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Dynapenic-abdominal obesity, as determined by low handgrip strength and high waist circumference values, was associated with increased risk of chronic kidney disease in postmenopausal women. The dynapenic-abdominal obese group displayed lower levels of an estimated glomerular filtration rate.

Inflammatory bowel disease is a chronic inflammatory disorder occurring in the gastrointestinal track. However, the efficacy of current therapeutic strategies has been limited and accompanied by side effects. In order to eliminate the limitations, herbal medicines have recently been developed for treatment of IBD. Peuraria Lobata(Peuraria L.) is one of the traditional herbal medicines that have anti-inflammatory effects. Bioavailability of Peuraria L., which is rich in isoflavones, is lower than that of their fermented forms. In this study, we generated fermented Peuraria L.extracts (fPue) and investigated the role of fPue in inflammation and intestinal barrier function in vitroand in vivo. As the mice or intestinal epithelial cells were treated with DSS/fPue, mRNA expression of pro-inflammatory cytokines was reduced and the architecture and expression of tight junction proteins were recovered, compared to the DSS-treated group. In summary, fPue treatment resulted in amelioration of DSS-induced inflammation in the colon, and the disrupted intestinal barrier was recovered as the expression and architecture of tight junction proteins were retrieved. These results suggest that use of fPue could be a new therapeutic strategy for treatment of IBD.

IMPORTANCE We observed a significant correlation between cerebrospinal fluid (CSF) levels of tau proteins and α-synuclein, but not β-amyloid 1-42 (Aβ1-42), and lower concentration of CSF biomarkers, as compared with healthy controls, in a cohort of entirely untreated patients with Parkinson disease (PD) at the earliest stage of the disease studied so far. OBJECTIVE To evaluate the baseline characteristics and relationship to clinical features of CSF biomarkers (Aβ1-42, total tau [T-tau], tau phosphorylated at threonine 181 [P-tau181], and α-synuclein) in drug-naive patients with early PD and demographically matched healthy controls enrolled in the Parkinson’s Progression Markers Initiative (PPMI) study. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study of the initial 102 research volunteers (63 patients with PD and 39 healthy controls) of the PPMI cohort. MAIN OUTCOMES AND MEASURES The CSF biomarkers were measured by INNO-BIA AlzBio3 immunoassay (Aβ1-42, T-tau, and P-tau181; Innogenetics Inc) or by enzyme-linked immunosorbent assay (α-synuclein). Clinical features including diagnosis, demographic characteristics, motor, neuropsychiatric, and cognitive assessments, and DaTscan were systematically assessed according to the PPMI study protocol. RESULTS Slightly, but significantly, lower levels of Aβ1-42, T-tau, P-tau181, α-synuclein, and T-tau/Aβ1-42 were seen in subjects with PD compared with healthy controls but with a marked overlap between groups. Using multivariate regression analysis, we found that lower Aβ1-42 and P-tau181 levels were associated with PD diagnosis and that decreased CSF T-tau and α-synuclein were associated with increased motor severity. Notably, when we classified patients with PD by their motor phenotypes, lower CSF Aβ1-42 and P-tau181 concentrations were associated with the postural instability–gait disturbance–dominant phenotype but not with the tremor-dominant or intermediate phenotype. Finally, we found a significant correlation of the levels of α-synuclein with the levels of T-tau and P-tau181. CONCLUSIONS AND RELEVANCE In this first report of CSF biomarkers in PPMI study subjects, we found that measures of CSF Aβ1-42, T-tau, P-tau181, and α-synuclein have prognostic and diagnostic potential in early-stage PD. Further investigations using the entire PPMI cohort will test the predictive performance of CSF biomarkers for PD progression.

Although the effect of obesity on drug disposition remains an important issue for clinicians, little is known about the effects of obesity on organic cation transporter 1 (OCT1) expression and activity. Here, we show that hepatic OCT1 expression was higher in mice fed a high-fat (HF) diet for 19 weeks compared with mice fed a control diet. Since HF diet-induced obese mice exhibited elevation of plasma proinflammatory cytokines, leptin, and insulin levels, we evaluated the effect of leptin, insulin, and tumor necrosis factor-alpha (TNF-α) on OCT1mRNA expression in HepG2 cells. Both leptin and insulin significantly increased OCT1mRNA expression in HepG2 cells, but TNF-αdid not. This finding was consistent with in vivoresults. Using the OCT1 substrate metformin, we further measured the extent of hepatic uptake of metformin in obese and lean mice using the ratio of hepatic concentration to plasma concentration of metformin at 1 h after administration. The hepatic uptake of metformin was significantly higher in mice fed a HF diet compared with lean mice. In conclusion, our results suggest, at least in part, that obesity might have an effect on the absorption or distribution pharmacokinetics of metformin through an increase in hepatic OCT1 expression.

