Development of composite plate for microwave antenna

Conference Name:2011 International Symposium on Advanced Packaging Materials, APM 2011. Conference Address: Xiamen, China. Time:October 25, 2011 - October 28, 2011.A new kind of machinable composite plate was developed for microwave antenna in this paper, in which ceramic powder of CaO-Li2O-Ln 2O3-TiO2 was mixed with PTFE polymer in different proportions. It was showed that the permittivity of the composite plate was enhanced from 4 to 15 with the increasing content of ceramic powder; meanwhile, the quality factor was maintained at 1000GHz. The antenna was obtained with the composite plate which was machined to suitable size and covered with copper electrodes. The antenna's bandwidth was about 60MHz and standing wave ratio was near 1.12. ? 2011 IEEE

Extensive beam test study of prototype MRPCs for the T0 detector at the CSR external-target experiment

The CSR External-target Experiment (CEE) will be the first large-scale nuclear physics experiment device at the Cooling Storage Ring (CSR) of the Heavy-Ion Research Facility in Lanzhou (HIRFL) in China. A new T0 detector has been proposed to measure the multiplicity, angular distribution and timing information of charged particles produced in heavy-ion collisions at the target region. Multi-gap resistive plate chamber (MRPC) technology was chosen as part of the construction of the T0 detector, which provides precision event collision times (T0) and collision geometry information. The prototype was tested with hadron and heavy-ion beams to study its performance. By comparing the experimental results with a Monte Carlo simulation, the time resolution of the MRPCs are found to be $\sim$ 50 ps or better. The timing performance of the T0 detector, including both detector and readout electronics, we found to fulfil the requirements of the CEE.Comment: 12 pages, 36 figure

Preface to Special Issue: Drug Transporters: Regulation and Roles in Therapeutic Strategies

Drug transporters are membrane proteins, mediating, across cell membranes, the absorption, distribution, and excretion of a diverse array of endogenous and exogenous substances such as nutrients, metabolites, toxins, and drugs [...

Topotecan and Ginkgolic Acid Inhibit the Expression and Transport Activity of Human Organic Anion Transporter 3 by Suppressing SUMOylation of the Transporter

Organic anion transporter 3 (OAT3), expressed at the basolateral membrane of kidney proximal tubule cells, facilitates the elimination of numerous metabolites, environmental toxins, and clinically important drugs. An earlier investigation from our laboratory revealed that OAT3 expression and transport activity can be upregulated by SUMOylation, a post-translational modification that covalently conjugates SUMO molecules to substrate proteins. Topotecan is a semi-synthetic derivative of the herbal extract camptothecin, approved by the FDA to treat several types of cancer. Ginkgolic acid (GA) is one of the major components in the extract of Ginkgo biloba leaves that has long been used in food supplements for preventing dementia, high blood pressure, and supporting stroke recovery. Both topotecan and GA have been shown to affect protein SUMOylation. In the current study, we tested our hypothesis that topotecan and GA may regulate OAT3 SUMOylation, expression, and transport function. Our data show that the treatment of OAT3-expressing cells with topotecan or GA significantly decreases the SUMOylation of OAT3 by 50% and 75%, respectively. The same treatment also led to substantial reductions in OAT3 expression and the OAT3-mediated transport of estrone sulfate, a prototypical substrate. Such reductions in cell surface expression of OAT3 correlated well with an increased rate of OAT3 degradation. Mechanistically, we discovered that topotecan enhanced the association between OAT3 and the SUMO-specific protease SENP2, a deSUMOylation enzyme, which contributed to the significant decrease in OAT3 SUMOylation. In conclusion, this study unveiled a novel role of topotecan and GA in inhibiting OAT3 expression and transport activity and accelerating OAT3 degradation by suppressing OAT3 SUMOylation. During comorbidity therapies, the use of topotecan or Ginkgo biloba extract could potentially decrease the transport activity of OAT3 in the kidneys, which will in turn affect the therapeutic efficacy and toxicity of many other drugs that are substrates for the transporter

Chloroquine and Hydroxychloroquine, as Proteasome Inhibitors, Upregulate the Expression and Activity of Organic Anion Transporter 3

Organic anion transporter 3 (OAT3), at the basolateral membrane of kidney proximal tubule cells, facilitates the elimination of numerous widely used drugs. Earlier investigation from our laboratory revealed that ubiquitin conjugation to OAT3 leads to OAT3 internalization from the cell surface, followed by degradation in the proteasome. In the current study, we examined the roles of chloroquine (CQ) and hydroxychloroquine (HCQ), two well-known anti-malarial drugs, in their action as proteasome inhibitors and their effects on OAT3 ubiquitination, expression, and function. We showed that in cells treated with CQ and HCQ, the ubiquitinated OAT3 was considerably enhanced, which correlated well with a decrease in 20S proteasome activity. Furthermore, in CQ- and HCQ-treated cells, OAT3 expression and OAT3-mediated transport of estrone sulfate, a prototypical substrate, were significantly increased. Such increases in OAT3 expression and transport activity were accompanied by an increase in the maximum transport velocity and a decrease in the degradation rate of the transporter. In conclusion, this study unveiled a novel role of CQ and HCQ in enhancing OAT3 expression and transport activity by preventing the degradation of ubiquitinated OAT3 in proteasomes

