Regulator of G-protein signaling 5 (RGS5), an inhibitor of Gα(q) and Gα(i) activation, has been reported to have antiatherosclerosis. Previous studies showed antiatherosclerotic effect of Korean red ...ginseng water extract (KRGE) via multiple signaling pathways. However, potential protective effect of KRGE through RGS5 expression has not been elucidated. Here, we investigated the antiatherosclerotic effect of KRGE in vivo and in vitro and its role on RGS5 mRNA expression. Elevated levels of total cholesterol, lactate dehydrogenase (LDH), and triglyceride (TG) in western diet groups of low-density lipoprotein receptor deficient LDLr−/− mice were reversed by oral administration of KRGE. KRGE suppressed transcriptional activity of tumor necrotic factor alpha (TNF-α), interleukin-6 (IL-6), and leptin in adipose tissue. It also potently repressed western diet-induced atheroma formation in aortic sinus. While KRGE showed reduced mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), IL-1β, IL-6, and TNF-α in LPS-stimulated RAW264.7 cells, it enhanced mRNA expression of RGS5. Moreover, RGS5 siRNA transfection of microglia cells pretreated with KRGE reversed its inhibitory effect on the expression of iNOS, COX-2, and IL-1β mRNA. In conclusion, KRGE showed antiatherosclerotic and anti-inflammatory effects in western diet fed LDLr−/− mice and this effect could partly be mediated by RGS5 expression.
ABSTRACT We present the first images of the v = 1 and v = 2 J = 1 → 0 SiO maser lines taken with KaVA, i.e., the combined array of the Korean Very Long Baseline Interferometry (VLBI) Network and the ...VLBI Exploration of Radio Astrometry (VERA), toward the OH/IR star WX Psc. The combination of long and short antenna baselines enabled us to detect a large number of maser spots, which exhibit a typical ring-like structure in both the v = 1 and v = 2 J = 1 → 0 SiO masers as those that have been found in previous VLBI observational results of WX Psc. The relative alignment of the v = 1 and v = 2 SiO maser spots are precisely derived from astrometric analysis, due to the absolute coordinates of the reference maser spot that were well determined in an independent astrometric observation with VERA. The superposition of the v = 1 and v = 2 maser spot maps shows a good spatial correlation between the v = 1 and v = 2 SiO maser features. Nevertheless, it is also shown that the v = 2 SiO maser spot is distributed in an inner region compared to the v = 1 SiO maser by about 0.5 mas on average. These results provide good support for the recent theoretical studies of the SiO maser pumping, in which both the collisional and the radiative pumping predict the strong spatial correlation and the small spatial discrepancy between the v = 1 and v = 2 SiO maser.
Abstract Background: S -amlodipine gentisate, consisting entirely of the ( S )-enantiomer, was developed to increase the potency and improve the safety profile of amlodipine. Regulatory requirements ...for marketing of S -amlodipine gentisate in Korea require comparison of this agent versus amlodipine racemate. Objective: This study was conducted to compare the pharmacodynamic (PD) and pharmacokinetic (PK) characteristics of the S -amlodipine formulation ( S -amlodipine gentisate) and amlodipine racemate (amlodipine besylate). Methods: This study consisted of 2 separate substudies; PD and PK parameters were evaluated separately. Both studies were conducted using a doubleblind, randomized, 2-period, 2-treatment, 2-sequence, double-dummy, single-dose crossover design with S -amlodipine 5 mg and amlodipine racemate 10 mg, separated by a 2-week washout period. Blood pressure (BP) and heart rate were measured in the sitting position before dosing and at 1, 2, 4, 5, 6, 7, 8, 10, 12, 14, 24, 48, and 72 hours after oral administration of S-amlodipine or amlodipine racemate. Impedance cardiography parameters (stroke volume, cardiac index, and systemic vascular resistance) were measured before and at 1, 2, 4, 5, 6, 7, 8, 10, and 12 hours after dosing. For PK assessments, serial blood samples were collected before dosing and at 