301 results on '"p-glycoproteins"'
Search Results
102. Researchers from Nanjing Medical University Detail Findings in ATP-Dependent Organic Anion Transporters (Hydrogen Sulfide Attenuates Lipopolysaccharide-induced Inflammation Via the P-glycoprotein and Nf-kappa B Pathway In Astrocytes).
- Published
- 2023
103. Boehringer Ingelheim Pharma GmbH & Co. KG Reports Findings in Omeprazole Therapy (Pharmacokinetic-Interactions of BI 425809, a Novel Glycine Transporter 1 Inhibitor, With Cytochrome P450 and P-Glycoprotein Substrates: Findings From In Vitro . . .).
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CYTOCHROME P-450 ,OMEPRAZOLE ,P-glycoprotein ,ATP-binding cassette transporters ,CARRIER proteins ,MEMBRANE transport proteins - Abstract
Boehringer Ingelheim Pharma GmbH & Co. KG Reports Findings in Omeprazole Therapy (Pharmacokinetic-Interactions of BI 425809, a Novel Glycine Transporter 1 Inhibitor, With Cytochrome P450 and P-Glycoprotein Substrates: Findings From In Vitro ...) Keywords: Antiulcer Agents; Europe; Germany; Glycine; Business; Ingelheim; Ion Pumps; Amino Acids; Cytochromes; Hemeproteins; Pharmacology; Glycoconjugates; P-Glycoproteins; Carrier Proteins; Pharmacokinetics; Clinical Research; Membrane Proteins; Drugs and Therapies; Health and Medicine; Peptides and Proteins; ATP-Binding Cassette Transporters; ATP-Dependent Organic Anion Transporters; Animal Health Companies; Anion Transport Proteins; Biopharmaceutical Companies; Clinical Trials and Studies; Gastrointestinal Agents; Glycoproteins; Healthcare Biotechnology Companies; Membrane Glycoproteins; Membrane Transport Proteins; Omeprazole Therapy; Pharmaceuticals; Proteins; Proton Pump Inhibitors EN Antiulcer Agents Europe Germany Glycine Business Ingelheim Ion Pumps Amino Acids Cytochromes Hemeproteins Pharmacology Glycoconjugates P-Glycoproteins Carrier Proteins Pharmacokinetics Clinical Research Membrane Proteins Drugs and Therapies Health and Medicine Peptides and Proteins ATP-Binding Cassette Transporters ATP-Dependent Organic Anion Transporters Animal Health Companies Anion Transport Proteins Biopharmaceutical Companies Clinical Trials and Studies Gastrointestinal Agents Glycoproteins Healthcare Biotechnology Companies Membrane Glycoproteins Membrane Transport Proteins Omeprazole Therapy Pharmaceuticals Proteins Proton Pump Inhibitors New research on Drugs and Therapies - Omeprazole Therapy is the subject of a report. This study evaluated potential drug-drug interactions with the glycine transporter-1 inhibitor BI 425809.". [Extracted from the article]
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- 2023
104. Study Results from State University of New York (SUNY) Buffalo Broaden Understanding of Kidney Transplants (Comparison of P-glycoprotein Function In Peripheral Blood Mononuclear Cells Ex Vivo In Stable Black and White Male and Female Kidney ...).
- Abstract
Buffalo, State:New York, United States, North and Central America, ATP-Dependent Organic Anion Transporters, Anion Transport Proteins, Biomedicine, Carrier Proteins, Drugs and Therapies, Glycoconjugates, Glycoproteins, Health and Medicine, Immunosuppressive Agents, Ion Pumps, Kidney Transplants, ATP-Binding Cassette Transporters, Membrane Glycoproteins, Membrane Proteins, Membrane Transport Proteins, Organ Transplants, Peptides and Proteins, Pharmaceuticals, Surgery, Tacrolimus Therapy, Transplant Medicine, Transplantation, P-Glycoproteins Keywords: Buffalo; State:New York; United States; North and Central America; ATP-Binding Cassette Transporters; ATP-Dependent Organic Anion Transporters; Anion Transport Proteins; Biomedicine; Carrier Proteins; Drugs and Therapies; Glycoconjugates; Glycoproteins; Health and Medicine; Immunosuppressive Agents; Ion Pumps; Kidney Transplants; Membrane Glycoproteins; Membrane Proteins; Membrane Transport Proteins; Organ Transplants; P-Glycoproteins; Peptides and Proteins; Pharmaceuticals; Surgery; Tacrolimus Therapy; Transplant Medicine; Transplantation EN Buffalo State:New York United States North and Central America ATP-Binding Cassette Transporters ATP-Dependent Organic Anion Transporters Anion Transport Proteins Biomedicine Carrier Proteins Drugs and Therapies Glycoconjugates Glycoproteins Health and Medicine Immunosuppressive Agents Ion Pumps Kidney Transplants Membrane Glycoproteins Membrane Proteins Membrane Transport Proteins Organ Transplants P-Glycoproteins Peptides and Proteins Pharmaceuticals Surgery Tacrolimus Therapy Transplant Medicine Transplantation 2023 FEB 2 (NewsRx) -- By a News Reporter-Staff News Editor at Drug Week -- A new study on Transplant Medicine - Kidney Transplants is now available. [Extracted from the article]
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- 2023
105. Phytotherapeutics: The Emerging Role of Intestinal and Hepatocellular Transporters in Drug Interactions with Botanical Supplements
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Ghulam Murtaza, Naveed Ullah, Farah Mukhtar, Shamyla Nawazish, Saiqa Muneer, and Mariam
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botanical supplements ,metabolism ,drug transporters ,P-glycoproteins ,organic anion transporting polypeptides ,Organic chemistry ,QD241-441 - Abstract
In herbalism, botanical supplements are commonly believed to be safe remedies, however, botanical supplements and dietary ingredients interact with transport and metabolic processes, affecting drug disposition. Although a large number of studies have described that botanical supplements interfere with drug metabolism, the mode of their interaction with drug transport processes is not well described. Such interactions may result in serious undesired effects and changed drug efficacy, therefore, some studies on interaction between botanical supplement ingredients and drug transporters such as P-gp and OATPs are described here, suggesting that the interaction between botanical supplements and the drug transporters is clinically significant.
