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Phytochemical investigation on the dried fruits of Casearia grewiifolia led to the identification of 10 new salicinoyl quinic acid derivatives (1-10), a new benzoyl quinic acid (11), and two known compounds (12 and 13). The structures of the new compounds were elucidated by interpreting 1D and 2D NMR spectroscopic data including HMBC and EXSIDE along with a chemical method for sugar unit analysis. All isolates were evaluated for their inhibitory activities against prostaglandin E2 (PGE2) production in ultraviolet B (UVB)-irradiated HaCat keratinocytes. Of the isolates tested, compounds 6 and 12 were found to inhibit PGE2 production with IC50 values of 20.5 and 28.8 μM, respectively.

Phytochemical investigation of the methanol extract of the aerial parts of Salvia plebeia aided by a proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA expression screening assay in HepG2 cells led to the identification of 19 compounds including one new norsesquiterpene (1), six new eudesmane sesquiterpenoids (2-5, 8, and 11), and 12 known compounds. The structures of all compounds were elucidated by interpretation of their 1D and 2D NMR spectroscopic and MS data. Furthermore, computational prediction of ECD or chemical shifts was used to propose the absolute configurations of the new structures. All isolates were assessed for their inhibitory activities against PCSK9 mRNA expression and PCSK9-low-density lipoprotein receptor (LDLR) interactions. None of the isolated compounds inhibited PCSK9 and LDLR interactions. However, compounds 1, 9, and 10 downregulated PCSK9 mRNA expression.

Moracin C from Morus alba fruits, also known as the mulberry, has been proven to exhibit inhibitory activities against lipoxygenase enzymes, TNF-α and interleukin-1β secretion, and proprotein convertase subtilisin/kexin type 9 expression. Despite the various pharmacological activities of moracin C, its pharmacokinetic characteristics have yet to be reported. Here, the pharmacokinetic parameters and tissue distribution of moracin C have been investigated in mice, and the plasma concentration of moracin C with multiple dosage regimens was simulated via pharmacokinetic modeling. Our results showed that moracin C was rapidly and well absorbed in the intestinal tract, and was highly distributed in the gastrointestinal tract, liver, kidneys, and lungs. Moracin C was distributed in the ileum, cecum, colon, and liver at a relatively high concentration compared with its plasma concentration. It was extensively metabolized in the liver and intestine, and its glucuronidated metabolites were proposed. In addition, the simulated plasma concentrations of moracin C upon multiple treatments (i.e., every 12 and 24 h) were suggested. We suggest that the pharmacokinetic characteristics of moracin C would be helpful to select a disease model for in vivo evaluation. The simulated moracin C concentrations under various dosage regimens also provide helpful knowledge to support its pharmacological effect.

Whole-transcriptome analysis of α-mangostin-treated HepG2 cells revealed that genes relevant to lipid and cholesterol metabolic processes responded to α-mangostin treatment. α-Mangostin downregulated a series of cholesterol biosynthetic genes, including SQLE, HMGCR, and LSS, and controlled specific cholesterol trafficking-associated genes such as ABCA1, SOAT1, and PCSK9. In particular, the downregulation of SREBP2 expression highlighted SREBP2 as a key transcriptional factor controlling lipid or cholesterol metabolic processes. Gene network analysis of SREBP2 and responses of its target proteins demonstrated that the effect of α-mangostin on HepG2 cells was mediated by the downregulation of SREBP2 expression, which was further supported by the reduction of the amount of SREBP2-SCAP complex. In the presence of exogenous cholesterols, α-mangostin downregulated SREBP2 expression and suppressed PCSK9 synthesis, which might contribute to the increased cholesterol uptake in cells, in part explaining the cholesterol-lowering effect of α-mangostin.

Even though butein can be a promising candidate for anti-inflammatory and anti-diabetic activities, it is poorly soluble limiting its availability for product development. Size reduction and solid dispersion (SD) were adopted independently to evaluate their feasibility for enhancement in solubility as well as bioavailability. To reduce the particle size, milling method was carried out under dry and wet conditions. For solid dispersion preparation, simple solvent evaporation method was used with hydrophilic excipients including PVP K-30 and Poloxamer 407. Physicochemical properties such as crystallinity, size, and kinetic solubility of prepared formulations were assessed using dynamic light scattering, X-ray powder diffraction, differential scanning calorimetry, and solubility. In vivo pharmacokinetic study was also conducted with selected samples. Butein is weakly basic with its pKa 6.76 and log P 3.81 based on the Henderson-Hasselbalch equation. High temperature and basic pH were degradative stresses as significant color change in solution. Milling decreased the size distribution down to 4.2 μm without dramatic change in the solubility. However, the solubility of solid dispersion increased from 3.15 up to 114.57 μg/mL, suggesting amorphous state increased solubility significantly. Its amorphous state was confirmed by DSC and PXRD. In addition, oral absorption of SD in vivo confirmed its enhanced pharmacokinetic parameters; faster Tmax, higher Cmax and AUC. Solid dispersion exhibited enhancement in pharmacokinetic parameters compared to size reduction, suggesting its feasibility for solid dispersion formulation.

Scutellaria baicalensis (SB), a herbal medicine, is commonly used to treat metabolic diseases, while Metformin (MF) is a widely used drug for type 2 diabetes. The purpose of this study was to investigate whether co-treatment of SB with MF could produce a potential therapeutic effect on high-fat and high-fructose diet (HFFD)-induced metabolic dysregulation. First, we optimized the dose of SB (100, 200, 400, and 800[Formula: see text]mg/kg) with MF (200[Formula: see text]mg/kg) in HFFD-induced C57BL6J mice. Next, the optimized dose of SB (400[Formula: see text]mg/kg) was co-administered with MF (50, 100, and 200[Formula: see text]mg/kg) in a similar animal model to find the effective combinations of SB and MF. Metabolic markers were determined in serum and tissues using different assays, histology, gene expression, and gut microbial population. The SB and MF co-treatment significantly decreased the body, liver, and VAT weights. The outcome of OGTT was improved, and the fasting insulin, HbA1c, TG, TC, LDL-c, AST, and ALT were decreased, while HDL-c was significantly increased. Histological analyses revealed maintained the integrity of liver, adipose tissue, and intestine prevented lipid accumulation in the liver and intestine and combated neuronal damage in the brain. Importantly, controlled the expression of PPAR[Formula: see text], and IL-6 genes in the liver, and expression of BDNF, Glut1, Glut3, and Glut4 genes in the brain. Treatment-specific gut microbial segregation was observed in the PCA chart. Our findings indicate that SB and MF co-treatment is an effective therapeutic approach for HFFD-induced metabolic dysregulation which is operated through the gut–liver–brain axis.

