Pharmacokinetic Alteration of Paclitaxel by Ferulic Acid Derivative

P-glycoprotein (P-gp) is known to be involved in multidrug resistance (MDR) and modulation of pharmacokinetic (PK) profiles of substrate drugs. Here, we studied the effects of synthesized ferulic acid (FA) derivatives on P-gp function in vitro and examined PK alteration of paclitaxel (PTX), a well-known P-gp substrate drug by the derivative. Compound 5c, the FA derivative chosen as a significant P-gp inhibitor among eight FA candidates by in vitro results, increased PTX AUCinf as much as twofold versus the control by reducing PTX elimination in rats. These results suggest that FA derivative can increase PTX bioavailability by inhibiting P-gp existing in eliminating organs

Discovery of a Novel Mutation in DNA Gyrase and Changes in the Fluoroquinolone Resistance of Helicobacter pylori over a 14-Year Period: A Single Center Study in Korea

The efficacy of fluoroquinolone-based eradication therapy largely depends on the fluoroquinolone resistance of H. pylori. The aim of this study was to investigate the changes in the primary resistance rate of H. pylori to fluoroquinolone and the mechanism of resistance in Korea. A total of 153 strains and 48 strains of H. pylori were isolated at a tertiary hospital in 2005/2006 and 2017/2018, respectively. The minimum inhibitory concentrations (MICs) of fluoroquinolone were determined by the serial 2-fold agar dilution method. DNA sequences in the quinolone resistance-determining regions of gyrA/gyrB were analyzed in resistant strains. Subsequent natural transformation study was performed to determine the association between gyrase mutation and resistance. The resistance rates increased from 19.0% (29/153) to 43.8% (21/48) both for levofloxacin and moxifloxacin. The MIC values for resistant strains increased from 2–8 µg/mL to 4–16 µg/mL over time. Mutation of gyrA was detected in 93.1% (27/29) and 100% (21/21) among the resistant strains in both periods, respectively. A novel Gly-85 mutation of gyrA was found and confirmed to be associated with fluoroquinolone resistance. Fluoroquinolone resistance rate of H. pylori has markedly increased over time in Korea. The resistance is mostly due to the point mutation of gyrA. Fluoroquinolone-containing regimens should be carefully selected in Korea, considering the increasing fluoroquinolone resistance

Flexible Adipose-Vascular Tissue Assembly Using Combinational 3D Printing for Volume-Stable Soft Tissue Reconstruction

A new concept, assembling cell-laden tissue modules, is for the first time proposed for soft tissue engineering. Adipose-vascular tissue modules composed of a synthetic polymer-based substructure and customized bioinks using planar 3D cell printing are engineered. Such tissue modules are systematically assembled into a synthetic polymer-based module holder fabricated with rotational 3D printing, resulting in the development of a flexible and volumetric tissue assembly. Whereas most of the previous studies about the construction of adipose tissue are limited to hypoxia, poor vascularization, rapid resorption, and mismatch in mechanical properties, it is aimed to realize the construction of nonhypoxic, flexible, and volume-stable tissue assembly in this study. The significance of engineered tissue assembly is proven through various in vitro and in vivo evaluations. In particular, stable volume and remarkable neovascularization/adipogenesis are observed in the implanted assembly over four weeks. Interestingly, the size of newly formed lipid droplets and the remodeled morphology in the assembly are comparable to those in native adipose tissue. As far as it is known, this work is a first report suggesting a cell printing-based tissue assembly for functional reconstruction of soft tissue.11Nsciescopu

PyeongChang 2018 Winter Olympic Games and athletes’ usage of ‘polyclinic’ medical services

ObjectiveThis paper aims to describe the medical service of two polyclinics of the PyeongChang Winter Olympic Games and to analyse the injury and illness of athletes who visited the polyclinics during the oilympic period in order to provide some insight with respect to the future construction and operation of polyclinics in mass gathering events such as the Olympic Games.MethodsThe PyeongChang Olympic Village was located near the Olympic Stadium for snow sports athletes and the Gangneung Olympic Village was located near the ice venues for ice sports athletes. During the Olympic Games, polyclinics were consisted of emergency service and outpatient clinics. We retrospectively analysed the electronic medical record data of athletes who visiting polyclinics between 9 February 2018 and 25 February 2018.ResultsDuring the Olympics, there were 1639 athlete encounters in both polyclinics. Among those, injuries of athletes were 237 (14% of all athlete encounters) in total, and the most common injured site was knee joint. Upper respiratory infection was the most frequent case in diseases of athlete encounters. Total 223 cases of image study were done, MRI was 44 cases.ConclusionThe PyeongChang Winter Olympic Games had the highest number of participants in the history of Winter Olympic Games. Overall 48% of athletes encountered polyclinics due to disease during the Games period. Upper respiratory infection and other seasonal diseases were more frequent this Olympic Games than before. Polyclinics were managed healthcare of athletes as well as injury and illness of athletes. In winter sports, a polyclinic and similar medical facilities should be prepare for diseases considering geography, weather as well as injuries and endemic diseases when planning future mass gathering events