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- 2017
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106. Convergent adaptive evolution - how insects master the challenge of cardiac glycoside-containing host plants.
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Dobler, Susanne, Petschenka, Georg, Wagschal, Vera, and Flacht, Lara
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INSECT-plant relationships , *PLANT adaptation , *PLANT evolution , *CARDIAC glycosides , *HOST plants - Abstract
Cardiac glycosides are a prime example of highly toxic plant secondary compounds, which block an essential transmembrane carrier in animals, the Na,K- ATPase. Nevertheless, over 100 insect species from diverse orders are known to feed on plants containing these compounds and in many cases these toxins are additionally sequestered without ill effect. We investigated whether the insects' adaptations for handling cardiac glycosides are based on a single physiological mechanism or whether various strategies have evolved across groups. We analyzed gene sequences of the Na,K- ATPase α-subunit from cardiac glycoside-adapted insects and screened for amino-acid substitutions which could alter the affinity of the enzyme toward cardiac glycosides. In representatives from five insect orders, separated by over 300 million years of evolutionary divergence, we uncovered amino-acid substitutions at identical positions. Especially striking is the convergent substitution of a histidine for the conserved asparagine at position 122, which we report here for the first time in a sawfly, Monophadnus latus Costa ( Hymenoptera: Tenthredinidae), and which was previously observed in the orders Lepidoptera, Coleoptera, Hemiptera, and Diptera. Prior in vitro expression and enzyme assays indicated that this substitution as well as combined substitutions with other residues result in a strongly increased cardenolide resistance of the Na,K- ATPase. The substitutions to threonine111 and histidine122 observed in M. latus are highly effective and were previously known only in lygaeid bugs. However, not all insects dealing with dietary cardenolides rely on target-site insensitivity as a mechanism of resistance. An impermeable gut or the exclusion of cardenolides from the nervous tissue with the greatest expression of Na,K- ATPase by the perineurium, the insect blood brain barrier, apparently represent alternative strategies. Immuno-histochemical data presented here support the existence of P-glycoprotein-like efflux transporters in insect gut membranes that might prevent the uptake of allelochemicals like cardenolides. [ABSTRACT FROM AUTHOR]
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- 2015
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107. Scabies-infested pregnant women: A critical therapeutic challenge
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Mourad Mokni, Olivier Chosidow, Charlotte Bernigaud, Sophie Gil, Amandine Weill, and Elisabeth Elefant
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Physiology ,Maternal Health ,Ectoparasitic Infections ,RC955-962 ,Glycobiology ,Benzoates ,Biochemistry ,Pediatrics ,law.invention ,Scabies ,Medical Conditions ,Randomized controlled trial ,law ,Pregnancy ,Arctic medicine. Tropical medicine ,Medicine and Health Sciences ,Breast Milk ,Skin ,Pharmaceutics ,Obstetrics and Gynecology ,Body Fluids ,Viewpoints ,Chemistry ,Infectious Diseases ,Breast Feeding ,Milk ,Physical Sciences ,Female ,Macrolides ,Public aspects of medicine ,RA1-1270 ,Anatomy ,Neglected Tropical Diseases ,Adult ,medicine.medical_specialty ,Drug Research and Development ,Tunisia ,Decision Making ,Sexually Transmitted Diseases ,Breast milk ,Research and Analysis Methods ,Beverages ,Pharmacotherapy ,Drug Therapy ,Internal medicine ,medicine ,Parasitic Diseases ,Humans ,Lactation ,Clinical Trials ,P-Glycoproteins ,Glycoproteins ,Nutrition ,Pharmacology ,Ivermectin ,business.industry ,Public Health, Environmental and Occupational Health ,Chemical Compounds ,Biology and Life Sciences ,medicine.disease ,Tropical Diseases ,Randomized Controlled Trials ,Diet ,Women's Health ,Salts ,Pregnant Women ,Clinical Medicine ,Neonatology ,business ,Breast feeding - Published
- 2021
108. Chapter One - ABC Transporters and Their Role in Protecting Insects from Pesticides and Their Metabolites.
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Merzendorfer, Hans
- Abstract
Insects are frequently exposed to toxic compounds either naturally produced by host plants to prevent feeding damage or artificially manufactured by man to control herbivores and vectors of diseases. As a result from co-evolutionary adaptation, many of these insects have developed strategies to avoid exposure or eliminate toxic effects by biotransformation and/or reduction of the effective cytosolic concentrations. The elimination of toxic compounds frequently involves phase I and phase II reactions which functionalise the molecules and increase their solubility in water. Excretion in turn may rely on the activity of ATP-binding cassette (ABC) transporters, integral membrane proteins of the ABC superfamily that utilise the energy derived from ATP hydrolysis to translocate a variety of different physiological metabolites and xenobiotics. In recent years, ABC transporters have raised special interest, because multidrug resistance-associated ABC genes particularly of subfamilies B and C have been linked with insecticide resistance. In addition, some ABC transporters have been shown to directly mediate toxic effects of insecticides and biopesticides, and several inhibitors may prove useful in potentiating insecticide toxicity. Increasing the knowledge on the specific physiological functions of ABC transporters and elucidation of ABC-mediated resistance mechanisms may help to identify novel compounds for insect control that are highly selective and environmentally safe. [ABSTRACT FROM AUTHOR]
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- 2014
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109. Effects of cholesterol content on activity of P-glycoproteins and membrane physical state, and consequences for anthelmintic resistance in the nematode Haemonchus contortus
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Isabelle Grasseau, Mickaël Riou, Elisabeth Blesbois, Christine Koch, Fabrice Guégnard, D. Kerboeuf, Yves Le Vern, Riou, Mickaël, Plateforme d'Infectiologie Expérimentale (PFIE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Infectiologie et Santé Publique (UMR ISP), Université de Tours-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Région centre-Val de Loire, Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
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Drug Resistance ,ATP-binding cassette transporter ,Anthelmintics ,Cholesterol ,Eggshell ,Fluidity ,MβCD ,P-glycoproteins ,Parasite ,Resistance ,030308 mycology & parasitology ,chemistry.chemical_compound ,Membrane fluidity ,nématode ,anthelmintics ,0303 health sciences ,biology ,eggshell ,Microbiology and Parasitology ,cholestérol ,haemoncus contortus ,Microbiologie et Parasitologie ,Cell biology ,[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology ,Infectious Diseases ,Membrane ,parasite ,Haemonchus ,Research Article ,Haemonchus contortus ,ATP Binding Cassette Transporter, Subfamily B ,Membrane Fluidity ,Veterinary (miscellaneous) ,fluidity ,résistance anthelmintique ,Xenobiotics ,lcsh:Infectious and parasitic diseases ,resistance ,03 medical and health sciences ,Animal Shells ,Animals ,lcsh:RC109-216 ,mβcd ,030304 developmental biology ,Cell Membrane ,cholesterol ,Transporter ,glycoprotéine membranaire ,biology.organism_classification ,p-glycoproteins ,chemistry ,Insect Science ,Animal Science and Zoology ,Parasitology ,Xenobiotic - Abstract