Novobiocin Is a Potent Inhibitor for Human Organic Anion Transporters

Organic anion transporters (OATs) mediate the body disposition of a diverse array of environmental toxins and clinically important drugs. Previous studies have shown that novobiocin, an inhibitor for breast cancer resistance proteins (BCRP), inhibited organic anion transport. However, its interactions with specific OATs are unknown. In the current study, we characterized the inhibitory effects of novobiocin on the function of human OATs (hOAT)1, hOAT3, and hOAT4. Kinetic study revealed that novobiocin inhibited OAT-mediated uptake in a competitive manner, with Ki of 14.87 ± 0.40 μM for hOAT1, Ki of 4.77 ± 1.12 μM for hOAT3, and Ki of 90.50 ± 7.50 μM for hOAT4. Furthermore, the cis- and trans-inhibition feature of novobiocin demonstrated that novobiocin was a potent inhibitor but not a substrate for hOAT1 (IC50 = 34.76 ± 0.31 μM), hOAT3 (IC50 = 4.987 ± 0.35 μM), and hOAT4 (IC50 = 92.68 ± 0.34 μM). We further showed that the effects of novobiocin on OATs were not mediated through a change in transporter protein abundance on the plasma membrane. Taken together, we conclude that novobiocin seems to interact with the substrate-binding sites of OATs from both the intracellular and the extracellular sides, and this interaction interferes with the substrate-binding site(s) on respective carriers, leading to an apparent reduction in carriers available for the substrates. Because BCRP is often expressed in the same tissue where multiple OATs are identified such as liver, kidney and placenta, when dissecting the contribution of BCRP to drug disposition using novobiocin as an inhibitor, its inhibitory effect to OATs has to be taken into consideration

Regulation of human organic anion transporter 3 by peptide hormone bradykinin. J Pharmacol Exp Ther

ABSTRACT Human organic anion transporter (hOAT) 3 belongs to a family of organic anion transporters that play critical roles in the body disposition of numerous clinically important drugs. In the current study, we examined the regulation of hOAT3 by peptide hormone bradykinin (BK) in COS-7 cells. BK (Յ500 nM) induced a concentration-and time-dependent stimulation of hOAT3 activity, kinetically revealed as an increased V max . Such an increase in V max resulted from an increased cell surface expression without a change in total cell expression of the transporter. BK-induced stimulation of hOAT3 activity could be prevented by treating hOAT3-expressing cells with staurosporine, a general inhibitor for protein kinase C (PKC). To obtain further information on which PKC isoform mediates BK regulation of hOAT3 activity, cellular distribution of various PKC isoforms was examined in cells treated with BK. We showed that BK treatment resulted in a significant translocation of PKC␦, PKC, and PKC from cytosol to membrane. We further showed that BK treatment enhanced association of hOAT3 with PKC␦, PKC, and PKC and that isoform-specific inhibitor for PKC␦, PKC, and PKC reversed BK effect on hOAT3 activity. We therefore concluded that BK stimulated hOAT3 activity through activation of PKC␦, PKC, and PKC, which then led to the redistribution of hOAT3 from the intracellular compartments to the cell surface and to the up-regulation of hOAT3 activity

The activity of organic anion transporter-3: Role of dexamethasone

Human organic anion transporter-3 (hOAT3) is richly expressed in the kidney, where it plays critical roles in the secretion, from the blood to urine, of clinically important drugs, such as anti-viral therapeutics, anti-cancer drugs, antibiotics, antihypertensives, and anti-inflammatories. In the current study, we examined the role of dexamethasone in hOAT3 transport activity in the kidney HEK293 cells. Cis-inhibition study showed that dexamethasone exhibited a concentration-dependent inhibition of hOAT3-mediated uptake of estrone sulfate, a prototypical substrate for the transporter, with IC50 value of 49.91 μM. Dixon plot analysis revealed that inhibition by dexamethasone was competitive with a Ki = 47.08 μM. In contrast to the cis-inhibition effect of dexamethasone, prolonged incubation (6 h) of hOAT3-expressing cells with dexamethasone resulted in an upregulation of hOAT3 expression and transport activity, kinetically revealed as an increase in the maximum transport velocity Vmax without meaningful alteration in substrate-binding affinity Km. Such upregulation was abrogated by GSK650394, a specific inhibitor for serum- and glucocorticoid-inducible kinases (sgk). Dexamethasone also enhanced sgk1 phosphorylation. Our study demonstrated that dexamethasone exhibits dual effects on hOAT3: it is a competitive inhibitor for hOAT3-mediated transport, and interestingly, when entering the cells, it stimulates hOAT3 expression and transport activity through sgk1. Keywords: Organic anion transporter, Drug transport, Regulation, Dexamethasone, Serum and glucocorticoid-inducible kinas