1. Treatment periods of P-glycoprotein (P-gp) inhibitors have revealed different efficacies. We have previously reported dose-dependent inhibition of P-gp in single-treatment with LC478. However, whether repeated treatment with LC478 can inhibit P-gp even at its ineffective single-treatment dose remains unknown. 2. Therefore, the purpose of this study was to assess the effect of repeated treatment (i.e., 7-day treatment) with LC478 on P-gp known to affect docetaxel bioavailability in rats. Effects of LC478 on P-gp mediated efflux and expression in MDCK-MDR1 cells, P-gp ATPase activity, and binding site with P-gp were evaluated.3. The 7-day treatment with LC478 increased docetaxel absorption via intestinal P-gp inhibition in rats. Intestinal concentrations of LC478 were 8.31-10.3 μM in rats after 7-day treatment of LC478. These concentrations were close to 10 μM that reduced P-gp mediated docetaxel efflux and P-gp expression in MDCK-MDR1 cells. Considering that intestinal LC478 concentrations after 1-day treatment were 2.68-4.19 μM, higher LC478 concentrations after 7-day treatment might have driven P-gp inhibition and increased docetaxel absorption. LC478 might competitively inhibit P-gp considering its stimulated ATPase activity and its binding site with nucleotide binding domain of P-gp. 4. Therefore, repeated treatment with LC478 can determine its feasibility for P-gp inhibition and changing docetaxel bioavailability.

Seven new prenylated flavonoids (1-7) and one new prenylated phenylpropiophenone (8) were isolated from roots and rhizomes of Sophora tonkinensis, along with nine known compounds (9-17). The structures 1-8 were elucidated by spectroscopic data analysis and comparison with reported values. Compounds 8 and 12 (7-methoxyebenosin) showed inhibitory activities against nitric oxide production in lipopolysaccharide-induced RAW264.7 cells, with IC50 values of 8.1 and 6.2 μM, respectively. They also significantly lowered expression of CSF2, TNF, and IL-1β. Lonchocarpol A (10) and erybraedin D (16) at concentrations of 20 μM downregulated proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA expression in HepG2 cells. Moreover, erybraedin D (16) inhibited PCSK9 protein synthesis (IC50 7.8 μM), while simultaneously activating AMP-activated protein kinase and acetyl-CoA carboxylase.

Ethnopharmacological relevance Penthorum chinense has been used in East Asia for the treatment of cholecystitis, infectious hepatitis, jaundice and to treat liver problems. Recent evidences provided the potential for the clinical use of P. chinense in the treatment of metabolic disease. Aim of the study: Based on the traditional use and recent evidences, we investigated the effects of constituents from P. chinense with modulation on proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein receptor (LDLR) expression, and the effect of the most active substance on cholesterol uptake, and genes relevant to lipid metabolism. Materials and methods The isolation of compounds from the BuOH-soluble extract of 80% methanol extract of P. chinense was conducted using chromatographic methods and the structures were established by interpreting spectroscopic data. Quantitative real time-PCR, and Western blot analysis were performed to monitor the regulatory activity on PCSK9 and LDLR expression. PCSK9-LDLR binding interaction was also tested. The cholesterol uptake in hepatocyte was measured using 1,1-dioctadecyl-3,3,3,3-tetramethylindocarbocyanine perchlorate (DiI)-labeled LDL cholesterol. Additionally, gene network analysis of LDLR and responses of its target proteins were carried out to discover genes germane to the effect of active compound on HepG2 cells. Moreover, we performed protein-protein interaction analysis via String and constructed the compound target network using Cytoscape. Results Two new neolignans and 37 known compounds were characterized from P. chinense. Of the isolated compounds, (7′E,8S)-2′,4,8-trihydroxy-3-methoxy-2,4′-epoxy-8,5′-neolign-7′-en-7-one (3), penthorin A (4) and methyl gallate (25) were found to suppress PCSK9 mRNA expression with IC50 values of 5.13, 15.56 and 11.66 μM, respectively. However, all the isolated compounds were found to be inactive in PCSK9-LDLR interaction assay. Additionally, a dibenzoxepine-type lignan analog, (7′E,8S)-2′,4,8-trihydroxy-3-methoxy-2,4′-epoxy-8,5′-neolign-7′-en-7-one (3) demonstrated to upregulate LDLR mRNA and protein expression via transcriptional factor sterol regulatory element-binding protein 2 (SREBP2). Furthermore, (7′E,8S)-2′,4,8-trihydroxy-3-methoxy-2,4′-epoxy-8,5′-neolign-7′-en-7-one (3) increase the LDL-cholesterol uptake in DiI-LDL assay. Conclusion (7′E,8S)-2′,4,8-trihydroxy-3-methoxy-2,4′-epoxy-8,5′-neolign-7′-en-7-one (3) seemed to increase potentially cholesterol uptake via the downregulation of PCSK9 and the activation of LDLR in hepatocytes. Moreover, SREBP2 was found to play an important role in regulation of PCSK9 and LDLR by (7′E,8S)-2′,4,8-trihydroxy-3-methoxy-2,4′-epoxy-8,5′-neolign-7′-en-7-one.

Natural products have been fundamental materials in drug discovery. Traditional strategies for observing natural products with novel structure and/or biological activity are challenging due to large cost and time consumption. Implementation of the MS/MS-based molecular networking strategy with the in silico annotation tool is expected to expedite the dereplication of secondary metabolites. In this study, using this tool, two new dilignans with a 2-phenyl-3-chromanol motif, obovatolins A (1) and B (2), were discovered from the stem barks of Magnolia obovata Thunb. along with six known compounds (3–8), expanding chemical diversity of lignan skeletons in this natural source. Their structures and configurations were elucidated using spectroscopic data. All isolates were evaluated for their PCSK9 mRNA expression inhibitory activity. Obovatolins A (1) and B (2), and magnolol (3) showed potent lipid controlling activities. To identify transcriptionally controlled genes by 1 along with downregulation of PCSK9, using small set of genes (42 genes) related to lipid metabolism selected from the database, focused bioinformatic analysis was carried out. As a result, it showed the correlations between gene expression under presence of 1, which led to detailed insight of the lipid metabolism caused by 1.

Background: Penthorum chinense has been used in East Asia for the treatment of cholecystitis, infectious hepatitis, and jaundice. So far there is no report regarding proprotein convertase subtilisin/kexin type 9 inhibitory constituents from this plant. The aim of the present study was to discover new active constituents with PCSK9 expression inhibitory activities from P. chinenseMethods: All structures were established by interpreting NMR spectroscopic data and MS data. Further experimental and calculated ECD data were used to determine the absolute configuration of the two new neolignans. To monitor the inhibitory activity on proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA expression and PCSK9-low density lipoprotein receptor (LDLR) interaction, quantitative real time-PCR, Western blot analysis, and an enzyme-linked immunosorbent assay (ELISA) method by a PCSK9-biotinylated-LDLR binding assay were performed.Results: 39 compounds were isolated and identified including two new oxepine-type neolignans, penthorinols A (1) and B (2) and a naturally occurring chalcone, 6'-hydroxy-2'-methoxychalcone-4'-O-β-D-glucopyranoside (20). Of all tested compounds, penthorin A (4) and methyl gallate (25) were found to suppress PCSK9 mRNA expression with IC50 values of 15.56 and 11.66 µM, respectively. Furthermore, penthorin A (4) and methyl gallate (25) downregulated PCSK9 protein expression. However, all compounds seemed to be inactive in PCSK9-LDLR interaction.Conclusion: In the present study, two new compounds was discovered from this plant and active constituents with PCSK9 expression inhibitory activities were suggested.

