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We aimed to investigate the underlying mechanisms for low bioavailability of Platycodin D (PD) in rats. The bioavailability of PD was 1.89% with different half-lives depending on the administration route (2.14 ± 0.18 h for intravenous injection vs 5.42 ± 1.9 h for oral administration). The mean absorption time was 6.3 h calculated from the mean residence time of both administration routes. Consistent with these parameters, rat intestinal permeability using 3 different intestinal segments showed a low but greatest permeability in lower ileum (0.05 × 10−6 cm/s in jejunum and upper ileum vs 0.13 × 10−6 cm/s in lower ileum). The involvement of efflux system, probably Mrps, in upper ileum, could be explained from the efflux ratio of 6.4 and reduced efflux ratio by an Mrp inhibitor, MK571. The recovery of unchanged PD after the intravenous and oral administration was 50% and 5.2%, respectively, suggesting the contribution of gastrointestinal metabolism. In the gastrointestinal content, 4 metabolites of PD were identified: acetylated PD (m/z 1265.6), deglucose PD (m/z 1061.5), deapiose PD (m/z 1091.5), and deapiose-dexylose-derhamnose PD (m/z 813.4). In conclusion, the intestinal first-pass effect such as the presence of efflux functions in the upper ileum, limited but steady intestinal permeability, and gastrointestinal metabolism could explain the low bioavailability and prolonged absorption time of orally administered PD.

To investigate the effects of extraction solvents and drying methods on Plectranthus hadiensis var. tomentosus quality, eight compounds were isolated and the content of active compounds with their antioxidant activities were compared. Compounds 1 and 2 were known antioxidants, whereas the low-density lipoprotein (LDL)-antioxidant activities of compounds 3, 5, 6, and 7 are reported for the first time, with IC50 values of 2.5, 3.8, 22.8, and 53.7 μM, respectively. Our analysis of 30‒95% ethanol extracts from freeze- and air-dried leaves and stems revealed a relationship between extract composition and antioxidant activity. The 95% ethanol extracts of freeze-dried stems (FDS) exhibited highest phenolic and flavonoid content, which were 1.40 and 2.67 times, respectively, greater than those of air-dried stems (ADS), and very high LDL-antioxidant and DPPH radical scavenging activities, which may have resulted from the phenolic ester rosmarinic acid (2), a major component of FDS extracts and potent antioxidant. In contrast, the 95% ethanol extracts of ADS exhibited relatively low antioxidant activity, possibly owing to the low antioxidant activity of the main components ayanin (7) and (+)-plectranthone (8). These results are important for the development of P. hadiensis var. tomentosus as an effective natural antioxidant material.

Cytochrome P450 (P450) and uridine 5'-diphospho-glucuronosyltransferase (UGT) are major metabolizing enzymes in the biotransformation of most drugs. Altered P450 and UGT activities are a potential cause of adverse drug-drug interaction. A method for the simultaneous evaluation of the activities of five P450s (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A) and four UGTs (UGT1A1, UGT1A4, UGT1A9, and UGT2B7) was developed using in vitro cocktail incubation and tandem mass spectrometry. The nine probe substrates used in this assay were phenacetin (CYP1A2), diclofenac (CYP2C9), S-mephenytoin (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), 7-ethyl-10-hydroxy-camptothecin (SN-38) (UGT1A1), trifluoperazine (UGT1A4), mycophenolic acid (UGT1A9), and naloxone (UGT2B7). This new method involves incubation of two cocktail doses and single cassette analysis. The two cocktail doses and the concentration of each probe substrate in vitro were determined to minimize mutual drug interactions among substrates. Cocktail A comprised phenacetin, diclofenac, S-mephenytoin, dextromethorphan, and midazolam, whereas cocktail B comprised SN-38, trifluoperazine, mycophenolic acid, and naloxone. In the incubation study of these cocktails, the reaction mixtures were pooled and simultaneously analyzed using liquid chromatography-tandem mass spectrometry. The method was validated by comparing inhibition data obtained from the incubation of each probe substrate alone with data from the cocktail method. The IC50 values obtained in both cocktail and individual incubations were in agreement with values previously reported in the literature. This cocktail method offers a rapid and robust way to simultaneously evaluate phase I and II enzyme inhibition profiles of many new chemical entities. This new method will also be useful in the drug discovery process and for advancing the mechanistic understanding of drug interactions.

