Hematological adverse effects and pharmacokinetics of ribavirin in pigs following intramuscular administration.

Ribavirin (RBV) is a synthetic guanosine analog that is used as a drug against various viral diseases in humans. The in vitro antiviral effects of ribavirin against porcine viruses were demonstrated in several studies. The purposes of this study were to evaluate the adverse effects and pharmacokinetics of ribavirin following its intramuscular (IM) injection in pigs. Ribavirin was formulated as a double-oil emulsion (RBV-DOE) and gel (RBV-Gel), which were injected into the pigs as single-dose IM injections. After injection of RBV, all of the pigs were monitored. The collected serum and whole blood samples were analyzed by liquid chromatography-tandem mass spectrometry and complete blood count analysis, respectively. All of the ribavirin-treated pigs showed significant decreases in body weight compared to the control groups. Severe clinical signs including dyspnea, anorexia, weakness, and depression were present in ribavirin-treated pigs until 5 days postinjection (dpi). The ribavirin-treated groups showed significant decrease in the number of red blood cells and hemoglobin concentration until 8 dpi. The mean half-life of the RBV-DOE and RBV-Gel was 27.949 ± 2.783 h and 37.374 ± 3.502 h, respectively. The mean peak serum concentration (Cmax ) and area under the serum concentration-time curve from time zero to infinity (AUCinf ) of RBV-DOE were 8340.000 ± 2562.577 ng/mL and 16 0095.430 ± 61 253.400 h·ng/mL, respectively. The Cmax and AUCinf of RBV-Gel were 15 300.000 ± 3764.306 ng/mL and 207526.260 ± 63656.390 h·ng/mL, respectively. The results of this study provided the index of side effect and pharmacokinetics of ribavirin in pigs, which should be considered before clinical application.

Functional interplay between p53 acetylation and H1.2 phosphorylation in p53-regulated transcription.

Linker histone H1.2 has been shown to suppress p53-dependent transcription through the modulation of chromatin remodeling; however, little is known about the mechanisms governing the antagonistic effects of H1.2 in DNA damage response. Here, we show that the repressive action of H1.2 on p53 function is negatively regulated via acetylation of p53 C-terminal regulatory domain and phosphorylation of H1.2 C-terminal tail. p53 acetylation by p300 impairs the interaction of p53 with H1.2 and triggers a rapid activation of p53-dependent transcription. Similarly, DNA-PK-mediated phosphorylation of H1.2 at T146 enhances p53 transcriptional activity by impeding H1.2 binding to p53 and thereby attenuating its suppressive effects on p53 transactivation. Consistent with these findings, point mutations mimicking modification states of H1.2 and p53 lead to a significant increase in p53-induced apoptosis. These data suggest that p53 acetylation-H1.2 phosphorylation cascade serves as a unique mechanism for triggering p53-dependent DNA damage response pathways.

Human papillomavirus type 16 E6 protein interacts with cystic fibrosis transmembrane regulator-associated ligand and promotes E6-associated protein-mediated ubiquitination and proteasomal degradation.

The PDZ proteins such as hDLG, hScrib and MAGIs function as the membrane-associated protein scaffolds and have been shown to interact with the high-risk human papillomavirus (HPV) E6s. In this report, we identify a Golgi-associated PDZ protein, cystic fibrosis transmembrane regulator-associated ligand (CAL) as a cellular target of HPV16 E6 by the proteomic approach. The carboxy-terminal PDZ-binding motif of HPV16 E6 specifically interacts with the PDZ domain of CAL, and the interaction enhances proteasome-mediated degradation of CAL. HPV16 E6 interacts with CAL more strongly and degrades it better than HPV18 E6 owing to the more compatible PDZ-binding motif. CAL is ubiquitinated by the E6/E6-associated protein (E6AP) complex or by E6AP alone, albeit less efficiently, which indicates that it could be a normal target of E6AP. Although it downregulates CAL at the transcript level, small interfering RNA-induced depletion of HPV16 E6 in Caski cells stabilizes CAL at the protein level, suggesting that HPV16 E6 mediates the proteasomal degradation of CAL in HPV-positive cervical cancer cells. HPV16 E6 may tightly regulate the vesicular trafficking processes by interacting with CAL, and such a modification can contribute to the development of cervical cancer.

Distribution of anti-HBs levels in Korean adults.

Exact titration of anti-HBs with mIU/mL unit is necessary in evaluating the success of HBV vaccination or in making a decision to increase the dose of HBV vaccination. Data of distribution of anti-HBs titers can contribute to cutting of public health costs by reducing unnecessary HBV booster doses. Moreover, anti-HBc is also an important marker for differentiation of vaccination-induced anti-HBs from infection-acquired anti-HBs. However, not much study about these subjects has been done in Korea. So we evaluated anti-HBs associated with anti-HBc and vaccination history. HBsAg and anti-HBs tests were done in 1,465 cases. The positive rates of HBsAg and anti-HBs were 4.5% and 74.6%, respectively. Anti-HBs positive rate was higher in the vaccinated group than that in the non-vaccinated group. The rates of anti-HBs positive cases with lower titers (10-< 100 mIU/mL) were 31.9%, while cases with higher titers (> or = 100 mIU/mL) were 68.1%. This suggested about 70% of anti-HBs-positive Korean adults (about 53% of the general adult population) have long-lasting immunity against HBV infection and may not require booster doses of HBV vaccination for a long time. Anti-HBs titers in the vaccine-induced anti-HBs group were higher than those in the infection-acquired anti-HBs group. No statistical differences were noted between male and female or among age groups. 25.7% of the HBsAg (-)/anti-HBs (-) group showed anti-HBc positive and HBV-DNA was detected in 11.1% among HBsAg (-)/anti-HBs (-)/anti-HBcAb (+) cases. Further study about post vaccination anti-HBs titer decay in Korean should be performed to help cut vaccination costs.