Eukaryote plasma membranes protect cells from chemical attack. Xenobiotics, taken up through passive diffusion, accumulate in the membranes, where they are captured by transporters, among which P-glycoproteins (Pgps). In nematodes such as Haemonchus contortus, eggshells and cuticles provide additional protective barriers against xenobiotics. Little is known about the role of these structures in the transport of chemical molecules. Pgps, members of the ABC transporter family, are present in eggshells and cuticles. Changes in the activity of these proteins have also been correlated with alterations in lipids, such as cholesterol content, in eggshells. However, the cellular mechanisms underlying these effects remain unclear. We show here that an experimental decrease in the cholesterol content of eggshells of Haemonchus contortus, with Methyl-beta-CycloDextrin (MβCD), results in an increase in membrane fluidity, favouring Pgp activity and leading to an increase in resistance to anthelmintics. This effect is modulated by the initial degree of anthelminthic resistance of the eggs. These results suggest that eggshell fluidity plays a major role in the modulation of Pgp activity. They confirm that Pgp activity is highly influenced by the local microenvironment, in particular sterols, as observed in some vertebrate models. Thus, eggshell barriers could play an active role in the transport of xenobiotics.Effets de la teneur en cholestérol sur l’activité des glycoprotéines P et sur l’état physique de la membrane, et conséquences pour la résistance aux anthelminthiques chez le nématode Haemonchus contortus.Les membranes plasmiques des eucaryotes protègent les cellules contre les attaques chimiques. Les xénobiotiques, absorbés par diffusion passive, s’accumulent dans les membranes où ils sont capturés par des transporteurs, parmi lesquels les glycoprotéines P (Pgp). Chez les nématodes, les coques des œufs et les cuticules constituent des barrières de protection supplémentaires contre les xénobiotiques. On en sait peu sur le rôle de ces structures dans le transport des molécules chimiques. Les Pgp, membres de la famille des transporteurs ABC, sont présents dans les coques et les cuticules. Des changements dans l’activité de ces protéines ont également été mis en corrélation avec des altérations des lipides, tels que la teneur en cholestérol, des coques des œufs. Cependant, les mécanismes cellulaires sous-jacents à ces effets restent flous. Nous montrons ici que la diminution expérimentale de la teneur en cholestérol des coques des œufs d’Haemonchus contortus, avec la méthyl-beta-cyclodextrine (MβCD), entraîne une augmentation de la fluidité membranaire favorisant l’activité des Pgp et une augmentation de la résistance aux anthelminthiques. Cet effet est modulé par le degré initial de résistance aux anthelminthiques des œufs. Ces résultats suggèrent que la fluidité de la coque joue un rôle majeur dans la modulation de l’activité des Pgp. Ils confirment que l’activité des Pgp est fortement influencée par le microenvironnement local, en particulier les stérols, comme observé dans certains modèles de vertébrés. Ainsi, les barrières de coques des oeufs pourraient jouer un rôle actif dans le transport des xénobiotiques.
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- 2020
110. The potential of Hypoxis hemerocallidea for herb-drug interaction.
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Fasinu, Pius S., Gutmann, Heike, Schiller, Hilmar, Bouic, Patrick J., and Rosenkranz, Bernd
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HYPOXEMIA , *DRUG-herb interactions , *HYPOXIDACEAE , *PLANT extracts , *AIDS , *CYTOCHROME P-450 , *ORAL drug administration , *CARRIER proteins - Abstract
Context: Aqueous decoction of Hypoxis hemerocallidea Fisch. & C.A. Mey. (Hypoxidaceae) ( Hypoxis) is widely consumed in Southern Africa by people living with HIV/AIDS, some of whom are on ARV and other medications. Objective: The aim of this study was to investigate the potential of the crude aqueous extracts of Hypoxis to inhibit major forms of CYP450 and transport proteins. Materials and methods: Corms of Hypoxis were water-extracted and incubated (in graded concentrations: 1--100 µg/mL) with human liver microsomes (20 min) to monitor the effects on phenacetin O-deethylation, coumarin 7-hydroxylation, bupropion hydroxylation, paclitaxel 6α-hydroxylation, diclofenac 4′-hydroxylation, S-mephenytoin 4′-hydroxylation, bufuralol 1′-hydroxylation, chlorzoxazone 6-hydroxylation, midazolam 1′-hydroxylation and testosterone 6β-hydroxylation as markers for the metabolic activities of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4/5, respectively. The generation of metabolites were monitored and quantified with the aid of LC-MS/MS. The potential of the extracts to inhibit human ATP-binding cassette transporter activity was assessed using recombinant MDCKII and LLC-PK1 cells over-expressing human breast cancer resistant protein and human P-glycoprotein , respectively (with Ko143 and cyclosporin A as positive controls). Similar assessment was performed with human organic anion transporting polypeptide (OATP1B1 and OATP1B3) using recombinant HEK293 cells over-expressing OATP1B1 and OATP1B3, respectively (with rifamycin and 10 µM atorvastatin as positive controls). Results: Extracts of Hypoxis inhibited the production of the metabolites of the substrates of the following enzymes (as compared to controls) with the indicated IC50 values (µg/mL): CYP1A2 (120.6), CYP2A6 (210.8), CYP2B6 (98.5), CYP2C8 (195.2), CYP2C9 (156) and CYP3A4/5 (185.4). The inhibition of the uptake activity of OATP1B1 and OATP1B3 were also observed with IC50 values of 93.4 and 244.8 μg/mL, respectively. Discussion: Extract concentrations higher than the estimated IC50 values are achievable in the gastrointestinal tract when traditional doses of Hypoxis are considered. This may have profound effects on presystemic metabolism of the drug substrates. If absorbed, systemic inhibition of metabolic enzymes/transporters by Hypoxis may be expected. Conclusion: The result suggests that there is the potential for HDI between Hypoxis and the substrates of the affected enzymes/transporters, if sufficient in vivo concentration of Hypoxis extracts is attained. [ABSTRACT FROM AUTHOR]
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- 2013
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111. P-glycoproteins play a role in ivermectin resistance in cyathostomins
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J.B. Matthews, Jürgen Krücken, Faith Burden, Gina Pinchbeck, Laura E Peachey, Anne Lespine, G. von Samson-Himmelstjerna, Jane E. Hodgkinson, Institute of Infection and Global Health, University of Liverpool, Moredun Research Institute [Penicuik, UK] (MRI), Donkey Sanctuary, Partenaires INRAE, ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Institute for Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, and Peachey, L.E.
