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Sample records for hinh vung hoat

  1. Effects of phenylpropanoids on human organic anion transporters hOAT1 and hOAT3.

    PubMed

    Kawasaki, Tatsuya; Takeichi, Yoshiyasu; Tomita, Masashi; Uwai, Yuichi; Epifano, Francesco; Fiorito, Serena; Taddeo, Vito A; Genovese, Salvatore; Nabekura, Tomohiro

    2017-08-05

    Human organic anion transporters hOAT1/SLC22A6 and hOAT3/SLC22A8 are highly expressed on the basolateral membrane of renal proximal tubules and mediate tubular uptake of anionic drugs from blood. They play an important role for drug disposition, and therefore close studies of their ligand recognition are important for drug therapy and development. In this study, we performed uptake experiments using HEK293 and fluorescent anion 6-carboxyfluorescein to asses the effects of phenylpropanoids on hOAT1 and hOAT3. We found that phenylpropanoids, 3-(4'-isopentenyloxyphenyl)-benzoic acid (IBA), 3-(4'-isopentenyloxy-3'-methoxyphenyl)-benzoic acid (IMBA), and 3-(4'-geranyloxy-3'-methoxy phenyl)-benzoic acid (GMBA) inhibited hOAT1 and hOAT3. The Ki values for hOAT1 were comparable to that of probenecid, a strong inhibitor of hOAT1 and hOAT3. While IBA demonstrated competitive inhibition, IMBA and GMBA showed mixed-type inhibition. After preincubation and washout, the inhibitory effects remained with IMBA and GMBA but not IBA, suggesting that the functional group at 3'-position is responsible for these differences. In conclusion, IBA, IMBA, and GMBA are inhibitors of hOAT1 and hOAT3. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Inhibitory effect of caffeic acid on human organic anion transporters hOAT1 and hOAT3: a novel candidate for food-drug interaction.

    PubMed

    Uwai, Yuichi; Ozeki, Yukihiro; Isaka, Tomonori; Honjo, Hiroaki; Iwamoto, Kikuo

    2011-01-01

    Several kinds of food have been shown to influence the absorption and metabolism of drugs, although there is little information about their effect on the renal excretion of drugs. In this study, we performed uptake experiments using Xenopus laevis oocytes to assess the inhibitory effects of chlorogenic acid, caffeic acid and quinic acid, which are contained in coffee, fruits and vegetables, on human organic anion transporters hOAT1 and hOAT3; these transporters mediate renal tubular uptake of anionic drugs from blood. Injection of hOAT1 and hOAT3 cRNA into oocytes stimulated uptake of typical substrates of hOAT1 and hOAT3 (p-aminohippurate and estrone sulfate, respectively); among the three compounds tested, caffeic acid most strongly inhibited these transporters. The apparent 50% inhibitory concentrations of caffeic acid were estimated to be 16.6 µM for hOAT1 and 5.4 µM for hOAT3. Eadie-Hofstee plot analysis showed that caffeic acid inhibited both transporters in a competitive manner. In addition to the transport of p-aminohippurate and estrone sulfate, that of antifolates and antivirals was inhibited by caffeic acid. These findings show that caffeic acid has inhibitory potential against hOAT1 and hOAT3, suggesting that renal excretion of their substrates could be affected in patients consuming a diet including caffeic acid.

  3. Development and characterization of immobilized human organic anion transporter-based liquid chromatographic stationary phase: hOAT1 and hOAT2.

    PubMed

    Kimura, T; Perry, J; Anzai, N; Pritchard, J B; Moaddel, R

    2007-11-15

    This paper reports the development of liquid chromatographic columns containing immobilized organic anion transporters (hOAT1 and hOAT2). Cellular membrane fragments from MDCK cells expressing hOAT1 and S2 cells expressing hOAT2 were immobilized on the surface of the immobilized artificial membrane (IAM) liquid chromatographic stationary phase. The resulting stationary phases were characterized by frontal affinity chromatography, using the marker ligand [3H]-adefovir for the hOAT1 and [14C]-p-aminohippurate for the hOAT2 in the presence of multiple displacers. The determined binding affinities (Kd) for eight OAT1 ligands and eight OAT2 ligands were correlated with literature values and a statistically significant correlation was obtained for both the hOAT1 and hOAT2 columns: r2=0.688 (p<0.05) and r2=0.9967 (p<0.0001), respectively. The results indicate that the OAT1 and OAT2 have been successfully immobilized with retention of their binding activity. The use of these columns to identify ligands to the respective transporters will be presented.

  4. Inhibitory effects of chemotherapeutics on human organic anion transporter hOAT4

    PubMed Central

    Toh, May Fern; Suh, Wonmo; Wang, Haoxun; Zhou, Peter; Hu, Longqin; You, Guofeng

    2016-01-01

    Human organic anion transporter 4 (hOAT4) belongs to a family of organic anion transporters which play critical roles in the body disposition of clinically important drugs. hOAT4 is expressed in the kidney and placenta. In the current study, we examined the inhibitory effects of 101 anticancer drugs from a clinical drug library on hOAT4 transport activity. The studies were carried out in hOAT4-expressing human kidney HEK-293 cells and human placenta BeWo cells. Among these drugs, only chlorambucil and cabazitaxel demonstrated more than 50% cis-inhibitory effect on hOAT4-mediated uptake of 3H-labeled estrone sulfate, a prototypical substrate for the transporter. The IC50 values for chlorambucil and cabazitaxel were 44.28 and 3.5 µM respectively. Dixon plot analysis revealed that inhibition by chlorambucil was competitive with a Ki = 55.73 µM whereas inhibition by cabazitaxel was non-competitive with a Ki = 1.78 µM. Our results demonstrated that chlorambucil and cabazitaxel were inhibitors of hOAT4. Furthermore, by comparing our data with clinically relevant exposures of these drugs, we conclude that the propensity for chlorambucil and cabazitaxel to cause drug-drug interaction through inhibition of hOAT4 is low. PMID:27335682

  5. Transport of the natural sweetener stevioside and its aglycone steviol by human organic anion transporter (hOAT1; SLC22A6) and hOAT3 (SLC22A8).

    PubMed

    Srimaroeng, Chutima; Chatsudthipong, Varanuj; Aslamkhan, Amy G; Pritchard, John B

    2005-05-01

    The natural sweetening agent stevioside and its aglycone metabolite, steviol, have been shown to inhibit transepithelial transport of para-aminohippurate (PAH) in isolated rabbit renal proximal tubules by interfering with basolateral entry. The aim of the present study was to determine which of the cloned basolateral organic anion transporters were involved in the renal transport of stevioside and steviol. This question was addressed in Xenopus laevis oocytes expressing human organic anion transporter 1 (hOAT1), 3 (hOAT3), and winter flounder OAT (fOat1). The parent compound, stevioside, had no inhibitory effect on either PAH (hOAT1) or ES (estrone sulfate; hOAT3) uptake. In contrast, steviol showed significant, dose-dependent inhibition of PAH and ES uptake in hOAT1- or hOAT3-expressing oocytes, respectively. The IC(50) of steviol for hOAT1-mediated PAH transport was 11.1 microM compared with 62.6 microM for hOAT3-mediated ES uptake. The Michaelis-Menten inhibition constants (K(i)) for steviol transport mediated by hOAT1 and hOAT3 were 2.0 +/- 0.3 and 5.4 +/- 2.0 microM, respectively. Trans-stimulation of PAH efflux by steviol was assessed to determine whether steviol itself was transported by hOAT1 or hOAT3. A low concentration of 1 microM steviol increased the efflux of [(3)H]PAH (trans-stimulated) via both hOAT1 and hOAT3. In addition, it was shown by electrophysiology that steviol entry induced inward current in fOat1-expressing oocytes. In conclusion, stevioside had no interaction with either hOAT1 or hOAT3, whereas hOAT1, hOAT3, and fOat1 were all shown to be capable of steviol transport and thus, can play a role in its renal transport and excretion.

  6. Inhibitory effect of medicinal plant-derived carboxylic acids on the human transporters hOAT1, hOAT3, hOATP1B1, and hOATP2B1.

    PubMed

    Zhang, Zhi-Yu; Si, Duan-Yun; Yi, Xiu-Lin; Liu, Chang-Xiao

    2014-02-01

    A significant number of organic carboxylic acids have been shown to influence the absorption and distribution of drugs mediated by organic anion transporters (OATs). In this study, uptake experiments were performed to assess the inhibitory effects of cinnamic acid, ferulic acid, oleanolic acid, deoxycholic acid, and cynarin on hOAT1, hOAT3, hOATP1B1, and hOATP2B1. After a drug-drug interaction (DDI) investigation, cinnamic acid, ferulic acid, deoxycholic acid, and cynarin were found and validated to inhibit hOAT1 in a competitive manner, and deoxycholic acid was found to be an inhibitor of all four transporters. The apparent 50% inhibitory concentrations of cinnamic acid, ferulic acid, deoxycholic acid, and cynarin were estimated to be 133.87, 3.69, 90.03 and 6.03 μmol·L(-1) for hOAT1, respectively. The apparent 50% inhibitory concentrations of deoxycholic acid were estimated to be 9.57 μmol·L(-1) for hOAT3, 70.54 μmol·L(-1) for hOATP1B1, and 168.27 μmol·L(-1) for hOATP2B1. Because cinnamic acid, ferulic acid, and cynarin are ingredients of food or food additives, the present study suggests there are new food-drug interactions to be disclosed. In addition, deoxycholic acid may be used as a probe for studying the correlation of OATs and OATPs.

  7. Peptide bond-forming reagents HOAt and HATU are not mutagenic in the bacterial reverse mutation test.

    PubMed

    Nicolette, John; Neft, Robin E; Vanosdol, Jessica; Murray, Joel

    2016-04-01

    The peptide bond-forming reagents 1-hydroxy-7-azabenzotriazole (HOAt, CAS 39968-33-7) and O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, CAS 148893-10-1) either have structural alerts, unclassified features or are considered out of domain when evaluated for potential mutagenicity with in silico programs DEREK and CaseUltra. Since they are commonly used reagents in pharmaceutical drug syntheses, they may become drug substance or drug product impurities and would need to be either controlled to appropriately safe levels or tested for mutagenicity. Both reagents were tested in the bacterial reverse mutation (Ames) test at Covance, under GLP conditions, following the OECD test guideline and ICH S2(R1) recommendations and found to be negative. Our data show that HOAt and HATU-common pharmaceutical synthesis reagents-are not mutagenic, and can be treated as ordinary drug impurities.

  8. The role of dileucine in the expression and function of human organic anion transporter 1 (hOAT1)

    PubMed Central

    Zhang, Qiang; Wu, Jinwei; Pan, Zui; You, Guofeng

    2011-01-01

    Human organic anion transporter hOAT1 plays a critical role in the body disposition of environmental toxins and clinically important drugs including anti-HIV therapeutics, anti-tumor drugs, antibiotics, anti-hypertensives, and anti-inflammatories. In the current study, we investigated the role of dileucine (L6L7) at the amino terminus of hOAT1 in the expression and function of the transporter. We substituted L6L7 with alanine (A) simultaneously. The resulting mutant transporter L6A/L7A showed no transport activity due to its complete loss of expression at the cell surface. Such loss of surface expression of L6A/L7A was consistent with a complete loss of an 80 kDa mature form and a dramatic decrease in a 60 kDa immature form of the mutant transporter in the total cell lysates. Treatment of L6A/L7A-expressing cells with proteasomal inhibitor resulted in a significant increase in the immature form of hOAT1, but not its mature form, whereas treatment of these cells with lysosomal inhibitor had no effect on the expression of the mutant transporters, suggesting that the mutant transporter was degraded through proteasomal pathway. The accumulation of mutant transporter in the endoplasmic reticulum (ER) was confirmed by coimmunolocalization of L6L7 with calnexin, an ER marker. Furthermore, treatment of L6A/L7A-expressing cells with sodium 4-phenylbutyrate (4PBA) and glycerol, two chemical chaperones, could not promote the exit of the immature form of the mutant transporter from the ER. Our data suggest that L6L7 are critical for the stability and ER export of hOAT1. PMID:21494320

  9. The oldest flora of the South China Block, and the stratigraphic bearings of the plant remains from the Ngoc Vung Series, northern Vietnam

    NASA Astrophysics Data System (ADS)

    Gonez, Paul; Nguyên Huu, Hung; Ta Hoa, Phuong; Clément, Gaël; Janvier, Philippe

    2012-01-01

    Several outcrops of the Late Silurian and Devonian of the Ngoc Vung Series, northern Vietnam, yielded plant remains. The Late Silurian localities delivered the earliest known flora of the South China block. Although the fossils are fragmentary, they complement our knowledge about the global composition of the flora. The major components of the flora are plants with dichotomous habit and terminal bivalvate sporangia, which are close relatives to zosterophylls, and zosterophylls. Plants with possible euphyllophyte affinities and bryophytes are occasionally present. This floral composition is similar to that of the rich, younger South China block assemblages from the Posongchong and Xujiachong Formations of China, considered Pragian in age. The South China block flora is therefore likely to have been dominated by zosterophylls and pre-zosterophylls at least from the Late Silurian to the Pragian (i.e. a 20 million years long period). It also strengthens the hypothesis that more derived plants were present on eastern Gondwana earlier that elsewhere, in the first steps of tracheophyte evolution. The Devonian localities of the Ngoc Vung Series delivered a thick fibrous stem fragment and a basal euphyllophyte. These latter plant remains provide some stratigraphic data. The large stem fragment is consistent with an Eifelian age for the Duong Dong Formation (part of the Ngoc Vung Series), as suggested by the brachiopod fauna. The accompanying basal euphyllophyte displays a combination of characters (axes 3-4 mm wide and lateral branchings) that is also consistent with an Eifelian age, but possibly more characteristic of the Emsian flora. It is therefore suggested that the stratigraphic range of the Duong Dong Formation might be extended down to the Emsian.

