Home About us Contact
|
Home About us Contact | ||
|
|
||
MDR
Terms modified by MDR Selected AbstractsIncrease in multidrug transport activity is associated with oocyte maturation in sea stars,DEVELOPMENT GROWTH & DIFFERENTIATION, Issue 9 2006Troy A. Roepke In this study, we report on the presence of efflux transporter activity before oocyte maturation in sea stars and its upregulation after maturation. This activity is similar to the multidrug resistance (MDR) activity mediated by ATP binding cassette (ABC) efflux transporters. In sea star oocytes the efflux activity, as measured by exclusion of calcein-am, increased two-fold 3 h post-maturation. Experiments using specific and non-specific dyes and inhibitors demonstrated that the increase in transporter activity involves an ABCB protein, P-glycoprotein (P-gp), and an ABCC protein similar to the MDR-associated protein (MRP)-like transporters. Western blots using an antibody directed against mammalian P-gp recognized a 45 kDa protein in sea star oocytes that increased in abundance during maturation. An antibody directed against sea urchin ABCC proteins (MRP) recognized three proteins in immature oocytes and two in mature oocytes. Experiments using inhibitors suggest that translation and microtubule function are both required for post-maturation increases in transporter activity. Immunolabeling revealed translocation of stored ABCB proteins to the plasma cell membrane during maturation, and this translocation coincided with increased transport activity. These MDR transporters serve protective roles in oocytes and eggs, as demonstrated by sensitization of the oocytes to the maturation inhibitor, vinblastine, by MRP and PGP-specific transporter inhibitors. [source] Gene,gene interactions between HNF4A and KCNJ11 in predicting Type 2 diabetes in womenDIABETIC MEDICINE, Issue 11 2007L. Qi Abstract Aims Recent studies indicate transcription factor hepatocyte nuclear factor 4, (HNF-4,, HNF4A) modulates the transcription of the pancreatic B-cell ATP-sensitive K+ (KATP) channel subunit Kir6.2 gene (KCNJ11). Both HNF4A and KCNJ11 have previously been associated with diabetes risk but little is known whether the variations in these genes interact with each other. Methods We conducted a prospective, nested case,control study of 714 incident cases of Type 2 diabetes and 1120 control subjects from the Nurses' Health Study. Results KCNJ11 E23K was significantly associated with an increased diabetes risk (odds ratio 1.26, 95% CI 1.03,1.53) while HNF4A P2 promoter polymorphisms were associated with a moderately increased risk at borderline significance. By using a logistic regression model, we found significant interactions between HNF4A rs2144908, rs4810424 and rs1884613 and KCNJ11 E23K (P for interaction = 0.017, 0.012 and 0.004, respectively). Carrying the minor alleles of the three HNF4A polymorphisms was associated with significantly greater diabetes risk in women carrying the KCNJ11 allele 23K, but not in those who did not carry this allele. Analyses using the multifactor dimensionality reduction (MDR) method confirmed the gene,gene interaction. We identified that the best interaction model included HNF4A rs2144908 and KCNJ11 E23K. Such a two-locus model showed the maximum cross-validation consistency of 10 out of 10 and a significant prediction accuracy of 54.2% (P = 0.01) on the basis of 1000-fold permutation testing. Conclusions Our data indicate that HNF4A P2 promoter polymorphisms may interact with KCNJ11 E23K in predicting Type 2 diabetes in women. [source] Potential multidrug resistance gene POHL: An ecologically relevant indicator in marine spongesENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 1 2001Anatoli Krasko Abstract Sponges are sessile filter feeders found in all aquatic habitats from the tropics to the arctic. Against potential environmental hazards, they are provided with efficient defense systems, e.g., protecting chaperones and/or the P-170/multidrug resistance pump system. Here we report on a further multidrug resistance pathway that is related to the pad one homologue (POH1) mechanism recently identified in humans. It is suggested that proteolysis is involved in the inactivation of xenobiotics by the POH1 system. Two cDNAs were cloned, one from the demosponge Geodia cydoniumand a second from the hexactinellid sponge Aphrocallistes vastus. The cDNA from G. cydonium, termed GCPOHL, encodes a deduced polypeptide with a size of 34,591 Da and that from A. vastus, AVPOHL, a protein of a calculated Mr of 34,282. The two sponge cDNAs are highly similar to each other as well as to the known sequences from fungi (Schizosaccharomyces pombe and Saccharomyces cerevisiae) and other Metazoa (from Schistosoma mansoni to humans). Under controlled laboratory conditions, the expression of the potential multidrug resistance gene POHL is, in G. cydonium, strongly upregulated in response to the toxins staurosporin (20 ,M) or taxol (50 ,M); the first detectable transcripts appear after 1 d and reach a maximum after 3 to 5 d of incubation. The relevance of the expression pattern of the G. cydonium gene POHL for the assessment of pollution in the field was determined at differently polluted sites in the area around Rovinj (Croatia; Mediterranean Sea, Adriatic Sea). The load of the selected sites was assessed by measuring the potency of XAD-7 concentrates of water samples taken from those places to induce the level of benzo[a]pyrene monooxygenase (BaPMO) in fish and to impair the multidrug resistance (MDR)/P-170 extrusion pump in clams. These field experiments revealed that the levels of inducible BaPMO activity in fish and of the MDR potential by the water concentrates are highly correlated with the level of expression of the potential multidrug resistance gene POHL in G. cydonium. This report demonstrates that the detoxification POH pathway, here mediated by the G. cydonium GCPOHL gene, is an additional marker for the assessment of the environmental load in a given marine area. [source] Inhibition of PI3K/Akt partially leads to the inhibition of PrPC -induced drug resistance in gastric cancer cellsFEBS JOURNAL, Issue 3 2009Jie Liang Cellular prion protein (PrPC), a glycosyl-phosphatidylinositol-anchored membrane protein with unclear physiological function, was previous found to be upregulated in adriamycin (ADR)-resistant gastric carcinoma cell line SGC7901/ADR compared to its parental