Postsurgical hypoparathyroidism is the most common complication of thyroid surgery. Conventional therapy with high-dose calcium and vitamin D can correct hypocalcemia but can increase the risk of hypercalciuria, renal stones, or ectopic calcification. The aim of the present study was to investigate the efficacy of a calcium-sensing receptor antagonist, also called a calcilytic (AXT914), in rat models of postsurgical hypoparathyroidism. Two postsurgical hypoparathyroidism rat models were made by hemi-parathyroidectomy or total parathyroidectomy with autotransplantation in 10-week-old female Wistar rats. AXT914 or vehicle was administered orally for 2 to 3 weeks. Serum PTH, calcium, and phosphorus levels, and the urinary excretion of calcium were measured. Autotransplanted parathyroid tissues were collected and examined histologically. In the hemi-parathyroidectomy model, the oral administration of the calcilytic AXT914 (5 and 10 mg/kg) for 2 weeks increased serum PTH and calcium levels and decreased serum phosphorus levels and urinary calcium excretion. In the total parathyroidectomy with autotransplantation model, the oral administration of AXT914 (10 mg/kg) for 3 weeks increased serum PTH and calcium levels and decreased serum phosphorus levels. The serum PTH and calcium levels increased by AXT914 were maintained for 1 week, even after discontinuation of the drug. In conclusion, AXT914 increased PTH secretion in rat models of postsurgical hypoparathyroidism, thereby correcting abnormal calcium and phosphorus homeostasis. Furthermore, AXT914 improved the functional recovery of autotransplanted parathyroid tissues.

The purpose of this study was to investigate the effect of photothermal treatment (PTT) with gold nanoshell (ANS) using a macrophage-mediated delivery system in a head and neck squamous cell carcinoma (HNSCC) cell line. To achieve this, ANS-loaded rat macrophages (ANS-MAs) were prepared via the coculture method with ANS. The human HNSCC (FaDu cell) and macrophage (rat macrophage; NR8383 cell) hybrid spheroid models were generated by the centrifugation method to determine the possibility of using ANS-MAs as a cancer therapy. These ANS-MAs were set into the tumor and macrophage hybrid spheroid model to measure PTT efficacy. Kinetic analysis of the spheroid growth pattern revealed that this PTT process caused a decreasing pattern in the volume of the hybrid model containing ANS-MAs (p<0.001). Comparison with empty macrophages showed harmony between ANS and laser irradiation for the generation of PTT. An annexin V/dead cell marker assay indicated that the PTT-treated hybrid model induced increasing apoptosis and dead cells. Further studies on the toxicity of ANS-MAs are needed to reveal whether it can be considered biocompatible. In summary, the ANS was prepared with a macrophage as the delivery method and protective carrier. The ANS was successfully localized to the macrophages, and their photoabsorption property was stationary. This strategy showed significant growth inhibition of the tumor and macrophage spheroid model under NIR laser irradiation. In vivo toxicology results suggest that ANS-MA is a promising candidate for a biocompatible strategy to overcome the limitations of fabricated nanomaterials. This ANS-MA delivery and PTT strategy may potentially lead to improvements in the quality of life of patients with HNSCC by providing a biocompatible, minimally invasive modality for cancer treatment.

Nonalcoholic fatty liver disease (NAFLD) arises from mitochondrial dysfunction under sustained imbalance between energy intake and expenditure, but the underlying mechanisms controlling mitochondrial respiration have not been entirely understood. Heterotrimeric G proteins converge with activated GPCRs to modulate cell-signaling pathways to maintain metabolic homeostasis. Here, we investigated the regulatory role of G protein α(12) (Gα(12)) on hepatic lipid metabolism and whole-body energy expenditure in mice. Fasting increased Gα(12) levels in mouse liver. Gα(12) ablation markedly augmented fasting-induced hepatic fat accumulation. cDNA microarray analysis from Gna12-KO liver revealed that the Gα(12)-signaling pathway regulated sirtuin 1 (SIRT1) and PPARα, which are responsible for mitochondrial respiration. Defective induction of SIRT1 upon fasting was observed in the liver of Gna12-KO mice, which was reversed by lentivirus-mediated Gα(12) overexpression in hepatocytes. Mechanistically, Gα(12) stabilized SIRT1 protein through transcriptional induction of ubiquitin-specific peptidase 22 (USP22) via HIF-1α increase. Gα(12) levels were markedly diminished in liver biopsies from NAFLD patients. Consistently, Gna12-KO mice fed a high-fat diet displayed greater susceptibility to diet-induced liver steatosis and obesity due to decrease in energy expenditure. Our results demonstrate that Gα(12) regulates SIRT1-dependent mitochondrial respiration through HIF-1α–dependent USP22 induction, identifying Gα(12) as an upstream molecule that contributes to the regulation of mitochondrial energy expenditure.

FMS-like receptor tyrosine kinase-3 (FLT3) belongs to the family of receptor tyrosine kinase (RTK), and the FLT3 mutation is observed in 1/3 of all acute myeloid leukemia (AML) patients. Potential FLT3 inhibitors have been investigated as potential therapeutic agents of AML. In this study, we identified a potent FLT3 inhibitor LDD1937 containing an indirubin skeleton. The potent inhibitory activity of LDD1937 against FLT3 was shown with an in vitro kinase assay (IC50 = 3 nM). The LDD1937 compound selectively inhibited the growth of MV-4-11 cells (GI50 = 1 nM) and induced apoptotic cell death. LDD1937 caused cell cycle arrest at the G2/M phase and increased the cell population at the sub-G1 phase. Phosphorylation of STAT5, which is the downstream signaling of FLT3, was significantly reduced by LDD1937 in a dose-dependent manner. The pharmacokinetic properties of LDD1937 were investigated in mice. Then, the in vivo anti-tumor effect was investigated using a MV-4-11 xenograft. With the intravenous administration of 5 and 10 mg/kg in nu/nu mice, the tumor volume and weight were significantly reduced compared to the control. LDD1937 is a promising therapeutic candidate to treat AML patients because of its ability to suppress tumor cell growth in vitro and in vivo.