- Subjects
0301 basic medicine ,Drug Resistance/genetics ,Levamisole/pharmacology ,[SDV]Life Sciences [q-bio] ,Horses/parasitology ,Drug Resistance ,ATP-binding cassette transporter ,Pharmacology ,Lactones/pharmacology ,Larva/drug effects ,Toxicology ,Lactones ,P-glycoproteins ,Ivermectin ,Anthelmintics/pharmacology ,Pharmacology (medical) ,Anthelmintic ,Cyathostomins ,Anthelmintic resistance ,Anthelmintics ,Strongyloidea ,chemistry.chemical_classification ,biology ,ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors ,030108 mycology & parasitology ,3. Good health ,Infectious Diseases ,Strongyloidea/drug effects ,Larva ,embryonic structures ,medicine.drug ,ATP Binding Cassette Transporter, Subfamily B ,Article ,lcsh:Infectious and parasitic diseases ,03 medical and health sciences ,In vivo ,biology.animal ,medicine ,Animals ,lcsh:RC109-216 ,Horses ,Ivermectin/pharmacology ,Third stage larvae ,urogenital system ,In vitro ,030104 developmental biology ,Levamisole ,chemistry ,Parasitology ,Equidae ,Glycoprotein - Abstract
Anthelmintic resistance is a global problem that threatens sustainable control of the equine gastrointestinal cyathostomins (Phylum Nematoda; Superfamily Strongyloidea). Of the three novel anthelmintic classes that have reached the veterinary market in the last decade, none are currently licenced in horses, hence current control regimens focus on prolonging the useful lifespan of licenced anthelmintics. This approach would be facilitated by knowledge of the resistance mechanisms to the most widely used anthelmintics, the macrocyclic lactones (ML). There are no data regarding resistance mechanisms to MLs in cyathostomins, although in other parasitic nematodes, the ABC transporters, P-glycoproteins (P-gps), have been implicated in playing an important role. Here, we tested the hypothesis that P-gps are, at least in part, responsible for reduced sensitivity to the ML ivermectin (IVM) in cyathostomins; first, by measuring transcript levels of pgp-9 in IVM resistant versus IVM sensitive third stage larvae (L3) pre-and post-IVM exposure in vitro. We then tested the effect of a range of P-gp inhibitors on the effect of IVM against the same populations of L3 using the in vitro larval development test (LDT) and larval migration inhibition test (LMIT). We demonstrated that, not only was pgp-9 transcription significantly increased in IVM resistant compared to IVM sensitive L3 after anthelmintic exposure (p, Graphical abstract Image 1, Highlights • Pgp-9 transcript levels were higher in ivermectin resistant versus susceptible cyathostomin populations. • P-gp inhibitors increased ivermectin effect against cyathostomins in vitro. • P-gp activity may play a role in ivermectin resistance in cyathostomins.
- Published
- 2017
112. Development and Validation of Liquid Chromatography-Tandem Mass Spectrometry Method for Detection and Quantification of Flunisolide in Tissue Culture Medium.
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Jadhav, M.P., Tang, Y., and Hochhaus, G.
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LIQUID chromatography-mass spectrometry , *CHEMICAL detectors , *TISSUE culture , *DEXAMETHASONE , *LIQUID-liquid extraction , *SEPARATION (Technology) , *ATMOSPHERIC pressure - Abstract
A robust, sensitive, and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method capable of quantifying flunisolide in the tissue culture matrix was developed and validated. Both flunisolide and dexamethasone (internal standard) were extracted from tissue culture medium, with 5% fetal bovine serum, 1% nonessential amino acids, and 1% penicillin/streptomycin by simple liquid–liquid extraction. The analytes were chromatographically separated (10 ng/mL for flunisolide) using a C8 column (4.6 mm × 150 mm; 5 µm particle size). The mobile phase was comprised of methanol:water (80:20v/v). The analytes were separated at baseline within 2.5 min. using a flow rate of 1 mL/min. Mass spectrometry detection was carried out in negative atmospheric pressure chemical ionization mode. The calibration curves for the analyte were linear over the range of 10–200 ng/mL (R2 ≥ 0.9968,n = 6). The inter and intra-batch mean percent accuracy ranged within 97.7–110.6% and the precision range was 3.5–10.4% (% coefficient of variation ≤15%). Stability studies revealed that the analyte was stable in the matrix for at least six hours at room temperature and at the end of three successive freeze and thaw cycles. The method reported here is specific for flunisolide quantification was also used in monolayer efflux assay using CaCo2cell lines, which will eventually aid P- glycoprotein transport studies for flunisolide. [ABSTRACT FROM AUTHOR]
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- 2013
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113. Potential contribution of P-glycoproteins to macrocyclic lactone resistance in the cattle parasitic nematode Cooperia oncophora.
