Behavioral and neurological effects of Vrk1 deficiency in zebrafish.

Vaccinia-related kinase 1 (VRK1) is a serine/threonine kinase, for which mutations have been reported cause to neurodegenerative diseases, including spinal muscular atrophy, characterized by microcephaly, motor dysfunction, and impaired cognitive function, in humans. Partial Vrk1 knockdown in mice has been associated with microcephaly and impaired motor function. However, the pathophysiological relationship between VRK1 and neurodegenerative disorders and the precise mechanism of VRK1-related microcephaly and motor function deficits have not been fully investigated. To address this, in this study, we established vrk1-deficient (vrk1-/-) zebrafish and found that they show mild microcephaly and impaired motor function with a low brain dopamine content. Furthermore, vrk1-/- zebrafish exhibited decreased cell proliferation, defects in nuclear envelope formation, and heterochromatin formation in the brain. To our knowledge, this is the first report demonstrating the important role of VRK1 in microcephaly and motor dysfunction in vivo using vrk1-/- zebrafish. These findings contribute to elucidating the pathophysiological mechanisms underlying VRK1-mediated neurodegenerative diseases associated with microcephaly.

High sucrose/fat diet and isosorbide mononitrate increase insulin resistance, nitric oxide production and myocardial apoptosis in a hypertensive rat model.

The present study aimed to investigate the association between insulin resistance (IR), nitric oxide (NO) production and myocardial apoptosis in a background of coexisting hypertension in a rodent animal model. A hypertensive rat model was established by feeding Wistar and spontaneously hypertensive rats (SHR) with a high sucrose/fat (HSF) diet for 12 weeks, in conjunction with isosorbide mononitrate (ISMN). Increased IR, NO content, apoptotic gene and protein expression, and morphological alterations within rat myocardium were evaluated. Following a total of 12 weeks of feeding with HSF and ISMN resulted in increased IR and NO content within the myocardial tissue of Wistar and SHR rats. HSF and ISMN activated myocardial apoptosis by downregulating the gene transcription and protein expression levels of the anti­apoptotic B­cell lymphoma 2 (Bcl­2), and increasing the pro­apoptotic Bcl­2 associated X protein. Apoptosis was demonstrated by DNA fragmentation in terminal deoxynucleotidyl­transferase­mediated dUTP nick end labelling assay. In all experiments, the combination of HSF and ISMN was associated with more pronounced effects, indicating the possible synergistic effects. In addition, the correlation analysis in the Wistar rats fed with HSF only, revealed a positive association between NO production and IR. The results of the present study indicated that HSF and ISMN simultaneously increased IR, NO production and myocardial apoptosis in the hypertensive rat model, and may therefore contribute to investigations into the long­term clinical use of ISMN in hypertensive patients.