Lamivudine belongs to the set of antiviral agents effective against hepatitis B virus infection. Given case reports on liver injuries after certain antiviral agent treatments, this study examined the effects of lamivudine on alanine aminotransferase (ALT) and total bilirubin (TB) using a medical system database. A total of 1,321 patients taking lamivudine alone or with others were evaluated using laboratory hits in an electronic medical system at Seoul National University Hospital from 2005 through 2011. The patients were grouped according to prior ALT results: G#1, ALT lt; 40 IU/L; G#2, 40 IU/L ≤ ALT lt; 120 IU/L; G#3, 120 IU/L ≤ ALT lt; 240 IU/L; and G#4, ALT ≥ 240 IU/L. In G#1 and G#2 patients, lamivudine or adefovir treatment decreased ALT and TB compared to prior values. In G#3 and G#4 patients with three times the upper limit of normal (ULN) ≤ ALT lt; 15 times the ULN, both ALT and TB were decreased after treatment with lamivudine alone, or adefovir following lamivudine therapy, indicating that lamivudine therapy ameliorated liver functions. However, in G#4 patients who experienced severely advanced hepatitis (ALT ≥ 15 times the ULN, or ≥ 600 IU/L), lamivudine augmented TBmax (6.3 → 13.3 mg/dL) despite a slight improvement in ALT (839 → 783 IU/L), indicative of exacerbation of bilirubinemia. Patients who used adefovir after lamivudine also showed a high incidence of hyperbilirubinemia when they experienced severely advanced hepatitis. Treatment with adefovir alone did not show the effect. In conclusion, lamivudine may increase the risk of hyperbilirubinemia in patients with severely advanced hepatitis, implying that caution should be exercised when using lamivudine therapy in certain patient populations.

The histologic responses to varied parameters of 1,927-nm fractional thulium fiber laser treatment have not yet been sufficiently elucidated.This study sought to evaluate histologic changes immediately after 1,927-nm fractional thulium fiber laser session at various parameters.The dorsal skin of Yucatan mini-pig was treated with 1,927-nm fractional thulium fiber laser at varied parameters, with or without skin drying. The immediate histologic changes were evaluated to determine the effects of varying laser parameters on the width and the depth of treated zones.The increase in the level of pulse energy widened the area of epidermal changes in the low power level, but increased the dermal penetration depth in the high power level. As the pulse energy level increased, the increase in the power level under the given pulse energy level more evidently made dermal penetration deeper and the treatment area smaller. Skin drying did not show significant effects on epidermal changes, but evidently increased the depth of dermal denaturation under both high and low levels of pulse energy.These results may provide important information to establish treatment parameters of the 1,927-nm fractional thulium fiber laser for various skin conditions.

In this study, inductively coupled plasma-mass spectrometry (ICP-MS) was used to determine the concentration of 15 elements (Mg, Al, K, Ca, Cr, Mn, Co, Ni, Cu, Zn, Rb, Sr, Cd, Ba, and Pb) of sesame seeds. Multivariate analysis was then performed to discriminate the origin of sesame seeds. Korean (48), Chinese (44), and Indian (21) samples were used to develop the calibration model. Another 10 samples were used to validate this model. All elements were significantly different (p

Ulmus pumila L. bark underwent distilled water extraction under three temperature condition (4°C, room temperature, or 80°C) and two extraction times (1, or 5 min) in order to develop a functional beverage products. Changes in yield, pH, color, total phenolic (TP) content, tannin content and antioxidant activity of the aqueous extracts were evaluated for each extraction temperature and duration. Extraction conditions did not affect yield or pH value of the extracts; however CIE b* values were high in extracts prepared under high extraction temperature (80°C) and long extraction duration (5 min) conditions. Both extraction temperature and duration affected the TP and tannin contents of the extracts; however, all extraction conditions resulted in ≥450 mg GAE/g TP content and ≥80 mg CE/g tannin content. All extracts exhibited ABTS and DPPH radical scavenging ability similar to that of vitamin C. Nitric oxide inhibition activity was lower in the 5 min duration sample than in the 1 min sample. The 4°C extraction temperature produced an extract with the highest reducing power and hydrogen peroxide values. Extraction temperature also affected sensory evaluation results with the 80°C extraction temperature producing significantly higher flavor, bitterness, and color score, than those obtained under 4°C and room temperature extraction conditions.

Mast cells and their mediators play important roles in chronic spontaneous urticaria (CSU) pathogenesis. Transglutaminase 2 (TG2) is expressed in activated mast cells and contributes to airway inflammation in allergic asthma.To investigate the role of TG2 in CSU.Patients with CSU (n = 72) and healthy controls (n = 51) were evaluated. Skin biopsy specimens were obtained from 5 patients with CSU and 2 healthy controls. Cord blood-derived human mast cells and peripheral blood-derived human mast cells were activated with IgE. TG2 activity and inflammatory mediators, such as histamine, leukotriene C4, and cytokines, were measured in serum or supernatant from cultured mast cells by enzyme-linked immunosorbent assay. Colocalization of mast cells and TG2 was determined in skin tissues by immunofluorescence.TG2 activity was significantly higher in serum samples from patients with CSU than in serum samples from healthy controls (P.001). Colocalization of mast cell surface marker c-kit and TG2 was significantly increased in the lesional skin of patients with CSU compared with that in healthy controls. The levels of histamine, leukotriene C4, tumor necrosis factor α, transforming growth factor β, and interleukins 4, 5, and 6 were significantly higher in patients with CSU than in healthy controls (P.001). Serum TG2 levels had positive correlations with each inflammatory mediator (P.001). TG2 activity was increased in cord blood-derived human mast cells (CBMCs) and peripheral blood-derived human mast cells activated with IgE compared with those without activation (P.05).Our findings suggest that TG2 expressed in and released from mast cells plays an important role in CSU pathogenesis.

An energy dispersive X-ray fluorescence (ED-XRF) spectrometer and a near infrared (NIR) spectrometer combined with chemometrics were applied for origin discrimination of 48 Korean, 44 Chinese, and 21 Indian sesame seed samples used for development of a discriminant calibration model. Multi-elemental ED-XRF analysis based on Mg, Al, Si, P, S, Cl, K, Ca, Mn, Fe, and Cu was used for comparisons among origins. All elements, except for Fe, showed differences and 96.5% of seed samples were assigned to the correct origin using discriminant analysis based on chemical analytical results. NIR measurements were performed for spectral scanning. Classification of seeds using NIR discriminant analysis achieved 89.4% of seed samples assigned to the correct origin. Both ED-XRF and NIR are useful as nondestructive tools for discrimination of sesame seed origins.