- Author
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Demeler, Janina, Krücken, Jürgen, AlGusbi, Salha, Ramünke, Sabrina, De Graef, Jessie, Kerboeuf, Dominique, Geldhof, Peter, Pomroy, William E., and von Samson-Himmelstjerna, Georg
- Subjects
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P-glycoprotein , *MACROCYCLIC compounds , *LACTONES , *IVERMECTIN , *DRUG resistance , *PARASITIC nematodes in mammals , *COOPERIA (Nematodes) - Abstract
Abstract: Resistance against macrocyclic lactones such as ivermectin is widespread among parasitic gastrointestinal nematodes of small ruminants and is rapidly increasing in cattle parasites. ABC transporters of the subfamily B, the so-called P-glycoproteins (Pgps) have been frequently implicated in ivermectin resistance and are a major cause of multi-drug resistance in protozoa and helminths. The Pgp inhibitor verapamil (VPL) dramatically enhanced susceptibility of the cattle parasitic nematode Cooperia oncophora to ivermectin in vitro as measured in a larval developmental assay and a larval migration inhibition assay using third stage larvae. Moreover, VPL completely restored susceptibility to ivermectin in a resistant isolate resulting in virtually identical dose–response curves of susceptible and resistant isolates in the presence of VPL. Further characterisation of the molecular mechanisms resulting in Pgp-mediated ivermectin resistance is still hampered by the lack of molecular and biochemical information for Pgps of parasitic nematodes. Using PCR with degenerate primers, fragments of four different C. oncophora Pgps could be amplified and the Conpgp-2, previously implicated in macrocyclic lactone resistance in Haemonchus contortus, and Conpgp-3 full-length cDNAs were obtained by RACE PCR. The pgp sequences presented here contribute important data required to systematically screen resistant C. oncophora isolates for up- or down-regulation of Pgps and for the detection of single nucleotide polymorphisms in Pgps to detect selection of specific Pgp alleles by anthelmintics as early as possible. [Copyright &y& Elsevier]
- Published
- 2013
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114. P-glycoproteins and other multidrug resistance transporters in the pharmacology of anthelmintics: Prospects for reversing transport-dependent anthelmintic resistance.
- Author
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Lespine, Anne, Ménez, Cécile, Bourguinat, Catherine, and Prichard, Roger K.
- Subjects
GLYCOPROTEINS ,MULTIDRUG resistance ,PHARMACOLOGY ,ANTHELMINTICS ,ATP-binding cassette transporters ,IVERMECTIN ,PHARMACOKINETICS - Abstract
Abstract: Parasitic helminths cause significant disease in animals and humans. In the absence of alternative treatments, anthelmintics remain the principal agents for their control. Resistance extends to the most important class of anthelmintics, the macrocyclic lactone endectocides (MLs), such as ivermectin, and presents serious problems for the livestock industries and threatens to severely limit current parasite control strategies in humans. Understanding drug resistance is important for optimizing and monitoring control, and reducing further selection for resistance. Multidrug resistance (MDR) ABC transporters have been implicated in ML resistance and contribute to resistance to a number of other anthelmintics. MDR transporters, such as P-glycoproteins, are essential for many cellular processes that require the transport of substrates across cell membranes. Being overexpressed in response to chemotherapy in tumour cells and to ML-based treatment in nematodes, they lead to therapy failure by decreasing drug concentration at the target. Several anthelmintics are inhibitors of these efflux pumps and appropriate combinations can result in higher treatment efficacy against parasites and reversal of resistance. However, this needs to be balanced against possible increased toxicity to the host, or the components of the combination selecting on the same genes involved in the resistance. Increased efficacy could result from modifying anthelmintic pharmacokinetics in the host or by blocking parasite transporters involved in resistance. Combination of anthelmintics can be beneficial for delaying selection for resistance. However, it should be based on knowledge of resistance mechanisms and not simply on mode of action classes, and is best started before resistance has been selected to any member of the combination. Increasing knowledge of the MDR transporters involved in anthelmintic resistance in helminths will play an important role in allowing for the identification of markers to monitor the spread of resistance and to evaluate new tools and management practices aimed at delaying its spread. [Copyright &y& Elsevier]
- Published
- 2012
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115. Nanomedicine against multidrug resistance in cancer treatment.
- Author
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Jie Gao, Si-Shen Feng, and Yajun Guo
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- 2012
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116. Effect of P-glycoprotein-mediated efflux on cerebrospinal fluid concentrations in rhesus monkeys
- Author
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Tang, Cuyue, Kuo, Yuhsin, Pudvah, Nicole T., Ellis, Joan D., Michener, Maria S., Egbertson, Melissa, Graham, Samuel L., Cook, Jacquelynn J., Hochman, Jerome H., and Prueksaritanont, Thomayant
- Subjects
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GLYCOPROTEINS , *CEREBROSPINAL fluid , *RHESUS monkeys , *LABORATORY monkeys , *EFFECT of drugs on the brain , *CENTRAL nervous system , *BLOOD-brain barrier , *PHYSIOLOGY , *THERAPEUTICS - Abstract
Abstract: Brain penetration of drugs which are subject to P-glycoprotein (Pgp)-mediated efflux is attenuated, as manifested by the fact that the cerebrospinal fluid concentration (C CSF), a good surrogate of the unbound brain concentration (C ub), is lower than the unbound plasma concentration (C up) for Pgp substrates. In rodents, the attenuation magnitude of brain penetration by Pgp-mediated efflux has been estimated by correlating the ratio of CSF to plasma exposures (C CSF/C p) with the unbound fraction in plasma (f u) upon the incorporation of the in vivo or in vitro Pgp-mediated efflux ratios (ERs). In the present work, we investigated the impact of Pgp-mediated efflux on C CSF in monkeys. Following intravenous administration to cisterna magna ported rhesus monkeys, the CSF and plasma concentrations were determined for 25 compounds from three discovery programs. We also evaluated their f u in rhesus plasma and ER in human and African green monkey MDR-transfected LLC-PK1 cells. These compounds varied significantly in the f u (0.025–0.73), and 24 out of 25 are considered Pgp substrates based on their appreciable directional transport (ER>2). The C CSF/C p was significantly lower than the corresponding f u (≥3-fold) for 16 compounds regardless of a significant correlation (R 2 =0.59, p =4×10−5) when the C CSF/C p was plotted against the f u. When the f u was normalized to the ER (f u/ER) the correlation was improved (R 2 =0.75, p =8×10−8). More importantly, only one compound showed the C CSF/C p that exceeded 3-fold of the normalized f u. The results suggest that the impact of Pgp-mediated efflux in monkeys, similar to the case in rodents, is reasonably reflected by the gradient between the free concentrations in plasma and in CSF. Therefore, f u and Pgp ER may serve as useful measurements in estimating in vivo C CSF/C p ratios in monkeys, and potentially in humans. [Copyright &y& Elsevier]
- Published
- 2009
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117. Development of predictive in silico model for cyclosporine- and aureobasidin-based P-glycoprotein inhibitors employing receptor surface analysis
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Zalloum, Hiba M. and Taha, Mutasem O.
