The concentrative nucleoside transporter family,SLC28

The SLC28 family consists of three subtypes of sodium-dependent, concentrative nucleoside transporters, CNT1, CNT2, and CNT3 (SLC28A1, SLC28A2, and SLC28A3, respectively), that transport both naturally occurring nucleosides and synthetic nucleoside analogs used in the treatment of various diseases. These subtypes differ in their substrate specificities: CNT1 is pyrimidine-nucleoside preferring, CNT2 is purine-nucleoside preferring, and CNT3 transports both pyrimidine and purine nucleosides. Recent studies have identified key amino acid residues that are determinants of pyrimidine and purine specificity of CNT1 and CNT2. The tissue distributions of the CNTs vary: CNT1 is localized primarily in epithelia, whereas CNT2 and CNT3 have more generalized distributions. Nucleoside transporters in the SLC28 and SLC29 families play critical roles in nucleoside salvage pathways where they mediate the first step of nucleotide biosynthesis. In addition, these transporters work in concert to terminate adenosine signaling. SLC28 family members are crucial determinants of response to a variety of anticancer and antiviral nucleoside analogs, as they modulate the entry of these analogs into target tissues. Further, this family is involved in the absorption and disposition of many nucleoside analogs. Several CNT single nucleoside polymorphisms (SNPs) have been identified, but have yet to be characterized.     

Drug uptake transporters in antiretroviral therapy

Current treatment of human immunodeficiency virus-1 (HIV-1) infection is effective, although it does not permanently suppress viral replication in all patients. Viral persistence, drug toxicity, and antiretroviral resistance are challenging barriers to successful treatment of HIV-1 infection. It has become increasingly apparent that the balance between drug influx and efflux transporter activity plays a critical role in the overall disposition of anti-HIV drugs in both cells and tissues. Thus, drug transporters directly influence the appearance of drug resistance and toxicity, and could also be related to persistence of HIV-1. We review the role of drug uptake transporters from the solute carrier (SLC) superfamily, their relation with specific antiretroviral drug disposition, and their efficacy in the tissues that absorb, metabolize, and eliminate anti-HIV drugs. Recent studies focusing on the role of drug uptake transporters in immune cells, key sites in the action of antiviral therapy, are highlighted.     

福建省有毒有害化学品专项整治效果报告

[目的]了解我省有毒有害化学品生产、销售和使用专项整治工作的效果。[方法]根据福建省专项整治工作方案，重点整治6类行业和4类企业，内容有危害项目申报、卫生培训、制度建立、警示标识、防护设施、场所检测和人员体检等14个项目。[结果]专项整治开展9个月后，用人单位危害项目申报率34．0％，用人单位负责人和劳动者的职业卫生知识培训率为32．4％和43．1％，场所检测率和合格率为69．6％和72．6％，职业健康体检率47．3％，7个类别企业的职业卫生管理也取得一定效果．行政处罚56起。[结论]本次专项整治首次摸清了全省的化学品用人单位的职业卫生基本情况，专项整治行动本身和体现防治效果的14项目调查，对化学品用人单位的职业病防治工作是一次有力的促进。     

Inhibitor selectivity of CNTs and ENTs

1. The concentrative nucleoside transporters (CNT; solute carrier family 28 (SLC28)) and the equilibrative nucleoside transporters (ENT; solute carrier family 29 (SLC29)) are important therapeutic targets but may also mediate toxicity or adverse events.

2. To explore the relative role of the base and the monosaccharide moiety in inhibitor selectivity we selected compounds that either harbor an arabinose moiety or a cytosine moiety, as these groups had several commercially available drug members.

3. The screening data showed that more compounds harboring a cytosine moiety displayed potent interactions with the CNTs than compounds harboring the arabinose moiety. In contrast, ENTs showed a preference for compounds with an arabinose moiety.

4. The correlation between CNT1 and CNT3 was good as five of six compounds displayed IC₅₀ values within the threefold threshold and one displayed a borderline 4-fold difference. For CNT1 and CNT2 as well as for CNT2 and CNT3 only two of six IC₅₀ values correlated and one displayed a borderline 4-fold difference. Interestingly, of the six compounds that potently interacted with both ENT1 and ENT2 only nelarabine displayed selectivity.

5. Our data show differences between inhibitor selectivities of CNTs and ENTs as well as differences within the CNT family members.