International Maritime Organization recognizes vessel-induced pollution as a global issue. The designation of the Baltic Sea as the special uncontaminated area was the beginning of the regulations for preventing marine pollution. In this regard, a process is needed which meets the provisions of MEPC. 227(64) for the specificity and constrained conditions of vessels, removes both nitrogen and phosphorus, requires convenient operation and low construction cost and is little affected by the load variation of inflow. This study used an SBR(sequencing batch reactor) and MBR(membrane bioreactor) combined process to iterate the stirring and aeration process and maintained the ratio of raw wastewater parameters (C:N:P) to be 10:3:1 in order to assess the quality and future availability of ultimate outflow in each time period of the stirring and aeration process. The removal efficiencies of COD and T-N exceeded 90% and 93% respectively. However, a detailed mechanism will be identified by a further study on nitrogen removal issues like DO aeration condition, stirring duration, ORP and NO3. As the removal efficiency of T-P exceeded 95%, the SBR and MBR process formed anaerobic and aerobic conditions without a separate coagulation process for removing phosphorus, thereby enabling easy phosphorus release and uptake. The optimal stirring and aeration condition seems to be 70&ndash, 50 min. A further study will be efficiently conducted by focusing on the water quality criteria of the Maritime Environment Protect Committee. 227 (64) for E. coli and chlorine and a detailed mechanism.

A rice genic male-sterility gene ms-h is recessive and has a pleiotropic effect on the chalky endosperm. After fine mapping, nucleotide sequencing analysis of the ms-h gene revealed a single nucleotide substitution at the 3'-splice junction of the 14th intron of the UDP-glucose pyrophosphorylase 1 (UGPase1; EC2.7.7.9) gene, which causes the expression of two mature transcripts with abnormal sizes caused by the aberrant splicing. An in vitro functional assay showed that both proteins encoded by the two abnormal transcripts have no UGPase activity. The suppression of UGPase by the introduction of a UGPase1-RNAi construct in wild-type plants nearly eliminated seed set because of the male defect, with developmental retardation similar to the ms-h mutant phenotype, whereas overexpression of UGPase1 in ms-h mutant plants restored male fertility and the transformants produced T(1) seeds that segregated into normal and chalky endosperms. In addition, both phenotypes were co-segregated with the UGPase1 transgene in segregating T(1) plants, which demonstrates that UGPase1 has functional roles in both male sterility and the development of a chalky endosperm. Our results suggest that UGPase1 plays a key role in pollen development as well as seed carbohydrate metabolism.

Scope The health beneficial effects of docosahexaenoic acid (DHA) have been attributed to its anti-inflammatory properties. However, the molecular mechanism underlying anti-inflammatory effects of DHA remains largely elusive. Methods and results In the present study, DHA was found to suppress the phosphorylation and nuclear translocation of signal transducer and activator of transcription 3 (STAT3) induced by Helicobacter pylori infection in human gastric cancer AGS cells. Notably, DHA induced expression of suppressor of cytokine signaling 3 (SOCS3), a negative regulator of STAT3. Knockdown of SOCS3 abolished the suppressive effect of DHA on STAT3(Tyr705) phosphorylation induced by H. pylori infection. DHA also induced nuclear translocation, DNA binding, and transcriptional activities of peroxisome proliferator-activated receptor gamma (PPARγ) in AGS cells. Knockdown of PPARγ inhibited the transcription of SOCS3 and attenuated the suppressive effect of DHA on phosphorylation of STAT3(Tyr705) induced by H. pylori. The PPARγ antagonist bisphenol A diglycidyl ether also mitigated the suppressive effect of DHA on H. pylori-induced phosphorylation of STAT3(Tyr705) . In addition, DHA inhibited the expression of c-Myc, which was attenuated in the AGS cells harboring SOCS3 specific siRNA. DHA also markedly decreased anchorage-independent growth of AGS cells infected by H. pylori. Conclusion DHA inhibits H. pylori-induced STAT3 phosphorylation in a PPARγ/SOCS3-dependent manner.