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CYCLOSPORINE , *IMMUNOSUPPRESSIVE agents , *P-glycoprotein , *PHARMACOLOGY , *GLYCOPROTEINS - Abstract
Abstract: P-glycoprotein (Pgp) is implicated in multiple drug resistance (MDR) exhibited by several types of cancer against a multitude of anticancer chemotherapeutic agents. This problem prompted several research groups to search for effective P-gp inhibitors. Cyclosporine A (CsA), aureobasidin A (AbA) and related analogues were reported to possess potent inhibitory actions against Pgp. In this work we employed receptor surface analysis (RSA) to construct two satisfactory receptor surface models (RSMs) for cyclosporine- and aureobasidin-based Pgp inhibitors. These pseudoreceptors were combined to achieve satisfactory three-dimensional quantitative structure activity relationship (3D-QSAR) for 68 different cyclosporine and aureobasidin derivatives. Upon validation against an external set of 16 randomly selected Pgp inhibitors, the optimal 3D-QSAR was found to be self-consistent and predictive (, ). The resulting 3D-QSAR was employed to probe the structural factors that control the inhibitory activities of cyclosporine and aureobasidin analogues against Pgp. [Copyright &y& Elsevier]
- Published
- 2008
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118. Reduced genetic variation of an Onchocerca volvulus ABC transporter gene following treatment with ivermectin
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Ardelli, B.F. and Prichard, R.K.
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ONCHOCERCA volvulus ,GENES ,IVERMECTIN ,GENETIC polymorphisms - Abstract
Summary: In some trichostrongyloid nematodes, the early stages of ivermectin (IVM) resistance have been characterized by a shift in allele frequency and reduced polymorphism at loci of P-glycoprotein genes, glutamate-gated chloride channel genes and γ-aminobutyric acid receptor genes. Mass treatment with IVM is an integral component of the onchocerciasis control programmes. Genetic variation of an Onchocerca volvulus ABC transporter homologue (OvABC-3) from several populations in Africa was examined to determine whether an association exists between alleles of this gene and IVM treatment. Allelic variation in a non-treated population from Ghana showed this locus to be highly polymorphic. However, variability was reduced in IVM-treated populations. χ
2 analysis of polymorph frequencies showed significant differences between untreated and treated samples collected in Ghana in 1999. There was less variability in this gene in samples collected in 2002 compared with the 1999 samples. In some treated populations, there appeared to be selection on OvABC-3-C. The observed reduction in variability could be expected in a control programme in which prevalence and intensity of infections are markedly reduced after years of vector control and IVM distribution. The reduction in polymorphism may not in itself indicate that these O. volvulus are IVM resistant, although it could indicate that selection for resistance is occurring. [Copyright &y& Elsevier]- Published
- 2007
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119. Tetrazole compounds: The effect of structure and pH on Caco-2 cell permeability.
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Young, Amber M., Audus, Kenneth L., Proudfoot, John, and Yazdanian, Mehran
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- *
TETRAZOLES , *HETEROCYCLIC compounds , *P-glycoprotein , *DRUGS , *PERMEABILITY , *GLYCOPROTEINS - Abstract
A tetrazole ring is often used in drug discovery as a replacement for the carboxylic acid group. Previous work indicates that compounds containing a tetrazole moiety show asymmetric permeability in Caco-2 cells characteristic of an efflux transporter substrate. The aim of this study is to determine which transporters are responsible for polarization of transport of tetrazole-containing compounds in Caco-2 cells. Results indicate that only select compounds with tetrazole moieties display asymmetric transport. Three compounds (two commercial drug products and one druglike structure) were selected for further studies. Losartan appears to be primarily a P-glycoprotein (P-gp) substrate, as previously reported, but MRP inhibitors such as MK-571 and rifampicin also affect the difference between apical to basolateral and basolateral to apical transport. Pemirolast and phenyltetrazole derivative C are sensitive to P-gp inhibition, but transport seems to be mediated by one or more of the MRP family of transporters. Additionally, lowering the pH from 7.4 to 4.0 eliminates the polarization of permeability in Caco-2 cells. These studies indicate that some tetrazole compounds are susceptible to efflux, therefore caution should be used when choosing an appropriate functional group to replace carboxylic acids when synthesizing a drug candidate. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:717–725, 2006 [ABSTRACT FROM AUTHOR]
- Published
- 2006
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120. Exploring Jolkinol D Derivatives To Overcome Multidrug Resistance in Cancer
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Mariana Reis, Omar Ahmed, Maria-José U. Ferreira, Gabriella Spengler, Hermann Lage, Joseph Molnár, and CIIMAR - Centro Interdisciplinar de Investigação Marinha e Ambiental
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0301 basic medicine ,verapamil ,Pharmaceutical Science ,Apoptosis ,animal cell ,ABCB1 protein, human ,jolkinol d derivative ,diterpene ,Analytical Chemistry ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,stereospecificity ,Euphorbia ,Multidrug Resistance Protein 1 ,jolkinoate a ,caspase 3 ,Drug Discovery ,jolkinoate b ,jolkinoate c ,Jolkinol D ,Moiety ,jolkinoate d ,animal ,Cytotoxicity ,multidrug resistance protein 1 ,antineoplastic agent ,stomach cancer ,jolkinoate n ,Molecular Structure ,Caspase 3 ,jolkinoate o ,Chemistry ,jolkinoate p ,jolkinoate q ,jolkinoate r ,jolkinoate s ,jolkinoate t ,jolkinoate u ,chemosensitization ,unclassified drug ,enzyme activity ,3. Good health ,chemosensitivity ,hydrolysis ,030220 oncology & carcinogenesis ,Molecular Medicine ,Diterpenes ,ATP Binding Cassette Transporter, Subfamily B ,Macrocyclic Compounds ,Stereochemistry ,Chemical structure ,antineoplastic activity ,malignant neoplasm ,chemistry ,Lymphoma, T-Cell ,doxorubicin ,Article ,Structure-Activity Relationship ,03 medical and health sciences ,pancreas cancer ,multidrug resistance ,Cell Line, Tumor ,Animals ,Humans ,Structure–activity relationship ,macrocyclic compound ,controlled study ,human ,P-Glycoproteins ,mouse ,lathyrane ,structure activity relation ,Pharmacology ,nonhuman ,drug resistance ,drug potentiation ,isolation and purification ,human cell ,Organic Chemistry ,tumor cell line ,multidrug resistance protein ,Antineoplastic Agents, Phytogenic ,Multiple drug resistance ,jolkinocarbonate b ,jolkinocarbonate a ,030104 developmental biology ,Complementary and alternative medicine ,Doxorubicin ,Drug Resistance, Neoplasm ,drug effects ,chemical structure ,Diterpene ,metabolism ,Chemosensitivity assay - Abstract
