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    Abstract

    Objective. To determine the role of cytochrome P450 (CYP)2C19 in N-demethylation of amitriptyline (AT) in healthy Chinese subjects.

    Methods. One hundred and one subjects were genotyped for CYP2C19 using polymerase chain reaction-restriction fragment length polymorphism analysis. Twelve unrelated adult men (19.7±0.6 years, 61.8±3.8 kg) were chosen and orally given a single dose of 50 mg AT, and the blood samples were drawn from a forearm vein at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, and 96 h after AT administration. Plasma concentrations of AT and nortriptyline (NT) were determined using high-performance liquid chromatography with an ultraviolet detector.

    Results. The mean area under the plasma concentration–time curve (AUCAT) of CYP2C19 poor metabolizers (PMs, n=6) was significantly higher than that of CYP2C19 extensive metabolizers (EMs, n=6) (2207±501 ng/ml·h–1 vs 1596±406 ng/ml·h–1, P<0.05). In contrast, the mean AUCNT(0–) of PMs was significantly lower than that of EMs (294±70 ng/ml·h–1 vs 684±130 ng/ml·h–1, P<0.0001). Other pharmacokinetic parameters such as clearance, half-life, maximum plasma concentration, and time to peak plasma concentration showed no significant difference between PMs and EMs (0.41±0.12 l /h·kg–1 vs 0.50±0.15 l /h·kg–1, 25.0±6.2 h vs 24.1±4.4 h, 96±25 ng/ml vs 75±27 ng/ml, 4.0±1.4 h vs 3.7±1.5 h, respectively).

    Conclusion. The genetic defects of CYP2C19 have a significant effect on AT pharmacokinetics, and CYP2C19 plays an important role in N-demethylation of AT in vivo at a clinically therapeutic dose.


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    Abstract

    This article gives a review on heavy metal pollution prevention and control, and it also discusses heavy metal pollutant discharge, prediction and evaluation of environmental impact, and pollution prevention and monitoring.


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    ABSTRACT

    Purpose

    Previous research has led to the recognition of a cGMP signaling pathway governing drug transport. This study is to investigate whether inhibitors of phosphodiesterase type 5 (PDE5), which increase intracellular cGMP levels, modulate the cytotoxicity and uptake of anti-cancer drugs in cancer cells.

    Methods

    The experiments were conducted with and without PDE5 inhibitors: dipyridamole, vardenafil, and/or sildenafil. The cytotoxicity of doxorubicin, cisplatin and oxaliplatin was determined in multiple cancer cell lines derived from different tissues. The cellular uptake of structurally diverse compounds was further examined in lung cancer cells with and without various endocytotic inhibitors. The tumor accumulation and the anti-tumor effect of trastuzumab were examined in a lung cancer xenograft mouse model.

    Results

    Dipyridamole could modulate the cytotoxicity of doxorubicin, cisplatin, and oxaliplatin in cancer cells. Particularly, PDE5 inhibitors increased cellular uptake of structurally diverse compounds into lung cancer cells both in vitro and in vivo. The effect of vardenafil on drug uptake could be blocked by endocytotic inhibitors. The growth of lung cancer xenograft in nude mice was significantly suppressed by addition of vardenafil to trastuzumab treatment.

    Conclusion

    PDE5 inhibitors may increase the efficacy of anti-cancer drugs by increasing endocytosis-mediated cellular drug uptake, and thus serve as adjuvant therapy for certain cancers such as lung cancer.


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    Abstract

    Introduction

    Apolipoprotein E (apoE) is a member of apolipoprotein family, and its gene polymorphisms seem to have some impact among patients with cardiovascular disease. However, its role in the lower extremity deep venous thrombosis (LEDVT) has not been well studied. The objective of this study was to investigate the potential association between APOE gene polymorphisms and LEDVT.

    Materials and methods

    A hospital-based case–control study was conducted in 300 patients with LEDVT by color-flow Doppler ultrasound and 300 age- and gender-matched healthy controls. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay was applied to assess the APOE gene polymorphisms.

    Results

    Patients with LEDVT had a significantly higher frequency of APOE E3/E4 genotype [odds ratio (OR) =1.48, 95% confidence interval (CI) = 1.05, 2.10; P = 0.03] than healthy controls. When stratifying by family history of LEDVT, it was found that patients with positive family history of LEDVT had a significantly higher frequency of APOE E3/E4 genotype (OR =1.68, 95% CI = 1.04, 0.95; P = 2.70). When stratifying by smoking status, presence of varicose veins, type 2 diabetes mellitus and any hormone administration before, no significant differences were found in any groups.

