Negligible Effect of Quercetin in the Pharmacokinetics of Sulfasalazine in Rats and Beagles: Metabolic Inactivation of the Interaction Potential of Quercetin with BCRP.

Breast cancer resistance protein (BCRP) mediates pharmacokinetic drug interactions. This study evaluated the potential of quercetin to inhibit and induce BCRP in vitro and in vivo. The inhibition of BCRP was investigated for quercetin and its metabolites using BCRP/mBcrp1-overexpressing MDCKII cells by flow cytometry. The induction of BCRP was investigated in LS174T cells using quantitative PCR. The expression of rat BCRP in rat small intestine, liver, and kidney was also measured after multiple administrations of quercetin in rats (50, 100, and 250 mg/kg, seven days). The in vivo pharmacokinetic changes of sulfasalazine following single or multiple administration of quercetin in rats and beagles were investigated. Although the induction effect of quercetin on BCRP was observed in vitro, the in vivo expression of rat BCRP was not changed by multiple quercetin administrations. Oral administration of quercetin did not affect the plasma concentration or pharmacokinetic parameters of sulfasalazine, regardless of dose and dosing period in either rats or beagles. In addition, the inhibitory effect of quercetin metabolites on BCRP/mBcrp1 was not observed. These results suggest that the in vivo drug interaction caused by quercetin via BCRP was negligible, and it may be related to the metabolic inactivation of quercetin for the inhibition of BCRP.

Three-dimensional virtual-surgery simulation-assisted asymmetric bilateral mandibular distraction osteogenesis for a patient with bilateral condylar fractures.

INTRODUCTION: Our objective was to report a patient treated with 3-dimensional virtual-surgery simulation-assisted asymmetric bilateral mandibular distraction osteogenesis. METHODS: A boy (age, 9.5 years) had mandibular hypoplasia and facial asymmetry, induced by bilateral condylar fractures at 4 years of age. The asymmetric bilateral mandibular distraction osteogenesis was planned to correct facial asymmetry and mandibular hypoplasia. The 3-dimensional virtual-surgery simulation results were 11 mm of horizontal distraction on the right side and 4.5 mm of horizontal and 18 mm of vertical distraction on the left side of the mandible. Bilateral ramus osteotomies were performed, and intraoral unidirectional distraction devices were inserted. After a 6-day latency period, distraction was performed at 1 mm per day, followed by a 5-month consolidation period. Transarch and interarch elastics and an acrylic plate were used during distraction and consolidation. Total treatment time was 30 months. RESULTS: Satisfactory outcomes were obtained (achievement ratios between postconsolidation results and simulated results: gonial angle, 106% and 103.9%; mandibular body length, 94.2% and 89.9%; ramus height, 104.1% and 94.5% [values of the right and left sides, respectively]). The chin-point deviation and the transverse cant of the maxillary occlusal plane were significantly improved (10.1 mm to 3.3 mm; -6.8° to -4.4°). At 53 months of follow-up, the Class I molar relationship was well maintained. The transverse cant of the maxillary occlusal plane was slightly improved to -3.7° during pubertal growth. CONCLUSIONS: Three-dimensional virtual-surgery simulation can help clinicians to determine the optimal vector and amount of distraction with high accuracy in complex cases requiring simultaneous correction of a hypoplastic mandible and facial asymmetry.

Change in maxillary incisor inclination during surgical-orthodontic treatment of skeletal Class III malocclusion: comparison of extraction and nonextraction of the maxillary first premolars.

INTRODUCTION: The purpose of this study was to investigate differences in preoperative decompensation and postoperative compensation of the maxillary incisors in patients with skeletal Class III malocclusion treated with 2-jaw surgery and extraction or nonextraction of the maxillary first premolars. METHODS: The subjects consisted of 50 skeletal Class III patients who had a normal maxillary position, prognathic mandible, and mild crowding in the maxillary arch (≤4 mm). All patients were treated with 2-jaw surgery. They were divided into 2 groups: group 1 (n = 25) had extraction of the maxillary first premolars, and group 2 (n = 25) had no extractions. Lateral cephalograms were analyzed before treatment (T0), 1 month before surgery (T1), 1 day after surgery (T2), and after debonding (T3). After measurement of the skeletodental variables, statistical analyses were performed. RESULTS: At T0, group 1 exhibited more compensated maxillary incisors compared with group 2 (U1-SN, P <0.001). Considerable preoperative decompensation in group 1 and negligible preoperative decompensation in group 2 occurred at T1 (ΔU1-SN, -9.1° vs 1.1°). Although maxillary incisor inclination significantly decreased with surgical movement of the maxilla at T2, this increased to compensate for the postsurgical skeletal relapse in both groups at T3. Although 24% of group 1 had a normal range of maxillary incisor inclination (U1-SN) at T0, it increased to 68% at T1. A dominant pattern of the subjects within the normal range of U1-SN was maintained in groups 1 and 2 (80% and 96% at T2, and 72% and 80% at T3, respectively). According to the achievement ratio, the U1-SN value became close to the norm mainly by preoperative decompensation in group 1 (95.5%) and by surgery in group 2 (130.2%). CONCLUSIONS: The results of this study might provide effective guidelines for predicting the amount and pattern of preoperative decompensation and postoperative compensation of the maxillary incisors in skeletal Class III patients treated with 2-jaw surgery.

A mechanism of immunoreceptor tyrosine-based activation motif (ITAM)-like sequences in the capsid protein VP2 in viral growth and pathogenesis of Coxsackievirus B3.

Coxsackievirus B3 (CVB3) is an RNA virus that mainly causes myocarditis. We have reported previously that immunoreceptor tyrosine-based activation motif (ITAM)-like sequences are contained in the capsid protein VP2 of CVB3. The substitution of two tyrosines for phenylalanines in the ITAM-like region causes attenuation of CVB3, possibly via defective viral assembly. In this study, we found that Syk, a downstream molecule of ITAM, interacts with the wild-type (WT) CVB3 VP0 protein, but not with the mutant CVB3 VP0 (called YYFF), and that an inhibitor of Syk reduced the growth of CVB3. The WT CVB3 activated nuclear factor kappa B (NF-κB), a protein activated by ITAM, and eventually induced the production of interleukin-6 (IL-6)-one of the proinflammatory cytokines induced by NF-κB-in macrophages. However, the YYFF form did not. In addition, viral VP2 protein may be dependent on the phosphorylation of an ITAM-like region that affected the activation of NF-κB. Taken together, these results suggest that the ITAM-like sequences in CVB3 VP2 can not only affect viral structure but also act as signals in pathogenesis.