cell line SGC7901. Overexpression of PrPC in gastric cancer has certain effects on drug accumulation through upregulation of P-glycoprotein (P-gp), which is suggested to play an important role in determining the sensitivity of tumor cells to chemotherapy and is linked to activation of the phosphatidylinositol-3-kinase/Akt (PI3K/Akt) pathway. In the present study, we further investigate the role of the PI3K/Akt pathway in PrPC -induced multidrug-resistance (MDR) in gastric cancer. Immunohistochemistry and confocal microscope detection suggest a positive correlation between PrPC and phosphorylated Akt (p-Akt) expression in gastric cancer. Using established stable PrPC transfectant cell lines, we demonstrated that the level of p-Akt was increased in PrPC -transfected cells. Inhibition of PrPC expression by RNA interference resulted in decreased p-Akt expression. Inhibition of the PI3K/Akt pathway by one of its specific inhibitors, LY294002, or by Akt small interfering RNA (siRNA) resulted in decreased multidrug resistance of SGC7901 cells, partly through downregulation of P-gp induced by PrPC. Taken together, our results suggest that PrPC -induced MDR in gastric cancer is associated with activation of the PI3K/Akt pathway. Inhibition of PI3K/Akt by LY2940002 or Akt siRNA leads to inhibition of PrPC -induced drug resistance and P-gp upregulation in gastric cancer cells, indicating a possible novel mechanism by which PrPC regulates gastric cancer cell survival. [source] Modulation of P-glycoprotein-mediated multidrug resistance by acceleration of passive drug permeation across the plasma membraneFEBS JOURNAL, Issue 23 2007Ronit Regev The drug concentration inside multidrug-resistant cells is the outcome of competition between the active export of drugs by drug efflux pumps, such as P-glycoprotein (Pgp), and the passive permeation of drugs across the plasma membrane. Thus, reversal of multidrug resistance (MDR) can occur either by inhibition of the efflux pumps or by acceleration of the drug permeation. Among the hundreds of established modulators of Pgp-mediated MDR, there are numerous surface-active agents potentially capable of accelerating drug transbilayer movement. The aim of the present study was to determine whether these agents modulate MDR by interfering with the active efflux of drugs or by allowing for accelerated passive permeation across the plasma membrane. Whereas Pluronic P85, Tween-20, Triton X-100 and Cremophor EL modulated MDR by inhibition of Pgp-mediated efflux, with no appreciable effect on transbilayer movement of drugs, the anesthetics chloroform, benzyl alcohol, diethyl ether and propofol modulated MDR by accelerating transbilayer movement of drugs, with no concomitant inhibition of Pgp-mediated efflux. At higher concentrations than those required for modulation, the anesthetics accelerated the passive permeation to such an extent that it was not possible to estimate Pgp activity. The capacity of the surface-active agents to accelerate passive drug transbilayer movement was not correlated with their fluidizing characteristics, measured as fluorescence anisotropy of 1-(4-trimethylammonium)-6-phenyl-1,3,5-hexatriene. This compound is located among the headgroups of the phospholipids and does not reflect the fluidity in the lipid core of the membranes where the limiting step of drug permeation, namely drug flip-flop, occurs. [source] New insights into the P-glycoprotein-mediated effluxes of rhodaminesFEBS JOURNAL, Issue 3 2003Chatchanok Loetchutinat Multidrug resistance (MDR) in tumour cells is often caused by the overexpression of the plasma drug transporter P-glycoprotein (P-gp). This protein is an active efflux pump for chemotherapeutic drugs, natural products and hydrophobic peptides. Despite the advances of recent years, we still have an unclear view of the molecular mechanism by which P-gp transports such a wide diversity of compounds across the membrane. Measurement of the kinetic characteristics of substrate transport is a powerful approach to enhancing our understanding of their function and mechanism. The aim of the present study was to further characterize the transport of several rhodamine analogues, either positively charged or zwitterionic. We took advantage of the intrinsic fluorescence of rhodamines and performed a flow-cytometric analysis of dye accumulation in the wild-type drug sensitive K562 that do not express P-gp and its MDR subline that display high levels of MDR. The measurements were made in real time using intact cells. The kinetic parameter, ka = VM/km, which is a measure of the efficiency of the P-gp-mediated efflux of a substrate was similar for almost all the rhodamine analogues tested. In addition these values were compared with those determined previously for the P-gp-mediated efflux of anthracycline. Our conclusion is that the compounds of these two classes of molecules, anthracyclines and rhodamines, are substrates of P-gp and that their pumping rates at limiting low substrate concentration are similar. The findings presented here are the first to show quantitative information about the kinetic parameters for P-gp-mediated efflux of rhodamine analogues in intact cells. [source] Modulation of multi-drug resistance (MDR) in Staphylococcus aureus by Osha (Ligusticum porteri L., Apiaceae) essential oil compoundsFLAVOUR AND FRAGRANCE JOURNAL, Issue 6 2005Pascale Cégiéla-Carlioz Abstract In a continuing project to characterize natural compounds with activity as modulators of MDR in Staphyloccocus aureus, Osha essential oil and extracts were evaluated. The aim of this work was to identify the active components as MDR modulators in the oil from the roots of Ligusticum porteri Coulter & Rose (Apiaceae). This essential oil was obtained by steam distillation or by solvent extraction and analysed by gas chromatography,mass spectrometry. Forty-two components were identified. Sabinyl acetate (1) (56.6%), (Z)-ligustilide (2) (12.9%) and sabinol (3) (3.3%) were the major components of water-distilled essential oil, while (Z)-ligustilide (2) (39.1%), sabinyl acetate (1) (34.6%) and 4-terpinyl acetate (4) (3.1%) were the major components of the dichloromethane extract. At a concentration of 100 µg/ml, the oil from hydrodistillation caused a two-fold potentiation, and the oil from solvent extraction caused a four-fold potentiation of the activity of the fluoroquinolone antibiotic norfloxacin against a