Macrocyclic monoacyl lathyrane derivatives bearing a benzoyl moiety were previously found to be strong ABCB1 modulators. To explore the effects of different substituents of the aromatic moiety, 14 new compounds (1.1-1.7, 1.10, and 2.1-2.4) were prepared from jolkinol D (1), obtained from Euphorbia piscatoria, and from jolkinodiol (2), its hydrolysis derivative. Compounds 1.8 and 1.9, having aliphatic moieties, were also obtained. The reversal of ABCB1-mediated MDR was evaluated through functional and chemosensitivity assays on the human ABCB1-gene-transfected L5178Y mouse T-lymphoma cell line. Structure-activity relationships showed that addition of electron-donating groups to the aromatic moiety improved the activity. The effects on the ATPase activity of the strongest modulator (1.3) and the inactive jolkinol D (1) were also investigated and compared. Moreover, in the chemosensitivity assay, most of the compounds interacted synergistically with doxorubicin. Compounds 1.1-1.10 and 2.1-2.4 were further assessed for their collateral sensitivity effect against the human cancer cells: EPG85-257 (gastric) and EPP85-181 (pancreatic), and the matching drug-selected cells EPG85-257RDB, EPG85-257RNOV, EPP85-181RDB, and EPP85-181RNOV. The most promising ones (1.8 and 1.10) along with compound 3, previously selected, were investigated as apoptosis inducers. The compounds were able to induce apoptosis through caspase-3 activation, with significant differences being observed between the parental and resistant cells. © 2017 The American Chemical Society and American Society of Pharmacognosy. This study was financially supported by Fundação para a Ciencia e a Tecnologia (FCT), Portugal (project PTDC/QEQ-MED/0905/2012; PhD grant SFRH/BD/72915/2010), German Egyptian Research Long-term Scholarship (GERLS) Program 2014 (57076387) provided by the German Academic Exchange Service (DAAD), and the contribution of the Foundation for Cancer Research Szeged, Hungary. We also acknowledge Carlos Cordeiro, Faculdade de Ciencias, Universidade de Lisboa, for HRMS data (FCT, REDE/1501/REM/2005).
- Published
- 2017
121. Multidrug resistance in parasites: ABC transporters, P-glycoproteins and molecular modelling
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Jones, P.M. and George, A.M.
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PARASITIC diseases , *PROTOZOA , *ARTHROPODA , *HELMINTHS - Abstract
Abstract: Parasitic diseases, caused by protozoa, helminths and arthropods, rank among the most important problems in human and veterinary medicine, and in agriculture, leading to debilitating sicknesses and loss of life. In the absence of vaccines and with the general failure of vector eradication programs, drugs are the main line of defence, but the newest drugs are being tracked by the emergence of resistance in parasites, sharing ominous parallels with multidrug resistance in bacterial pathogens. Any of a number of mechanisms will elicit a drug resistance phenotype in parasites, including: active efflux, reduced uptake, target modification, drug modification, drug sequestration, by-pass shunting, or substrate competition. The role of ABC transporters in parasitic multidrug resistance mechanisms is being subjected to more scrutiny, due in part to the established roles of certain ABC transporters in human diseases, and also to an increasing portfolio of ABC transporters from parasite genome sequencing projects. For example, over 100 ABC transporters have been identified in the Escherichia coli genome, but to date only about 65 in all parasitic genomes. Long established laboratory investigations are now being assisted by molecular biology, bioinformatics, and computational modelling, and it is in these areas that the role of ABC transporters in parasitic multidrug resistance mechanisms may be defined and put in perspective with that of other proteins. We discuss ABC transporters in parasites, and conclude with an example of molecular modelling that identifies a new interaction between the structural domains of a parasite P-glycoprotein. [Copyright &y& Elsevier]
- Published
- 2005
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122. Accumulation of ivermectin in the brain of sea bream, Sparus aurata after intraperitoneal administration
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Katharios, Pantelis, Pavlidis, Michalis, and Iliopoulou-Georgudaki, Joan
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IVERMECTIN , *BRAIN , *FISHES , *NEUROSCIENCES - Abstract
Ivermectin, which is widely used in veterinary and human, has been considered safe due to its inability to penetrate into the central nervous system of higher vertebrates. This paper presents data on the ability of the drug to cross the blood–brain barrier of the marine teleost sea bream, Sparus aurata and accumulate in the brain. The concentration of the drug in the brain and the serum of the fish was assessed by the use of a direct competitive ELISA commercial kit. Our results showed a rapid uptake of the substance by the brain of the fish reaching a maximum concentration of 98.9 ng g−1 8 h post treatment. The trend of the absorption of the drug in brain followed that of the blood. Concentration of the drug in the brain remained high at each sampling point over the 24 h duration of the experiment. In view of these findings, the need of study of the role of the blood–brain barrier and particularly the multidrug resistance mechanism in sea bream is outlined. [Copyright &y& Elsevier]
- Published
- 2004
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123. Formulation and Physiological and Biopharmaceutical Issues in the Development of Oral Lipid-Based Drug Delivery Systems.