OSH6 (Oryza sativa Homeobox6) is an ortholog of lg3 (Liguleless3) in maize. We generated a novel allele, termed OSH6-Ds, by inserting a defective Ds element into the third exon of OSH6, which resulted in a truncated OSH6 mRNA. The truncated mRNA was expressed ectopically in leaf tissues and encoded the N-terminal region of OSH6, which includes the KNOX1 and partial KNOX2 subdomains. This recessive mutant showed outgrowth of bracts or produced leaves at the basal node of the panicle. These phenotypes distinguished it from the OSH6 transgene whose ectopic expression led to a "blade to sheath transformation" phenotype at the midrib region of leaves, similar to that seen in dominant Lg3 mutants. Expression of a similar truncated OSH6 cDNA from the 35S promoter (35S::DeltaOSH6) confirmed that the ectopic expression of this product was responsible for the aberrant bract development. These data suggest that OSH6-Ds interferes with a developmental mechanism involved in bract differentiation, especially at the basal nodes of panicles.

Salicornia herbacea L. is one of the halophytic herbs that grow in salt marshes and on muddy seashores. It has been reported to exhibit their bioactivities including anti-diabetic, antioxidant and ...

Glyceollins, a family of phytoalexins, are de novo synthesized from daidzein in the soybean upon exposure to some types of fungus. Glyceollins have been reported to induce antioxidant and phase II ...

Pterocarpans are known to have antifungal and anti-inflammatory properties. However, little is known about the changes in transcriptional profiles in response to a pterocarpan-high soybean leaf extract (PT). Therefore, this study investigated the effects of PT on blood glucose and lipid levels, as well as on the inflammation-related gene expression based on a peripheral blood mononuclear cells (PBMCs) mRNA sequencing analysis in Korean overweight and obese subjects with mild metabolic syndrome. The participants were randomly assigned to two groups and were administered either placebo (starch, 3 g/day) or PT (2 g/day) for 12 weeks. The PT intervention did not change body weight, body fat percentage and body mass index (BMI). However, PT significantly decreased the glycosylated hemoglobin (HbA1c), plasma glucose, free fatty acid, total cholesterol, and non-HDL cholesterol levels after 12 weeks. Furthermore, PT supplementation significantly lowered the homeostatic index of insulin resistance, as well as the plasma levels of inflammatory markers. Finally, the mRNA sequencing analysis revealed that PT downregulated genes related to immune responses. PT supplementation is beneficial for the improvement of metabolic syndrome by altering the fasting blood and plasma glucose, HbA1c, plasma lipid levels and inflammation-related gene expression in PBMCs.

Helicobacter pylroi (H. pylori) infection has been considered to be one of the high risk factors of gastritis and gastric cancer, but its pathogenic implication is still poorly understood. Recent studies indicate that constitutive activation of the signal transducer and activator of transcription 3 (STAT3) plays an important role in inflammation-associated carcinogenesis. In our previous study, we found that the phosphorylation of STAT3 at Tyr705 was increased in H. pylori plus high salt diet-induced gastritis in a mouse model. The similar results were observed in human gastric AGS cells co-cultured with H. pylori. Interestingly, H. pylori induced phosphorylation of STAT3 at not only Tyr705 but also Ser727. However, the phosphorylation of two residues exhibited different profiles in human gastric epithelial cells upon H. pylori treatment. The phosphor-Tyr705 increased at early time of H. pylori infection and then decreased immediately, but phosphor-Ser727 increased thereafter which was first discovered in our present study. Phosphorylation of STAT3 is an essential event for inducing the expression of anti-apoptotic/survival proteins, such as Bcl-XL, BcL-2, survivin and c-Myc which contribute to gastric carcinogenesis. Levels of all these proteins were elevated in H. pylori-infected AGS cells. In conclusion, H. pylori induces phosphorylation of STAT3 at both Tyr705 and Ser727 residues. The role of phospohorylation of STAT3 at the Serine 727 residue in H. pylori-induced gastritis and gastric cancer is under investigation. Citation Format: Juan-Yu Piao, Hee-Geum Lee, Hyeon-Geum Ji, Hyeong-Joon Han, Hoang Kieu Chi Ngo, Do-Hee Kim, Su-Jung Kim, Sung-Young Lee, Young-Joon Surh. Helicobacter pylori induces phosphorylation of STAT3 Tyr705 and Ser727 in human gastric epithelial cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2592. doi:10.1158/1538-7445.AM2013-2592