  10. Prevalence of vision impairment and refractive error in school children in Ba Ria – Vung Tau province, Vietnam

    PubMed Central

    Paudel, Prakash; Ramson, Prasidh; Naduvilath, Thomas; Wilson, David; Phuong, Ha Thanh; Ho, Suit M; Giap, Nguyen V

    2014-01-01

    Background To assess the prevalence of vision impairment and refractive error in school children 12–15 years of age in Ba Ria – Vung Tau province, Vietnam. Design Prospective, cross-sectional study. Participants 2238 secondary school children. Methods Subjects were selected based on stratified multistage cluster sampling of 13 secondary schools from urban, rural and semi-urban areas. The examination included visual acuity measurements, ocular motility evaluation, cycloplegic autorefraction, and examination of the external eye, anterior segment, media and fundus. Main Outcome Measures Visual acuity and principal cause of vision impairment. Results The prevalence of uncorrected and presenting visual acuity ≤6/12 in the better eye were 19.4% (95% confidence interval, 12.5–26.3) and 12.2% (95% confidence interval, 8.8–15.6), respectively. Refractive error was the cause of vision impairment in 92.7%, amblyopia in 2.2%, cataract in 0.7%, retinal disorders in 0.4%, other causes in 1.5% and unexplained causes in the remaining 2.6%. The prevalence of vision impairment due to myopia in either eye (–0.50 diopter or greater) was 20.4% (95% confidence interval, 12.8–28.0), hyperopia (≥2.00 D) was 0.4% (95% confidence interval, 0.0–0.7) and emmetropia with astigmatism (≥0.75 D) was 0.7% (95% confidence interval, 0.2–1.2). Vision impairment due to myopia was associated with higher school grade and increased time spent reading and working on a computer. Conclusions Uncorrected refractive error, particularly myopia, among secondary school children in Vietnam is a major public health problem. School-based eye health initiative such as refractive error screening is warranted to reduce vision impairment. PMID:24299145

  11. Prevalence of vision impairment and refractive error in school children in Ba Ria - Vung Tau province, Vietnam.

    PubMed

    Paudel, Prakash; Ramson, Prasidh; Naduvilath, Thomas; Wilson, David; Phuong, Ha Thanh; Ho, Suit M; Giap, Nguyen V

    2014-04-01

    To assess the prevalence of vision impairment and refractive error in school children 12-15 years of age in Ba Ria - Vung Tau province, Vietnam. Prospective, cross-sectional study. 2238 secondary school children. Subjects were selected based on stratified multistage cluster sampling of 13 secondary schools from urban, rural and semi-urban areas. The examination included visual acuity measurements, ocular motility evaluation, cycloplegic autorefraction, and examination of the external eye, anterior segment, media and fundus. Visual acuity and principal cause of vision impairment. The prevalence of uncorrected and presenting visual acuity ≤6/12 in the better eye were 19.4% (95% confidence interval, 12.5-26.3) and 12.2% (95% confidence interval, 8.8-15.6), respectively. Refractive error was the cause of vision impairment in 92.7%, amblyopia in 2.2%, cataract in 0.7%, retinal disorders in 0.4%, other causes in 1.5% and unexplained causes in the remaining 2.6%. The prevalence of vision impairment due to myopia in either eye (-0.50 diopter or greater) was 20.4% (95% confidence interval, 12.8-28.0), hyperopia (≥2.00 D) was 0.4% (95% confidence interval, 0.0-0.7) and emmetropia with astigmatism (≥0.75 D) was 0.7% (95% confidence interval, 0.2-1.2). Vision impairment due to myopia was associated with higher school grade and increased time spent reading and working on a computer. Uncorrected refractive error, particularly myopia, among secondary school children in Vietnam is a major public health problem. School-based eye health initiative such as refractive error screening is warranted to reduce vision impairment. © 2013 The Authors. Clinical & Experimental Ophthalmology published by Wiley Publishing Asia Pty Ltd on behalf of Royal Australian and New Zealand College of Ophthalmologists.

  12. Mutational analysis of the role of GXXXG motif in the function of human organic anion transporter 1 (hOAT1)

    PubMed Central

    Duan, Peng; Wu, Jinwei; You, Guofeng

    2011-01-01

    Human organic anion transporter hOAT1 plays a critical role in the body disposition of environmental toxins and clinically important drugs including anti-HIV therapeutics, anti-tumor drugs, antibiotics, anti-hypertensives, and anti-inflammatories. hOAT1 has two GXXXG motifs in its transmembrane domains 2 and 5, a motif linked to the protein processing and oligomerization of other proteins. In the current study, we substituted glycine of these GXXXG motifs with alanine and evaluated the effect of such mutations on the expression and function of hOAT1. Mutations of GXXXG motif in the transmembrane domain 2 resulted in mutants G144A and G148A, both of which had no transport activity due to complete loss in the surface and total cell expression of the transporter protein. Treatment of G144A- and G148A-expressing cells with proteasomal inhibitor resulted in the recovery of ER-resident immature form of hOAT1, but not its surface-resident mature form, whereas treatment of these cells with lysosomal inhibitor had no effect on the expression of the mutant transporters. Mutations of GXXXG motif in the transmembrane domain 5 resulted in mutants G223A and G227A, among which only G227 had dramatic reduction of transport activity due to dramatic loss in the surface and total cell expression of the transporter. The reduction in the surface expression of G227 was consistent with the decrease in maximum transport velocity Vmax. Treatment of G227A-expressing cells with proteasomal inhibitor or lysosomal inhibitor resulted in partial recovery of both the immature form and the mature form of hOAT1 in the total cell extracts. However, such partial recovery of the mature form in total cell extracts did not lead to the partial recovery of surface expression and function of the transporter. Our data suggest that the GXXXG motifs in transmembrane domains 2 and 5 play critical roles in the stability of hOAT1. PMID:21340049

  13. Entecavir Interacts with Influx Transporters hOAT1, hCNT2, hCNT3, but Not with hOCT2: The Potential for Renal Transporter-Mediated Cytotoxicity and Drug–Drug Interactions

    PubMed Central

    Mandíková, Jana; Volková, Marie; Pávek, Petr; Navrátilová, Lucie; Hyršová, Lucie; Janeba, Zlatko; Pavlík, Jan; Bárta, Pavel; Trejtnar, František

    2016-01-01

    Entecavir (ETV) is one of the most potent agents for the treatment of the hepatitis B viral infection. The drug is principally eliminated by the kidney. The goal of this study was to investigate the potential of ETV to interact in vitro with the renal SLC transporters hOAT1, hOCT2, hCNT2 and hCNT3. Potential drug–drug interactions of ETV at the renal transporters with antiviral drugs known to be excreted by the kidney (adefovir, tenofovir, cidofovir) as well as transporter-dependent cytotoxicity were also examined. Interactions with the selected transporters along with cytotoxicity were studied in several transiently transfected cellular models using specific substrates and inhibitors. ETV was found to be both a substrate and inhibitor of hOAT1 (IC50 = 175.3 μM), hCNT2 (IC50 = 241.9 μM) and hCNT3 (IC50 = 278.4 μM) transporters, although it interacted with the transporters with relatively low affinities. ETV inhibited the cellular uptake of adefovir, tenofovir, and cidofovir by hOAT1; however, effective inhibition was shown at ETV concentrations exceeding therapeutic levels. In comparison with adefovir, tenofovir, and cidofovir, ETV displayed no transporter-mediated cytotoxicity in cells transfected with hOAT1, hCNT2, and hCNT3. No significant interaction of ETV with hOCT2 was detected. The study demonstrates interactions of ETV with several human renal transporters. For the first time, an interaction of ETV with the hCNTs was proved. We show that the potency of ETV to cause nephrotoxicity and/or clinically significant drug-drug interactions related to the tested transporters is considerably lower than that of adefovir, tenofovir, and cidofovir. PMID:26779022

  14. Expression studies and functional characterization of renal human organic anion transporter 1 isoforms.

    PubMed

    Bahn, Andrew; Ebbinghaus, Christian; Ebbinghaus, Diana; Ponimaskin, Evgeni G; Fuzesï, Laszlo; Burckhardt, Gerhard; Hagos, Yohannes

    2004-04-01

    The human organic anion transporter 1 (hOAT1) facilitates the basolateral entry of organic anions such as endogenous metabolites, xenobiotics, and drugs into the proximal tubule cells. In the present study we investigated the general occurrence of hOAT1 isoforms in the kidneys and performed functional characterizations. Kidney specimens of 10 patients were analyzed by reverse transcription-polymerase chain reaction. We detected hOAT1-2 as the main transcript in almost all patients, and weak transcripts of hOAT1-1, hOAT1-3, and hOAT1-4 in many of them. An evaluation of the renal distribution showed all four mRNAs mostly restricted to the cortex. Western blot analysis of membrane fractions from two kidney specimens yielded two bands corresponding to the observed mRNA expression, suggesting hOAT1-3 and hOAT1-4 to be expressed on the protein level in vivo. This observation is further supported by immunofluorescence analyses of all four cloned hOAT1 isoforms transiently transfected in COS 7 cells. Functional characterizations did not show any transport activity of hOAT1-3 and hOAT1-4 for the tested substrates. Cotransfection studies of each of them with hOAT1-1 did not alter fluorescein uptake indicating no regulatory impact of these isoforms. Further functional comparisons of hOAT1-1 and hOAT1-2 in fluorescein uptake studies exhibited almost identical affinities for fluorescein with Michaelis constants of 11.6 +/- 3.7 microM (hOAT1-1) and 11.9 +/- 6.4 microM (hOAT1-2), and similar sensitivities to inhibition by p-aminohippurate [IC(50): 16 microM (hOAT1-1), 10 microM (hOAT1-2)], urate [IC(50): 440 microM (hOAT1-1), 385 microM (hOAT1-2)], and furosemide (IC(50): 14 microM (hOAT1-1), 20 microM (hOAT1-2)], implying functional equivalence.

  15. Potent inhibitors of human organic anion transporters 1 and 3 from clinical drug libraries: discovery and molecular characterization.

    PubMed

    Duan, Peng; Li, Shanshan; Ai, Ni; Hu, Longqin; Welsh, William J; You, Guofeng

    2012-11-05

    Transporter-mediated drug-drug interactions in the kidney dramatically influence the pharmacokinetics and other clinical effects of drugs. Human organic anion transporters 1 (hOAT1) and 3 (hOAT3) are the major transporters in the basolateral membrane of kidney proximal tubules, mediating the rate-limiting step in the elimination of a broad spectrum of drugs. In the present study, we screened two clinical drug libraries against hOAT1 and hOAT3. Of the 727 compounds screened, 92 compounds inhibited hOAT1 and 262 compounds inhibited hOAT3. When prioritized based on the peak unbound plasma concentrations of these compounds, three inhibitors for hOAT1 and seven inhibitors for hOAT3 were subsequently identified with high inhibitory potency (>95%). Computational analyses revealed that inhibitors and noninhibitors can be differentiated from each other on the basis of several physicochemical features, including number of hydrogen-bond donors, number of rotatable bonds, and topological polar surface area (TPSA) for hOAT1; and molecular weight, number of hydrogen-bond donors and acceptors, TPSA, partition coefficient (log P(7.4)), and polarizability for hOAT3. Pharmacophore modeling identified two common structural features associated with inhibitors for hOAT1 and hOAT3, viz., an anionic hydrogen-bond acceptor atom, and an aromatic center separated by ∼5.7 Å. Such model provides mechanistic insights for predicting new OAT inhibitors.

  16. Regulation of human organic anion transporter 4 by parathyroid hormone-related protein and protein kinase A

    PubMed Central

    Duan, Peng; Li, Shanshan; You, Guofeng

    2012-01-01

    Human organic anion transporter 4 (hOAT4) belongs to a family of organic anion transporters that play critical roles in the body disposition of clinically important drugs, including anti-human immunodeficiency virus therapeutics, anti-tumor drugs, antibiotics, antihypertensives, and anti-inflammatories. hOAT4 is abundantly expressed in the kidney and placenta. In the current study, we examined the regulation of hOAT4 by parathyroid hormone-related protein (PTHrP) and protein kinase A (PKA) in kidney COS-7 cells. PTHrP induced a time- and concentration-dependent stimulation of hOAT4 transport activity. The stimulation of hOAT4 activity by PTHrP mainly resulted from an increased cell surface expression without a change in total cell expression of the transporter. Activation of PKA by Bt2-cAMP also resulted in a stimulation of hOAT4 activity through an increased cell surface expression of the transporter. However, PTHrP-induced stimulation of hOAT4 activity could not be prevented by treating hOAT4-expressing cells with the PKA inhibitor H89. We concluded that both PTHrP and activation of PKA stimulate hOAT4 activity through redistribution of the transporter from intracellular compartments to the cell surface. However, PTHrP regulates hOAT4 activity by mechanisms independent of PKA pathway. PMID:23097748

  17. POTENT INHIBITORS OF HUMAN ORGANIC ANION TRANSPORTERS 1 AND 3 FROM CLINICAL DRUG LIBRARIES: DISCOVERY AND MOLECULAR CHARACTERIZATION

    PubMed Central

    Duan, Peng; Li, Shanshan; Ai, Ni; Hu, Longqin; Welsh, William J.; You, Guofeng

    2012-01-01

    Transporter-mediated drug-drug interactions in the kidney dramatically influence the pharmacokinetics and other clinical effects of drugs. Human organic anion transporters 1 (hOAT1) and 3 (hOAT3) are the major transporters in the basolateral membrane of kidney proximal tubules, mediating the rate-limiting step in the elimination of a broad spectrum of drugs. In the present study, we screened two clinical drug libraries against hOAT1 and hOAT3. Of the 727 compounds screened, 92 compounds inhibited hOAT1 and 262 compounds inhibited hOAT3. When prioritized based on the peak unbound plasma concentrations of these compounds, three inhibitors for hOAT1 and seven inhibitors for hOAT3 were subsequently identified with high inhibitory potency (>95%). Computational analyses revealed that inhibitors and non-inhibitors can be differentiated from each other on the basis of several physico-chemical features, including: number of hydrogen-bond donors, number of rotatable bonds, and topological polar surface area (TPSA) for hOAT1; and molecular weight, number of hydrogen-bond donors and acceptors, TPSA, partition coefficient (Log P7.4), and polarizability for hOAT3. Pharmacophore modeling identified two common structural features associated with inhibitors for hOAT1 and hOAT3, viz., an anionic hydrogen-bond acceptor atom, and an aromatic center separated by ~5.7 Å. Such model provides mechanistic insights for predicting new OAT inhibitors. PMID:22973893

  18. Potential for food-drug interactions by dietary phenolic acids on human organic anion transporters 1 (SLC22A6), 3 (SLC22A8), and 4 (SLC22A11).

