Effect of a New Prokinetic Agent DA-9701 Formulated with Corydalis Tuber and Pharbitidis Semen on Cytochrome P450 and UDP-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes

DA-9701 is a new botanical drug composed of the extracts of Corydalis tuber and Pharbitidis semen, and it is used as an oral therapy for the treatment of functional dyspepsia in Korea. The inhibitory potentials of DA-9701 and its component herbs, Corydalis tuber and Pharbitidis semen, on the activities of seven major human cytochrome P450 (CYP) enzymes and four UDP-glucuronosyltransferase (UGT) enzymes in human liver microsomes were investigated using liquid chromatography-tandem mass spectrometry. DA-9701 and Corydalis tuber extract slightly inhibited UGT1A1-mediated etoposide glucuronidation, with 50% inhibitory concentration (IC50) values of 188 and 290 μg/mL, respectively. DA-9701 inhibited CYP2D6-catalyzed bufuralol 1′-hydroxylation with an inhibition constant (Ki) value of 6.3 μg/mL in a noncompetitive manner. Corydalis tuber extract competitively inhibited CYP2D6-mediated bufuralol 1′-hydroxylation, with a Ki value of 3.7 μg/mL, whereas Pharbitidis semen extract showed no inhibition. The volume in which the dose could be diluted to generate an IC50 equivalent concentration (volume per dose index) value of DA-9701 for inhibition of CYP2D6 activity was 1.16 L/dose, indicating that DA-9701 may not be a potent CYP2D6 inhibitor. Further clinical studies are warranted to evaluate the in vivo extent of the observed in vitro interactions

Effects of Marital Status and Income on Hypertension: The Korean Genome and Epidemiology Study (KoGES)

Objectives: This study aimed to analyze the associations of income, marital status, and health behaviors with hypertension in male and female over 40 years of age in the Korea. Methods: The data were derived from the Korean Genome and Epidemiology Study (KoGES; 4851-302) which included 211 576 participants. To analyze the relationships of income, marital status, and health behaviors with hypertension in male and female over 40 years of age, multiple logistic regression was conducted with adjustments for these variables. Results: The prevalence of hypertension increased linearly as income decreased. The odds ratio for developing hypertension in people with an income of <0.5 million Korean won (KRW) compared to ≥6.0 million KRW was 1.55 (95% confidence interval [CI], 1.25 to 1.93) in the total population, 1.58 (95% CI, 1.27 to 1.98) in male, and 1.07 (95% CI, 0.35 to 3.28) in female. The combined effect of income level and marital status on hypertension was significant. According to income level and marital status, in male, low income and divorce were most associated with hypertension (1.76 times; 95% CI, 1.01 to 3.08). However, in female, the low-income, married group was most associated with hypertension (1.83 times; 95% CI, 1.71 to 1.97). Conclusions: The results of this study show that it is necessary to approach male and female marital status separately according to income in health policies to address inequalities in the prevalence of hypertension

MUC1 expressing tumor growth was retarded after human mucin 1 (MUC1) plasmid DNA immunization

Introduction: Naked DNA is one of the attractive tools for vaccination studies. We studied naked DNA vaccination against the human tumor antigen, mucin, which is encoded by the MUC1 gene. Methods: We constructed the pcDNA3.0-MUC1 (pcDNA-MUC1) plasmid expressing an underglycosylated MUC1 protein. BALB/c mice were immunized intradermally thrice at 2-weeks intervals with pcDNA-MUC1. Two weeks after the last immunization, tumor challenge experiments were performed using either the CT26 or TA3HA tumor cell lines, both of which transduce human MUC1. Results: Immune cell population monitoring from pcDNA-MUC1-immunized animals indicated that immune cell activation was induced by MUC1-specific immunization. Using intracellular fluorescence activated cell sorting and enzyme-linked immunosorbent spot assay, we reported that interferon-γ secreting CD8+ T cells were mainly involved in MUC1-specific immunization. In all mice immunized with MUC1 DNA, tumor growth inhibition was observed, whereas control mice developed tumors (p < 0.001). Conclusion: Our results suggest that intradermal immunization with MUC1 DNA induces MUC1-specific CD8+ T cell infiltration into tumors, elicits tumor-specific Th1-type immune response, and inhibits tumor growth

Reciprocal Relationship Between Depression and Internet Gaming Disorder in Children: A 12-month Follow-Up of the iCURE Study Using Cross-Lagged Path Analysis