    Conclusion

    Our study suggested that APOE E3/E4 genotype was associated with a higher LEDVT risk. Additional studies are needed to confirm this finding.


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    Abstract

    Membrane transporters play critical roles in moving a variety of anticancer drugs across cancer cell membrane, thereby determining chemotherapy efficacy and/or toxicity. The retention of anticancer drugs in cancer cells is the result of net function of efflux and influx transporters. The ATP-binding cassette (ABC) transporters are mainly the efflux transporters expressing at cancer cells, conferring the chemo-resistance in various malignant tumors, which has been well documented over the past decades. However, the function of influx transporters, in particular the solute carriers (SLC) in cancer cells, has only been recently well recognized to have significant impact on cancer therapy. The SLC transporters not only directly bring anticancer agents into cancer cells but also serve as the uptake mediators of essential nutrients for tumor growth and survival. In this review, we concentrate on the interaction of SLC transporters with anticancer drugs and nutrients, and their impact on chemo-sensitivity or -resistance of cancer cells. The differential expression patterns of SLC transporters between normal and tumor tissues may be well utilized to achieve specific delivery of chemotherapeutic agents.


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    Abstract

    The contents of Pb, Cd, Cr, As, and Hg was investigated in the neighboring areas of a lead smelting enterprise and the metals contamination of soil was evaluated with the methodologies of the single factor index and Nemerow integrated index. It is found that the content of heavy metals in the neighboring areas has no obvious difference from the reference points. And the soil contamination of heavy metals varies by elements, the contamination index follows the pollution order: Cd>Hg>Cr>As>Pb. The pollution degree of Cd is at high level and Hg at low level, but Cr and As reached the warning level. Therefore, the lead smelting enterprises should not only control lead but also other heavy metals as Cd.


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    Abstract

    Cisplatin (CDDP) nephrotoxicity is one of the most common side effects in cancer treatment, causing the disruption of chemotherapy. In this study, we analyzed the influence of nongenetic factors on CDDP-induced nephrotoxiciy using the data from 182 CDDP-treated and 52 carboplatin (CBP)-treated patients. The mean change of eGFR (100 % to baseline) in CDDP-treated patients was −9.2 %, which was significantly lower than that in the population with CBP therapy. By using the chi-squared test and multivariate logistic regression analysis, age (≥50 years) is found associated with CDDP-induced nephrotoxicity, with odds ratio (OR) of 9.167 and 11.771, respectively. Three- and 18-month-old mice were employed to study the age-dependent susceptibility of CDDP-induced nephrotoxicity. Biochemical parameters, histopathogical examination, and mRNA biomarkers indicated that old mice were subjected to more severe kidney injury. In addition, old mice accumulated more CDDP in kidney than young mice, and the protein level of CDDP efflux transporter, MATE1, in aged mice kidney was 35 % of that in young mice. Moreover, inflammatory receptor TLR4 was higher in the kidney of old mice, indicating the alteration of inflammatory signaling in old mice. After CDDP administration, the induced alterations of TNF-α, ICAM-1, and TLR4 were more extensive in old mice. To summarize, aging increased the susceptibility of CDDP-induced renal function decline or nephrotoxicity.


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    Abstract

    Objectives

    This study aimed to evaluate the effects of moderately increased maternal dietary energy intake during gestation on foetal skeletal muscle development and metabolism with pig as a model.

    Methods

    Twelve primiparous purebred Large White sows (initial body weight 135.5 ± 1.6 kg) were allocated to one of two energy intake treatments: normal-energy-intake group (Con, 30.96 MJ DE/day) as recommended by the National Research Council (NRC; 2012) and high-energy-intake group (HE, 34.15 MJ DE/day). The nutritional treatments were introduced from mating to day 90 of gestation. On day 90 of gestation, foetuses were examined by morphological, biochemical and molecular analysis of the longissimus muscle. Umbilical vein serum hormones were measured.

    Results

    Sow body weight was increased in HE group compared with Con group (P < 0.05), whereas foetal myofibre density was decreased (P < 0.05). Meanwhile, protein concentration, creatine kinase and lactate dehydrogenase activities and umbilical vein serum triiodothyronine (T3) concentration were decreased in HE foetuses (P < 0.05). Maternal HE diets decreased the mRNA abundance of muscle growth-related genes, myosin heavy-chain (MYH/MyHC) genes (MYH2 and MYH1) and insulin-like growth factor 1 and insulin growth factor-binding protein 5 (P < 0.05). Furthermore, the protein expressions of myogenic differentiation factor 1, myogenin and fast-MyHC isoforms were reduced in HE foetuses (P < 0.05).