norfloxacin-resistant strain possessing the NorA MDR efflux transporter, the major chromosomal drug pump in this pathogen. Copyright © 2005 John Wiley & Sons, Ltd. [source] Genetic changes in the evolution of multidrug resistance for cultured human ovarian cancer cellsGENES, CHROMOSOMES AND CANCER, Issue 12 2007Timon P. H. Buys The multidrug resistant (MDR) phenotype is often attributed to the activity of ATP-binding cassette (ABC) transporters such as P-glycoprotein (ABCB1). Previous work has suggested that modulation of MDR may not necessarily be a single gene trait. To identify factors that contribute to the emergence of MDR, we undertook integrative genomics analysis of the ovarian carcinoma cell line SKOV3 and a series of MDR derivatives of this line (SKVCRs). As resistance increased, comparative analysis of gene expression showed conspicuous activation of a network of genes in addition to ABCB1. Functional annotation and pathway analysis revealed that many of these genes were associated with the extracellular matrix and had previously been implicated in tumor invasion and cell proliferation. Further investigation by whole genome tiling-path array CGH suggested that changes in gene dosage were key to the activation of several of these overexpressed genes. Remarkably, alignment of whole genome profiles for SKVCR lines revealed the emergence and decline of specific segmental DNA alterations. The most prominent alteration was a novel amplicon residing at 16p13 that encompassed the ABC transporter genes ABCC1 and ABCC6. Loss of this amplicon in highly resistant SKVCR lines coincided with the emergence of a different amplicon at 7q21.12, which harbors ABCB1. Integrative analysis suggests that multiple genes are activated during escalation of drug resistance, including a succession of ABC transporter genes and genes that may act synergistically with ABCB1. These results suggest that evolution of the MDR phenotype is a dynamic, multi-genic process in the genomes of cancer cells. © 2007 Wiley-Liss, Inc. [source] A novel method to identify gene,gene effects in nuclear families: the MDR-PDTGENETIC EPIDEMIOLOGY, Issue 2 2006E.R. Martin Abstract It is now well recognized that gene,gene and gene,environment interactions are important in complex diseases, and statistical methods to detect interactions are becoming widespread. Traditional parametric approaches are limited in their ability to detect high-order interactions and handle sparse data, and standard stepwise procedures may miss interactions that occur in the absence of detectable main effects. To address these limitations, the multifactor dimensionality reduction (MDR) method [Ritchie et al., 2001: Am J Hum Genet 69:138,147] was developed. The MDR is wellsuited for examining high-order interactions and detecting interactions without main effects. The MDR was originally designed to analyze balanced case-control data. The analysis can use family data, but requires a single matched pair be selected from each family. This may be a discordant sib pair, or may be constructed from triad data when parents are available. To take advantage of additional affected and unaffected siblings requires a test statistic that measures the association of genotype with disease in general nuclear families. We have developed a novel test, the MDR-PDT, by merging the MDR method with the genotype-Pedigree Disequilibrium Test (geno-PDT)[Martin et al., 2003: Genet Epidemiol 25:203,213]. MDR-PDT allows identification of single-locus effects or joint effects of multiple loci in families of diverse structure. We present simulations to demonstrate the validity of the test and evaluate its power. To examine its applicability to real data, we applied the MDR-PDT to data from candidate genes for Alzheimer disease (AD) in a large family dataset. These results show the utility of the MDR-PDT for understanding the genetics of complex diseases. Genet. Epidemiol. 2006. © 2005 Wiley-Liss, Inc. [source] PLAGUE AND POWER RELATIONSGEOGRAFISKA ANNALER SERIES B: HUMAN GEOGRAPHY, Issue 4 2007Rodrick Wallace ABSTRACT Public policy and economic practice, quintessential expressions of institutional cognition, create an opportunity structure constituting a tunable, highly patterned,,non-white noise' in a generalized epidemiological stochastic resonance that can efficiently amplify unhealthy living and working conditions, particularly within highly concentrated, marginalized urban populations, to evoke infectious disease outbreaks. This is especially true for the infections carried by socially generated ,risk behaviours' which are usually adaptations to histories of resource deprivation or marginalization. A number of local epidemics originating in such ecological keystone communities may subsequently undergo a policy and structure-driven phase transition to become a coherent pandemic, a spreading plague which can entrain more affluent populations into the disease ecology of marginalization. We use this approach to contrast the ecological resilience of apartheid and egalitarian social systems, and apply these perspectives to the forthcoming social and geographical diffusion of multiple drug resistant (MDR) HIV from present AIDS epicentres to the rest of the United States. [source] Using analytic signal to determine magnetization/density ratios of geological structuresGEOPHYSICAL JOURNAL INTERNATIONAL, Issue 1 2009Wen-Bin Doo SUMMARY The Poisson theorem provides a simple relationship between the gravity and magnetic potentials, which is useful in interpreting joint data sets of gravity and magnetic data. Based on the simple Poisson theorem, magnetization/density ratio (MDR) can be estimated. However, potential field data is often ambiguous in datum level and multisources interference that may cause bias in interpretation. Here, we propose an improved Poisson theorem to estimate MDR by using analytic signals of gravity and magnetic data. The major advantage of using the analytic signal is that we can also determine the sources locations and boundaries supposing that we know the ambient magnetic parameters. Besides, we can also avoid the determination error from uncertain datum levels. We demonstrate the feasibility of the proposed method in 2-D and 3-D synthetic models. The proposed method is also applied to a profile across the offshore area of northern Taiwan. Comparing with the reflection seismic profile, our result can help identify