Mitochondria play a crucial role in tubular injury in diabetic kidney disease (DKD). MitoQ is a mitochondria-targeted antioxidant that exerts protective effects in diabetic mice, but the mechanism underlying these effects is not clear. We demonstrated that mitochondrial abnormalities, such as defective mitophagy, mitochondrial reactive oxygen species (ROS) overexpression and mitochondrial fragmentation, occurred in the tubular cells of db/db mice, accompanied by reduced PINK and Parkin expression and increased apoptosis. These changes were partially reversed following an intraperitoneal injection of mitoQ. High glucose (HG) also induces deficient mitophagy, mitochondrial dysfunction and apoptosis in HK-2 cells, changes that were reversed by mitoQ. Moreover, mitoQ restored the expression, activity and translocation of HG-induced NF-E2-related factor 2 (Nrf2) and inhibited the expression of Kelch-like ECH-associated protein (Keap1), as well as the interaction between Nrf2 and Keap1. The reduced PINK and Parkin expression noted in HK-2 cells subjected to HG exposure was partially restored by mitoQ. This effect was abolished by Nrf2 siRNA and augmented by Keap1 siRNA. Transfection with Nrf2 siRNA or PINK siRNA in HK-2 cells exposed to HG conditions partially blocked the effects of mitoQ on mitophagy and tubular damage. These results suggest that mitoQ exerts beneficial effects on tubular injury in DKD via mitophagy and that mitochondrial quality control is mediated by Nrf2/PINK.
Voriconazole is a broad‐spectrum antifungal agent commonly used to treat invasive fungal infections. Voriconazole has significant intraindividual and interindividual pharmacokinetics variability in different patient populations. Pharmacokinetic data of voriconazole in patients with liver dysfunction were limited. The aims of this study were to evaluate the population pharmacokinetics of voriconazole in patients with liver dysfunction and to identify the factors that affect voriconazole pharmacokinetics. A total of 166 samples taken from 57 patients with liver dysfunction were included in the study. A one‐compartment pharmacokinetic model with first‐order absorption and elimination was used to describe the data. Voriconazole clearance (CL) was 0.58 L/h, the volume of distribution (Vd) was 134 L, and oral bioavailability (F) was 80.8%. This study showed that platelet count was significantly associated with voriconazole pharmacokinetic parameters. CYP2C19 polymorphisms had no effect on voriconazole pharmacokinetic parameters. Voriconazole CL was significantly decreased in patients with liver dysfunction. This study provides useful pharmacokinetics information for patients with liver dysfunction while highlighting the value of therapeutic drug monitoring in adjusting doses.
These results suggest that the recommended dose and halved maintenance dose may be inappropriate in patients with Child-Pugh class B and C cirrhosis due to the high C, and that voriconazole C should be monitored earlier to avoid AEs.
Six new cyathane diterpenoids, cyahookerins
A–F (1–6), as well as nine
known analogues (7–15), were isolated
from the liquid culture of
the basidiomycete Cyathus hookeri. Their structures
were elucidated on the basis of extensive spectroscopic analyses (1D
and 2D NMR, HRESIMS, and ECD), and the absolute configurations of
compounds 1 and 4 were determined by single-crystal
X-ray crystallography. Compounds 1 and 2 represent the first unusual cyathane acetals featuring a dioxolane
ring. Compounds 1–6 displayed differential
nerve growth factor-induced neurite outgrowth-promoting activity in
PC-12 cells at concentrations of 10 μM. In addition, cyahookerin
B (2), cyathin E (9), cyathin B2 (12), and cyathin Q (13) showed significant
nitric oxide production inhibition in Lipopolysaccharide (LPS)-activated
BV-2 microglial cells with IC50 values of 12.0, 6.9, 10.9,
and 9.1 μM, respectively. Similar binding modes of the four
compounds were indicated by molecular-docking studies, and structure–activity
relationships are discussed.
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