Activation of the M3AChR and Notch1/HSF1 Signaling Pathway by Choline Alleviates Angiotensin II-Induced Cardiomyocyte Apoptosis.

Angiotensin II- (Ang II-) induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure. Choline exerts cardioprotective effects; however, its effects on Ang II-induced cardiomyocyte apoptosis are unclear. In this study, the role and underlying mechanism of choline in regulating Ang II-induced cardiomyocyte apoptosis were investigated using a model of cardiomyocyte apoptosis, which was induced by exposing neonatal rat cardiomyocytes to Ang II (10-6 M, 48 h). Choline promoted heat shock transcription factor 1 (HSF1) nuclear translocation and the intracellular domain of Notch1 (NICD) expression. Consequently, choline attenuated Ang II-induced increases in mitochondrial reactive oxygen species (mtROS) and promotion of proapoptotic protein release from mitochondria, including cytochrome c, Omi/high-temperature requirement protein A2, and second mitochondrial activator of caspases/direct inhibitor of apoptosis-binding protein with low P. The reversion of these events attenuated Ang II-induced increases in cardiomyocyte size and numbers of terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling-positive cells, presumably via type 3 muscarinic acetylcholine receptor (M3AChR). Indeed, downregulation of M3AChR or Notch1 blocked choline-mediated upregulation of NICD and nuclear HSF1 expression, as well as inhibited mitochondrial apoptosis pathway and cardiomyocyte apoptosis, indicating that M3AChR and Notch1/HSF1 activation confer the protective effects of choline. In vivo studies were performed in parallel, in which rats were infused with Ang II for 4 weeks to induce cardiac apoptosis. The results showed that choline alleviated cardiac remodeling and apoptosis of Ang II-infused rats in a manner related to activation of the Notch1/HSF1 pathway, consistent with the in vitro findings. Taken together, our results reveal that choline impedes oxidative damage and cardiomyocyte apoptosis by activating M3AChR and Notch1/HSF1 antioxidant signaling, and suggest a novel role for the Notch1/HSF1 signaling pathway in the modulation of cardiomyocyte apoptosis.

Dynamic Neural Network Changes Revealed by Voxel-Based Functional Connectivity Strength in Left Basal Ganglia Ischemic Stroke.

OBJECTIVE: This study intends to track whole-brain functional connectivity strength (FCS) changes and the lateralization index (LI) in left basal ganglia (BG) ischemic stroke patients. METHODS: Twenty-five patients (N = 25; aged 52.73 ± 10.51 years) with five visits at <7, 14, 30, 90, and 180 days and 26 healthy controls (HCs; N = 26; 51.84 ± 8.06 years) were examined with resting-state functional magnetic resonance imaging (rs-fMRI) and motor function testing. FCS and LI were calculated through constructing the voxel-based brain functional network. One-way analysis of covariance (ANOVA) was first performed to obtain longitudinal FCS and LI changes in patients among the five visits (Bonferroni corrected, P < 0.05). Then, pairwise comparisons of FCS and LI were obtained during the five visits, and the two-sample t test was used to examine between-group differences in FCS [family-wise error (FWE) corrected, P < 0.05] and LI. Correlations between connectivity metrics (FCS and LI) and motor function were further assessed. RESULTS: Compared to HCs, decreased FCS in the patients localized in the calcarine and inferior occipital gyrus (IOG), while increased FCS gathered in the middle prefrontal cortex (MPFC), middle frontal gyrus, and insula (P < 0.05). The LI and FCS of patients first decreased and then increased, which showed significant differences compared with HCs (P < 0.05) and demonstrated a transition at the 30-day visit. Additionally, LI at the third visit was significantly different from those at the other visits (P < 0.05). No significant longitudinal correlations were observed between motor function and FCS or LI (P > 0.05). CONCLUSION: Focal ischemic stroke in the left BG leads to extensive alterations in the FCS. Strong plasticity in the functional networks could be reorganized in different temporal dynamics to facilitate motor recovery after BG stroke, contribute to diagnosing the disease course, and estimate the intervention treatment.

Determination of pharmacokinetic parameters of vitamin K1 in rats after an intravenous infusion.

Pharmacokinetic parameters of vitamin K1 have a large range of values in different literature. The aim of this study was to determine the pharmacokinetic parameters of vitamin K1 following post-constant speed intravenous infusion (PCSII) to provide rational pharmacokinetic parameters of vitamin K1 and compare these with results of noncompartmental analysis following intravenous injection (IV). After 15 hours intravenous infusion of vitamin K1 in rats, the logarithmic concentration-time curve of vitamin K1 was fit to a linear equation following PCSII (R2  = 0.9599 ± 0.0096). Then, half-time (T1/2 ), apparent volume of distribution (Vd ), and clearance rate (CL) were estimated successively. T1/2 of vitamin K1 was 4.07 ± 0.41 hour, CL was 89.47 ± 3.60 mL/h, and Vd was 525.38 ± 54.45 mL in rats following PCSII. There was no significant difference in pharmacokinetic parameters of vitamin K1 among different sampling times. For noncompartmental analysis, T1/2 and mean residence time (MRTINF ) for a sampling duration of 6h were shorter than those of 12 hours or 24 hours sampling duration following IV (P < .05, P < .01). In addition, T1/2 of vitamin K1 was obviously different from MRT-equated half-time (T1/2,MRT )(P < .05). Vd and CL of vitamin K1 following PCSII were larger than those following IV based on noncompartmental analysis (P < .01). The results demonstrated that drug distribution in the body was balanced and the Napierian logarithmic concentration-time curve of vitamin K1 fit to a linear equation following PCSII. Vitamin K1 has a long T1/2 and a relatively large Vd following PCSII.

Projections of Brodmann Area 6 to the Pyramidal Tract in Humans: Quantifications Using High Angular Resolution Data.

Primate studies indicate that the pyramidal tract (PyT) could originate from Brodmann area (BA) 6. However, in humans, the accurate origin of PyT from BA 6 is still uncertain owing to difficulties in visualizing anatomical features such as the fanning shape at the corona radiata and multiple crossings at the semioval centrum. High angular-resolution diffusion imaging (HARDI) could reliably replicate these anatomical features. We explored the origin of the human PyT from BA 6 using HARDI. With HARDI data of 30 adults from the Massachusetts General Hospital-Human Connectome Project (MGH-HCP) database and the HCP 1021 template (average of 1021 HCP diffusion data), we visualized the PyT at the 30-averaged group level and the 1021 large-sample level and validated the observations in each of the individuals. Endpoints of the fibers within each subregion were quantified. PyT fibers originating from the BA 6 were consistently visualized in all images. Specifically, the bilateral supplementary motor area (SMA) and dorsal premotor area (dPMA) were consistently found to contribute to the PyT. PyT fibers from BA 6 and those from BA 4 exhibited a twisting topology. The PyT contains fibers originating from the SMA and dPMA in BA 6. Infarction of these regions or aging would result in incomplete provision of information to the PyT and concomitant decreases in motor planning and coordination abilities.