Isoliquiritigenin (isoLQ), a chalcone found in licorice, has shown a variety of biological activity including anti-inflammatory and antioxidative effects, and the distribution of isoLQ in gastrointestinal tract was higher than any other tissues. Thus, we evaluated whether or not isoLQ attenuated the dextran sulfate sodium (DSS)-induced colitis by observing the physiological changes (body weight loss, diarrhea, bleeding stool, overall disease activity index (DAI) scores, colon length), histopathological analysis and myeloperoxidase (MPO) activities of esophagus and colon. Also, the MAPK pathways including phosphorylation of ERK1/2, p38, and AKT, and the activation of NK-κB were evaluated in colon tissue. Interestingly, the reduction of body weight and colon length, increase of diarrhea, bloody stool, DAI scores and MPO activity, and histologic disturbances in DSS-induced colitis were recovered by isoLQ treatment. Also, isoLQ treatment suppressed the phosphorylation of ERK1/2 and p38, and the activation of NK-κB compared to those in DSS-induced colitis mice. In addition, the distributions of isoLQ in colon were relatively higher in DSS-induced colitis models. All of these results suggested that isoLQ has potential activity to ameliorate the DSS-induced colitis through the inhibition of MAPK pathway.

Maackiapterocarpan B, one of the pterocarpan analogs found in Sophora tonkinensis, is known to display pharmacological activities. However, the anti-inflammatory effects of maackiapterocarpan B and its molecular mechanism have yet to be clearly elucidated. In the present study, the effects of maackiapterocarpan B on macrophage-mediated inflammation in vitro were assessed. Maackiapterocarpan B inhibited the production of nitric oxide, the expression of tumor necrosis factor α, colony stimulating factor 2, interleukin-1β and interleukin-6, and the activation of nuclear factor-κB and mitogen-activated protein kinases in lipopolysaccharide-stimulated macrophages. These observations suggest the potential of maackiapterocarpan B in the treatment of inflammatory diseases.

In this study, we aimed to isolate chemical compounds from the aerial parts of Aster koraiensis Nakai and to determine their proprotein convertase/kexin type 9 (PCSK9) mRNA expression inhibitory activities. Two new eudesmane-type sesquiterpenes, 1β,4β,13-trihydroxy-trans-eudesm-6-ene-1-O-β-glucopyranoside (1) and 6″-O-(syringoyl)-1β,6β,9β,11-tetrahydroxy-trans-eudesm-3-en-6-O-β- d -glucopyranoside (2), along with 20 known compounds were isolated. All the isolated structures were confirmed by measuring 1D and 2D NMR spectroscopic data and comparing with their reported values. Among the isolates, gymnasterkoreayne B (21) and gymnasterkoreayne E (22) exhibited potent inhibitory effects on PCSK9 expression with IC50 values of 47.9 and 42.9 µM, respectively, and also increased LDLR expression. Our study provides insights into the use of these polyacetylenes or A. koraiensis extracts for cholesterol-lowering treatment.

Investigation of components of the chloroform-soluble and ethyl acetate-soluble extracts of the aerial parts of Chromolaena odorata L. selected by PCSK9 mRNA expression monitoring assay in HepG2 cells led to the isolation of a new stilbene dimer, (+)-8b-epi-ampelopsin A (1), and 30 known compounds (2–31). The structures of the isolates were established by interpretation of NMR spectroscopic data and the stereochemistry of the new stilbene (1) was proposed based on ECD and NMR calculations. Among the isolates, 1, 5,6,7,4′-tetramethoxyflavanone (6), 5,6,7,3′,4′-pentamethoxyflavanone (7), acacetin (18), and uridine (21) were found to inhibit PCSK9 mRNA expression with IC50 values of 20.6, 21.4, 31.7, 15.0, and 13.7 µM, respectively. Furthermore, the most abundant isolate among the selected compounds, 6, suppressed PCSK9 and low-density lipoprotein receptor protein expression in addition to downregulating the mRNA expression of HNF-1α.

Whole-transcriptome analysis and western blotting of sauchinone-treated HepG2 cells demonstrated that sauchinone regulated genes relevant to cholesterol metabolism and synthesis. In particular, it was found that the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) was downregulated, and the expression of low density lipoprotein receptor (LDLR) was upregulated in sauchinone-treated HepG2 cells. Consequently, LDL-cholesterol (LDL-C) uptake was increased. As a transcriptional regulator of PCSK9 expression, sterol regulatory elements binding protein-2 (SREBP-2) was proposed by transcriptome analysis and western blotting. Oral administration of sauchinone increased hepatic LDLR through PCSK9 inhibition in obese mice and showed the reduced serum LDL-C levels and downstream targets of SREBP-2. Thus, it is evident that sauchinone reduces hepatic steatosis by downregulating the expression of hepatic PCSK9 via SREBP-2.

Sauchinone, an active lignan isolated from the aerial parts of Saururus chinensis (Saururaceae), exhibits anti-inflammatory, anti-obesity, anti-hyperglycemic, and anti-hepatic steatosis effects. As herb–drug interaction (HDI) through cytochrome P450s (CYPs)-mediated metabolism limits clinical application of herbs and drugs in combination, this study sought to explore the enzyme kinetics of sauchinone towards CYP inhibition in in vitro human liver microsomes (HLMs) and in vivo mice studies and computational molecular docking analysis. In in vitro HLMs, sauchinone reversibly inhibited CYP2B6, 2C19, 2E1, and 3A4 activities in non-competitive modes, showing inhibition constant (Ki) values of 14.3, 16.8, 41.7, and 6.84 μM, respectively. Also, sauchinone time-dependently inhibited CYP2B6, 2E1 and 3A4 activities in vitro HLMs. Molecular docking study showed that sauchinone could be bound to a few key amino acid residues in the active site of CYP2B6, 2C19, 2E1, and 3A4. When sibutramine, clopidogrel, or chlorzoxazone was co-administered with sauchinone to mice, the systemic exposure of each drug was increased compared to that without sauchinone, because sauchinone reduced the metabolic clearance of each drug. In conclusion, when sauchinone was co-treated with drugs metabolized via CYP2B6, 2C19, 2E1, or 3A4, sauchinone–drug interactions occurred because sauchinone inhibited the CYP-mediated metabolic activities.

Herb–drug interaction (HDI) limits clinical application of herbs and drugs, and inhibition of herbs towards uridine diphosphate (UDP)-glucuronosyltransferases (UGTs) has gained attention as one of the important reasons to cause HDIs. Sauchinone, an active lignan isolated from aerial parts of Saururus chinensis (Saururacease), possesses anti-oxidant, anti-inflammatory, and anti-viral activities. In pharmacokinetics of sauchinone, sauchinone is highly distributed to the liver, forming extensive metabolites of sauchinone via UGTs in the liver. Thus, we investigated whether sauchinone inhibited UGTs to explore potential of sauchinone–drug interactions. In human liver microsomes (HLMs), sauchinone inhibited activities of UGT1A1, 1A3, 1A6, and 2B7 with IC50 values of 8.83, 43.9, 0.758, and 0.279 μM, respectively. Sauchinone also noncompetitively inhibited UGT1A6 and 2B7 with Ki values of 1.08 and 0.524 μM, respectively. In in vivo interaction study using mice, sauchinone inhibited UGT2B7-mediated zidovudine metabolism, resulting in increased systemic exposure of zidovudine when sauchinone and zidovudine were co-administered together. Our results indicated that there is potential HDI between sauchinone and drugs undergoing UGT2B7-mediated metabolism, possibly contributing to the safe use of sauchinone and drug combinations.

