many limitations, gene therapy is still emerging as a potential alternative for patients who are not candidates for traditional revascularization procedures, like angioplasty or vein grafts. This review focuses on recent approaches in the development of new gene delivery vectors, with great respect to newly discovered AAV serotypes and their modified forms. Moreover, some new cardiovascular gene therapy strategies have been highlighted, such as combination of different angiogenic growth factors or simultaneous application of genes and progenitor cells in order to obtain stable and functional blood vessels in ischemic tissue.
Vascular endothelial growth factor (VEGF) is the major molecule governing angiogenesis, defined as the growth of blood vessels from vascular structure. There is abundant evidence that nitric oxide (NO) is an effector molecule mediating the activity of VEGF. By binding to its receptors, VEGF initiates the signaling cascades leading to NO production and angiogenic activation of endothelial cells. Recent data show that NO induces VEGF synthesis in numerous cell types, including vascular smooth muscle cells, macrophages, keratinocytes, and tumor cells. NO enhances VEGF production by augmenting its expression through activation of Akt kinase, followed by induction of several transcription factors, of which stabilization of hypoxia-inducible factor (HIF-1) is the critical step. With respect to its effect on VEGF expression, NO mimics hypoxia, the classical activator of HIF-1 and VEGF synthesis. The effect of NO on VEGF production is also mediated by heme oxygenase, an enzyme generating carbon monoxide, which appears to stimulate VEGF release. In this review, we attempt to elucidate the molecular mechanisms underlying the effects of NO on VEGF synthesis. We also discuss some discrepant data and suggest explanations for various aspects of the NO-VEGF relationship.