the existence of a deep-seated igneous body beneath the area of Mienhuayu and Pengchiagu islands off northern Taiwan. [source] Hyaluronan oligosaccharides sensitize lymphoma resistant cell lines to vincristine by modulating P-glycoprotein activity and PI3K/Akt pathwayINTERNATIONAL JOURNAL OF CANCER, Issue 5 2008Rosalía I. Cordo Russo Abstract Multidrug resistance (MDR) is one of the main reasons for failure of cancer therapy. It may be mediated by overexpression of ATP-dependent efflux pumps or by alterations in survival or apoptotic pathways. Fragments generated by enzymatic degradation of hyaluronan (oHA) were able to modulate growth and cell survival and sensitize MDR breast cancer cells to cytotoxic drugs. In this work the relationship between oHA and MDR in lymphoid malignancies was analyzed using murine lymphoma cell lines resistant to doxorubicin (LBR-D160) or vincristine (LBR-V160) and a sensitive line (LBR-). After oHA treatment, higher apoptosis levels were observed in the resistant cell lines than in the sensitive one. Besides, oHA sensitized LBR-D160 and LBR-V160 to vincristine showing increased apoptosis induction when used in combination with vincristine. Native hyaluronan failed to increase apoptosis levels. As different survival factors could be modulated by hyaluronan, we investigated the PI3K/Akt pathway through PIP3 production and phosphorylated Akt (p-Akt) and survivin expression was also evaluated. Our results showed that oHA decreased p-Akt in the 3 cell lines while anti-CD44 treatment abolished this effect. Besides, survivin was downregulated only in LBR-V160 by oHA. When Pgp function was evaluated, we observed that oHA were able to inhibit Pgp efflux in murine and human resistant cell lines in a CD44-dependent way. In summary, we report for the first time that oHA per se modulate MDR in lymphoma cells by decreasing p-Akt as well as Pgp activity, thus suggesting that oHA could be useful in combination with classical chemotherapy in MDR hematological malignancies. © 2007 Wiley-Liss, Inc. [source] Reversal of doxorubicin resistance in breast cancer cells by photochemical internalizationINTERNATIONAL JOURNAL OF CANCER, Issue 11 2006Pei-Jen Lou Abstract Multiple drug resistance (MDR) is a problem that seriously reduces the efficacy of many chemotherapy agents. One mechanism for MDR is increased acidification of endocytic vesicles and increased cytosol pH, so weak base chemotherapeutic agents, including doxorubicin, are trapped in endocytic vesicles and exhibit a drug resistant phenotype. Treatments that selectively reverse this accumulation may therefore reverse the MDR phenotype. Photochemical internalization (PCI) is a novel technology developed for site-specific enhancement of the therapeutic efficacy of macromolecules by selective photochemical rupture of endocytic vesicles and consequent release of endocytosed macromolecules into the cytosol. This study evaluates PCI for release of doxorubicin from endocytic vesicles in MDR cells. Two breast cancer cell lines, MCF-7 and MCF-7/ADR (the latter resistant to doxorubicin), were selected. They were found equally sensitive to photochemical treatment with the photosensitiser TPPS2a (disulfonated meso-tetraphenylporphine) and light. On exposure to doxorubicin alone, the IC50 (drug concentration for 50% reduction in colony formation) was 0.1 ,M for MCF-7 and 1 ,M for MCF-7/ADR. After PCI (photochemical treatment followed by doxorubicin), the IC50 concentration was 0.1 ,M for both cell lines. Comparable changes were seen with assay of cell viability using 3-(4,5-dimethyltiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). On fluorescence microscopy in MCF-7/ADR cells, doxorubicin localised in granules identified as lysosomes. After PCI, doxorubicin was released into the cytosol and entered cell nuclei, as was seen in MCF-7 cells without PCI. In conclusion, PCI reversed the MDR phenotype of doxorubicin resistant breast cancer cells by endo-lysosomal release of the drug. The technique is a promising new approach to tackling the problem of MDR. © 2006 Wiley-Liss, Inc. [source] Overexpression and significance of prion protein in gastric cancer and multidrug-resistant gastric carcinoma cell line SGC7901/ADRINTERNATIONAL JOURNAL OF CANCER, Issue 2 2005Jingping Du Abstract In our previous work, cellular prion protein (PrPc) was identified as an upregulated gene in adriamycin-resistant gastric carcinoma cell line SGC7901/ADR compared to its parental cell line SGC7901. Here we investigate the expression of PrPc in gastric cancer and whether it was involved in multidrug resistance (MDR) of gastric cancer. We demonstrated that PrPc was ubiquitously expressed in gastric cancer cell lines and tissues. PrPc conferred resistance of both P-glycoprotein (P-gp)-related and P-gp-nonrelated drugs on SGC7901, which was accompanied by decreased accumulation and increased releasing amount of adriamycin in PrPc-overexpressing cell line. Inhibition of PrPc expression by antisense or RNAi technology could partially reverse multidrug-resistant phenotype of SGC7901/ADR. PrPc significantly upregulated the expression of the classical MDR-related molecule P-gp but not multidrug resistance associated protein and glutathione S-transferase pi. The PrPc-induced MDR could be partially reversed by P-gp inhibitor verapamil. PrPc could also suppress adriamycin-induced apoptosis and alter the expression of Bcl-2 and Bax, which might be another pathway contributing to PrPc-related MDR. The further study of the biological functions of PrPc may be helpful for understanding the mechanisms of occurrence and development of clinical gastric carcinoma and PrPc-related MDR and developing possible strategies to treat gastric cancer. [source] Altered conjugate formation and altered apoptosis of multidrug-resistant human leukemia cell line affects susceptibility to killing by activated natural killer (NK) cellsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2004Robin S. Treichel Abstract Most leukemias that exhibit P-glycoprotein (P-gp)-associated multidrug resistance (MDR) exhibit reduced susceptibility to immune cytotoxicity mediated by natural killer (NK) cells. To explore this phenomenon we investigated N6/ADR, a doxorubicin-selected, P-gp-positive variant of the human acute lymphoblastic leukemia (ALL) cell line NALM6. Each stage of the NK cytolytic pathway, (binding, activation and killing) was evaluated to