    Conclusion

    Our results suggest that moderately increased maternal dietary energy intake delays the differentiation and maturation in skeletal muscle of the foetus on day 90 of gestation.


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    Abstract

    This paper introduces a notion of gradient and an infimal-convolution operator that extend properties of solutions of Hamilton Jacobi equations to more general spaces, in particular to graphs. As a main application, the hypercontractivity of this class of infimal-convolution operators is connected to some discrete version of the log-Sobolev inequality and to a discrete version of Talagrand’s transport inequality.


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    Abstract

    Purpose

    Lamivudine, a characterized substrate for human multidrug and toxin extrusion protein 1 (hMATE1) in vitro, was commonly used with indinavir as a therapy against human immunodeficiency virus (HIV). We aimed to investigate whether mouse MATE1 is involved in the disposition of lamivudine in vivo, and whether there is any transporter-mediated interaction between indinavir and lamivudine.

    Methods

    The role of MATE1 in the disposition of lamivudine was determined using Mate1 wild type (+/+) and knockout (−/−) mice. The inhibitory potencies of indinavir on lamivudine uptake mediated by OCT2 and MATE1 were determined in human embryonic kidney 293 (HEK 293) cells stably expressing these transporters. The role of MATE1 in the interaction between indinavir and lamivudine in vivo was determined using Mate1 (+/+) and Mate1 (−/−) mice.

    Results

    The plasma concentrations and tissue accumulation of lamivudine were markedly elevated in Mate1 (−/−) mice as compared to those in Mate1 (+/+) mice. Indinavir significantly increased the pharmacokinetic exposure of lamivudine in mice; however, the effect by indinavir was significantly less pronounced in Mate1 (−/−) mice as compared to Mate1(+/+) mice.

    Conclusion

    MATE1 played an important role in lamivudine pharmacokinetics. Indinavir could cause drug-drug interaction with lamivudine in vivo via inhibition of MATE1 and additional mechanism.


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    Abstract

    Transfer RNAs (tRNAs), traditionally considered to participate in protein translation, were interspersed in the entire genome. Recent studies suggested that dysregulation was observed in not only tRNAs, but also tRNA derivatives generated by the specific cleavage of pre- and mature tRNAs in the progression of cancer. Accumulating evidence had identified that certain tRNAs and tRNA derivatives were involved in proliferation, metastasis and invasiveness of cancer cell, as well as tumor growth and angiogenesis in several malignant human tumors. This paper reviews the importance of the dysregulation of tRNAs and tRNA derivatives during the development of cancer, such as breast cancer, lung cancer, and melanoma, aiming at a better understanding of the tumorigenesis and providing new ideas for the treatment of these cancers.


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    Abstract

    We developed a panel of multiplex quantitative real-time reverse transcription polymerase chain reaction (mqRT-PCR) assay consisting of seven internally controlled qRT-PCR assays to detect 16 different respiratory viruses. We compared the new mqRT-PCR with a previously reported two-tube mRT-PCR assay using 363 clinical sputum specimens. The mqRT-PCR assay performed comparably with the two-tube assay for most viruses, offering the advantages of quantitative analysis, easier performance, lower susceptibility to contamination, and shorter turnaround time in laboratories equipped with conventional real-time PCR instrumentation, and it could therefore be a valuable tool for routine surveillance of respiratory virus infections in China.


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    Abstract

    Purpose

    The organic cation transporters (OCTs) and multidrug and toxin extrusions (MATEs), located in the basolateral and apical membrane of proximal tubular cells respectively, are crucial determinants of renal elimination and/or toxicity of cationic drugs such as cisplatin. The purpose of this study was to discover selective OCT inhibitors over MATEs, and explore their potential to protect against cisplatin-induced nephrotoxicity that is clinically common.

    Methods

    The inhibition by select compounds on the uptake of the probe substrate metformin was assessed in HEK293 cells overexpressing human OCT2, OCT1, MATE1, MATE2-K, and mouse Oct2, Oct1, and Mate1. Furthermore, the effects of carvedilol on organic cation transporter-mediated cellular and renal accumulation of metformin and cisplatin, and particularly the toxicity associated with cisplatin, were investigated in HEK293 cells and mice.