    PubMed

    Wang, Li; Sweet, Douglas H

    2012-10-15

    Phenolic acids exert beneficial health effects such as anti-oxidant, anti-carcinogenic, and anti-inflammatory activities and show systemic exposure after consumption of common fruits, vegetables, and beverages. However, knowledge regarding which components convey therapeutic benefits and the mechanism(s) by which they cross cell membranes is extremely limited. Therefore, we determined the inhibitory effects of nine food-derived phenolic acids, p-coumaric acid, ferulic acid, gallic acid, gentisic acid, 4-hydroxybenzoic acid, protocatechuic acid, sinapinic acid, syringic acid, and vanillic acid, on human organic anion transporter 1 (hOAT1), hOAT3, and hOAT4. In the present study, inhibition of OAT-mediated transport of prototypical substrates (1 μM) by phenolic acids (100 μM) was examined in stably expressing cell lines. All compounds significantly inhibited hOAT3 transport, while just ferulic, gallic, protocatechuic, sinapinic, and vanillic acid significantly blocked hOAT1 activity. Only sinapinic acid inhibited hOAT4 (~35%). For compounds exhibiting inhibition > ~60%, known clinical plasma concentration levels and plasma protein binding in humans were examined to select compounds to evaluate further with dose-response curves (IC(50) values) and drug-drug interaction (DDI) index determinations. IC(50) values ranged from 1.24 to 18.08 μM for hOAT1 and from 7.35 to 87.36 μM for hOAT3. Maximum DDI indices for gallic and gentisic acid (≫0.1) indicated a very strong potential for DDIs on hOAT1 and/or hOAT3. This study indicates that gallic acid from foods or supplements, or gentisic acid from salicylate-based drug metabolism, may significantly alter the pharmacokinetics (efficacy and toxicity) of concomitant therapeutics that are hOAT1 and/or hOAT3 substrates.

  19. Serum- and glucocorticoid-inducible kinase sgk2 stimulates the transport activity of human organic anion transporters 1 by enhancing the stability of the transporter

    PubMed Central

    Xu, Da; Huang, Haozhe; Toh, May Fern; You, Guofeng

    2016-01-01

    Human organic anion transporter 1 (hOAT1) belongs to a family of organic anion transporters that play critical roles in the body disposition of clinically important drugs, including anti-viral therapeutics, anti-cancer drugs, antibiotics, antihypertensives, and anti-inflammatories. hOAT1 is abundantly expressed in the kidney and brain. In the current study, we examined the regulation of hOAT1 by serum- and glucocorticoid-inducible kinase 2 (sgk2) in the kidney COS-7 cells. We showed that sgk2 stimulated hOAT1 transport activity. Such stimulation mainly resulted from an increased cell surface expression of the transporter, kinetically revealed as an increased maximal transport velocity V max without significant change in substrate-binding affinity K m. We further showed that stimulation of hOAT1 activity by sgk2 was achieved by preventing hOAT1 degradation. Our co-immunoprecipitation experiment revealed that the effect of sgk2 on hOAT1 was through a direct interaction between these two proteins. In conclusion, our study demonstrated that sgk2 stimulates hOAT1 transport activity by enhancing the stability of the transporter. This study provides the insights into sgk2 regulation of hOAT1-mediated transport in normal physiology and disease. PMID:27335683

  20. Competitive inhibition of human organic anion transporters 1 (SLC22A6), 3 (SLC22A8) and 4 (SLC22A11) by major components of the medicinal herb Salvia miltiorrhiza (Danshen).

    PubMed

    Wang, Li; Sweet, Douglas H

    2013-01-01

    When herbal products are used in combination therapy with drugs, alterations in pharmacokinetics, pharmacodynamics, and toxicity can result. Many active components of herbal products are organic anions, and human organic anion transporter 1 (hOAT1, SLC22A6), hOAT3 (SLC22A8), and hOAT4 (SLC22A11) have been identified as potential sites of drug-drug interactions. Therefore, we assessed the effects of lithospermic acid (LSA), rosmarinic acid (RMA), salvianolic acid A (SAA), salvianolic acid B (SAB), and tanshinol (TSL), components of the herbal medicine Danshen, on the function of these transporters. Kinetic analysis demonstrated a competitive mechanism of inhibition for all five. K(i) values (µM) were estimated as 20.8 ± 2.1 (LSA), 0.35 ± 0.06 (RMA), 5.6 ± 0.3 (SAA), 22.2 ± 1.9 (SAB), and 40.4 ± 12.9 (TSL) on hOAT1 and as 0.59 ± 0.26 (LSA), 0.55 ± 0.25 (RMA), 0.16 ± 0.03 (SAA), 19.8 ± 8.4 (SAB), and 8.6 ± 3.3 (TSL) on hOAT3. No significant inhibition of hOAT4 activity by TSL was observed. Using published human pharmacokinetic values, unbound C(max)/K(i) ratios were calculated as an indicator of in vivo drug-drug interaction potential. Analysis indicated a strong interaction potential for RMA and TSL on both hOAT1 and hOAT3 and for LSA on hOAT3. Thus, herb-drug interactions may occur in vivo in situations of co-administration of Danshen and clinical therapeutics known to be hOAT1/hOAT3 substrates.

  1. Human renal organic anion transporter 4 operates as an asymmetric urate transporter.

    PubMed

    Hagos, Yohannes; Stein, Daniel; Ugele, Bernhard; Burckhardt, Gerhard; Bahn, Andrew

    2007-02-01

    Human organic anion transporter 4 (hOAT4) is located at the apical membrane of proximal tubule cells and involved in renal secretion and reabsorption of endogenous substances as well as many drugs and xenobiotics. This study reevaluated the physiologic role, transport mode, and driving forces of hOAT4. 6-Carboxyfluorescein (6-CF) uptake into HEK293 cells that stably expressed hOAT4 was saturable, resulting in a K(m) of 108 muM. 6-CF as well as [(3)H]estrone sulfate ([(3)H]ES) accumulation by HEK293-hOAT4 cells were abolished by ES, dehydroepiandrosterone sulfate, sulfinpyrazone, benzbromarone, and probenecid, whereas several OA, including p-aminohippurate (PAH), lactate, pyrazinoate, nicotinate, glutarate, and the diuretic hydrochlorothiazide (HCTZ) exhibited a slight or a NS inhibitory effect. PAH and glutarate are not taken up by HEK293-hOAT4 cells, but they trans-stimulated 6-CF and [(3)H]ES uptake, indicating an asymmetric interaction of hOAT4 with these substrates. In chloride-free medium, HEK293-hOAT4-mediated [(3)H]PAH efflux was almost abolished, whereas addition of ES restored it comparable to Ringer solution, consistent with a physiologic ES/PAH or PAH/Cl(-) exchange mode of hOAT4. Moreover, an acidification of the uptake medium increased 6-CF as well as [(3)H]ES uptake, which was reduced by nigericin, suggesting that hOAT4 also can operate as an OA/OH(-) exchanger. hOAT4 facilitates substantial uptake of [(14)C]urate, which was elevated 2.6-fold by intracellular HCTZ. Thus, hOAT4 is the long-postulated, low-affinity apical urate anion exchanger that facilitates HCTZ-associated hyperuricemia.

  2. Interactions of stevioside and steviol with renal organic anion transporters in S2 cells and mouse renal cortical slices.

    PubMed

    Srimaroeng, Chutima; Jutabha, Promsuk; Pritchard, John B; Endou, Hitoshi; Chatsudthipong, Varanuj

    2005-06-01

    Our previous studies have shown that both stevioside and steviol inhibited transepithelial transport of para-aminohippurate (PAH) in isolated rabbit renal proximal tubules by interfering with organic anion transport system. The current study examined the direct interactions of stevioside and steviol with specific organic anion transporters. S2 cells expressing human organic anion transporters (hOAT1, hOAT2, hOAT3, and hOAT4) and an intact renal epithelium were used to determine the inhibitory effect of stevioside and steviol on organic anion transport. Stevioside at 0.5-1 mM showed no interaction with any OAT. In contrast, steviol markedly inhibited substrate uptake in all S2hOAT cells. Steviol had low IC50 for hOAT1 (11.4 microM) and hOAT3 (36.5 microM) similar to that of probenecid, whereas IC50 for hOAT2 (1000 microM) and hOAT4 (285 microM) was much higher. Results obtained in mouse renal cortical slices were very similar; that is, stevioside was without inhibitory effect and steviol was a potent inhibitor of PAH and estrone sulfate (ES) transport. Stevioside has no interaction with human or mouse OATs. In contrast, steviol interacts directly with human OATs, in particular, hOAT1 and hOAT3, with a potency approximating probenecid, suggesting that the inhibition of OAT-mediated transport by steviol could alter renal drug clearance.

  3. Short-term and long-term effects of protein kinase C on the trafficking and stability of human organic anion transporter 3

    PubMed Central

    Zhang, Qiang; Suh, Wonmo; Pan, Zui; You, Guofeng

    2012-01-01

    Human organic anion transporter 3 (hOAT3) belongs to a family of organic anion transporters that play critical roles in the body disposition of numerous clinically important drugs. Therefore, understanding the regulation of this transporter has profound clinical significance. In the current study, we investigated the short-term and long-term regulation of hOAT3 by protein kinase C (PKC). We showed that short-term activation of PKC by phobol 12-Myristate 13-Acetate (PMA) inhibited hOAT3 activity through accelerating its internalization from cell surface to intracellular recycling endosomes. The colocalization of hOAT3 with EEA1-positive recycling endosomes was demonstrated by immunolocalization with confocal microscopy. Furthermore, we showed that long-term activation of PKC resulted in the enhanced degradation of cell surface hOAT3. The pathways for hOAT3 degradation were further examined using proteasomal and lysosomal inhibitors. Our results showed that both proteasomal inhibitors and the lysosomal inhibitors significantly blocked hOAT3 degradation. These results demonstrate that PKC plays critical roles in the trafficking and the stability of hOAT3. PMID:22773962

  4. Serum- and Glucocorticoid-Inducible Kinase SGK2 Regulates Human Organic Anion Transporters 4 via Ubiquitin Ligase Nedd4-2

    PubMed Central

    Wang, Haoxun; Xu, Da; Toh, May Fern; Pao, Alan C.; You, Guofeng

    2016-01-01

    Human organic anion transporter 4 (hOAT4) belongs to a family of organic anion transporters that play critical roles in the body disposition of clinically important drugs, including anti-viral therapeutics, anti-cancer drugs, antibiotics, antihypertensives, and anti-inflammatories. hOAT4 is abundantly expressed in the kidney and placenta. In the current study, we examined the regulation of hOAT4 by serum- and glucocorticoid-inducible kinase 2 (sgk2) in the kidney COS-7 cells. We showed that sgk2 stimulated hOAT4 transport activity. Such stimulation mainly resulted from an increased cell surface expression of the transporter, kinetically revealed as an increased maximal transport velocity Vmax without significant change in substrate-binding affinity Km. We further showed that regulation of hOAT4 activity by sgk2 was mediated by ubiquitin ligase Nedd4-2. Overexpression of Nedd4-2 enhanced hOAT4 ubiquitination, and inhibited hOAT4 transport activity, whereas overexpression of ubiquitin ligase-dead mutant Nedd4-2/C821A or siRNA knockdown of endogenous Nedd4-2 had opposite effects on hOAT4. Our co-immunoprecipitation experiment revealed that sgk2 weakened the association between hOAT4 and Nedd4-2. In conclusion, our study demonstrated for the first time that sgk2 stimulated hOAT4 transport activity by abrogating the inhibition effect of Nedd4-2 on the transporter. PMID:26740304

  5. The role of Nedd4-1 WW domains in binding and regulating human organic anion transporter 1.

    PubMed

    Xu, Da; Wang, Haoxun; Gardner, Carol; Pan, Zui; Zhang, Ping L; Zhang, Jinghui; You, Guofeng

    2016-08-01

    Human organic anion transporter 1 (hOAT1), expressed at the basolateral membrane of kidney proximal tubule cells, mediates the active renal secretion of a diverse array of clinically important drugs, including anti-human immunodeficiency virus therapeutics, antitumor drugs, antibiotics, antihypertensives, and anti-inflammatories. We have previously demonstrated that posttranslational modification of hOAT1 by ubiquitination is an important mechanism for the regulation of this transporter. The present study aimed at identifying the ubiquitin ligase for hOAT1 and its mechanism of action. We showed that overexpression of neural precursor cell expressed, developmentally downregulated (Nedd)4-1, an E3 ubiquitin ligase, enhanced hOAT1 ubiquitination, decreased hOAT1 expression at the cell surface, and inhibited hOAT1 transport activity. In contrast, overexpression of the ubiquitin ligase-dead mutant Nedd4-1/C867S was without effects on hOAT1. Furthermore, knockdown of endogenously expressed Nedd4-1 by Nedd4-1-specific small interfering RNA reduced hOAT1 ubiquitination. Immunoprecipitation experiments in cultured cells and rat kidney slices and immunofluorescence experiments in rat kidney slices showed that there was a physical interaction between OAT1 and Nedd4-1. Nedd4-1 contains four protein-protein interacting WW domains. When these WW domains were inactivated by mutating two amino acid residues in each of the four WW domains (Mut-WW1: V210W/H212G, Mut-WW2: V367W/H369G, Mut-WW3: I440W/H442G, and Mut-WW4: I492W/H494G, respectively), only Mut-WW2 and Mut-WW3 significantly lost their ability to bind and to ubiquitinate hOAT1. As a result, Mut-WW2 and Mut-WW3 were unable to suppress hOAT1-mediated transport as effectively as wild-type Nedd4-1. In conclusion, this is the first demonstration that Nedd4-1 regulates hOAT1 ubiquitination, expression, and transport activity through its WW2 and WW3 domains.