identify the alterations responsible for the reduced cytotoxicity of the variant relative to its drug-sensitive parental line. The major cause of the decreased susceptibility to NK cytolysis was found to be reduced conjugate formation by the MDR variant. Activation of NK effectors by parental and MDR cells with concomitant release of tumor necrosis factor-alpha (TNF-,) correlated with conjugate formation. N6/ADR was also more resistant than NALM6 to antibody-dependent cellular cytotoxicity and to cytotoxic factors released from NK cells as measured both by 51Cr-release and by DNA fragmentation. This is the first report of a P-gp-positive leukemic line that exhibits reduced conjugate formation as well as increased resistance to NK-mediated killing mechanisms. Our results suggest caution in the use of NK-based immunotherapy as an alternative treatment for multidrug-resistant leukemias. © 2003 Wiley-Liss, Inc. [source] Association of genomic imbalances with drug resistance and thermoresistance in human gastric carcinoma cellsINTERNATIONAL JOURNAL OF CANCER, Issue 6 2003Holger Tönnies Abstract Therapy resistance is the major obstacle to advances in successful cancer treatment. To characterize chromosomal alterations associated with different types of acquired MDR and thermoresistance, we applied CGH to compare a unique panel of human gastric carcinoma cells consisting of the parental, drug-sensitive and thermosensitive cancer cell line EPG85-257P, the atypical MDR variant EPG85-257RNOV, the classical MDR subline EPG85-257RDB and their thermoresistant counterparts EPG85-257P-TR, EPG85-257RNOV-TR and EPG85-257RDB-TR. CGH with genomic DNA prepared from these cell lines as probes successfully identified genomic gains and/or losses in chromosomal regions encoding putative genes associated with drug resistance and/or thermoresistance. These genes included various members of the families of ABC transporters and molecular chaperones. The importance of these cell variant-specific genomic imbalances in the development of MDR and thermoresistance is discussed and remains to be elucidated. © 2002 Wiley-Liss, Inc. [source] Enzymatic oxidation products of spermine induce greater cytotoxic effects on human multidrug-resistant colon carcinoma cells (LoVo) than on their wild-type counterpartsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2002Annarica Calcabrini Abstract The occurrence of resistance to cytotoxic agents in tumor cells, associated with several phenotypic alterations, is one of the major obstacles to successful anticancer chemotherapy. A new strategy to overcome MDR of human cancer cells was studied, using BSAO, which generates cytotoxic products from spermine, H2O2 and aldehyde(s). The involvement of these products in causing cytotoxicity was investigated in both drug-sensitive (LoVo WT) and drug-resistant (LoVo DX) colon adenocarcinoma cells. Evaluation of clonogenic cell survival showed that LoVo DX cells are more sensitive than LoVo WT cells. Fluorometric assay and treatments performed in the presence of catalase demonstrated that the cytotoxicity was due mainly to the presence of H2O2. Cytotoxicity was eliminated in the presence of both catalase and ALDH. Transmission electron microscopic observations showed more pronounced mitochondrial modifications in drug-resistant than in drug-sensitive cells. Mitochondrial functionality studies performed by flow cytometry after JC-1 labeling revealed basal hyperpolarization of the mitochondrial membrane in LoVo DX cells. After treatment with BSAO and spermine, earlier and higher mitochondrial membrane depolarization was found in LoVo DX cells than in drug-sensitive cells. In addition, higher basal ROS production in LoVo DX cells than in drug-sensitive cells was detected by flow-cytometric analysis, suggesting increased mitochondrial activity in drug-resistant cells. Our results support the hypothesis that mitochondrial functionality affects the sensitivity of cells to the cytotoxic enzymatic oxidation products of spermine, which might be promising anticancer agents, mainly against drug-resistant tumor cells. © 2002 Wiley-Liss, Inc. [source] Secular and multidecadal warmings in the North Atlantic and their relationships with major hurricane activityINTERNATIONAL JOURNAL OF CLIMATOLOGY, Issue 2 2010David B. Enfield Abstract Analysis of recent literature finds weaknesses in arguments to the effect that the Atlantic multidecadal oscillation (AMO),roughly 50,90 year fluctuations in North Atlantic sea surface temperatures,is externally forced by anthropogenic aerosols and greenhouse gases rather than an internal climate mode, plus indications from other sources that the contrary may be true. We are led to the conclusion that the AMO is probably comprised of both natural and anthropogenic forcing in ways that preclude a physically based separation of the two, using the limited historical data sets. A straightforward quadratic fitting of trend to temperature data accounts for some of the 20th century nonlinearity in secular warming and separates the secular and multidecadal components of variability without inherent assumptions about the nature of the multidecadal fluctuations. Doing this shows that the 20th century secular ocean warming in the North Atlantic is about equal to the peak-to-peak amplitude of the multidecadal fluctuations. However, over the last quarter-century (1975,2000) the most recent multidecadal warming has been almost three times the secular sea surface temperature (SST) increase over the main development region (MDR) for major Atlantic hurricanes. In the last quarter-century the multidecadal increase in late summer Atlantic warm pool (AWP) size (area of SSTs in excess of 28 °C) has been 36%, and the secular increase, 14%. Projections to the year 2025 show that the cumulative change in summer warm pool size since 1975 will depend critically on whether a subsequent cooling in the multidecadal cycle occurs, comparable to the warming between 1975 and 2000 AD. This places a high premium on understanding to what extent the AMO is a man-made or a natural phenomenon. Copyright © 2009 Royal Meteorological Society [source] Prevalence, species distribution and antimicrobial resistance of enterococci isolated from dogs and cats in the United StatesJOURNAL OF APPLIED MICROBIOLOGY, Issue 4 2009C.R. Jackson Abstract Aims:, The contribution of dogs and cats as reservoirs of antimicrobial