Pharmacological and mechanistic study of PS1, a Pdia4 inhibitor, in ß-cell pathogenesis and diabetes in db/db mice.

Pdia4 has been characterized as a key protein that positively regulates ß-cell failure and diabetes via ROS regulation. Here, we investigated the function and mechanism of PS1, a Pdia4 inhibitor, in ß-cells and diabetes. We found that PS1 had an IC50 of 4 µM for Pdia4. Furthermore, PS1 alone and in combination with metformin significantly reversed diabetes in db/db mice, 6 to 7 mice per group, as evidenced by blood glucose, glycosylated hemoglobin A1c (HbA1c), glucose tolerance test, diabetic incidence, survival and longevity (P < 0.05 or less). Accordingly, PS1 reduced cell death and dysfunction in the pancreatic ß-islets of db/db mice as exemplified by serum insulin, serum c-peptide, reactive oxygen species (ROS), islet atrophy, and homeostatic model assessment (HOMA) indices (P < 0.05 or less). Moreover, PS1 decreased cell death in the ß-islets of db/db mice. Mechanistic studies showed that PS1 significantly increased cell survival and insulin secretion in Min6 cells in response to high glucose (P < 0.05 or less). This increase could be attributed to a reduction in ROS production and the activity of electron transport chain complex 1 (ETC C1) and Nox in Min6 cells by PS1. Further, we found that PS1 inhibited the enzymatic activity of Pdia4 and mitigated the interaction between Pdia4 and Ndufs3 or p22 in Min6 cells (P < 0.01 or less). Taken together, this work demonstrates that PS1 negatively regulated ß-cell pathogenesis and diabetes via reduction of ROS production involving the Pdia4/Ndufs3 and Pdia4/p22 cascades.

Quantitative three-dimensional power Doppler sonography for assessment of the fetal renal blood flow in normal gestation.

Renal blood flow is very important to fetal hemodynamics. To assess the development of fetal renal vascularization and blood flow in normal gestation, we measured the fetal renal vascularization and blood flow in healthy fetuses using three-dimensional (3-D) power Doppler sonography and quantitative 3-D power Doppler histogram analysis. This study was undertaken with a prospective, cross-sectional design. In total, 106 healthy singletons with gestational ages between 20 and 40 weeks were included. The 3-D power Doppler sonography and quantitative histogram analyses were used to assess the fetal renal vascularization index (VI), flow index (FI) and vascularization-flow index (VFI) in each case. Our results showed that all the VI, FI and VFI increased significantly with gestational age (GA). Using GA as the independent variable, the linear regression equations for fetal renal VI, FI and VFI were VI = 0.214 x GA - 3.5289 (r = 0.84, n = 106, p < 0.0001); FI = 0.3326 x GA + 35.224 (r = 0.33, n = 106, p < 0.001); and VFI = 0.1047 x GA - 1.8064 (r = 0.82, n = 106, p < 0.0001). Our study indicates that normal fetal renal vasculature and blood flow increase with the advancement of gestational age. In addition to our previous study for fetal renal volume using 3-D sonography, our data in this series may serve as a reference for further studies of fetal renal blood flow in abnormal conditions.

Assessment of placental fractional moving blood volume using quantitative three-dimensional power doppler ultrasound.

To test the hypothesis that the placental fractional moving blood volume is different with advancing gestational age (GA), we assessed the vascularization index (VI), flow index (FI), and vascularization-flow index (VFI) of the placenta in normal pregnancy by using three-dimensional (3-D) power Doppler ultrasound (US). We enrolled 100 healthy pregnant women with gestational age between 20 to 40 weeks for this study. Three-dimensional power Doppler ultrasonography was used to assess the VI, FI and VFI in each case. Our results showed that the linear regression equations for VI, FI and VFI, by using GA as the independent variable, were VI = 0.27107 x GA -4.02748 (r = 0.84, p < 0.0001), FI = 0.56115 x GA + 34.28945 (r = 0.49, p < 0.001), and VFI = 0.15663 x GA -2.53810 (r = 0.82, p < 0.0001), respectively. In addition, the VI, FI and VFI values of the placental flow were also positively correlated with the fetal growth indices, namely, biparietal diameter, occipitofrontal diameter, head circumference, abdominal circumference and estimated fetal weight (all p values < 0.001). In conclusion, our study illustrates that the fractional moving blood volume of the placenta is positively correlated with the increment of gestational age and the fetal growth indices. Our data may be used as a reference in the assessment of the placental fractional moving blood volume using the quantitative 3-D power Doppler US.