Objectives: Previous studies have reported an association between Internet gaming disorder (IGD) and depression, but the directionality of the relationship remains unclear. Therefore, we examined the reciprocal relationship between level of depressive symptoms and IGD among children in a longitudinal study. Methods: Research panels for this study consisted of 366 elementary-school students in the iCURE study. All participants were current Internet users, so they could be considered an at-risk population for IGD. Self-reported severity of IGD features and level of depression were assessed by the Internet Game Use-Elicited Symptom Screen and Children’s Depression Inventory, respectively. Follow-up assessment was completed after 12 months. We fitted cross-lagged structural equation models to investigate the association between the two variables at two time points contemporaneously. Results: The cross-lagged analysis revealed that level of depression at baseline significantly predicted severity of IGD features at the 12-month follow-up (β = 0.15, p = .003). Severity of IGD features at baseline also significantly predicted level of depression at the 12-month follow-up (β = 0.11, p = .018), controlling for possible confounding factors. Conclusions: The cross-lagged path analysis indicates a reciprocal relationship between severity of IGD features and level of depressive symptoms. Understanding the reciprocal relationship between depressive symptoms and severity of IGD features can assist in interventions to prevent both conditions. These findings provide theoretical support for prevention and remediation plans for IGD and depressive symptoms among children

JNK pathway is involved in the inhibition of inflammatory target gene expression and NF-kappaB activation by melittin

<p>Abstract</p> <p>Background</p> <p>Bee venom therapy has been used to treat inflammatory diseases including rheumatoid arthritis in humans and in experimental animals. We previously found that bee venom and melittin (a major component of bee venom) have anti-inflammatory effect by reacting with the sulfhydryl group of p50 of nuclear factor-kappa B (NF-κB) and IκB kinases (IKKs). Since mitogen activated protein (MAP) kinase family is implicated in the NF-κB activation and inflammatory reaction, we further investigated whether activation of MAP kinase may be also involved in the anti-inflammatory effect of melittin and bee venom.</p> <p>Methods</p> <p>The anti-inflammatory effects of melittin and bee venom were investigated in cultured Raw 264.7 cells, THP-1 human monocytic cells and Synoviocytes. The activation of NF-κB was investigated by electrophoretic mobility shift assay. Nitric oxide (NO) and prostaglandin E₂(PGE₂) were determined either by Enzyme Linked Immuno Sorbent Assay or by biochemical assay. Expression of IκB, p50, p65, inducible nitric oxide synthetase (iNOS), cyclooxygenase-2 (COX-2) as well as phosphorylation of MAP kinase family was determined by Western blot.</p> <p>Results</p> <p>Melittin (0.5–5 μg/ml) and bee venom (5 and 10 μg/ml) inhibited lipopolysaccharide (LPS, 1 μg/ml) and sodium nitroprusside (SNP, 200 μM)-induced activation of c-Jun NH2-terminal kinase (JNK) in RAW 264.7 cells in a dose dependent manner. However, JNK inhibitor, anthra [1,9-cd]pyrazole-6 (2H)-one (SP600215, 10–50 μM) dose dependently suppressed the inhibitory effects of melittin and bee venom on NF-κB dependent luciferase and DNA binding activity via suppression of the inhibitory effect of melittin and bee venom on the LPS and SNP-induced translocation of p65 and p50 into nucleus as well as cytosolic release of IκB. Moreover, JNK inhibitor suppressed the inhibitory effects of melittin and bee venom on iNOS and COX-2 expression, and on NO and PGE₂generation.</p> <p>Conclusion</p> <p>These data show that melittin and bee venom prevent LPS and SNP-induced NO and PGE₂production via JNK pathway dependent inactivation of NF-κB, and suggest that inactivation of JNK pathways may also contribute to the anti-inflammatory and anti-arthritis effects of melittin and bee venom.</p

Evaluation of the transporter-mediated herb-drug interaction potential of DA-9801, a standardized dioscorea extract for diabetic neuropathy, in human in vitro and rat in vivo