  6. Interaction between rhein acyl glucuronide and methotrexate based on human organic anion transporters.

    PubMed

    Yuan, Yuan; Yang, Hua; Kong, Linghua; Li, Yuan; Li, Ping; Zhang, Hongjian; Ruan, Jianqing

    2017-09-07

    Rhein, a major bioactive compound of many medicinal herbs and the prodrug of diacerein, is often used with low dose of methotrexate as drug combination to treat rheumatoid arthritis. In this study, potential drug-drug interaction between methotrexate and rhein was investigated based on organic anion transporters (OAT). Our study demonstrated that rhein acyl glucuronide (RAG), the major metabolite of rhein in the human blood circulation, significantly inhibited the uptake of p-aminohippurate in hOAT1 transfected cells with IC50 value of 691 nM and estrone sulfate uptake in hOAT3 transfected cells with IC50 value of 78.5 nM. As the substrate of both hOAT1 and hOAT3, the methotrexate transport was significantly inhibited by RAG in hOAT1 transfected cells at 50 μM and hOAT3 transfected cells at 1 μM by 69% and 87%, respectively. Further in vivo study showed that after co-administrated with RAG in rats the AUC0-24 values of methotrexate increased from 3109 to 5370 ng/mL*hr and the t1/2 was prolonged by 40.5% (from 7.4 to 10.4 h), demonstrating the inhibitory effect of RAG on methotrexate excretion. In conclusion, rhein acyl glucuronide could significantly decrease the transport of methotrexate by both hOAT1 and hOAT3. The combination use of rhein, diacerein or other rhein-containing herbs with methotrexate may cause obvious drug-drug interaction and require close monitoring for potential drug interaction in clinical practice. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Coordination of Gaze and Speech in Communication between Children with Hearing Impairment and Normal-Hearing Peers

    ERIC Educational Resources Information Center

    Sandgren, Olof; Andersson, Richard; van de Weijer, Joost; Hansson, Kristina; Sahlén, Birgitta

    2014-01-01

    Purpose: To investigate gaze behavior during communication between children with hearing impairment (HI) and normal-hearing (NH) peers. Method: Ten HI-NH and 10 NH-NH dyads performed a referential communication task requiring description of faces. During task performance, eye movements and speech were tracked. Using verbal event (questions,…

  8. Coordination of Gaze and Speech in Communication between Children with Hearing Impairment and Normal-Hearing Peers

    ERIC Educational Resources Information Center

    Sandgren, Olof; Andersson, Richard; van de Weijer, Joost; Hansson, Kristina; Sahlén, Birgitta

    2014-01-01

    Purpose: To investigate gaze behavior during communication between children with hearing impairment (HI) and normal-hearing (NH) peers. Method: Ten HI-NH and 10 NH-NH dyads performed a referential communication task requiring description of faces. During task performance, eye movements and speech were tracked. Using verbal event (questions,…

  9. Cercarial glycocalyx of Schistosoma mansoni activates human complement.

    PubMed Central

    Samuelson, J C; Caulfield, J P

    1986-01-01

    Human complement activation by cercariae and schistosomula of the human parasite Schistosoma mansoni was studied in vitro. Cercariae are composed of tails which are shed after infection of the host and bodies which transform into the larvae or schistosomula after infection. After incubation in fresh normal human serum (NHS), cercarial tails bound more anti-C3 antibodies than did cercarial bodies (CB), and the tails were rapidly lysed, while the attached CB remained intact. Complement activation by cercariae was dependent on the alternative pathway but was independent of antibody, as shown by C3 deposition by hypogammaglobulinemic human sera. By transmission microscopy, the fibrillar glycocalyx on both CB and tails was stained by NHS but not by heat-inactivated serum (HI-NHS). The glycocalyx was labeled with periodate and tritiated borohydride, and parasites were incubated in NHS and HI-NHS. After solubilization, the labeled glycocalyx on organisms incubated in NHS but not HI-NHS bound anti-C3 antibodies. Of the CB incubated with eserine sulfate to prevent transformation, 78% +/- 10% were dead after culture for 24 h in NHS. In contrast, 21% +/- 12% of the CB were dead after culture in HI-NHS. Schistosomula incubated in NHS bound 37% of the amount of anti-C3 antibodies bound by cercariae but were not killed by NHS. In conclusion, the cercarial glycocalyx activated human complement, and schistosomula were less susceptible to killing than cercariae because they had less glycocalyx and activated less complement. Images PMID:3940995

  10. U. S. Naval Forces, Vietnam Monthly Historical Supplement for March 1967

    DTIC Science & Technology

    1967-05-29

    gunfire missions were conducted by Coast Quard cutters against camouflaged Viet Cong positions along the shore of the Delta, southwest of Vung Tau, On...and Coast Quard cutters conducted several gunfire missions. At noon on h March, PCF 71 and USCOC POINT KENNEDY conducted a gunfire mission against

  11. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies.

    PubMed

    Hill, George; Cihlar, Tomas; Oo, Charles; Ho, Edmund S; Prior, Ken; Wiltshire, Hugh; Barrett, Jo; Liu, Baulian; Ward, Penny

    2002-01-01

    Oseltamivir is an ester prodrug of the active metabolite [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), a potent and selective inhibitor of neuraminidase enzyme of influenza virus. Oseltamivir is rapidly hydrolyzed by hepatic carboxylesterases to Ro 64-0802, which is then exclusively excreted by glomerular filtration and active tubular secretion without further metabolism. In vivo and in vitro studies were conducted to evaluate the renal drug-drug interaction potential of oseltamivir. Crossover studies were conducted in healthy subjects in which oral oseltamivir was administered alone and coadministered with probenecid, cimetidine, or amoxicillin. Probenecid completely blocked the renal secretion of Ro 64-0802, increasing systemic exposure (area under the curve) by 2.5-fold, but no interaction was observed with cimetidine or amoxicillin. These in vivo data show that Ro 64-0802 is secreted via an organic anion pathway, but Ro 64-0802 does not inhibit amoxicillin renal secretion. In vitro effects of Ro 64-0802 on the human renal organic anionic transporter 1 (hOAT1) were investigated using novel Chinese hamster ovary cells stably transfected with hOAT1. Ro 64-0802 was found to be a low-efficiency substrate for hOAT1 and a very weak inhibitor of hOAT1-mediated transport of p-aminohippuric acid (PAH). Ro 64-0802 did not inhibit the hOAT1-mediated transport of amoxicillin. In contrast, probenecid effectively inhibited the transport of PAH, Ro 64-0802, and amoxicillin via hOAT1. These in vitro observations are consistent with the in vivo data, validating the usefulness of the in vitro system for evaluating such drug-drug interaction. The study results demonstrate that oseltamivir has a low drug-drug interaction potential at the renal tubular level due to inhibition of hOAT1.

  12. Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3.

    PubMed

    Ikemura, Kenji; Hamada, Yugo; Kaya, Chinatsu; Enokiya, Tomoyuki; Muraki, Yuichi; Nakahara, Hiroki; Fujimoto, Hajime; Kobayashi, Tetsu; Iwamoto, Takuya; Okuda, Masahiro

    2016-10-01

    Pemetrexed, a multitargeted antifolate, is eliminated by tubular secretion via human organic anion transporter 3 (hOAT3). Although proton pump inhibitors (PPIs) are frequently used in cancer patients, the drug interaction between PPIs and pemetrexed remains to be clarified. In this study, we examined the drug interaction between pemetrexed and PPIs in hOAT3-expressing cultured cells, and retrospectively analyzed the impact of PPIs on the development of hematologic toxicity in 108 patients who received pemetrexed and carboplatin treatment of nonsquamous non-small cell lung cancer for the first time between January 2011 and June 2015. We established that pemetrexed was transported via hOAT3 (Km = 68.3 ± 11.1 µM). Lansoprazole, rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan inhibited hOAT3-mediated uptake of pemetrexed in a concentration-dependent manner. The inhibitory effect of lansoprazole was much greater than those of other PPIs and the apparent IC50 value of lansoprazole against pemetrexed transport via hOAT3 was 0.57 ± 0.17 µM. The inhibitory type of lansoprazole was competitive. In a retrospective study, multivariate analysis revealed that coadministration of lansoprazole, but not other PPIs, with pemetrexed and carboplatin was an independent risk factor significantly contributing to the development of hematologic toxicity (odds ratio: 10.004, P = 0.005). These findings demonstrated that coadministration of lansoprazole could exacerbate the hematologic toxicity associated with pemetrexed, at least in part, by competitive inhibition of hOAT3. Our results would aid clinicians to make decisions of coadministration drugs to avoid drug interaction-induced side effects for achievement of safe and appropriate chemotherapy with pemetrexed. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  13. Catalytic Ester–Amide Exchange Using Group (IV) Metal Alkoxide–Activator Complexes

    PubMed Central

    Han, Chong; Lee, Jonathan P.; Lobkovsky, Emil; Porco, John A.

    2005-01-01

    A process for preparation of amides from unactivated esters and amines has been developed using a catalytic system comprised of group (IV) metal alkoxides in conjunction with additives including 1-hydroxy-7-azabenzotriazole (HOAt). In general, ester–amide exchange proceeds using a variety of structurally diverse esters and amines without azeotropic reflux to remove the alcohol byproduct. Initial mechanistic studies on the Zr(Ot-Bu)4–HOAt system revealed that the active catalyst is a novel, dimeric zirconium complex as determined by X-ray crystallography. PMID:16011366

  14. Regulation of renal organic anion transporter 3 (SLC22A8) expression and function by the integrity of lipid raft domains and their associated cytoskeleton.

    PubMed

    Srimaroeng, Chutima; Cecile, Jennifer Perry; Walden, Ramsey; Pritchard, John B

    2013-01-01

    In humans and rodents, organic anion transporter 3 (Oat3) is highly expressed on the basolateral membrane of renal proximal tubules and mediates the secretion of exogenous and endogenous anions. Regulation of Oat3 expression and function has been observed in both expression system and intact renal epithelia. However, information on the local membrane environment of Oat3 and its role is limited. Lipid raft domains (LRD; cholesterol-rich domains of the plasma membrane) play important roles in membrane protein expression, function and targeting. In the present study, we have examined the role of LRD-rich membranes and their associated cytoskeletal proteins on Oat3 expression and function. LRD-rich membranes were isolated from rat renal cortical tissues and from HEK-293 cells stably expressing human OAT3 (hOAT3) by differential centrifugation with triton X-100 extraction. Western blots were subsequently analyzed to determine protein expression. In addition, the effect of disruption of LRD-rich membranes was examined on functional Oat3 mediated estrone sulfate (ES) transport in rat renal cortical slices. Cytoskeleton disruptors were investigated in both hOAT3 expressing HEK-293 cells and rat renal cortical slices. Lipid-enriched membranes from rat renal cortical tissues and hOAT3-expressing HEK-293 cells showed co-expression of rOat3/hOAT3 and several lipid raft-associated proteins, specifically caveolin 1 (Cav1), β-actin and myosin. Moreover, immunohistochemistry in hOAT3-expressing HEK-293 cells demonstrated that these LRD-rich proteins co-localized with hOAT3. Potassium iodide (KI), an inhibitor of protein-cytoskeletal interaction, effectively detached cytoskeleton proteins and hOAT3 from plasma membrane, leading to redistribution of hOAT3 into non-LRD-rich compartments. In addition, inhibition of cytoskeleton integrity and membrane trafficking processes significantly reduced ES uptake mediated by both human and rat Oat3. Cholesterol depletion by methyl

  15. Regulation of Renal Organic Anion Transporter 3 (SLC22A8) Expression and Function by the Integrity of Lipid Raft Domains and their Associated Cytoskeleton

    PubMed Central

    Srimaroeng, Chutima; Cecile, Jennifer Perry; Walden, Ramsey; Pritchard, John B.

    2013-01-01

    Background/Aims In humans and rodents, organic anion transporter 3 (Oat3) is highly expressed on the basolateral membrane of renal proximal tubules and mediates the secretion of exogenous and endogenous anions. Regulation of Oat3 expression and function has been observed in both expression system and intact renal epithelia. However, information on the local membrane environment of Oat3 and its role is limited. Lipid raft domains (LRD; cholesterol-rich domains of the plasma membrane) play important roles in membrane protein expression, function and targeting. In the present study, we have examined the role of LRD-rich membranes and their associated cytoskeletal proteins on Oat3 expression and function. Methods LRD-rich membranes were isolated from rat renal cortical tissues and from HEK-293 cells stably expressing human OAT3 (hOAT3) by differential centrifugation with triton X-100 extraction. Western blots were subsequently analyzed to determine protein expression. In addition, the effect of disruption of LRD-rich membranes was examined on functional Oat3 mediated estrone sulfate (ES) transport in rat renal cortical slices. Cytoskeleton disruptors were investigated in both hOAT3 expressing HEK-293 cells and rat renal cortical slices. Results Lipid-enriched membranes from rat renal cortical tissues and hOAT3-expressing HEK-293 cells showed co-expression of rOat3/hOAT3 and several lipid raft-associated proteins, specifically caveolin 1 (Cav1), β-actin and myosin. Moreover, immunohistochemistry in hOAT3-expressing HEK-293 cells demonstrated that these LRD-rich proteins co-localized with hOAT3. Potassium iodide (KI), an inhibitor of protein-cytoskeletal interaction, effectively detached cytoskeleton proteins and hOAT3 from plasma membrane, leading to redistribution of hOAT3 into non-LRD-rich compartments. In addition, inhibition of cytoskeleton integrity and membrane trafficking processes significantly reduced ES uptake mediated by both human and rat Oat3. Cholesterol

  16. Synthesis, crystal structure, characterization and biological activity of 2,5-hexanedione bis(isonicotinylhydrazone) and N-(2,5-dimethyl-1H-pyrrol-1-yl)isonicotinamide complexes.