Background: Particulate matter (PM) is one of the principal causes of human respiratory disabilities resulting from air pollution. Animal models have been applied to discover preventive and therapeutic drugs for lung diseases caused by PM. However, the induced severity of lung injury in animal models using PM varies from study to study due to disparities in the preparation of PM, and the route and number of PM administrations. In this study, we established an in vivo model to evaluate PM-induced lung injury in mice. Results: PM dispersion was prepared using SRM2975. Reactive oxygen species were increased in MLE 12 cells exposed to this PM dispersion. In vivo studies were conducted in the PM single challenge model, PM multiple challenge model, and PM challenge with ovalbumin-induced asthma using the PM dispersion. No histopathological changes were observed in lung tissues after a single injection of PM, whereas mild to moderate lung inflammation was obtained in the lungs of mice exposed to PM three times. However, fibrotic changes were barely seen, even though transmission electron microscopy (TEM) studies revealed the presence of PM particles in the alveolar macrophages and alveolar capillaries. In the OVA-PM model, peribronchial inflammation and mucous hypersecretion were more severe in the OVA+PM group than the OVA group. Serum IgE levels tended to increase in OVA+PM group than in OVA group. Conclusions: In this study, we established a PM-induced lung injury model to examine the lung damage induced by PM. Based on our results, repeated exposures of PM are necessary to induce lung inflammation by PM alone. PM challenge, in the presence of underlying diseases such as asthma, can also be an appropriate model for studying the health effect of PM.

Nitric oxide (NO) is produced by NO synthases (nNOS, iNOS, and eNOS) expressed in various human tissues and depending on the amount of NO produced in each tissue, the physiological function of NO is determined. However, due to the difficulty in obtaining normal human tissues, little is known about the basal levels of each of the three NOS mRNAsand proteins expressed constitutively in various human tissues. Results of the present study indicate that the basal levels of each of the three NOS mRNAs and proteins expressed in various regions of brain and peripheral tissues are different both in their sizes and in their contents. In Northern blot analysis, two different-sized mRNAs were found for each NOS isozymes: for the nNOS, ∼12 and <12 kb mRNAs; for the iNOS, 4.2 and 4.5 kb mRNAs; for the eNOS, 4.2 and 4.4 kb mRNAs. In the Western blot, several different-sized NOS proteins were detected (∼160, ∼140, and ∼130 kDa for nNOS; ∼130 kDa for iNOS and eNOS) with tissue-specific expression patterns. These differential expression patterns of NOS mRNAs and proteins were caused by alternative splicing in the open-reading frame, and 5′- and/or 3′-untranslated regions of NOS mRNAs. These results suggest that regulation for differential expression of the three NOSgenes in various human tissues may occur by alternative splicing of the NOS mRNAs in tissue-specific patterns.

To assess the effect of gender, age, and smoking habits on the in vivo activities of CYP1A2, flavin‐containing monooxygenase (FMO), and xanthine oxidase in Korean subjects. One hundred thirty‐three age‐ and gender‐matched healthy Korean volunteers (age range, 21 to 78 years; mean age, 35.3 ± 16.6 years) with and without smoking habits participated. After drinking a cup of coffee (200 mL) that contained 110 mg caffeine, a 1‐hour urine sample (between 4 and 5 hours) was collected and caffeine metabolites were analyzed by HPLC. There were marked individual variations in CYP1A2 [(1,7‐dimethylurate + paraxanthine)/caffeine], FMO (theobromine/caffeine), and xanthine oxidase (1‐methylurate/1‐methylxanthine) activities (14‐, 42‐, and 9‐fold, respectively). However, the mean values of these enzyme activities in the nonsmokers were not different between men and women. In the nonsmoking subjects in their 20s, the mean values of CYP1A2 and FMO activities (13.5 ± 5.9 and 2.1 ± 1.9, respectively) were higher than those (7.9 ± 1.8 and 0.95 ± 0.22) of older decennial age groups. Xanthine oxidase activities were the same for all age groups (subjects in their 20s through their 70s). CYP1A2 activity of the smokers (20.0 ± 9.6) was higher than that of the nonsmokers (10.8 ± 5.8; P< .001). Similarly, the FMO activity in smokers (3.4 ± 2.7) was higher than that of the nonsmokers (1.8 ± 1.7; P< .001). The xanthine oxidase activity (1.3 ± 0.5) was not increased in smokers (1.4 ± 0.5; P= .46). Results of this caffeine metabolism study conducted with age‐ and gender‐matched healthy Korean volunteers with and without smoking habits provided the baseline and the widely varying interindividual activities of CYP1A2, FMO, and xanthine oxidase in a Korean population. The results also suggested that drugs metabolized by CYP1A2 and FMO may require individualized dose adjustment according to the age and smoking habits of the subjects. (Clin Pharmacol Ther 2000;67:258–66.) Clinical Pharmacology & Therapeutics(2000) 67, 258–266; doi: 10.1067/mcp.2000.104617