Bioactivity-guided fractionation for the stems of leaves of Larrea nitida Cav., using interleukin-6 (IL-6) inhibitory assay in human mast cells (HMC-1), led to the isolation of three new compounds with an unprecedented skeleton in nature (1–3) and three known compounds (4–6). Their structures were elucidated through extensive spectroscopic analysis. The three new compounds were elucidated as two new spiroketones, nitidaones A (1), and B (2) and one new biphenyl analog, nitidaol (3). The known compounds were identified as nordihydroguaiaretic acid (4), 7,3′,4′-tri-O-methylquercetin (5) and ayanin (6). All the isolates were tested for their inhibitory activity against IL-6 production in HMC-1 cells. Of them, compounds 1, 3–6 showed potent anti-inflammatory activity, with IC50 values of 12.8, 17.5, 14.9, 22.9, and 17.8 µM, respectively.

Synthetic natural gas(SNG), acquired from coal, is regarded as an alternative to natural gas since a rise in natural gas due to high oil price can be coped with it. In the present study, 11-liter heavy duty compressed natural gas(CNG) engine was employed in order to examine the combustion and emission characteristics of SNG. The simulated SNG, made up 90.95% of methane, 6.05% propane and 3% hydrogen was used in the experiment. Power output, thermal efficiency, combustion stability and emission characteristics were compared to those with CNG at the same engine operating conditions. Knocking phenomenon was also analyzed at 1260 rpm, full load condition. Combustion with SNG was more stable than CNG. Nitrogen oxides emissions increased while Carbon dioxides emissions decreased. Anti-knocking characteristics were improved with SNG.

Stoichiometric combustion engine with Three-way catalyst had an advantage that can reduce the harmful emissions effectively. Fuel equivalence ratio controlled from engine is very important because Fuel equivalence ratio with high conversion efficiency was narrow. This study analyzed the conversion efficiency under whole range of operating area for to evaluate the performance of three-way catalyst. In order to identify the Optimum conversion efficiency, the conversion efficiency due to change the control value of fuel equiv-alence ratio was investigated. The result show that conversion efficiency of emissions(more than 95%) has dis-covered by means of fuel equivalence ratio control at each test condition. As engine power increases, optimal fuel equivalence ratio tended to increase linearly under operating conditions of similar exhaust gas temperature. Key words : HCNG(Hydrogen- Compressed Natural gas Blends), stoichiometri c, TWC(Three-way Catalyst), conversion efficiency, equivalence ratio

As numerous herbal products have been used as dietary supplements or functional foods, the demands of the pharmacokinetic and pharmacodynamic characteristics of active compounds are increasing in order to secure a consistent outcome (i.e., efficiency and safety). In this study, the pharmacokinetics including tissue distribution, metabolism, and protein binding of isoliquiritigenin, a chalcone found in Glycyrrhiza glabra, and its metabolite, liquiritigenin, at various doses in mice are reported. Also, correlations between the preferential tissue distribution and pharmacological effect of isoliquiritigenin in certain organs were investigated using the in vivo gastroprotective effect of isoliquiritigenin in mice with indomethacin-induced ulcer. The absorbed fraction of isoliquiritigenin was high, but the absolute bioavailability was low mainly due to its metabolism. In spite of the low bioavailability, the gastroprotective effect of isoliquiritigenin was attributed to its high distribution in the stomach. Isoliquiritigenin prevented the occurrence of gastric ulcers by indomethacin, which is associated with increased gastric mucous secretion because the pretreatment with isoliquiritigenin presumably counteracted the decreased cyclooxygenase 2 by indomethacin. This may suggest that the pharmacokinetic properties of isoliquiritigenin are useful to predict its efficacy as a gastroprotective agent in a target organ such as the stomach.

In this study, the anti-inflammatory effects of mangosteen extract (MGE) on dextran sulfate sodium (DSS)-induced colitis in mice and nuclear factor (NF)-κB pathway modulation were investigated. Acute colitis was induced by administering 3% DSS in drinking water for 7 days, and three groups of Institute of Cancer Research mice were treated with 30 and 120 mg/kg MGE or 5-aminosalicylic acid for 7 days; an additional two groups of mice served as healthy and disease controls. The results indicated that MGE significantly prevented weight loss, reduced disease activity index scores, and preserved colon length compared with the findings in the untreated colitis group. MGE downregulated the NF-κB pathway by inhibiting the phosphorylation of IκB and IKK in a dose-dependent manner. These findings suggest that MGE alleviates ulcerative colitis by modulating the NF-κB pathway.

Background Neuropeptides have been recently reported as having an important role in wound repair, and relief from pain and itching sensation. The aim of this study was to evaluate the effect of neuropeptides on the wound healing process in hypertrophic scar formation that accompanies severe pain and itching sensation. Methods We collected forty-three hypertrophic scar specimens from hypertrophic scar release and skin graft under general anesthesia. Immunohistochemical stains for protein gene product (PGP) 9.5, substance P (SP), and calcitonin gene-related peptide (CGRP) were performed. Pain and itching over the scar were recorded using verbal numerical rating scale (VNRS). Results In the epidermis, PGP 9.5, SP, and CGRP were significantly increased in hypertrophic scars compared with matched unburned skin. In the reticular dermis, SP and CGRP were significantly increased in hypertrophic scars compared with control. The pain and itching verbal numerical rating scale in scar group were significantly higher compared to control. In the papillary dermis, the PGP represented significant correlation with Itching P (correlation coefficient 0.698) and the SP represented significant correlation with pain N (correlation coefficient −0.671). In the reticular dermis, the SP represented significant correlation with pain N (correlation coefficient −0.614) and CGRP represented significant correlation with pain P/Itching P (correlation coefficient 0.801/0.611). Conclusions Neuropeptides such as PGP 9.5, SP, and CGRP seem to affect scarring via sensory neurotransmission, it have a regulatory role for pain and itching sensation in hypertrophic scars.