    PubMed

    Jeragh, Bakir; Ali, Mayada S; El-Asmy, Ahmed A

    2015-01-01

    The reaction between 2,5-hexanedione and isonicotinic acid hydrazide in EtOH gave two products. The ethanol insoluble product was identified as 2,5-hexanedione bis(isonicotinylhydrazone) [HINH] and the soluble ethanol product as N-(2,5-dimethyl-1H-pyrrol-1-yl)isonicotinamide [DINA]. A series of Cr(3+), Fe(3+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), Hg(2+) and Pd(2+) complexes of HINH and Co(2+), Cu(2+), Zn(2+) and Hg(2+) complexes of DINA have been synthesized and structurally characterized. Based on the elemental analysis, mass spectra and molar conductance, the complexes have assigned the proposed imperical formulae. The crystal structures of N-(2,5-dimethyl-1H-pyrrol-1-yl)isonicotinamide and its Zn(2+) and Hg(2+) complexes have been solved by X-ray diffraction having [Zn(DINA)2Cl2] and [Hg(DINA)2Cl2] in a tetrahedral structure. In the DINH complexes, the ligand coordinates as a monodentate through the pyridine nitrogen. On the other hand, HINH behaves as a tetradentate (neutral or binegative) manner with the two metal ions. The magnetic moments and electronic spectra of all complexes provide tetrahedral, square-planar, trigonal biyramid and/or octahedral structure. The thermal decomposition of the complexes revealed the outer and inner solvents as well as the end product. The steady part of [Zn(DINA)2Cl2] and [Hg(DINA)2Cl2] thermograms till 303 and 286 °C indicates the absence of any outside solvents. All compounds have activity against bacteria more than fungi. [Cd4(HINH)Cl8]·3H2O has the highest values.

  17. Bearing Stake Exercise: Sound Speed and other Environmental Variability

    DTIC Science & Technology

    1978-09-01

    xwas sex eral meters-pcr- econd higher than that for other exercise sites, cansed by hinh salinit) PGI\\M aur RSIW in a ielatixely unmixed form. The...NAVAL OCEAN SYSTEMS CENTER IV SAN DIEGO, CALIF~ORNIA 92152 k; [ ¶ NAVAL OCEAN RESEARCH AND DEVELOPMENT ACTIVITY NST L Station, Mississippi 39529...9 -- ’Ž CO~NFD TAL CONFID[NTIAL FOREWORD (C) The BEARING STAKE Exercise was. conducted by the Naval Ocean Systems Center (NOSC) under the

  18. JPRS Report, East Asia. Southeast Asia, Vietnam: TAP CHI CONG SAN, No. 7, July 1989.

    DTIC Science & Technology

    1990-01-29

    in Dam Doi District in Minh Hai Province have demolished the dams and are raising shrimp in the fields. If we invest properly (intensive investment...Pham Ngoc Quang ] .. 2 Human Motivation in Socialist Construction [Le Xuan Vu] 4 Research—Exchange of Opinions Man and Class [Thien Nhan and Hoang...Experience The Vung Tau-Con Dao Special Zone—10 Years [Le Quang Thanh] 13 A Few Thoughts on the Revolution in Production Relationships [Thanh Son

  19. Project: Submicron Phononics I. 1. The Problematics of Phonon Disturbances in d.c. Semiconductor Transport.

    DTIC Science & Technology

    1985-10-01

    ishorens on tne electronic mobiity introduces a nonlinear .slnetro~nic response, because tine phonon-distributions and tnnr, fre thne rates for carrier...transport noneuilibrium phonons to be used in heated displaced and hinh optical excitation of semiconductors. maxwellian (HDM) models of nonlinear transport...N2 E -- "-hr, ’ltrIut t.i iih VII T.. - -" - 3.5r-o 30 N 5310 % .0TL30K n. - , - - 10 tm/ FLOW- CHART MAIN PROGAM 1 A- I A STA ~ B Q L , (D ?PE AUtM

  20. Southeast Asia Report

    DTIC Science & Technology

    1987-03-17

    Indonesia ," according to Sukarno, must be nationalism, "neither Javanese nationalism, nor Sumatran nationalism, nor the nationalism of Borneo, or of...1000 North Glebe Road, Arlington, Virginia 22201. JPRS-SEA-87-038 17 MARCH 1987 SOUTHEAST ASIA REPORT CONTENTS INDONESIA LAOS ’Extremist...Assistance (Tran Ngoc Chuc; TAP CHI HOAT DONG KHOA HOC, Dec 86) 113 /9987 d - INDONESIA •EXTREMIST’ ISLAMIC BOARDING SCHOOL UNDERGOING

  1. Immunological Interrelationships of Coliform Heat-Labile and Heat-Stable Enterotoxins

    DTIC Science & Technology

    1981-09-01

    FA, Engert RF: Immunological interrelationships between cholera toxin and the heat -labile and hoat-stable enterotoxins of coliform bacteria . Infec...When Date Enterd) -3- SUMMARY These investigations (a) established the fact that species of coliform bacteria other than ETEC strains of E. coZi...elaborate enterotoxins which alter gastrointestinal physiology, and (b) showed that immunization with either E. coli (ETEC) LT or ST toxin arouses an

  2. Inhibitory effect of JBP485 on renal excretion of acyclovir by the inhibition of OAT1 and OAT3.

    PubMed

    Ye, Jianghao; Liu, Qi; Wang, Changyuan; Meng, Qiang; Peng, Jinyong; Sun, Huijun; Kaku, Taiichi; Liu, Kexin

    2012-09-29

    The purpose is to investigate whether the targets of drug-drug interactions (DDIs) between JBP485 and acyclovir are OAT1 and OAT3 in kidney. Plasma concentration and accumulative urinary excretion of acyclovir in vivo, uptake of acyclovir in kidney slices and uptake of acyclovir in human (h) OAT1/ hOAT3-human embryonic kidney (HEK) 293 cells in vitro were performed to examine the effect of JBP485 on urinary excretion of acyclovir. The plasma concentration of acyclovir was increased markedly and accumulative urinary excretion and renal clearance of acyclovir were decreased significantly after intravenous administration of acyclovir in combination with JBP485. JBP485 (a substrate for OAT1 and OAT3), p-aminohippurate (PAH) (a substrate for OAT1) and benzylpenicillin (PCG) (a substrate for OAT3) could decrease the uptake of acyclovir in kidney slices and in hOAT1-/hOAT3-HEK293 cells. These results suggest that JBP485 inhibits the renal excretion of acyclovir by inhibiting renal transporters OAT1 and OAT3 in vivo and in vitro. Our results indicate the possibility of DDI between dipeptide and acyclovir.

  3. Controlled rotation mechanism of DNA strand exchange by the Hin serine recombinase

    PubMed Central

    Xiao, Botao; McLean, Meghan M.; Lei, Xianbin; Marko, John F.; Johnson, Reid C.

    2016-01-01

    DNA strand exchange by serine recombinases has been proposed to occur by a large-scale rotation of halves of the recombinase tetramer. Here we provide the first direct physical evidence for the subunit rotation mechanism for the Hin serine invertase. Single-DNA looping assays using an activated mutant (Hin-H107Y) reveal specific synapses between two hix sites. Two-DNA “braiding” experiments, where separate DNA molecules carrying a single hix are interwound, show that Hin-H107Y cleaves both hix sites and mediates multi-step rotational relaxation of the interwinding. The variable numbers of rotations in the DNA braid experiments are in accord with data from bulk experiments that follow DNA topological changes accompanying recombination by the hyperactive enzyme. The relatively slow Hin rotation rates, combined with pauses, indicate considerable rotary friction between synapsed subunit pairs. A rotational pausing mechanism intrinsic to serine recombinases is likely to be crucial for DNA ligation and for preventing deleterious DNA rearrangements. PMID:27032966

  4. Controlled rotation mechanism of DNA strand exchange by the Hin serine recombinase.

    PubMed

    Xiao, Botao; McLean, Meghan M; Lei, Xianbin; Marko, John F; Johnson, Reid C

    2016-04-01

    DNA strand exchange by serine recombinases has been proposed to occur by a large-scale rotation of halves of the recombinase tetramer. Here we provide the first direct physical evidence for the subunit rotation mechanism for the Hin serine invertase. Single-DNA looping assays using an activated mutant (Hin-H107Y) reveal specific synapses between two hix sites. Two-DNA "braiding" experiments, where separate DNA molecules carrying a single hix are interwound, show that Hin-H107Y cleaves both hix sites and mediates multi-step rotational relaxation of the interwinding. The variable numbers of rotations in the DNA braid experiments are in accord with data from bulk experiments that follow DNA topological changes accompanying recombination by the hyperactive enzyme. The relatively slow Hin rotation rates, combined with pauses, indicate considerable rotary friction between synapsed subunit pairs. A rotational pausing mechanism intrinsic to serine recombinases is likely to be crucial for DNA ligation and for preventing deleterious DNA rearrangements.

  5. Lipolysis and thermogenesis in adipose tissues as new potential mechanisms for metabolic benefits of dietary fiber.

    PubMed

    Han, Shu-Fen; Jiao, Jun; Zhang, Wei; Xu, Jia-Ying; Zhang, Weiguo; Fu, Chun-Ling; Qin, Li-Qiang

    2017-01-01

    Dietary fiber consumption is associated with reduced risk for the development of noncommunicable diseases. The aim of the present study was to evaluate the effects of cereal dietary fiber on the levels of proteins involved in lipolysis and thermogenesis in white adipose tissue (WAT) and brown adipose tissue (BAT) of C57 BL/6 J mice fed a high-fat diet (HFD). Male C57BL/6 J mice were fed normal chow diet (Chow), HFD, HFD plus oat fiber (H-oat), or HFD plus wheat bran fiber (H-wheat) for 24 wk. Body weight and food intake were recorded weekly. Serum adiponectin was assayed by an enzyme-linked immunosorbent assay kit. Western blotting was used to assess the protein expressions of adipose triacylglycerol lipase (ATGL), cAMP protein kinase catalytic subunit (cAMP), protein kinase A (PKA), perilipin A, hormone-sensitive lipase (HSL), uncoupling protein 1 (UCP1), fibroblast growth factor 21 (FGF-21), β3-adrenergic receptor (β3AR), and proliferator-activated receptor gamma coactivator-1 α (PGC-1 α) in the WAT and BAT. At the end of the feeding period, body and adipose tissues weight in both H-oat and H-wheat groups were lower than in the HFD group. Mice in the H-oat and H-wheat groups showed an increasing trend in serum adiponectin level. Compared with the HFD group, cereal dietary fiber increased protein expressions involved in the lipolysis and browning process. Compared with the H-wheat group, H-oat was more effective in protein expressions of PKA, PGC-1 α, and UCP1 of the WAT samples. Compared with the H-oat group, H-wheat was more effective in protein expressions of PKA, ATGL, UCP1, β3AR, and FGF-21 of the BAT samples. Taken together, our results suggested that cereal dietary fiber enhanced adipocyte lipolysis by the cAMP-PKA-HSL pathway and promoted WAT browning by activation of UCP1, and consequently reduced visceral fat mass in response to HFD feeding. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Organic Anion Transporter 3 (Oat3/Slc22a8) Interacts with Carboxyfluoroquinolones and Deletion Increases Systemic Exposure to Ciprofloxacin

    PubMed Central

    VanWert, Adam L.; Srimaroeng, Chutima; Sweet, Douglas H.

    2010-01-01

    Carboxyfluoroquinolones, such as ciprofloxacin, are employed for numerous infectious diseases. Renal secretion is a major determinant of their systemic and urinary concentration, but the specific transporters involved are virtually unknown. In vivo studies implicate the organic anion transporter (OAT) family as a pivotal component of carboxyfluoroquinolone renal secretion. Therefore, this study identified the specific renal basolateral OAT(s) involved, thereby highlighting potential sources of carboxyfluoroquinolone-drug interactions and variable efficacy. Two heterologous expression systems, Xenopus laevis oocytes and cell monolayers, were employed to determine the roles of murine and human renal basolateral mOat1/hOAT1 and mOat3/hOAT3. Ciprofloxacin was transported by mOat3 in both systems (Km, 70±6 μM), and demonstrated no interaction with mOat1 or hOAT1. Furthermore, ciprofloxacin, norfloxacin, ofloxacin, and gatifloxacin exhibited concentration-dependent inhibition of transport on mOat3 in cells, with inhibition constants of 198±39, 558±75, 745±165, and 941±232 μM, respectively. Ciprofloxacin and gatifloxacin also inhibited hOAT3. Subsequently, in vivo elimination of ciprofloxacin was assessed in wild-type and Oat3 null mice (Oat3(-/-)). Oat3(-/-) mice exhibited significantly elevated plasma levels of ciprofloxacin at clinically-relevant concentrations (P<0.05, males; P<0.01, females). Oat3(-/-) mice also demonstrated a reduced volume of distribution (27%, P<0.01, males; 14%, P<0.01, females) and increased area under the concentration-time curve (25%, P<0.05, males; 33%, P<0.01, females). Female Oat3(-/-) mice had a 35% (P<0.01) reduction in total clearance of ciprofloxacin relative to wild-type. Additionally, putative ciprofloxacin metabolites were significantly elevated in Oat3(-/-) mice. The present findings indicate that polymorphisms of, and drug interactions on, hOAT3 may influence carboxyfluoroquinolone efficacy, especially in urinary tract

  7. Enhanced Reactivity in Nucleophilic Acyl Substitution Ion/Ion Reactions Using Triazole-Ester Reagents

    NASA Astrophysics Data System (ADS)

    Bu, Jiexun; Peng, Zhou; Zhao, Feifei; McLuckey, Scott A.