A non-invasive urine analysis method to determine the in-vivo flavin-containing monooxygenase (FMO) activity catalysing N-oxidation of ranitidine (RA) was developed and used to phenotype a Korean population. FMO activity was assessed by the molar concentration ratio of RA and RANO in the bulked 8h urine. This method was used to determine the FMO phenotypes of 210 Korean volunteers (173 men and 37 women, 110 nonsmokers and 100 smokers). Urinary RA/RANO ratio, representing the metabolic ratio and the reciprocal index of FMO activity, ranged from 5.67–27.20 (4.8-fold difference) and was not different between men and women (P0.76) or between smokers and nonsmokers (P0.50). The frequencies of RA/RANO ratios were distributed in a trimodal fashion. Among the 210 Korean subjects, 93 (44.3) were fast metabolizers, 104 (49.5) were intermediate metabolizers and 13 (6.2) were slow metabolizers. Subsequently, the relationship between the ranitidine N-oxidation phenotypes and FMO3genotypes, determined by the presence of two previously identified mutant alleles (Glu158Lys FMO3/Lys158and Glu308Gly FMO3/Gly308alleles) commonly found in our Korean population was examined. The results showed that subjects who were homozygous and heterozygous for either one or both of the FMO3/Lys158and FMO3/Gly308mutant alleles had significantly lower in-vivo FMO activities than those with homozygous wild-type alleles (FMO3/Glu158and FMO3/Glu308) (P<0.001, Mann–Whitney U-test). Furthermore, the FMO activities of subjects with either FMO3/Lys158or FMO3/Gly308mutant alleles were almost identical to those having both FMO3 mutant alleles (FMO3/Lys158and FMO3/Gly308). These two mutant alleles located, respectively, at exons 4 and 7 in the FMO3gene appeared to be strongly linked by cis-configuration in Koreans. Therefore, we concluded that presence of FMO3/Lys158and FMO3/Gly308mutant alleles in FMO3gene is responsible for the low ranitidine N-oxidation (FMO3 activity) in our Korean population.

Bacterial infections are a major cause of chronic infections and mortality. Innate immune control is crucial for protection against bacterial pathogens. Bile acids facilitate intestinal absorption of lipid-soluble nutrients and modulate various metabolic pathways through the farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5). Here, we identified a new role of FXR and TGR5 in promoting inflammasome activation during bacterial infection. Caspase-1/11 activation and release of cleaved interleukin (IL)-1β in FXR- and TGR5-deficient mouse bone marrow-derived macrophages upon Listeria monocytogenesor Escherichia coliinfection was significantly reduced. In contrast, FXR- or TGR5-deficiency did not affect the transcription of caspase-1/11 and IL-1β. Inflammasome activation is critical for host immune defense against bacterial infections. Consistent with this, the deletion of FXR or TGR5 impaired effective clearance of L. monocytogenesor E. coli in vitroand in vivo, which was associated with greater mortality and bacterial burden than that of wild-type mice. Pretreatment with an FXR agonist decreased bacterial burden in vitroand increased survival in vivo. Thus, FXR and TGR5 promote inflammasome-mediated antimicrobial responses and may represent novel antibacterial therapeutic targets.

Flavin-containing monooxygenase (FMO) activity was determined in 82 Korean volunteers by taking molar concentration ratio of theobromine and caffeine present in the 1 h urine (between 4 and 5 h) samples collected after administration of a cup of coffee containing 110 mg of caffeine. Among 82 volunteers, there were 19 women and 63 men (30 smokers and 52 nonsmokers). Volunteers were divided into two groups comprising low (0.53–2.99) and high (3.18–11.95) FMO activities separated by an antimode of 3.18. Peripheral bloods were sampled from these volunteers and their genomic DNAs were amplified by polymerase chain reaction with oligonucleotides designed from intronic sequences of human FMO3gene. Comparing nucleotide sequences of the amplified FMO3gene originating from randomly selected individuals with low and high FMO activities, nine point mutations were identified in the open reading frame sequences. Among these nine mutations, three FMO3 mutant types (FMO3/Stop148, Lys158and Gly308) were selected and correlated with FMO activities observed in our Korean population. A rare FMO3/Stop148mutant allele originating from FMO3/GIy148occurred by substitution of G442T in exon 4 and yielded a premature TGA stop codon. The stop codon was detected in one individual having the second lowest FMO activity and he had the mutation in heterozygous state. In a pedigree study, he was found to have inherited the mutation from his mother who also had a heterozygous stop codon and equally low FMO activity. In our volunteers, two other common mutations were detected in exons 4 and 7. The one in exon 4 resulted from a G472A change eliminating a HinfIrestriction site and produced an amino acid substitution from Glu158 to Lys. The other mutation in exon 7 resulted from an A923G change generating a DraIIrestriction site and produced a non-conservative replacement of Glu308to Gly. Based on the secondary structure maps of FMO3 enzyme proteins for these two mutant types, FMO3/Gly308mutation transformed the helix structure into a sheet shape and indicated that dysfunctional FMO3 may be produced. FMO3/Lys158mutation did not alter the secondary structure. Approximately 80 of volunteers with homozygous and/or heterozygous mutations on either one or two of these mutations had low FMO activities. Thus, individuals with these FMO3gene mutations may have defective metabolic activity for many clinically used drugs and dietary plant alkaloids which are oxidized primarily by hepatic FMO3.