BACKGROUND Bioactives extracted from cactus (Opuntia ficus-indica) stems were investigated for their chemopreventive activities using human cancer cells in vitro. The bioactives present in crude extracts were detected and quantified using high-performance liquid chromatography. RESULTS Among all the extracts, such as hexane, ethyl acetate (EtOAc), acetone, methanol (MeOH), and MeOH:water (80:20), the MeOH extract had the highest amount of polyphenolic compounds and the acetone extract exhibited the most potent effect at scavenging the 2,2,-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS•+) radical. In addition, most of the extracts, with the exception of hexane, exhibited significant cytotoxicity in human SW480 colon and MCF7 breast cancer cells. Overall, the SW480 cells were more sensitive than the MCF7 cells to the cytotoxic effect of the O. ficus-indica extracts (OFEs). Cell death by OFE treatment caused significant inhibition of cyclooxygenase-2 and increased the Bax/Bcl2 ratio in both SW480 and MCF7 cell lines. However, degradation of poly (ADP-ribose) polymerase was significantly increased by OFE only in the MCF7 cells, thereby inducing apoptosis. CONCLUSION These findings demonstrate the health-benefit roles, including anti-oxidative and anti-proliferative activities as well as pro-apoptotic effects, of bioactive compounds in OFEs, suggesting a chemopreventive role in human cancer cells. © 2014 Society of Chemical Industry

The aim of this study was to investigate pesticide residues in 2,877 market vegetables in the northernarea of Seoul in 2013. Pesticide residues in the samples were analysed by multiresidue method for 285 pesticides usingGC-ECD/NPD and HPLC-DAD/FLD. 385 samples(13.4%) were detected with pesticide residues at or below MRL,and 15 samples(0.5%) were found to detect pesticide residues exceeding MRL. The most frequently detected sampleswere sedum(63.6%), chamnamul(45.8%), leek(44.5%) and green&red pepper(30.8%). Among the 15 violated sam-ples, leek(5 cases) and welsh onion(4 cases) showed the highest violation rate. A total of 74 samples(18.5%) containedmultiple pesticide residues in one vegetable. Procymidone, chlorofenapyr and cypermethrin were the pesticide mostfrequently found. As a tool of risk assessment through the consumption of pesticide detectable agricultural products,the ratio of estimated daily intake (EDI) to acceptable daily intake (ADI) was calculated into the range of1.05~28.61%. The results have meant that there was no health risk through dieting commercial agricultural productsdetected with pesticide residues. Key words : pesticide residues, agricultural products, risk assessment, %ADI

The fruit of Schisandra chinensis is a well-known herbal medicine and dietary supplement due to a variety of biological activities including antihepatotoxic and antihyperlipidemic activities. However, the simultaneous validation methodology and pharmacokinetic investigation of nine lignans of S. chinensis extract in biological samples have not been proved yet. Thus, the present study was undertaken to develop the proper sample preparation method and simultaneous analytical method of schisandrol A, gomisin J, schisandrol B, tigloylgomisin H, angeloylgomisin H, schisandrin A, schisandrin B, gomisin N, and schisandrin C in the hexane-soluble extract of S. chinensis to apply for the pharmacokinetic study in rats. All intra- and interprecisions of nine lignans were below 13.7% and accuracies were 85.1-115% and it is enough to evaluate the pharmacokinetic parameters after both intravenous and oral administration of hexane-soluble extract of S. chinensis to rats.

P-glycoprotein (P-gp)-mediated efflux of docetaxel in the gastrointestinal tract mainly impedes its oral chemotherapy. Recently, LC478, a novel di-substituted adamantyl derivative, was identified as a non-cytotoxic P-gp inhibitor in vitro. Here, we assessed whether LC478 enhances the oral bioavailability of docetaxel in vitro and in vivo. LC478 inhibited P-gp mediated efflux of docetaxel in Caco-2 cells. In addition, 100 mg/kg of LC478 increased intestinal absorption of docetaxel, which led to an increase in area under plasma concentration-time curve (AUC) and absolute bioavailability of docetaxel in rats. According to U.S. FDA criteria (I, an inhibitor concentration in vivo tissue)/(IC50, inhibitory constant in vitro) &gt, 10 determines P-gp inhibition between in vitro and in vivo. The values 15.6&ndash, 20.5, from (LC478 concentration in intestine, 9.37&ndash, 12.3 &mu, M)/(IC50 of LC478 on P-gp inhibition in Caco-2 cell, 0.601 &mu, M) suggested that 100 mg/kg of LC478 sufficiently inhibited P-gp to enhance oral absorption of docetaxel. Moreover, LC478 inhibited P-gp mediated efflux of docetaxel in the ussing chamber studies using rat small intestines. Our study demonstrated that the feasibility of LC478 as an ideal enhancer of docetaxel bioavailability by P-gp inhibition in dose (concentration)-dependent manners.

Isoliquiritigenin, a chalcone found in licorice has shown a variety of biological activities including antioxidative, anti-inflammatory, estrogenic, chemopreventive and antitumor effects. Thus, pharmacokinetics of isoliquiritigenin and its metabolites [liquiritigenin, glucuronidated isoliquiritigenin (M1), and glucuronidated liquiritigenin (M2)] after intravenous and oral administration of isoliquiritigenin was evaluated in rats. The pharmacokinetics of isoliquiritigenin, liquiritigenin, M1, and M2 showed no dose dependence after both intravenous and oral administration of isoliquiritigenin. Although approximately 92.0 % of the oral isoliquiritigenin was absorbed, the extent of the absolute bioavailability value was only 11.8 % of the oral dose. The low absolute bioavailability value of isoliquiritigenin might be due to the considerable metabolism of isoliquiritigenin in the small intestine and liver. This was supported by the facts that the ratios of AUCM1/AUCisoLQ and AUCM2/AUCisoLQ were high (over 0.25), isoliquiritigenin disappeared, and M1 and M2 were formed mainly in S9 fractions of the liver and small intestine. The affinities of liquiritigenin, isoliquiritigenin, M1, and M2 were high in the liver, small intestine, large intestine, and/or kidney.

Compression ratio is an important factor affecting engine performance and emission characteristics since thermal efficiency of spark ignition engine can be theoretically improved by increasing compression ratio. In order to evaluate the effect of compression ratio change in HCNG engine, natural gas engine was employed using HCNG30 (CNG 70 vol%, hydrogen 30 vol%). Combustion and emission characteristics of CNG and HCNG fuel was analyzed with respect to the change of compression ratio at each operating condition. The results showed that thermal efficiency improved and CH 4 , CO 2 emission decreased with the increase in compression ratio while NO x emissions were decreased at a certain excess air ratio condition. Higher thermal efficiency and further reduction of exhaust emissions can be achieved by the increase of compression ratio and the retard of spark timing. Key words : Compression ratio(압축비), Emission characteristics(배기특성), Hydrogen-natural gas blends(수소-천연가스 혼합연료), Power output(출력성능), Excess air ratio(공기과잉률)