    2017-02-01

    The acyl substitution reactions between 1-hydroxy-7-aza-benzotriazole (HOAt)/1-hydroxy-benzotriazole (HOBt) ester reagents and nucleophilic side chains on peptides have been demonstrated in the gas phase via ion/ion reactions. The HOAt/HOBt ester reagents were synthesized in solution and ionized via negative nano-electrospray ionization. The anionic reagents were then reacted with doubly protonated model peptides containing amines, guanidines, and imidazoles in the gas phase. The complexes formed in the reaction cell were further probed with ion trap collision induced dissociation (CID) yielding either a covalently modified analyte ion or a proton transfer product ion. The covalent reaction yield of HOAt/HOBt ester reagents was demonstrated to be higher than the yield with N-hydroxysuccinimide (NHS) ester reagents over a range of equivalent conditions. Density functional theory (DFT) calculations were performed with a primary amine model system for both triazole-ester and NHS-ester reactants, which indicated a lower transition state barrier for the former reagent, consistent with experiments. The work herein demonstrates that the triazole-ester reagents are more reactive, and therefore less selective, than the analogous NHS-ester reagent. As a consequence, the triazole-ester reagents are the first to show efficient reactivity with unprotonated histidine residues in the gas phase. For all nucleophilic sites and all reagents, covalent reactions are favored under long time, low amplitude activation conditions. This work presents a novel class of reagents capable of gas-phase conjugation to nucleophilic sites in analyte ions via ion/ion chemistry.

  8. Enhanced Reactivity in Nucleophilic Acyl Substitution Ion/Ion Reactions Using Triazole-Ester Reagents

    NASA Astrophysics Data System (ADS)

    Bu, Jiexun; Peng, Zhou; Zhao, Feifei; McLuckey, Scott A.

    2017-07-01

    The acyl substitution reactions between 1-hydroxy-7-aza-benzotriazole (HOAt)/1-hydroxy-benzotriazole (HOBt) ester reagents and nucleophilic side chains on peptides have been demonstrated in the gas phase via ion/ion reactions. The HOAt/HOBt ester reagents were synthesized in solution and ionized via negative nano-electrospray ionization. The anionic reagents were then reacted with doubly protonated model peptides containing amines, guanidines, and imidazoles in the gas phase. The complexes formed in the reaction cell were further probed with ion trap collision induced dissociation (CID) yielding either a covalently modified analyte ion or a proton transfer product ion. The covalent reaction yield of HOAt/HOBt ester reagents was demonstrated to be higher than the yield with N-hydroxysuccinimide (NHS) ester reagents over a range of equivalent conditions. Density functional theory (DFT) calculations were performed with a primary amine model system for both triazole-ester and NHS-ester reactants, which indicated a lower transition state barrier for the former reagent, consistent with experiments. The work herein demonstrates that the triazole-ester reagents are more reactive, and therefore less selective, than the analogous NHS-ester reagent. As a consequence, the triazole-ester reagents are the first to show efficient reactivity with unprotonated histidine residues in the gas phase. For all nucleophilic sites and all reagents, covalent reactions are favored under long time, low amplitude activation conditions. This work presents a novel class of reagents capable of gas-phase conjugation to nucleophilic sites in analyte ions via ion/ion chemistry.

  9. An Investigation of a Thermal Ice-Prevention System for a C-40 Cargo Airplane. 1 - Analysis of the Thermal Design for Wings, Empennage and Windshield

    DTIC Science & Technology

    1945-02-01

    clents could tie calc air flow rate to obt rise, and (3) the ca drops to ascertain t These phases arc dis tlons of tho roport. freedom of design. An...rate and the pressure drop to pecificatlon . The analysis therefore orininatlon of (l) the boundary-layer which the external hoat-transfor coeffl...above arblent air from the heated-air source was assumed to bo 300° F. If a 10° air-temperature drop is assumed tetveen the heated-air source and

  10. Trip Report of Field Search for Exercise Desert Rock Documentation Conducted by Representatives of The Adjutant General 18 June 1978 to 14 July 1978

    DTIC Science & Technology

    1978-08-04

    tna e:endituro of 17,929 =an hours and 61.1. aquipont unours. Tho clean up of destroyed oqulpMent in display aro-.s for Exercise DEvSIST ROCK V and AFS...Shot ,a .5 vmre offoctive. " 3’rocedurot Hoat "cnsitive paper ".’i plocad In positions exposed to direct thermal radiation and in po.i- (tons shiolded...to measure radiation in the trenches. At L.zX yards and 200 yards papers were exposed in a horizontal position on the surface of the grotud vith no

  11. JPRS Report, East Asia, Southeast Asia

    DTIC Science & Technology

    2007-11-02

    Food Problems 45 Feed Shortage Affects Livestock Production 45 Peasants in Debt to State ™ March 1988 TAP CHI HOAT DONG KHOA HOC Table of Contents...slowly burning over issues that threaten to divide us, to set us against one another, to keep us in perpetual bondage under a foreign power—yet the...cannot register real economic progress for as long as it has no clear-cut policy on debt -servicing. We continue to spend 50 percent of our export

  12. A Comparative Study of Weights and Sizes of Flat-Plate Exhaust-Gas-to-Air Heat Exchangers with and without Fins

    DTIC Science & Technology

    1947-07-01

    tests of both heat exchangers, air or-d exhauj’t-gaa flow rates wtre mnr.sur’sd with venturi motors located downstream from the heat exchanger. Air...cas— flow ratoa aa di.torrin.jd froo the venturi notor. TEST rBOCEDUPE Flii^it toatJn3 of tho host exchangers wr.3 conduced to evaluate their tho...Static pressures upstrean and downctroTa frca tho hoat- oxchangor core wore raacurod with etat5c tubos , and air flow rates ware raacurcd vith n vonturi

  13. War time experiences of triage and resuscitation: Australian Army nurses in the Vietnam War, 1967-1971.

    PubMed

    Biedermann, N E; Harvey, N R

    2001-07-01

    The experiences of nurses in war is prolifically described in the North American scholarly literature, and in the Australian nursing literature to a lesser extent. The literature describes the plights and achievements of nurses caring for soldiers and civilians often under the most undesirable of circumstances. A central focus of war time nursing is the resuscitation of critically wounded soldiers. This paper addresses the experiences of the Australian Army nurses who were involved in the triage and resuscitation of critically wounded allied and enemy soldiers in the Vietnam War between 1967 and 1971. As part of a research study to explore and analyse the nature of nursing work in the Vietnam War, seventeen Vietnam veteran nurses were interviewed about their experiences. This paper explores the progression of the triage department in the Australian military hospital in Vung Tau, and it highlights that the majority of the nurses who took part in this study were clinically unprepared, particularly as emergency nurses.

  14. Transport of cimetidine by flounder and human renal organic anion transporter 1.

    PubMed

    Burckhardt, Birgitta C; Brai, Stefan; Wallis, Sonke; Krick, Wolfgang; Wolff, Natascha A; Burckhardt, Gerhard

    2003-03-01

    The H(2)-receptor antagonist cimetidine is efficiently excreted by the kidneys. In vivo studies indicated an interaction of cimetidine not only with transporters for basolateral uptake of organic cations but also with those involved in excretion of organic anions. We therefore tested cimetidine as a possible substrate of the organic anion transporters cloned from winter flounder (fROAT) and from human kidney (hOAT1). Uptake of [(3)H]cimetidine into fROAT-expressing Xenopus laevis oocytes exceeded uptake into control oocytes. At -60-mV clamp potential, 1 mM cimetidine induced an inward current, which was smaller than that elicited by 0.1 mM PAH. Cimetidine concentrations exceeding 0.1 mM decreased PAH-induced inward currents, indicating interaction with the same transporter. At pH 6.6, no current was seen with 0.1 mM cimetidine, whereas at pH 8.6 a current was readily detectable, suggesting preferential translocation of uncharged cimetidine by fROAT. Oocytes expressing hOAT1 also showed [(3)H]cimetidine uptake. These data reveal cimetidine as a substrate for fROAT/hOAT1 and suggest that organic anion transporters contribute to cimetidine excretion in proximal tubules.

  15. Peptide cotransporter 1 in intestine and organic anion transporters in kidney are targets of interaction between JBP485 and lisinopril in rats.

    PubMed

    Guo, Xinjin; Meng, Qiang; Liu, Qi; Wang, Changyuan; Mao, Qi; Sun, Huijun; Peng, Jinyong; Kaku, Taiichi; Liu, Kexin

    2012-01-01

    The purpose of this study was to clarify the pharmacokinetic mechanism of interaction between JBP485 (cyclo-trans-4-L-hydroxyprolyl-L-serine, a dipeptide with antihepatitis activity) and lisinopril (an angiotensin-converting enzyme inhibitor) in vitro and in vivo. When JBP485 and lisinopril were administered orally simultaneously, the plasma concentrations of the two drugs were decreased significantly, but few changes were observed after simultaneous intravenous administration of the two drugs. The uptake of JBP485 and lisinopril in everted intestinal sacs and in HeLa cells transfected with human peptide cotransporter 1 (PEPT1), as well as absorption of JBP485 and lisinopril after jejunal perfusion were reduced after simultaneous drug administration, which suggested that the first target of drug interaction was PEPT1 in the intestine during the absorption process. The cumulative urinary excretions and renal clearance of the two drugs were decreased after intravenous co-administration, while uptakes of the two drugs in kidney slices and hOAT1/hOAT3-transfected HEK293 cells were decreased. These results indicated that the second target of drug-drug interaction was located in the kidney. These findings confirmed that the pharmacokinetic mechanism of interaction between JBP485 and lisinopril could be explained by their inhibition of the same transporters in the intestinal mucosa (PEPT1) and kidneys (OATs).

  16. Neutrophil extracellular traps can activate alternative complement pathways.

    PubMed

    Wang, H; Wang, C; Zhao, M-H; Chen, M

    2015-09-01

    The interaction between neutrophils and activation of alternative complement pathway plays a pivotal role in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). ANCAs activate primed neutrophils to release neutrophil extracellular traps (NETs), which have recently gathered increasing attention in the development of AAV. The relationship between NETs and alternative complement pathway has not been elucidated. The current study aimed to investigate the relationship between NETs and alternative complement pathway. Detection of components of alternative complement pathway on NETs in vitro was assessed by immunostain and confocal microscopy. Complement deposition on NETs were detected after incubation with magnesium salt ethyleneglycol tetraacetic acid (Mg-EGTA)-treated human serum. After incubation of serum with supernatants enriched in ANCA-induced NETs, levels of complement components in supernatants were measured by enzyme-linked immunosorbent assay (ELISA). Complement factor B (Bb) and properdin deposited on NETs in vitro. The deposition of C3b and C5b-9 on NETs incubated with heat-inactivated normal human serum (Hi-NHS) or EGTA-treated Hi-NHS (Mg-EGTA-Hi-NHS) were significantly less than that on NETs incubated with NHS or EGTA-treated NHS (Mg-EGTA-NHS). NETs induced by ANCA could activate the alternative complement cascade in the serum. In the presence of EGTA, C3a, C5a and SC5b-9 concentration decreased from 800·42 ± 244·81 ng/ml, 7·68 ± 1·50 ng/ml, 382·15 ± 159·75 ng/ml in the supernatants enriched in ANCA induced NETs to 479·07 ± 156·2 ng/ml, 4·86 ± 1·26 ng/ml, 212·65 ± 44·40 ng/ml in the supernatants of DNase I-degraded NETs (P < 0·001, P = 0·008, P < 0·001, respectively). NETs could activate the alternative complement pathway, and might thus participate in the pathogenesis of AAV. © 2015 British Society for Immunology.

  17. Neutrophil extracellular traps can activate alternative complement pathways

    PubMed Central

    Wang, H; Wang, C; Zhao, M-H; Chen, M

    2015-01-01

    The interaction between neutrophils and activation of alternative complement pathway plays a pivotal role in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). ANCAs activate primed neutrophils to release neutrophil extracellular traps (NETs), which have recently gathered increasing attention in the development of AAV. The relationship between NETs and alternative complement pathway has not been elucidated. The current study aimed to investigate the relationship between NETs and alternative complement pathway. Detection of components of alternative complement pathway on NETs in vitro was assessed by immunostain and confocal microscopy. Complement deposition on NETs were detected after incubation with magnesium salt ethyleneglycol tetraacetic acid (Mg-EGTA)-treated human serum. After incubation of serum with supernatants enriched in ANCA-induced NETs, levels of complement components in supernatants were measured by enzyme-linked immunosorbent assay (ELISA). Complement factor B (Bb) and properdin deposited on NETs in vitro. The deposition of C3b and C5b-9 on NETs incubated with heat-inactivated normal human serum (Hi-NHS) or EGTA-treated Hi-NHS (Mg-EGTA-Hi-NHS) were significantly less than that on NETs incubated with NHS or EGTA-treated NHS (Mg-EGTA-NHS). NETs induced by ANCA could activate the alternative complement cascade in the serum. In the presence of EGTA, C3a, C5a and SC5b-9 concentration decreased from 800·42 ± 244·81 ng/ml, 7·68 ± 1·50 ng/ml, 382·15 ± 159·75 ng/ml in the supernatants enriched in ANCA induced NETs to 479·07 ± 156·2 ng/ml, 4·86 ± 1·26 ng/ml, 212·65 ± 44·40 ng/ml in the supernatants of DNase I-degraded NETs (P < 0·001, P = 0·008, P < 0·001, respectively). NETs could activate the alternative complement pathway, and might thus participate in the pathogenesis of AAV PMID:25963026

  18. Optimized Reaction Conditions for Amide Bond Formation in DNA-Encoded Combinatorial Libraries.

    PubMed

    Li, Yizhou; Gabriele, Elena; Samain, Florent; Favalli, Nicholas; Sladojevich, Filippo; Scheuermann, Jörg; Neri, Dario

    2016-08-08

    DNA-encoded combinatorial libraries are increasingly being used as tools for the discovery of small organic binding molecules to proteins of biological or pharmaceutical interest. In the majority of cases, synthetic procedures for the formation of DNA-encoded combinatorial libraries incorporate at least one step of amide bond formation between amino-modified DNA and a carboxylic acid. We investigated reaction conditions and established a methodology by using 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide, 1-hydroxy-7-azabenzotriazole and N,N'-diisopropylethylamine (EDC/HOAt/DIPEA) in combination, which provided conversions greater than 75% for 423/543 (78%) of the carboxylic acids tested. These reaction conditions were efficient with a variety of primary and secondary amines, as well as with various types of amino-modified oligonucleotides. The reaction conditions, which also worked efficiently over a broad range of DNA concentrations and reaction scales, should facilitate the synthesis of novel DNA-encoded combinatorial libraries.