In Vitro and in Vivo Evaluation of Phenylbutenoid Dimers as Inhibitors of P‑Glycoprotein

The expression of P-glycoprotein (P-gp), an ATP-dependent efflux transporter, is closely associated with the failure of chemotherapy and drug absorption. Two synthesized optically active phenylbutenoid dimers, 3<i>S</i>-(3,4-dimethoxyphenyl)-4<i>R</i>-{(<i>E</i>)-3,4-dimethoxystyryl}­cyclohex-1-ene (<b>1</b>) and 3<i>R</i>-(3,4-dimethoxyphenyl)-4<i>S</i>-{(<i>E</i>)-3,4-dimethoxystyryl}­cyclohex-1-ene (<b>2</b>), were tested for their P-gp inhibitory effects by measuring cellular accumulation and efflux of daunomycin in P-gp-overexpressed human breast cancer cells (MCF-7/ADR). Compound <b>2</b> significantly increased the accumulation of daunomycin (539%) and decreased the efflux of this compound (55.4%), and similar results were observed for <b>1</b>. ATPase assays and Western blot analysis were performed to identify the mechanisms by which compounds <b>1</b> and <b>2</b> inhibit P-gp. In addition, changes in the pharmacokinetic profile of paclitaxel coadministered with <b>2</b> in rats were evaluated. Paclitaxel (25 mg/kg) when orally administered with <b>2</b> (5 mg/kg) improved its relative bioavailability by 185%. Compound <b>2</b> effectively improved cellular accumulation by reducing the efflux of daunomycin and significantly enhanced oral exposure to paclitaxel. Therefore, compound <b>2</b> may be useful for improving oral exposure and cellular availability of drugs that are also substrates of P-gp

Botulinum Neurotoxin Type A Induces TLR2-Mediated Inflammatory Responses in Macrophages

<div><p>Botulinum neurotoxin type A (BoNT/A) is the most potent protein toxin and causes fatal flaccid muscle paralysis by blocking neurotransmission. Application of BoNT/A has been extended to the fields of therapeutics and biodefense. Nevertheless, the global response of host immune cells to authentic BoNT/A has not been reported. Employing microarray analysis, we performed global transcriptional profiling of RAW264.7 cells, a murine alveolar macrophage cell line. We identified 70 genes that were modulated following 1 nM BoNT/A treatment. The altered genes were mainly involved in signal transduction, immunity and defense, protein metabolism and modification, neuronal activities, intracellular protein trafficking, and muscle contraction. Microarray data were validated with real-time RT-PCR for seven selected genes including <i>tlr2</i>, <i>tnf</i>, <i>inos</i>, <i>ccl4</i>, <i>slpi</i>, <i>stx11</i>, and <i>irg1</i>. Proinflammatory mediators such as nitric oxide (NO) and tumor necrosis factor alpha (TNFα) were induced in a dose-dependent manner in BoNT/A-stimulated RAW264.7 cells. Increased expression of these factors was inhibited by monoclonal anti-Toll-like receptor 2 (TLR2) and inhibitors specific to intracellular proteins such as c-Jun N-terminal kinase (JNK), extracellular signal–regulated kinase (ERK), and p38 mitogen–activated protein kinase (MAPK). BoNT/A also suppressed lipopolysaccharide-induced NO and TNFα production from RAW264.7 macrophages at the transcription level by blocking activation of JNK, ERK, and p38 MAPK. As confirmed by TLR2-/- knock out experiments, these results suggest that BoNT/A induces global gene expression changes in host immune cells and that host responses to BoNT/A proceed through a TLR2-dependent pathway, which is modulated by JNK, ERK, and p38 MAPK.</p></div

Dose-dependent production of NO (A), TNFα (B), and IL-6 (C) in BoNT/A-treated RAW264.7 cells.

<p>Cells were incubated with BoNT/A (0, 1, 2, 5, and 10 nM) or 1 μg/ml LPS as a positive control for 24 h at 37°C. Culture supernatants were collected, and the levels of NO, TNFα, and IL-6 were measured. Values are the mean ± SD of three replicates for each group.</p

BoNT/A inhibited LPS-induced production of TNFα and NO in a dose- and time-dependent manner in RAW264.7 macrophages.

<p>RAW264.7 cells were treated with 0 to 1 nM BoNT/A for 24 h (A and B) or with 1 nM BoNT/A for 0 to 24 h and then stimulated with or without 1 μg/ml LPS (C and D). Culture media were collected at 24 h to measure NO (A and C) and TNFα (B and D) concentrations using the Griess reaction and sandwich ELISA, respectively. Three independent experiments were performed, and the data shown are the mean ± SD.</p