Signal transducer and activator of transcription 3 (STAT3) modulates a variety of genes involved in the regulation of critical functions, including cell proliferation, differentiation, apoptosis, angiogenesis, metastasis, and immunity. For many cancers, elevated levels of STAT3 signaling have been associated with a poor prognosis and the development of chemotherapy resistance. In this study, we investigated the inhibitory effects of a novel small-molecule inhibitor of STAT3, STX-0119, on the cell viability and survival of human lung cancer cells. STX-0119 inhibited activated STAT3 and the expression of STAT3-regulated oncoproteins such as c-Myc, cyclin D1, and survivin in lung cancer cells. STX-0119 also decreased the amount of STAT3 in the nuclear fraction as well as induced apoptosis of these lung cancer cell lines as evidenced by increases in apoptotic cells (Annexin V positive) and poly (ADP-ribose) polymerase (PARP) cleavage. The efficacy of STX-0119 in a mouse xenograft model was confirmed. However, a hematological side effect, which had not been previously reported, was observed. The level of white blood cells was significantly lowered when treated at the dose at which STX-0119 alone showed a significant tumor-suppressive effect. In conclusion, we suggest that STX-0119 may be a potent therapeutic agent against lung cancer. Consideration of the side effect suggests, it is necessary to study whether low-dose STX-0119 is effective for lung treatment with a combination of classic lung cancer therapeutics.

Nanocrystalline ceria-doped scandia-stabilized zirconia (1Ce10ScSZ) powders were prepared via the co-precipitation process for solid oxide fuel cell. The effects of the calcination temperature on different properties of the as-synthesized powders, such as phase evolution, crystalline size, and specific surface area were investigated. The synthesized powders calcined at 900?°C showed a specific surface area of 5 m2 g-1 and crystalline size of 28.2 nm, and ionic conductivity of 0.07S cm-1 as measured at 750?°C. An anode-supported electrolyte with a thin electrolyte layer of 6µm composed of the synthesized 1Ce10ScSZ powders was fabricated using the tape-casting and co-sintering techniques for a solid oxide fuel cell (SOFC) single cell. The open-circuit voltage of the single cell thus obtained was 1.11 V at 750?°C, indicating the dense microstructure of the electrolyte layer. A power density of 0.9W cm-2 was obtained for the SOFC single cell at 1.5A cm-2 and 750?°C. The SOFC single cell fabricated using the nanocrystalline 1CeScSZ electrolyte exhibited good performance because of the drastic reductions in the ohmic resistances.

Nanocrystalline ceria-doped scandia-stabilized zirconia (1Ce10ScSZ) powders were prepared via the co-precipitation process for solid oxide fuel cell. The effects of the calcination temperature on different properties of the as-synthesized powders, such as phase evolution, crystalline size, and specific surface area were investigated. The synthesized powders calcined at 900 °C showed a specific surface area of 5 m2 g−1 and crystalline size of 28.2 nm, and ionic conductivity of 0.07S cm−1 as measured at 750 °C. An anode-supported electrolyte with a thin electrolyte layer of 6μm composed of the synthesized 1Ce10ScSZ powders was fabricated using the tape-casting and co-sintering techniques for a solid oxide fuel cell (SOFC) single cell. The open-circuit voltage of the single cell thus obtained was 1.11 V at 750 °C, indicating the dense microstructure of the electrolyte layer. A power density of 0.9W cm−2 was obtained for the SOFC single cell at 1.5A cm−2 and 750 °C. The SOFC single cell fabricated using the nanocrystalline 1CeScSZ electrolyte exhibited good performance because of the drastic reductions in the ohmic resistances.