  19. Roles of organic anion transporters in the renal excretion of perfluorooctanoic acid.

    PubMed

    Nakagawa, Hatsuki; Hirata, Taku; Terada, Tomohiro; Jutabha, Promsuk; Miura, Daisaku; Harada, Kouji H; Inoue, Kayoko; Anzai, Naohiko; Endou, Hitoshi; Inui, Ken-Ichi; Kanai, Yoshikatsu; Koizumi, Akio

    2008-07-01

    Perfluorooctanoic acid, an environmental contaminant, is found in both wild animals and human beings. There are large species and sex differences in the renal excretion of perfluorooctanoic acid. In the present study, we aimed to characterize organic anion transporters 1-3 (OAT1-3) in human beings and rats to investigate whether the species differences in the elimination kinetics of perfluorooctanoic acid from the kidneys can be attributed to differences in the affinities of these transporters for perfluorooctanoic acid. We used human (h) and rat (r) OAT transient expression cell systems and measured the [(14)C] perfluorooctanoic acid transport activities. Both human and rat OAT1 and OAT3 mediated perfluorooctanoic acid transport to similar degrees. Specifically, the kinetic parameters, K(m), were 48.0 +/- 6.4 microM for h OAT1; 51.0 +/- 12.0 microM for rOAT1; 49.1 +/- 21.4 microM for hOAT3 and 80.2 +/- 17.8 microM for rOAT3, respectively. These data indicate that both human and rat OAT1 and OAT3 have high affinities for perfluorooctanoic acid and that the species differences in its renal elimination are not attributable to affinity differences in these OATs between human beings and rats. In contrast, neither hOAT2 nor rOAT2 transported perfluorooctanoic acid. In conclusion, OAT1 and OAT3 mediated perfluorooctanoic acid transport in vitro, suggesting that these transporters also transport perfluorooctanoic acid through the basolateral membrane of proximal tubular cells in vivo in both human beings and rats. Neither human nor rat OAT2 mediated perfluorooctanoic acid transport. Collectively, the difference between the perfluorooctanoic acid half-lives in human beings and rats is not likely to be attributable to differences in the affinities of these transporters for perfluorooctanoic acid.

  20. The inhibition of human multidrug and toxin extrusion 1 is involved in the drug-drug interaction caused by cimetidine.

    PubMed

    Matsushima, Soichiro; Maeda, Kazuya; Inoue, Katsuhisa; Ohta, Kin-ya; Yuasa, Hiroaki; Kondo, Tsunenori; Nakayama, Hideki; Horita, Shigeru; Kusuhara, Hiroyuki; Sugiyama, Yuichi

    2009-03-01

    Cimetidine is known to cause drug-drug interactions (DDIs) with organic cations in the kidney, and a previous clinical study showed that coadministration of cimetidine or probenecid with fexofenadine (FEX) decreased its renal clearance. FEX was taken up into human kidney by human organic anion transporter (hOAT) 3 (SLC22A8), but the mechanism of its luminal efflux has not been clarified. The present study examined the molecular mechanism of these DDIs. Saturable uptake of FEX was observed in human kidney slices, with K(m) and V(max) values of 157+/-7 microM and 418+/-16 nmol/15 min/g kidney, respectively. Cimetidine only slightly inhibited its uptake even at 100 microM, far greater than its clinically relevant concentration, whereas 10 microM probenecid markedly inhibited its uptake. As candidate transporters for the luminal efflux of FEX, we focused on human multidrug and toxin extrusions MATE1 (SLC47A1) and MATE2-K (SLC47A2). Saturable uptake of FEX could be observed in human embryonic kidney 293 cells expressing human MATE1 (hMATE1), whereas hMATE2-K-specific uptake of FEX was too small to conduct its further kinetic analysis. The hMATE1-mediated uptake clearance of FEX was inhibited by cimetidine in a concentration-dependent manner, and it was decreased to 60% of the control value in the presence of 3 microM cimetidine. Taken together, our results suggest that the DDI of FEX with probenecid can be explained by the inhibition of renal uptake mediated by hOAT3, whereas the DDI with cimetidine is mainly caused by the inhibition of hMATE1-mediated efflux of FEX rather than the inhibition of its renal uptake process.

  1. Viet Nam steps up offshore E and D push

    SciTech Connect

    Not Available

    1992-06-22

    This paper reports on Viet Nam's offshore exploration and development. Hanoi tentatively awarded three of five remaining blocks of prime offshore South China Sea acreage to companies from Europe and the Far East, with a fourth such award reported imminent. And state owned Petrovietnam signed a production sharing contract (PSC) covering acreage in the same area to a combine of British Petroleum Co. plc and Norway's Den norske stats oljeselskap AS. Retention of one block in the area covered by Viet Nam's second bidding round fueled speculation Hanoi is holding it in reserve for U.S. companies to enter bidding, pending easing of U.S. trade sanctions against Viet Nam, Agence France France (AFP) reported. Second round blocks have been carved from a concession held by Vietsovpetro, a joint venture of Petrovietnam and the former Soviet Union. All are in the southern Con Sun basin of the South China Sea off the port of Vung Tao and on trend with Viet Nam's only producing oil fields.

  2. Larval morphology and complex vocal repertoire of Rhacophorus helenae (Anura: Rhacophoridae), a rare flying frog from Vietnam.

    PubMed

    Vassilieva, Anna B; Gogoleva, Svetlana S; Poyarkov, Nikolay A Jr

    2016-06-24

    We present new data on the distribution, reproduction, larval morphology and vocalization of Rhacophorus helenae (Rhacophoridae), a narrowly distributed frog from southern Vietnam. Two new populations of R. helenae were discovered during field surveys in the lowland monsoon forests in Dong Nai and Ba Ria-Vung Tau provinces in 2010-2013. Spawning was observed in May 2013. Egg clutches containing small (2.3±0.1 mm) unpigmented eggs were embedded in a foam nest and suspended high on trees above temporary ponds. The tadpoles of R. helenae have a morphology typical of pond-dwelling Rhacophorus larvae with a moderate tail length and a labial tooth row formula of 5(2-5)/3. Postmetamorphic juveniles differed from adult frogs in the features of their coloration and less developed webbing. The complex vocal repertoire of R. helenae included five types of tonal, wideband and pulsed calls and several transitional signal types differentiated by frequency and amplitude parameters. Calls were uttered as singular signals (pulsed calls) or within non-stereotyped series of variable duration (other call types). The complex structure of the advertisement call markedly distinguishes R. helenae from other members of the Rhacophorus reinwardtii species complex.

  3. Scenario-based tsunami hazard assessment for the coast of Vietnam from the Manila Trench source

    NASA Astrophysics Data System (ADS)

    Hong Nguyen, Phuong; Cong Bui, Que; Ha Vu, Phuong; The Pham, Truyen

    2014-11-01

    This paper assesses the impact of tsunamis in the East Vietnam Sea potentially originated from a giant rupture along the Manila Trench to the Vietnamese coast. Tsunami heights and arrival times to the major forecast points along the Vietnamese coast are computed using COMCOT model. The results of the worst case scenario (Mw = 9.3) and two extreme scenarios were used to assess the tsunami hazards. The simulation results show that Vietnamese coast can be divided into three parts with different levels of tsunami hazard. The highest threat exists along the coasts of Central and North-Central Vietnam, from Quang Binh to Ba Ria - Vung Tau provinces, with maximum wave height of 18 m observed near Quang Ngai coast, and a tsunami would reach this coastline in two hours at the earliest. The northern coastal zone of Vietnam has lower tsunami hazard. In the worst case scenario, maximum amplitudes of tsunami waves at Hai Phong sea port and Nam Dinh city, North Vietnam, are 3.5 m and 3.7 m, respectively, while the travel times to these sites are much longer, over 8 h. The southern coastal zone of Vietnam has very low tsunami hazard. In the worst case scenario, the maximum amplitude at Ca Mau is 0.12 m, while the travel time is over 10 h.

  4. Weaver ant role in cashew orchards in Vietnam.

    PubMed

    Peng, Renkang; Lan, La Pham; Christian, Keith

    2014-08-01

    Cashew (Anacardium occidentale L.) is a very important source of income for more than 200,000 farmer households in Vietnam. The present cashew productivity in Vietnam is low and unstable, and pest damage is partly responsible for this. Cashew farmers rely on pesticides to minimize the damage, resulting in adverse impacts on farm environment and farmers' health. Weaver ants (Oecophylla spp) are effective biocontrol agents of a range of cashew insect pests in several cashew-growing countries, and these ants are widely distributed in Vietnam. The aim of this study is to evaluate the potential of weaver ants in cashew orchards in Vietnam. Field surveys and field experiment were conducted in five cashew orchards from July 2006 to January 2008 in Binh Phuoc, Dong Nai, and Ba Ria Vung Tau provinces, Vietnam. Based on the field surveys, the most important pests that damage flushing foliar and floral shoots and young cashew fruits and nuts were mosquito bugs, brown shoot borers, blue shoot borers, and fruit-nut borers. The damage caused by each of these pests was significantly lower on trees with weaver ants compared with trees without the ants, showing that the ants were able to keep these pest damages under the control threshold. Regular monitoring of the field experiment showed that weaver ants were similar to insecticides for controlling mosquito bugs, blue shoot borers, fruit-nut borers, leaf rollers, and leaf miners. Aphids did not become major pests in plot with weaver ants. To manage insect pest assemblage in cashew orchards, an integrated pest management using weaver ants as a major component is discussed.

  5. Functional expression of pig renal organic anion transporter 3 (pOAT3).

    PubMed

    Hagos, Yohannes; Braun, Isabella M; Krick, Wolfgang; Burckhardt, Gerhard; Bahn, Andrew

    2005-05-01

    With the cloning of pig renal organic anion transporter 1 (pOAT1) (Biochimie 84 (2002) 1219) we set up a model system for comparative studies of cloned and natively isolated membrane located transport proteins. Meanwhile, another transport protein involved in p-aminohippurate (PAH) uptake on the basolateral side of the proximal tubule cells was identified, designated organic anion transporter 3 (OAT3). To explore the contribution of pOAT1 to the PAH clearance in comparison to OAT3, it was the aim of this study to extend our model by cloning of the pig ortholog of OAT3. Sequence comparisons of human organic anion transporter 3 (hOAT3) with the expressed sequence tag (EST) database revealed a clone and partial sequence of the pig renal organic anion transporter 3 (pOAT3) ortholog. Sequencing of the entire open reading frame resulted in a protein of 543 amino acid residues encoded by 1632 base pairs (EMBL Acc. No. AJ587003). It showed high homologies of 81%, 80%, 76%, and 77% to the human, rabbit, rat, and mouse OAT3, respectively. A functional characterization of pOAT3 in Xenopus laevis oocytes yielded an apparent Km (Kt) for [3H]estrone sulfate of 7.8 +/- 1.3 microM. Moreover, pOAT3 mediated [3H]estrone sulfate uptake was almost abolished by 0.5 mM of glutarate, dehydroepiandosterone sulfate, or probenecid consistent with the hallmarks of OAT3 function.

  6. Convergent Synthesis of Novel Muramyl Dipeptide Analogues: Inhibition of Porphyromonas gingivalis-Induced Pro-inflammatory Effects by High Doses of Muramyl Dipeptide.

    PubMed

    Cai, Bin; Panek, James S; Amar, Salomon

    2016-07-28

    Porphyromonas gingivalis (P.g.)-induced TNF-α can be affected by muramyl dipeptide (MDP) in a biphasic concentration-dependent manner. We found that in P.g.-exposed macrophages, treatment with 10 μg/mL of MDP (MDP-low) up-regulated TNF-α by 29%, while 100 μg/mL or higher (MDP-high) significantly decreased it (16% to 38%). MDP-high was found to affect the ubiquitin-editing enzyme A20 and activator protein 1 (AP1). An AP1 binding site was found in the promoter region of A20. A20 promoter activity was up-regulated after transfection of AP1 cDNA in cells. Four analogues of MDP (3-6) were prepared through a convergent strategy involving the synthesis of two unique carbohydrate fragments, 7a and 7b, using the peptide coupling reagents, EDCI and HOAt. Analogue 4 improved MDP function and P.g.-induced activities. We propose a new signaling pathway for TNF-α induction activated after exposing macrophages to both P.g. and MDP-high or analogue 4.