Life cycle alternation between arthropod and mammals forces the Lyme disease spirochete, Borrelia burgdorferi , to adapt to different host milieus by utilizing diverse carbohydrates. Glycerol and chitobiose are abundantly present in the Ixodes tick. B. burgdorferi can utilize glycerol as a carbohydrate source for glycolysis and chitobiose to produce N -acetylglucosamine (GlcNAc), a key component of the bacterial cell wall. A recent study reported that Rrp1, a response regulator that synthesizes cyclic diguanylate (c-di-GMP), governs glycerol utilization in B. burgdorferi . In this report, we found that the rrp1 mutant had growth defects and formed membrane blebs that led to cell lysis when GlcNAc was replaced by chitobiose in the growth medium. The gene chbC encodes a key chitobiose transporter of B. burgdorferi . We found that the expression level of chbC was significantly repressed in the mutant and that constitutive expression of chbC in the mutant successfully rescued the growth defect, indicating a regulatory role of Rrp1 in chitobiose uptake. Immunoblotting and transcriptional studies revealed that Rrp1 is required for the activation of bosR and rpoS and that its impact on chbC is most likely mediated by the BosR-RpoS regulatory pathway. Tick-mouse infection studies showed that although the rrp1 mutant failed to establish infection in mice via tick bite, exogenous supplementation of GlcNAc into unfed ticks partially rescued the infection. The finding reported here provides us with new insight into the regulatory role of Rrp1 in carbohydrate utilization and virulence of B. burgdorferi .

Recently, extracts from the pericarp of mangosteen, Garcinia mangostana L., exhibited various pharmacological properties such as anti-oxidative, anti-inflammatory, anti-bacterial and chemopreventive activities. Albeit it has diverse application, there is little information about its pharmacokinetic aspects. Thus, the present study was undertaken to develop the simultaneous determination of α- and γ-mangostins (α- and γ-MG), major and active compounds, from extracts for the application of pharmacokinetic studies in mice using combined liquid chromatography–tandem mass-spectrometry and microsampling systems. The intra- and inter-validation, precision, accuracy, stability, recovery and matrix effects of α- and γ-MG were conducted in mouse plasma. Based on the developed analytical methods, pharmacokinetic parameters of α- and γ-MG after intravenous and oral administration of mangosteen extract were calculated. In sample preparation steps, the biological samples were deproteinized by acetonitrile and chromatographic separation was accomplished on a C18 column. The detection was accomplished by multiple-reaction monitoring scanning after electrospray ionization source in the positive ionization mode. The optimized mass transition ion pairs (m/z) for quantitation were 411.062 → 354.900, 397.384 → 340.900, and 808.379 → 527.200 for α- and γ-MG and docetaxel (internal standard), respectively. The total run time was 5 min. The results provided a meaningful basis for the preclinical and clinical application of mangosteen extract.

This study was performed to analyze 48 kinds of pesticide residues using gas chromatography (GC)/nitrogen phosphorous detector, GC/micro electron capture detector, GC/mass selective detector, and high performance liquid chromatograph/diode array detector in 186 fresh ginseng samples collected in the Seoul area from 2010 to 2011. Fresh ginseng dietary intakes were estimated using the data from the 2009 Korea National Health and Nutrition examination survey. Residual pesticides were detected in 79 samples (42.5%) with eight different fungicides. Only 20 samples (10.8%) exceeded the maximum residue limits (MRLs) for pesticides registered by the Korea Food & Drug Administration. Among them, tolclofos-methyl residues (10.2%) exceeded the MRL for fresh ginseng in 18 ginseng seedlings and one of the two-year old fresh ginseng plants, and the residual level in just one ginseng seedling violated the MRL for pyrimethanil. The results showed that residual pesticides levels in marketable fresh ginseng around Seoul were relatively safe. The percent acceptable daily intake (%ADI) was calculated using pesticide residues in fresh ginseng and dietary intakes of fresh ginseng. The risk caused by pesticide residues in fresh ginseng was very low.

As emission regulation for vehicle has been reinforced, many researches carried out for HCNG(hydrogen-natural gas blends) fuel to the conventional compressed natural gas (CNG) engine. However, abnormal combustion such as backfire, pre-ignition or knocking can be caused due to high combus- tion speed of hydrogen and it can result in over heating of engine or reduction of thermal efficiency and power output. In the present study, improvement of combustion performance was observed with HCNG fuel since it can extend a flammability limit. Knocking characteristics for CNG and HCNG fuel were investigated. Feasibility of HCNG fuel was evaluated by checking the knock margin according to excess air ratio. The oper- ation of engine with HCNG was stable at minimum advance for best torque(MBT) spark timing and knock phe- nomena were not detected. However, it is necessary to prepare higher knock tendency since possibility of knock is higher with HCNG fuel.

The present study was undertaken to investigate the pharmacokinetics of isoliquiritigenin (isoLQ) as determined by the automated dosing/blood sampling (ABS) and traditional manual blood sampling techniques in awake and freely moving mice using combined liquid chromatography tandem mass spectrometry. Pharmacokinetic comparison was conducted by allocating mice into two groups; an ABS group (intravenous study and oral studies, n = 5 each) and a manual group (intravenous and oral studies; n = 5 each). Significant differences in pharmacokinetic parameters (area under the curve and clearances) were observed between ABS and manual groups. This could be mainly due to the blood sampling site difference (via heart puncture in traditional manual group and via carotid artery in ABS groups). The low F of isoLQ could be mainly due to a considerable gastrointestinal and/or hepatic first-pass effect and not to incomplete absorption. The driving force for distribution and elimination of drugs is its concentration in the arterial blood. Therefore, the ABS method was found to be a useful drug development tool for accelerating the process of preclinical in vivo studies and for obtaining reliable and accurate pharmacokinetic parameters in mice. Copyright © 2013 John Wiley & Sons, Ltd.

1. The metformin and Scutellariae radix extract (SB) combination has been previously reported to enhance anti-diabetic activity. Considering that organic cation transporters (OCTs) and multi-drug and toxin extrusion proteins (MATEs) in the liver and kidney are determinant factors on hepatic distribution and renal clearance of metformin, the effects of SB on OCT or MATE-mediated systemic exposure of metformin as well as on glucose tolerance and hypoglycemia were examined. 2. Although SB inhibited metformin uptake through human transporters OCT1 and MATE1 in vitro, the systemic exposures of metformin in vivo rats were not altered after metformin treatment with and without SB due to unchanged renal excretion of metformin. 3. However, 28-day metformin treatment with SB decreased the mRNA level of hepatic MATE1 in rats, resulting in reduced biliary excretion of metformin and thereby higher concentration of metformin in the liver. In addition, in rats with 28-day metformin treatment with SB, glucose tolerance and plasma lactate level were enhanced, while hypoglycemia was not detected. 4. Thus in rats, intervention of SB on transporter-mediated metformin transportation partially improves glucose tolerance without hypoglycemia and increases hepatic distribution of metformin. Also the further investigations in humans are required to clarify the relevance of these findings to the clinical significance.