resistant enterococci remains largely undefined. This is increasingly important considering the possibility of transfer of bacteria from companion animals to the human host. In this study, dogs and cats from veterinary clinics were screened for the presence of enterococci. Methods and Results:, A total of 420 enterococci were isolated from nasal, teeth, rectal, belly and hindquarters sites of 155 dogs and 121 cats from three clinics in Athens, GA. Eighty per cent (124 out of 155) of the dogs and 60% (72 out of 121) of the cats were positive for enterococci. From the total number of dog samples (n = 275), 32% (n = 87) were from hindquarter, 31% (n = 86) were rectal, and 29% (n = 79) were from the belly area. The majority of isolates originated from rectal samples (53 out of 145; 37%) from cats. The predominant species identified was Enterococcus faecalis (105 out of 155; 68%) from dogs and E. hirae (63 out of 121; 52%) from cats. Significantly more E. faecalis were isolated from rectal samples than any other enterococcal species (P < 0·05) for both dogs and cats suggesting site specific colonization of enterococcal species. The highest levels of resistance were to ciprofloxacin in E. faecium (9 out of 10; 90%), chloramphenicol resistance in E. faecalis (17 out of 20; 85%) and gentamicin resistance in E. faecalis (19 out of 24; 79%) from dog samples and nitrofurantoin resistance in E. faecium (15 out of 19; 79%) from cats. Multi-drug resistance (MDR) (resistance ,2 antimicrobials) was observed to as few as two and as many as eight antimicrobials regardless of class. Conclusion:, This study demonstrated that dogs and cats are commonly colonized with antimicrobial resistant enterococci. Significance and Impact of the Study:, Dogs and cats may act as reservoirs of antimicrobial resistance genes that can be transferred from pets to people. [source] A novel genotypic test for rapid detection of multidrug-resistant Mycobacterium tuberculosis isolates by a multiplex probe arrayJOURNAL OF APPLIED MICROBIOLOGY, Issue 4 2007S.-L. Zhang Abstract Aims:, To develop and evaluate a novel genotypic test for rapid detection of rifampicin and isoniazid resistance of multidrug-resistant (MDR) Mycobacterium tuberculosis isolates by a multiplex probe array. Methods and Results:, A multiplex probe array was designed for genotypic test to simultaneously screen the mutations of rpoB, katG, inhA and ahpC genes, associated with rifampin and isoniazid resistance in M. tuberculosis, with a probe detecting one of the recently confirmed genetic markers of isoniazid resistance ahpC -6 and -9 locus added. By using the genotypic test developed, 52 MDR isolates were identified, among which 46 isolates had mutations in rpoB (88·5%) and 45 at codon 315 of katG, regulatory region of inhA and oxyR - ahpC intergenic region (86·5%), whereas all 35 susceptible isolates identified showed a wild-type hybridization pattern. The sensitivity and specificity were 88·5% and 100% for rifampicin resistance, and 86·5% and 100% for isoniazid resistance, respectively. Conclusion:, A rapid and simultaneous detection of rifampicin and isoniazid resistance caused by the mutations of rpoB, katG, inhA and ahpC genes in M. tuberculosis isolates could be achieved by a multiplex probe array developed. Significance and Impact of the Study:, This genotypic test protocol has the potential to be developed on clinical application for the rapid detection of drug resistant M. tuberculosis isolates before an efficient chemotherapy is initiated. [source] Differential regulation of P-glycoprotein genes in primary rat hepatocytes by collagen sandwich and drugsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2002Chow H. Lee Abstract P-glycoprotein (Pgp) is a small family of plasma membrane proteins, which are capable of transporting substrates across cell membranes. Class I and II Pgp are able to transport drugs and have been shown to mediate multidrug resistance (MDR). Class III Pgp is a long chain phospholipid transporter and does not mediate MDR. The regulation of all three Pgp genes is still poorly understood. For instance, it is not clear if the three Pgp genes are co-regulated or differentially regulated by external stimuli. This study examined the effect of drugs and collagen sandwich system on expression and transcription of all the three Pgp genes in primary rat hepatocytes. Consistent with previous findings, dramatic overexpression (25-fold) of Class II Pgp mRNA was seen, upon culturing of hepatocytes onto a single layered collagen gel. Hepatocytes sandwiched between two layers of collagen gel exhibited decreased (4.5-fold) Class II Pgp mRNA expression as compared to the single layer system. Treatment of hepatocytes cultured on the single layer collagen system with cytoskeletal disrupting (cytochalasin D, colchicine) but not cytoskeletal stabilizing (phalloidin, taxol) drugs, suppressed Class II Pgp expression. In all cases, no change in Class II Pgp transcription was observed as demonstrated by nuclear run-on studies. This suggests that collagen configuration and drugs affect Class II Pgp mRNA expression predominantly through post-transcriptional mechanisms. In contrast, parallel increases in mRNA expression and transcription of Class I Pgp gene were observed upon culturing of hepatocytes, in the collagen sandwich system, and treatment with some drugs (cytochalasin D, colchicine, and phalloidin). This suggests that Class I Pgp gene is regulated primarily via transcriptional mechanisms by these stimuli. On the other hand, Class III Pgp gene appears to be post-transcriptionally co-regulated with Class II Pgp gene by treatment with the drugs, while collagen configuration affected both transcription and post-transcription of Class III Pgp gene. Finally, dose-dependent studies using cycloheximide provided further evidence that the two MDR-associated genes are not co-regulated. This study has implications for future studies on the molecular mechanisms of Pgp gene regulation. J. Cell. Biochem. 