  7. Multiple synthesis by the multipin method as a methodological tool.

    PubMed

    Bray, A M; Valerio, R M; DiPasquale, A J; Greig, J; Maeji, N J

    1995-01-01

    The multipin method of peptide synthesis is demonstrated as a potent methodological tool, where large numbers of comparative studies can be performed concurrently. Two studies are presented. In each study, the test peptides were simultaneously synthesized, and the products examined by high throughput ion spray mass spectrometry and reverse-phase HPLC. In the first study, comprising 24 experiments, peptides 1 (AELFSTHYLAFKEDYSQ-NH2) and 2 (LKDFRVYFREGRDQLWKGPG-NH2) were prepared using Fmoc-Axx/BOP/HOBt/NMM [100 : 100 : 100 : 150 mM) and Fmoc-AXX/HATU/HOAt/NMM (100 : 100 : 100 : 150 nM) with 60, 90 and 120 min coupling times. The two reagent combinations were found to give comparable results. The second study compared the N-terminal coupling of Fmoc-Asn-OH, Fmoc-Asn(Mbh)-OH, Fmoc-Asn(Mtt)-OH, Fmoc-Asn(Tmob)-OH and Fmoc-Asn(Trt)-OH in the synthesis of seven test peptides: 3, NVQAAIDYIG-cyclo(KP): 4. NTVQAAIDYIG-cyclo(KP): 5. NRVYVHPFNL: 6. NRVYVHPFHL: 7. NEAYVHDAPVRSLN: 8. NQLVVPSEGLYLIYSQVLFK; 9, NPNANPNANPNA. A total of 33 experiments were performed. Peptides 3 and 4 were selected to highlight the effect of steric bulk of each Asn derivative on coupling efficiency. Reagent efficiency, as measured by target peptide purity, was as follows: Fmoc-Asn(Tmob)-OH > Fmoc-Asn-OH > Fmoc-Asn(Mtt)-OH = Fmoc-Asn(Trt)-OH > Fmoc-Asn(Mbh)-OH.

  8. Coral Geochemical Proxy Records Of The East Asian Winter Monsoon And Hydrological Conditions In The Central Vietnam From 1978-2004 AD

    NASA Astrophysics Data System (ADS)

    Chang, C.; Shen, C.; Chen, Y.; Chiang, H.; Lam, D. D.; Ngai, N.

    2007-12-01

    Monthly-resolution geochemical proxies, including δ18O, δ13C, Sr/Ca, and Ba/Ca, in a living Porites coral head, collected from Son Tra Island, a near-shore island located at the north tip of Vung Da Nang Bay, central Vietnam (16°12'59.4", 108°1'57.1"), was used to quantitatively reconstruct records of sea surface temperature (SST), sea surface salinity (SSS), seasonality of rainfall, and regional terrestrial input during a period of 1978-2004 AD. By comparing the 1/4-century geochemical data, five features are exhibited. (1) The coral Sr/Ca-inferred summer SSTs correspond well with the 1°x1° instrumental data to suggest that the regional SST record can be retrieved from this local coral head. (2) Interannual variation of coral winter SST data does not follow regional instrumental values. The harmonic phenomenon between coral inferred winter SST dynamic and the surface pressure difference, between the southern South China Sea (SCS) (0-10°N, 105-115°E) and the northern SCS (22.5-32.5°N, 112-122°E), indicating that the cold local SST induced by East Asian winter monsoon was addressed in the Son Tra coral. (3) 1‰ seasonal anomaly of δ18O residual (Δδ18O) suggests a 2-4-psu seasonal salinity change between dry and wet seasons. (4) The synchronous intra-annual changes of δ18O and Ba/Ca data suggest that the rainy season is from late summer to winter, which is consistent with the meteorological record. (5) The high Ba/Ca background level of 10 μmol/mol in 1992-2004, 2-3 times larger than the averaged value of 4 μmol/mol in 1978-1992, indicates an enhanced terrestrial sediment discharge into the bay over the past 10 years. Ba records probably reflect an impact of human activity on hydrological change since the Vietnam War.

  9. Detection of Area Changes in River Mouthbars at the Mekong River Delta using ALOS/PALSAR data

    NASA Astrophysics Data System (ADS)

    Tanaka, A.; Uehara, K.; Tamura, T.; Saito, Y.

    2011-12-01

    other seasonal changing factors, such as the mean monthly sea level at Vung Tau hydrometeorological station, lower Mekong mainstream monthly discharge at Kratie, eastern Cambodia, and rainfall at Chau Doc in the Mekong River Delta. Moreover, it is highly likely that tidal height at the time of SAR data acquisition clearly reflect the area by examining over half-day intervals for ascending and descending images. To monitor the area changes over longer time intervals further investigation combing another SAR data is required. It will also be useful to apply to other regions to reach more comprehensive and comparable analysis.

  10. Nucleoside transporter proteins as biomarkers of drug responsiveness and drug targets

    PubMed Central

    Pastor-Anglada, Marçal; Pérez-Torras, Sandra

    2015-01-01

    Nucleoside and nucleobase analogs are currently used in the treatment of solid tumors, lymphoproliferative diseases, viral infections such as hepatitis and AIDS, and some inflammatory diseases such as Crohn. Two gene families are implicated in the uptake of nucleosides and nucleoside analogs into cells, SCL28 and SLC29. The former encodes hCNT1, hCNT2, and hCNT3 proteins. They translocate nucleosides in a Na+ coupled manner with high affinity and some substrate selectivity, being hCNT1 and hCNT2 pyrimidine- and purine-preferring, respectively, and hCNT3 a broad selectivity transporter. SLC29 genes encode four members, being hENT1 and hENT2 the only two which are unequivocally implicated in the translocation of nucleosides and nucleobases (the latter mostly via hENT2) at the cell plasma membrane. Some nucleoside-derived drugs can also interact with and be translocated by members of the SLC22 gene family, particularly hOCT and hOAT proteins. Inter-individual differences in transporter function and perhaps, more importantly, altered expression associated with the disease itself might modulate the transporter profile of target cells, thereby determining drug bioavailability and action. Drug transporter pharmacology has been periodically reviewed. Thus, with this contribution we aim at providing a state-of-the-art overview of the clinical evidence generated so far supporting the concept that these membrane proteins can indeed be biomarkers suitable for diagnosis and/or prognosis. Last but not least, some of these transporter proteins can also be envisaged as drug targets, as long as they can show “transceptor” functions, in some cases related to their role as modulators of extracellular adenosine levels, thereby providing a functional link between P1 receptors and transporters. PMID:25713533

  11. [Risk factors for smoking in persons over 45].

    PubMed

    Jóźwiak, Paulina; Wierzejska, Ewelina; Szmagaj, Aleksandra; Biskupska, Maria

    2014-01-01

    cigarettes was associated with hinh level of LDL cholesterol. The smokers aged over 45 can be generally characterized as strongly addicted and have been smoking for many years. Anti-tobacco activities targeted at this group should be intensified in order to reduce the number of cigarettes smoked daily. These interventions should take into account group characteristics and its needs.

  12. Heterogeneous δ18O in the mantle wedge beneath Medicine Lake and Mt. Shasta volcanoes (California): ancient or modern subduction signature?

    NASA Astrophysics Data System (ADS)

    Martin, E.; Bindeman, I.; Grove, T.

    2008-12-01

    This study presents new analyses of O-isotopes in olivine phenocrysts from most primitive high alumina olivine tholeiite (HAOT) from Medicine Lake volcano (MLV; California) with MgO > 8%. The measured δ18OOl-values range from 4.69‰ to 5.49‰, with an average of 5.07‰ (n = 12), which is low relatively to the mantle olivine values (5.2‰±±0.2‰). We compare these data to O-isotopes measured in olivine phenocrysts from the most primitive lavas from Mount Shasta, which show high δ18OOl-values relatively to the olivine mantle value, 5.89-6.08‰ in HAOT (n = 2), 5.31-5.81‰ in basaltic andesite (BA; n = 7) and 5.54-5.85‰ in primitive magnesian andesite (PMA; n = 5). The primitive crystal poor nature of these lavas, Mg# > 0.65, and the fact that we analyzed olivine, the first mineral to crystallize in these lavas, allow us a good assessment to mantle-derived magmas. The HOAT are known to be generated by nearly anhydrous melting of spinel peridotite, which makes them a good indicator of the composition of the mantle unaffected by the present day subduction fluids. Therefore it appears that the mantle beneath MLV has a low- to mantle-like δ18OOl with variation of up to 0.8‰. However, beneath Mt Shasta the mantle has a relatively high δ18OOl and more homogeneous (based on two samples). Overall, it appears that the arc mantle of the South Cascade segment is heterogeneous with more than 1.3‰ variation in δ18OOl. The question that we address here is: Is the high-δ18O signature measured in olivine phenocrysts from BA and PMA from Mt Shasta come from the preexisting mantle source itself or from the present subduction fluids? If we consider BA and PMA to be generated by high-δ18O fluids flux melting in the present subduction environment, how can we explain high-δ18O values measured in HAOT? The heterogeneous character of the mantle in the South Cascades could be due to ancient subduction fluids more and more depleted during the slab dehydration that fluxed

  13. [(68)Ga]FSC-(RGD)3 a trimeric RGD peptide for imaging αvβ3 integrin expression based on a novel siderophore derived chelating scaffold-synthesis and evaluation.

    PubMed

    Knetsch, Peter A; Zhai, Chuangyan; Rangger, Christine; Blatzer, Michael; Haas, Hubertus; Kaeopookum, Piriya; Haubner, Roland; Decristoforo, Clemens

    2015-02-01

    Over the last years Gallium-68 ((68)Ga) has received tremendous attention for labeling of radiopharmaceuticals for positron emission tomography (PET). (68)Ga labeling of biomolecules is currently based on bifunctional chelators containing aminocarboxylates (mainly DOTA and NOTA). We have recently shown that cyclic peptide siderophores have very good complexing properties for (68)Ga resulting in high specific activities and excellent metabolic stabilities, in particular triacetylfusarinine-C (TAFC). We postulated, that, starting from its deacetylated form (Fusarinine-C (FSC)) trimeric bioconjugates are directly accessible to develop novel targeting peptide based (68)Ga labeled radiopharmaceuticals. As proof of principle we report on the synthesis and (68)Ga-radiolabeling of a trimeric FSC-RGD conjugate, [(68)Ga]FSC-(RGD)3, targeting αvβ3 integrin, which is highly expressed during tumor-induced angiogenesis. Synthesis of the RGD peptide was carried out applying solid phase peptide synthesis (SPPS), followed by the coupling to the siderophore [Fe]FSC via in situ activation using HATU/HOAt and DIPEA. Subsequent demetalation allowed radiolabeling of FSC-(RGD)3 with (68)Ga. The radiolabeling procedure was optimized regarding peptide amount, reaction time, temperature as well buffer systems. For in vitro evaluation partition coefficient, protein binding, serum stability, αvβ3 integrin binding affinity, and tumor cell uptake were determined. For in vitro tests as well as for the biodistribution studies αvβ3 positive human melanoma M21 and αvβ3 negative M21-L cells were used. [(68)Ga]FSC-(RGD)3 was prepared with high radiochemical yield (>98%). Distribution coefficient was -3.6 revealing a hydrophilic character, and an IC50 value of 1.8±0.6 nM was determined indicating a high binding affinity for αvβ3 integrin. [(68)Ga]FSC-(RGD)3 was stable in PBS (pH7.4), FeCl3- and DTPA-solution as well as in fresh human serum at 37°C for 2hours. Biodistribution assay

  14. [68Ga]FSC-(RGD)3 a trimeric RGD peptide for imaging αvβ3 integrin expression based on a novel siderophore derived chelating scaffold—synthesis and evaluation

    PubMed Central

    Knetsch, Peter A.; Zhai, Chuangyan; Rangger, Christine; Blatzer, Michael; Haas, Hubertus; Kaeopookum, Piriya; Haubner, Roland; Decristoforo, Clemens

    2015-01-01

    Over the last years Gallium-68 (68Ga) has received tremendous attention for labeling of radiopharmaceuticals for positron emission tomography (PET). 68Ga labeling of biomolecules is currently based on bifunctional chelators containing aminocarboxylates (mainly DOTA and NOTA). We have recently shown that cyclic peptide siderophores have very good complexing properties for 68Ga resulting in high specific activities and excellent metabolic stabilities, in particular triacetylfusarinine-C (TAFC). We postulated, that, starting from its deacetylated form (Fusarinine-C (FSC)) trimeric bioconjugates are directly accessible to develop novel targeting peptide based 68Ga labeled radiopharmaceuticals. As proof of principle we report on the synthesis and 68Ga-radiolabeling of a trimeric FSC-RGD conjugate, [68Ga]FSC-(RGD)3, targeting αvβ3 integrin, which is highly expressed during tumor-induced angiogenesis. Synthesis of the RGD peptide was carried out applying solid phase peptide synthesis (SPPS), followed by the coupling to the siderophore [Fe]FSC via in situ activation using HATU/HOAt and DIPEA. Subsequent demetalation allowed radiolabeling of FSC-(RGD)3 with 68Ga. The radiolabeling procedure was optimized regarding peptide amount, reaction time, temperature as well buffer systems. For in vitro evaluation partition coefficient, protein binding, serum stability, αvβ3 integrin binding affinity, and tumor cell uptake were determined. For in vitro tests as well as for the biodistribution studies αvβ3 positive human melanoma M21 and αvβ3 negative M21-L cells were used. [68Ga]FSC-(RGD)3 was prepared with high radiochemical yield (> 98%). Distribution coefficient was − 3.6 revealing a hydrophilic character, and an IC50 value of 1.8 ± 0.6 nM was determined indicating a high binding affinity for αvβ3 integrin. [68Ga]FSC-(RGD)3 was stable in PBS (pH 7.4), FeCl3- and DTPA-solution as well as in fresh human serum at 37 °C for 2 hours. Biodistribution assay confirmed