     

Interaction of benzopyranone derivatives and related compounds with human concentrative nucleoside transporters 1, 2 and 3 heterologously expressed in porcine PK15 nucleoside transporter deficient cells. Structure-activity relationships and determinants of transporter affinity and selectivity

Unlike the major equilibrative nucleoside transporters, there is a dearth of potent specific inhibitors of concentrative nucleoside transporters (CNTs). We investigated the interaction of benzopyranone derivatives and related compounds with human (h) CNTs in newly established PK15NTD transfectant cells stably expressing hCNT1 or hCNT2, and previously established PK15NTD/hCNT3 cells. Flavones exhibited the highest inhibitory activity against hCNT2 and hCNT3, whereas the most potent selective inhibitor of hCNT1 was a coumarin derivative. hCNT3 was the only transporter that exhibited moderate sensitivity to the chalcones tested. The most active compound was 6-hydroxy-7-methoxyflavone, which was hCNT3-specific with an IC₅₀ of 0.57 ± 0.20 μM, and over 40-fold more potent than the standard CNT inhibitor, phloridzin (IC₅₀ of 25 ± 3.5 μM). The SAR (Structure-Activity Relationship) shows that high potency against all three hCNTs is conferred by the presence of hydroxyl substituents at both the 7- and 8-positions of flavones and isoflavones. CoMFA (Comparative Molecular Field Analysis) and CoMSIA (Comparative Molecular Similarity Indices Analysis) 3D-QSAR (three-Dimensional Quantitative Structure-Activity Relationship) modeling indicated that electrostatic and hydrophobic properties were the most influential for interactions between the flavonoids and hCNT1, while electrostatic, hydrophobic and hydrogen bond donor properties were predominate for interactions with hCNT2 and hCNT3. The 3D-QSAR results also suggested possible commonalities in hydrogen bonding interactions of flavonoids and nucleosides, suggesting similarities between the hCNT-binding sites of the two classes of compounds. We report the most potent and selective non-nucleoside CNT inhibitors to date; which may serve as research tools and/or leads for further inhibitor development.     

河口县农村集中式供水水质检测结果分析

目的:了解河口县农村集中式供水的水质状况,为政府及相关部门对农村饮水工程的建设与管理提供科学依据。方法:对河口县46个自然村基本情况进行现场调查,并进行水质检测分析。结果:736份农村饮用水水样合格率仅为12.91%,丰水期水质与枯水期水质无显著性差异(P>0.05),出厂水与末梢水水质无显著性差异(P>0.05)。结论:河口县农村集中式供水水质卫生状况较差,受微生物污染非常严重,加强对农村饮水安全工程管理和饮水消毒刻不容缓。     

Plants with neurobiological activity as potential targets for drug discovery

Significant number of studies has been performed to find alternatives or treatments for diseases of the nervous forum by identifying structures with activity at the central nervous system (CNS). However most of the screenings are usually conducted on an ad hoc basis and not systematically.     

Ribavirin uptake by cultured human choriocarcinoma (BeWo) cells and Xenopus laevis oocytes expressing recombinant plasma membrane human nucleoside transporters

We investigated the mechanism of the transport of ribavirin (1-beta-D-ribofuranosyl-1,2,4-trizole-3-carboxamide) into placental epithelial cells using human choriocarcinoma (BeWo) cells and Xenopus oocytes expressing human nucleoside transporters. In BeWo cells, when a relatively low concentration (123 nM) of ribavirin was used, both Na(+)-dependent uptake and -independent uptake of ribavirin were observed. On the other hand, when a higher concentration (100 microM) of ribavirin was used, Na(+)-independent uptake was observed, but there was only a slight Na(+)-dependent uptake. In Xenopus oocytes, influxes of ribavirin mediated by hCNT2 (concentrative nucleoside transporter 2), hCNT3 (concentrative nucleoside transporter 3), hENT1 (equilibrative nucleoside transporter 1) and hENT2 (equilibrative nucleoside transporter 2) were saturable, and apparent K(m) values were 18.0 microM, 14.2 microM, 3.46 mM and 3.71 mM, respectively. These data indicate that hCNT2 and hCNT3 have higher affinity for ribavirin than do hENT1 and hENT2. Moreover, analysis by RT-PCR showed that BeWo cells express mRNA of hCNT3, hENT1 and hENT2. These results suggest that ribavirin is taken up by BeWo cells via both the high-affinity Na(+)-dependent transporter hCNT3 and the low-affinity Na(+)-independent transporters hENT1 and hENT2.     

中心血站应急供血存在的问题及对策

<正>2006年在郑州召开了全国血液管理工作会议,就全国血站机构的设置做了长远规划,并且指出在有条件的地区,率先实行血液集中化检测的工作。血液集中化检测可以优化资源配置,集中全区的物力、人力资源,尽最大努力地保证了血