1, 2, 4, 6, 8, 10, 12, 14, 24, 48, 72, 96, 120, 144, and 168 hours after dosing, and drug concentrations were determined by HPLC-MS/MS. Adverse events (AEs) were collected using self-report or general health-related questions. Results: The PD study included 24 healthy men (mean SD age, 23.1 3.1 years; weight, 69.2 6.1 kg), and the PK study included 24 different healthy men (mean age, 25.1 2.1 years; weight, 65.9 5.9 kg). There were no statistically significant differences between the treatment groups in terms of systolic BP, diastolic BP, or heart rate by repeated-measures ANOVA. Likewise, in the analysis of impedance cardiography, the treatment groups did not display any significant differences in stroke volume, cardiac index, or systemic vascular resistance by repeatedmeasures ANOVA. The mean (SD) AUC0–last was 129.7 (62.8) ng · h/mL after dosing with S -amlodipine and 129.0 (59.6) ng · h/mL after dosing with amlodipine racemate. The geometric mean ratio ( S -amlodipine: amlodipine racemate) of the S -amlodipine AUC0−last was 1.01 (90% CI, 0.90–1.13). In the PD study, 4 AEs in 3 volunteers (3/24; 12.5%) and 8 AEs in 5 volunteers (5/24; 20.8%) were reported after dosing with S -amlodipine and amlodipine racemate, respectively. In the PK study, 18 AEs in 11 volunteers (11/24; 45.8%) and 20 AEs in 9 volunteers (9/24; 37.5%) were reported after dosing with S -amlodipine and amlodipine racemate, respectively. Five volunteers reported AEs after dosing with both S-amlodipine and amlodipine racemate. For the PD and PK studies combined, 30 AEs were judged to be possibly related to S -amlodipine (16 cases) or amlodipine racemate (14 cases). Twenty AEs were judged not to be related to S-amlodipine (6 cases) or amlodipine racemate (14 cases). The most common AEs considered at least possibly related to the study drug in both studies were headache (18 cases) and nausea (3 cases). Conclusions: In these single-dose studies, no significant differences were found in PD (hemodynamic) or PK parameters between S -amlodipine 5 mg and amlodipine racemate 10 mg. S -amlodipine had a safety profile comparable to that of amlodipine racemate in these healthy male volunteers.
Abstract Objective While compulsive ordering and arranging, and a preoccupation with symmetry are common presentations of obsessive–compulsive disorder (OCD), little attention has been given to these ...types of symptoms in the assessment of patients with OCD. The goal of the present study was to develop and evaluate psychometric properties for the objective and quantitative measurement of compulsive symptoms related to symmetry and arranging. Methods Thirty-five normal volunteers performed computer-simulated environment tasks under four different conditions with or without a target and distraction. Primary dependent variables included several indices of time and manipulation of arranging behaviors. We evaluated the validity of the task by comparing the novel behavioral measures with standardized measures such as the Symmetry, Ordering and Arranging Questionnaire (SOAQ), Obsessive Compulsive Inventory-Revised (OCI-R), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Barratt Impulsiveness Scale (BIS-11), and Quality of Life Scale (WHOQOL). Results We found a significant positive correlation between the arrangement time (time to complete the task) with the SOAQ score and the “ordering” subscore of the OCI-R. In addition, the number of manipulations was positively correlated with the SOAQ score and the “ordering” subscore of the OCI-R. There were no significant correlations between behavioral parameters and other scales measuring constructs less relevant to the symptoms of OCD related to ordering/symmetry. There was only a significant main effect of the target on the arrangement time. Conclusion This study demonstrates the good convergent and discriminant validity of this task as a novel behavioral measure for the assessment of arranging compulsion symptoms. We can infer from the results that subjects are likely to spend more time in compulsive arranging when the target for the task is given.