86: 12,20, 2002. © 2002 Wiley-Liss, Inc. [source] Multidrug resistance in haematological malignanciesJOURNAL OF INTERNAL MEDICINE, Issue 5 2000P. Sonneveld Abstract. Sonneveld P (University Hospital Rotterdam , Dijkzigt, The Netherlands). Multidrug resistance in haematological malignancies (Internal Medicine in the 21st Century). J Intern Med 2000; 247: 521,534. The development of refractory disease in acute myeloid or lymphoblastic leukaemias (AML, ALL) and multiple myeloma (MM) is frequently associated with the expression of one or several multidrug resistance (MDR) genes. MDR1, MRP1 and LRP have been identified as important adverse prognostic factors in AML, T-ALL and MM. Recently, it has become possible to reverse clinical multidrug resistance by blocking P-glycoprotein-mediated drug efflux. The potential relevance of these reversal agents of MDR and potential new approaches to treat refractory disease are discussed. [source] Association of candidate susceptible loci with chronic infection with hepatitis B virus in a Chinese populationJOURNAL OF MEDICAL VIROLOGY, Issue 3 2010Ding-Qiang Chen Abstract A number of genetic loci have been proposed to be associated with persistent hepatitis B virus (HBV) infection. This study aimed to evaluate the association and interaction of susceptible genes with HBV persistence in a Chinese population. A total of 17 polymorphisms in 9 candidate genes were studied in 361 Chinese chronic hepatitis B patients and 304 patients who recovered spontaneously. Distributions of susceptible polymorphisms were examined in healthy Chinese and Caucasian populations. Gene,gene interactions were tested by the multifactor dimensionality reduction (MDR) method. The TNF ,308 G/G genotype and G allele, IL-10RB codon 47 A allele, and MCP-1 ,2518 G/G genotype and G allele were more frequent in patients than controls (P,<,0.01, after multiple corrections Pc,<,0.05), while the frequencies of TNF ,308 A/G genotype and IL-10 ,592 A/A genotype were significantly higher in controls than in the patient group (Pc,<,0.05). The frequencies of the risk allele MCP-1 ,2518 G and CTLA4 6230 G were much higher in Chinese than in the Caucasian groups (P,<,0.001). An interaction between CCR5 ,2459, TNFA ,863, IL-10RB codon 47, and MCP-1 ,2518 was detected by MDR (P,=,0.001). The results indicate that genetic determinants may affect the outcome of HBV infection in both independent and synergic manners. J. Med. Virol. 82:371,378, 2010. © 2010 Wiley-Liss, Inc. [source] Fluoroquinolone efflux mediated by ABC transportersJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2008Ana I. Alvarez Abstract Quinolones and fluoroquinolones are broad spectrum bactericidal drugs, which are widely used in both human and veterinary medicine. These drugs can quite easily enter cells and are often used to treat intracellular pathogens. Some fluoroquinolones have been reported to undergo efflux, which could explain their low bioavailability. There is a growing need to understand resistance mechanisms to quinolones, involving for instance mutations or the action of efflux pumps. Several members of the ATP-binding cassette (ABC) drug efflux transporter family (MDR, MRP, ABCG2) significantly affect the pharmacokinetic disposition of quinolones. Active secretory mechanisms common to all fluoroquinolones have been suggested, as well as competition between fluoroquinolones at transporter sites. For grepafloxacin and its metabolites, MRP2 has been demonstrated to mediate biliary excretion. However, MDR1 is responsible for grepafloxacin intestinal secretion. Recently it has been shown that ciprofloxacin and enrofloxacin are efficiently transported ABCG2 substrates which are actively secreted into milk. It appears that multiple ABC transporters contribute to the overall secretion of fluoroquinolones. The objective of this work is to review the recent advances in insights into ABC transporters and their effects on fluoroquinolone disposition and resistance including data on drug secretion into milk. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:3483,3493, 2008 [source] Enaminones: Exploring additional therapeutic activitiesJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 10 2007Ivan O. Edafiogho Abstract Enaminones, enamines of ,-dicarbonyl compounds, have been known for many years. Their early use has been relegated to serving as synthetic intermediates in organic synthesis and of late, in pharmaceutical development. Recently, the therapeutic potential of these entities has been realized. This review provides the background and current research in this area with emphasis of these agents as potential anticonvulsants, their proposed mechanisms of action, and as potential modulators of multidrug resistance (MDR). © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2509,2531, 2007 [source] Tacrolimus is a class II low-solubility high-permeability drug: The effect of P-glycoprotein efflux on regional permeability of tacrolimus in ratsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 3 2002Shigeki Tamura Abstract The objective of this study is to investigate the role of P-glycoprotein (P-gp), a membrane efflux pump associated with multidrug resistance (MDR) and a known substrate for tacrolimus, in determining the regional intestinal permeability of tacrolimus in rats. Thus, isolated segments of rat jejunum, ileum, or colon were perfused with tacrolimus solutions containing polyethoxylated hydrogenated castor oil 60 surfactant, and with or without verapamil, a P-gp substrate used to reverse the MDR phenotype. The results indicated that the intrinsic permeability of tacrolimus in the jejunum, calculated on the basis of the concentration of non-micellized free tacrolimus, was quite high (,,1.4,×,10,4 cm/s). The apparent permeability (Papp) in the jejunum was unaffected by the presence of verapamil; however, the Papp in the ileum and the colon increased significantly in the presence of verapamil and were similar to the values observed in the jejunum. The results suggest that systemic absorption of tacrolimus from the gastrointestinal tract could be significantly affected by P-gp efflux mechanisms. It is also possible that differences in P-gp function at various intestinal sites in a subject or at a given intestinal site in various subjects could lead to large intra- and interindividual variability in bioavailability of tacrolimus following oral administration. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:719,729, 2002 [source] CJY, an isoflavone, reverses P-glycoprotein-mediated multidrug-resistance in doxorubicin-resistant human myelogenous leukaemia (K562/DOX) cellsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2007Bian-Sheng Ji In an effort to develop safe and effective multidrug-resistance (MDR) reversing agents, the effect of CJY, an isoflavone, on the P-glycoprotein (P-gp) function and P-gp-mediated MDR was evaluated in doxorubicin-resistant human myelogenous leukaemia (K562/DOX) cells. The results showed that CJY caused a marked increase in accumulation and a notable decrease in efflux of rhodamine 123 (Rh123). The inhibitory effect of the agent on P-gp function persisted for at least 120 min after removal of 2.5 ,M CJY from the incubation medium. The doxorubicin-induced cytotoxicity, apoptosis and cell cycle perturbations were significantly potentiated by CJY. The intracellular accumulation of doxorubicin was also enhanced. The compound exhibited potent effects in-vitro on the reversal of P-gp-mediated MDR, suggesting that it could become a candidate as an effective MDR reversing agent in cancer chemotherapy. [source] Reversal of cancer multidrug resistance by green tea polyphenolsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2004Yuying Mei The aim of this study was to examine the effect and mechanism of green tea polyphenols (TP) on reversal of multidrug resistance (MDR) in a carcinoma cell line. Using the MTT assay, TP was examined for its modulating effects on the drug-resistant KB-A-1 cells and drug-sensitive KB-3,1 cells. When 10 ,g mL,1 (-)-epigallocatechin gallate (EGCG) or 40 ,g mL,1 TP were present simultaneously with doxorubicin (DOX), the IC50 of DOX on KB-A-1 cells decreased from 10.3 ± 0.9 ,g mL,1 to 4.2 ± 0.2 and 2.0 ± 0.1 ,g mL,1, respectively. TP and EGCG enhanced the DOX cytotoxicity on KB-A-1 cells by 5.2-and 2.5-times, respectively, but did not show a modulating effect on KB-3,1 cells. This indicated that both TP and EGCG had reversal effects on the MDR phenotype in-vitro. A KB-A-1 cell xenograft model was established, and the effect of TP on reversing MDR in-vivo was determined. Mechanistic experiments were conducted to examine the uptake, efflux and accumulation of DOX. Cloning and expression of the nucleotide binding domain of the human MDR1 gene in Escherichia coli was established, and by using colorimetry to examine the activity of ATPase to hydrolyse ATP, the ATPase activity of target nucleotide binding domain protein was determined. TP exerted its reversal effects through the inhibition of ATPase activity, influencing the function of P-glycoprotein, and causing a decreased extrusion of anticancer drug and an increased accumulation of anticancer drug in drug resistant cells. Using reverse transcription-polymerase chain reaction, the inhibitory effect of TP on MDR1 gene expression was investigated. Down-regulation of MDR1 gene expression was the main effect, which resulted in the reversal effect of TP on the MDR phenotype. TP is a potent MDR modulator with potential in the treatment of P-glycoprotein mediated MDR cancers. [source] Triton-X-100-modified polymer and microspheres for reversal of multidrug resistanceJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2001Zhi Liu Triton X-100 is a non-ionic detergent capable of reversing multidrug resistance (MDR) due to its interaction with cell membranes. However, it interacts with cells in a non-specific way, causing cytotoxicity. This work aimed to develop polymeric chemosensitizers that possess the ability to reverse MDR and lower toxic side effects. When being delivered to tumours, the polymeric chemosensitizers may also have longer retention times in tumours than the free detergent. Triton-X-100-immobilized dextran microspheres (T-MS) and inulin (T-IN) were prepared and characterized. Their cytotoxicity against multidrug-resistant Chinese hamster ovary cells (CHRC5) was compared with that of free Triton X-100 solutions. The in-vitro effect of the products on 3H-vinblastine accumulation by CHRC5 cells was determined. Both T-MS and T-IN showed a marked decrease in the cytotoxicity, as compared with free Triton solutions at equivalent concentrations. Drug accumulation by CHRC5 cells was increased over two fold in the presence of T-MS or T-IN. These results suggest that polymeric drug carriers with MDR-reversing capability and lower cytotoxicity may be prepared by immobilization of chemosensitizers. [source] Nosocomial infections and antimicrobial resistance in critical care medicineJOURNAL OF VETERINARY EMERGENCY AND CRITICAL CARE, Issue 1 2006Jennifer S. Ogeer-Gyles DVM Abstract Objective: To review the human and companion animal veterinary literature on nosocomial infections and antimicrobial drug resistance as they pertain to the critically ill patient. Data sources: Data from human and veterinary sources were reviewed using PubMed and CAB. Human data synthesis: There is a large amount of published data on nosocomially-acquired bloodstream infections, pneumonia, urinary tract infections and surgical site infections, and strategies to minimize the frequency of these infections, in human medicine. Nosocomial infections caused by multi-drug-resistant (MDR) pathogens are a leading cause of increased patient morbidity and mortality, medical treatment costs, and prolonged hospital stay. Epidemiology and risk factor analyses have shown that the major risk factor for the development of antimicrobial resistance in critically ill human patients is heavy antibiotic usage. Veterinary data synthesis: There is a paucity of information on the development of antimicrobial drug resistance and nosocomially-acquired infections in critically ill small animal veterinary patients. Mechanisms of antimicrobial drug resistance are universal, although the selection effects created by antibiotic usage may be less significant in veterinary patients. Future studies on the development of antimicrobial drug resistance in critically ill animals may benefit from research that has been conducted in humans. Conclusions: Antimicrobial use in critically ill patients selects for antimicrobial drug resistance and MDR nosocomial pathogens. The choice of antimicrobials should be prudent and based on regular surveillance studies and accurate microbiological diagnostics. Antimicrobial drug resistance is becoming an increasing problem in veterinary medicine, particularly in the critical care setting, and institution-specific strategies should be developed to prevent the emergence of MDR infections. The collation of data from tertiary-care veterinary hospitals may identify trends in antimicrobial drug resistance patterns in nosocomial pathogens and aid in formulating guidelines for antimicrobial use. [source] | |||||||||||||||||||