BACKGROUND: Drug transporters play important roles in the absorption, distribution, and elimination of drugs and thereby, modulate drug efficacy and toxicity. With a growing use of poly pharmacy, concurrent administration of herbal extracts that modulate transporter activities with drugs can cause serious adverse reactions. Therefore, prediction and evaluation of drug-drug interaction potential is important in the clinic and in the drug development process. DA-9801, comprising a mixed extract of Dioscoreae rhizoma and Dioscorea nipponica Makino, is a new standardized extract currently being evaluated for diabetic peripheral neuropathy in a phase II clinical study. METHOD: The inhibitory effects of DA-9801 on the transport functions of organic cation transporter (OCT)1, OCT2, organic anion transporter (OAT)1, OAT3, organic anion transporting polypeptide (OATP)1B1, OATP1B3, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) were investigated in HEK293 or LLC-PK1 cells. The effects of DA-9801 on the pharmacokinetics of relevant substrate drugs of these transporters were also examined in vivo in rats. RESULTS: DA-9801 inhibited the in vitro transport activities of OCT1, OCT2, OAT3, and OATP1B1, with IC(50) values of 106, 174, 48.1, and 273 μg/mL, respectively, while the other transporters were not inhibited by 300 μg/mL DA-9801. To investigate whether this inhibitory effect of DA-9801 on OCT1, OCT2, and OAT3 could change the pharmacokinetics of their substrates in vivo, we measured the pharmacokinetics of cimetidine, a substrate for OCT1, OCT2, and OAT3, and of furosemide, a substrate for OAT1 and OAT3, by co-administration of DA-9801 at a single oral dose of 1,000 mg/kg. Pre-dose of DA-9801 5 min or 2 h prior to cimetidine administration decreased the C(max) of cimetidine in rats. However, DA-9801 did not affect the elimination parameters such as half-life, clearance, or amount excreted in the urine, suggesting that it did not inhibit elimination process of cimetidine, which is governed by OCT1, OCT2, and OAT3. Moreover, DA-9801 did not affect the pharmacokinetic characteristics of furosemide, as evidenced by its unchanged pharmacokinetic parameters. CONCLUSION: Inhibitory effects of DA-9801 on OCT1, OCT2, and OAT3 observed in vitro may not necessarily translate into in vivo herb-drug interactions in rats even at its maximum effective dose

Nonlinear impact of the Arctic Oscillation on extratropical surface air temperature

The Arctic Oscillation (AO) is the leading climate mode of sea level pressure (SLP) anomalies during cold season in the Northern Hemisphere. To a large extent, the atmospheric climate anomalies associated with positive and negative phases of the AO are opposite to each other, indicating linear impact. However, there is also significant nonlinear relationship between the AO and other winter climate variability. We investigate nonlinear impacts of the AO on surface air temperature (SAT) using reanalysis data and a multi-millennial long climate simulation. It is found that SAT response to the AO, in terms of both spatial pattern and magnitude, is almost linear when the amplitude of the AO is moderate. However, the response becomes quite nonlinear as the amplitude of the AO becomes stronger. First, the pattern shift in SAT depends on AO phase and magnitude, and second, the SAT magnitude depends on AO phase. In particular, these nonlinearities are distinct over the North America and Eurasian Continent. Based on the analyses of model output, we suggest that the nonlinear zonal advection term is one of the critical components in generating nonlinear SAT response, particularly over the North America. Key Points: - We investigate nonlinear impacts of the AO on surface air temperature - The response becomes nonlinear for the strong AO events - The nonlinear advection is a critical component for the nonlinear SAT respons

A Case of Wilson's Disease in Patient with Mildly Elevated Liver Enzymes

Wilson's disease is an autosomal recessive disorder affecting copper transport; it results in the accumulation of copper in the liver, brain, and other organs. Wilson's disease is the most common inherited liver disease with more than 500 cases reported in Korea. An impairment in biliary excretion process leads to copper accumulation in the liver, which progressively damages the liver, leading to cirrhosis. Since effective treatment is available for this disease, early and correct diagnosis is very important. Here, we report a case of Wilson's disease with mildly elevated liver enzyme levels in a 29-year-old breast-feeding woman with weight loss

Understanding medical students’ empathy based on Enneagram personality types

Purpose High self-awareness can promote communication and empathy. The Enneagram is a well-known personality tool to enhance self-awareness. We evaluated differences in empathy among medical students using the Enneagram typology. Methods This cross-sectional study included first and second grade students at the Inje University College of Medicine. The Jefferson Scale of Empathy was used to measure empathy and the Korean Enneagram Personality Type Indicator was used for examining personality characteristics. Empathy scores were analyzed according to the Triads, Hornevian group, Harmonic group, and each Enneagram type. Results The Instinctive triad, the Withdrawns, and the Positive outlook group were the most common, and the Feeling triad, the Assertives, and the Emotional realness group were the least common. Students in the Feeling triad and the Dutifuls had higher compassionate care (CC) scores as compared to their counterparts. Type 2 and 6 students showed the two highest empathy and CC scores. The empathy score of type 3 students was the lowest. Type 7 had the lowest CC score but the highest perspective taking score. Conclusion These differences in empathy according to Enneagram personality types can be applied to medical education to maintain and improve medical students’ empathy