To prepare polymers based on the vegetable oils, an acrylic monomer with long alkyl chain, (2-(acryloyloxy) ethyl oleate) (AEO)), was prepared by the reaction of hydroxyl ethyl acrylate (HEA) with ...methyl oleate (MO), in which the MO, having very similar structure to the bio-diesel, was the one derived from Linseed oil. For the formation of the AEO, Novozyme-435, the Candida antarctica lipase B loaded on the acrylic resin, was used as a catalyst. To optimize its reaction condition, effects of experimental factors, such as, different enzymes, reaction temperature, water activity of enzyme, concentration of enzyme used, and molar ratio of HEA and MO, were studied. The AEO was then, after characterization using several analytical methods, polymerized by the radical polymerization, using benzoyl peroxide (BPO) as a catalyst. The Mn of the polymers prepared under different experimental conditions was in the range from 20,000 to 30,000 g/mol.
Purpose Cystic fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, is rare among non-Caucasians. We aimed to identify the clinical features and ...CFTR mutations in Korean children. Methods We included 18 pediatric patients with CF diagnosed using sweat chloride test or genetic analysis for 30 years. HEK293 cells were transfected with wild-type CFTR, ΔF508-CFTR, and L441P-CFTR mutant plasmids for 24 hours and treated with CFTR correctors (VX809 and VX661). Results The median age at diagnosis was 9.2 years. Eleven patients had growth retardation, and 6 had a respiratory failure at diagnosis. Genetic analysis was used for all patients, while sweat testing was for 8 patients. At diagnosis, the median z scores of forced expiratory volume in one second (FEV1), FEV1/forced vital capacity, and forced expiratory flow at 25%–75% of forced vital capacity were −3.61 (−5.78, 1.78), −3.38 (−4.40, −0.60), and −4.45 (−5.78, 0.54), respectively. Two patients were treated with dornase alfa and only one with CFTR modulator. Patients were followed up for 3.7 years as a median. Four patients died at 10.6 years, with 4.2 years of post-diagnosis survival. The most common mutation was exon 16-17b deletion (19.4%). Among 11 single nucleotide variants, c.1322T>C (p.Leu441Pro, L441P) was detected in 4 patients. In the functional assay, L441P-CFTR correction was well restored by CFTR correctors compared with ΔF508. Conclusions CF is extremely rare in Korean children and is caused by different mutations from those commonly observed in Caucasians. Early diagnosis and treatment availability may improve outcomes. CFTR modulators may be effective for Asian patients with rare CFTR mutations, c.1322T>C (p.Leu441Pro).
The influence of the heat shock protein 90 (hsp90) inhibitor SNX5422 alone or in combination with the histone deacetylase (HDAC) inhibitors PXD101, suberoylanilide hydroxamic acid (SAHA), and ...trichostatin A (TSA) on survival of anaplastic thyroid carcinoma (ATC) cells was investigated. In 8505C and CAL62 cells, SNX5422 caused cell death with concomitant changes in the expression of hsp90 client proteins. After treatment of both SNX5422 and PXD101, SAHA and TSA, compared with treatment of SNX5422 alone, cell viability was diminished, whereas inhibition rate and cytotoxic activity were enhanced. All of the combination index values were lower than 1.0, suggesting the synergism between SNX5422 and PXD101, SAHA and TSA in induction of cell death. In cells treated with both SNX5422 and PXD101, SAHA and TSA, compared with cells treated with SNX5422 alone, the protein levels of Akt, phospho-4EBP1, phospho-S6 K, and survivin were diminished, while those of γH2AX, acetyl. histone H3, acetyl. histone H4, cleaved PARP, and cleaved caspase-3 were enhanced. In conclusion, these results demonstrate that SNX5422 has a cytotoxic activity in conjunction with alterations in the expression of hsp90 client proteins in ATC cells. Moreover, SNX5422 synergizes with HDAC inhibitors in induction of cytotoxicity accompanied by the suppression of PI3K/Akt/mTOR signaling and survivin, and the overexpression of DNA damage-related proteins in ATC cells.