    Results

    Five selective OCT inhibitors were identified through the screening of forty-one drugs previously reported as the inhibitors of OCTs and/or MATEs. Among them, carvedilol showed the most selectivity on OCTs over MATEs (IC50: 3.6 μM for human OCT2, 103 μM for human MATE1 and 202 μM for human MATE2-K) in the cellular assays in vitro, with the selectivity in mice as well. Moreover, carvedilol treatment could significantly decrease cisplatin accumulation and ameliorate its toxicity both in vitro in cells and in vivo in mouse kidney.

    Conclusions

    Our data indicate that selective inhibition of OCTs by carvedilol may protect from cisplatin-induced nephrotoxicity by restraining the cellular entry of cisplatin via OCTs, while having no impact on its elimination through MATEs.


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    Abstract

    Background

    Numerous protocols for viral enrichment and genome amplification have been created. However, the direct identification of viral genomes from clinical specimens using next-generation sequencing (NGS) still has its challenges. As a selected viral nucleic acid extraction method may determine the sensitivity and reliability of NGS, it is still valuable to evaluate the extraction efficiency of different extraction kits using clinical specimens directly.

    Results

    In this study, we performed qRT-PCR and viral metagenomic analysis of the extraction efficiency of four commonly used Qiagen extraction kits: QIAamp Viral RNA Mini Kit (VRMK), QIAamp MinElute Virus Spin Kit (MVSK), RNeasy Mini Kit (RMK), and RNeasy Plus Micro Kit (RPMK), using a mixed respiratory clinical sample without any pre-treatment. This sample contained an adenovirus (ADV), influenza virus A (Flu A), human parainfluenza virus 3 (PIV3), human coronavirus OC43 (OC43), and human metapneumovirus (HMPV). The quantity and quality of the viral extracts were significantly different among these kits. The highest threshold cycle(Ct)values for ADV and OC43 were obtained by using the RPMK. The MVSK had the lowest Ct values for ADV and PIV3. The RMK revealed the lowest detectability for HMPV and PIV3. The most effective rate of NGS data at 67.47% was observed with the RPMK. The other three kits ranged between 12.1–26.79% effectiveness rates for the NGS data. Most importantly, compared to the other three kits the highest proportion of non-host reads was obtained by the RPMK. The MVSK performed best with the lowest Ct value of 20.5 in the extraction of ADV, while the RMK revealed the best extraction efficiency by NGS analysis.

    Conclusions

    The evaluation of viral nucleic acid extraction efficiency is different between NGS and qRT-PCR analysis. The RPMK was most applicable for the metagenomic analysis of viral RNA and enabled more sensitive identification of the RNA virus genome in respiratory clinical samples. In addition, viral RNA extraction kits were also applicable for metagenomic analysis of the DNA virus. Our results highlighted the importance of nucleic acid extraction kit selection, which has a major impact on the yield and number of viral reads by NGS analysis. Therefore, the choice of extraction method for a given viral pathogen needs to be carefully considered.


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    Abstract

    Purpose

    The organic cation transporters (OCTs) and multidrug and toxin extrusions (MATEs) together are regarded as an organic cation transport system critical to the disposition and response of many organic cationic drugs. Patient response to the analgesic morphine, a characterized substrate for human OCT1, is highly variable. This study was aimed to examine whether there is any organic cation transporter-mediated drug and drug interaction (DDI) between morphine and commonly co-administrated drugs.

    Methods

    The uptake of morphine and its inhibition by six drugs which are commonly co-administered with morphine in the clinic were assessed in human embryonic kidney 293 (HEK293) cells stably expressing OCT1, OCT2 and MATE1. The in vivo interaction between morphine and the select irinotecan was determined by comparing the disposition of morphine in the absence versus presence of irinotecan treatment in mice.

    Results

    The uptake of morphine in the stable HEK293 cells expressing human OCT1 and OCT2 was significantly increased by 3.56 and 3.04 fold, respectively, than that in the control cells, with no significant uptake increase in the cells expressing human MATE1. All of the six drugs examined, including amitriptyline, fluoxetine, imipramine, irinotecan, ondansetron, and verapamil, were inhibitors of OCT1/2-mediated morphine uptake. The select irinotecan significantly increased the plasma concentrations and decreased hepatic and renal accumulation of morphine in mice.

    Conclusions

    Morphine is a substrate of OCT1 and OCT2. Clinician should be aware that the disposition of and thus the response to morphine may be altered by co-administration of an OCT1/2 inhibitor, such as irinotecan.