Abstract We investigated whether the clinical response to aripiprazole differed according to the Taq1A polymorphism in the dopamine D2 receptor (DRD2) gene. In this 26-week, prospective, open-label, ...double-blind, parallel-group study, 90 patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder were recruited and divided into two groups according to their DRD2 genotype (A1A1, n = 14; A1A2+A2A2, n = 76). The efficacy assessment included Positive and Negative Syndrome Scale (PANSS) scores and Clinical Global Impression (CGI) scores. Extrapyramidal symptoms were assessed using the Simpson–Angus Scale (SAS), Abnormal Involuntary Movement Scale (AIMS), and Barnes Akathisia Rating Scale (BAS). Plasma prolactin levels were also measured. Patients with the A1A1 genotype showed a more favorable therapeutic response to aripiprazole when assessed using the PANSS ratio. The changes in the SAS score from baseline to week 4 also differed according to the genotype group. There were no significant differences in the changes in the CGI, AIMS, and BAS scores or plasma prolactin level between the two genotype groups. The results suggest an association between the DRD2 Taq1A polymorphism status and the variation in the clinical response to aripiprazole.
We studied the effect of apigenin in combination with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on cell survival and the influence of AKT inhibition on the combined effect ...of apigenin with TRAIL in anaplastic thyroid carcinoma (ATC) cells.
The human 8505C and CAL62 ATC cell lines were used.
Apigenin in combination with TRAIL, compared to apigenin alone, reduced cell viability and Bcl2 protein levels, elevated the percentage of dead cells, as well as the protein levels of cleaved PARP and phospho-ERK1/2. The protein levels of Bcl-xL, Bax, Bid, total ERK1/2, and total and phospho-AKT were unchanged. Administration of wortmannin further reduced cell viability, and elevated the percentage of dead cells, cytotoxic activity and cleaved PARP protein levels.
Apigenin synergizes with TRAIL through regulation of Bcl2 family proteins in inducing cytotoxicity, and suppression of AKT potentiates synergistic cytotoxicity of apigenin with TRAIL in ATC cells.
Purpose
The influence of the dipeptidyl peptidase-IV inhibitor, gemigliptin alone or in combination with metformin on survival, proliferation, and migration of thyroid carcinoma cells was ...investigated.
Methods
SW1736 and TPC-1 human thyroid carcinoma cells were used.
Results
Gemigliptin and metformin caused cell death in a dose-dependent manner. In cells treated with both gemigliptin and metformin, compared with metformin alone, all of the combination index values were lower than 1.0, suggesting synergistic cytotoxicity of two agents. Cell viability, the percentage of viable cells, ATP levels, and mitochondrial membrane potential decreased; however, cytotoxic activity, and the protein levels of cleaved PARP, phospho-Akt and phospho-AMP-activated protein kinase (AMPK) increased. Administration of wortmannin, but not compound C, further decreased cell viability, and further increased cytotoxic activity. Moreover, compared with control, cell proliferation and migration as well as the protein levels of p53, p21, vascular cell adhesion molecule-1 (VCAM-1), and phospho-extracellular signal-regulated kinase (ERK) 1/2 decreased. The decrement of matrix metalloproteinase-2 and matrix metalloproteinase-9 protein levels was cell specific.
Conclusions
Our results demonstrate that gemigliptin induces cytotoxic activity, and has a synergistic activity with metformin in inducing cytotoxicity via regulation of Akt and AMPK in thyroid carcinoma cells. Furthermore, gemigliptin augments the inhibitory effect of metformin on proliferation and migration through involvement of matrix metalloproteinase-2, matrix metalloproteinase-9, p53, p21, VCAM-1, and ERK in thyroid carcinoma cells.
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