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Wasan, Kishor M.
- Subjects
DRUG receptors ,DOSE-effect relationship in pharmacology ,POLYCYCLIC compounds - Abstract
The rapidly increasing availability of drug receptor structural characteristics has permitted the receptor-guided synthesis of potential new drug molecules. This synthesis strategy frequently results in the creation of polycyclic and highly hydrophobic compounds, with attendant poor oral bioavailability resulting from low solubility and slow dissolution rate in the primarily aqueous contents of the gastrointestinal (GI) tract. In an attempt to improve the solubility-limited bioavailability associated with these compounds, formulators have turned to the use of lipid excipients in which the compounds can be solubilized prior to oral administration. This new class of excipients presents the pharmaceutical scientist with a number of new challenges at all stages of the formulation development process, beginning with the excipient selection and stability assessment of the prototype formulation, up to and including scale-up and mass production of the final market-image product. The interaction of lipid-based formulations with the gastrointestinal system and associated digestive processes presents additional challenges and opportunities that will be understood more fully as we begin to unravel the intricacies of the GI processing of lipid excipients. For example, an increasing body of evidence has shown that certain lipids are capable of inhibiting both presystemic drug metabolism and drug efflux by the gut wall mediated by p-glycoprotein (PGP). And, it is well known that lipids are capable of enhancing lymphatic transport of hydrophobic drugs, thereby reducing drug clearance resulting from hepatic first-pass metabolism. This review addresses the current state of knowledge regarding oral lipid-based formulation development and scale-up issues and the physiological and biopharmaceutical aspects pertinent to the development of an orally bioavailable and efficacious dosage form. [ABSTRACT FROM AUTHOR]
- Published
- 2001
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124. Transepithelial transport of P-glycoprotein substrate by the Malpighian tubules of the desert locust
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Jeremy E. Niven, Marta Rossi, and Davide De Battisti
- Subjects
0301 basic medicine ,Malpighian tubule system ,Insecticides ,Physiology ,Glycobiology ,ATP-binding cassette transporter ,01 natural sciences ,Biochemistry ,010104 statistics & probability ,chemistry.chemical_compound ,Medicine and Health Sciences ,Cell Analysis ,P-glycoprotein ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Animals ,Biological Transport ,Body Fluids ,Grasshoppers ,Ion Transport ,Kinetics ,Malpighian Tubules ,Xenobiotics ,Transendothelial and Transepithelial Migration ,Multidisciplinary ,biology ,Physics ,Drosophila Melanogaster ,Eukaryota ,Classical Mechanics ,Agriculture ,Animal Models ,Insects ,Bioassays and Physiological Analysis ,Subfamily B ,Cell Division Analysis ,Experimental Organism Systems ,Physical Sciences ,Medicine ,Insect Pests ,Drosophila ,Anatomy ,Agrochemicals ,Research Article ,Member 1 ,Arthropoda ,Science ,ATP Binding Cassette Transporter ,Dye Dilution ,Context (language use) ,Fluid Mechanics ,Research and Analysis Methods ,Continuum Mechanics ,03 medical and health sciences ,Pests ,Model Organisms ,0101 mathematics ,Desert locust ,P-Glycoproteins ,Ion transporter ,Secretion ,Glycoproteins ,QL ,QP0001 ,Organisms ,Biology and Life Sciences ,Fluid Dynamics ,Locusts ,biology.organism_classification ,QP ,Invertebrates ,030104 developmental biology ,chemistry ,biology.protein ,Animal Studies ,Schistocerca ,Xenobiotic ,Physiological Processes - Abstract
Extrusion of xenobiotics is essential for allowing animals to remove toxic substances present in their diet or generated as a biproduct of their metabolism. By transporting a wide range of potentially noxious substrates, active transporters of the ABC transporter family play an important role in xenobiotic extrusion. One such class of transporters are the multidrug resistance P-glycoprotein transporters. Here, we investigated P-glycoprotein transport in the Malpighian tubules of the desert locust (Schistocerca gregaria), a species whose diet includes plants that contain toxic secondary metabolites. To this end, we studied transporter physiology using a modified Ramsay assay in which ex vivo Malpighian tubules are incubated in different solutions containing the P-glycoprotein substrate dye rhodamine B in combination with different concentrations of the P-glycoprotein inhibitor verapamil. To determine the quantity of the P-glycoprotein substrate extruded we developed a simple and cheap method as an alternative to liquid chromatography-mass spectrometry, radiolabelled alkaloids or confocal microscopy. Our evidence shows that: (i) the Malpighian tubules contain a P-glycoprotein; (ii) tubule surface area is positively correlated with the tubule fluid secretion rate; and (iii) as the fluid secretion rate increases so too does the net extrusion of rhodamine B. We were able to quantify precisely the relationships between the fluid secretion, surface area, and net extrusion. We interpret these results in the context of the life history and foraging ecology of desert locusts. We argue that P-glycoproteins contribute to the removal of xenobiotic substances from the haemolymph, thereby enabling gregarious desert locusts to maintain toxicity through the ingestion of toxic plants without suffering the deleterious effects themselves.
- Published
- 2019
125. 99mTc-MIBI uptake as a marker of mitochondrial membrane potential in cancer cells and effects of MDR1 and verapamil
- Author
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Kyung-Ho Jung, Seung Hwan Moon, Jin Hee Lee, Sun-pyo Hong, Jeeyun Lee, Kyung-Han Lee, Young Seok Cho, and Jin Won Park
- Subjects
0301 basic medicine ,Colorectal cancer ,Physiology ,Cell Membranes ,Glycobiology ,Cancer Treatment ,ATP-binding cassette transporter ,Matrix metalloproteinase ,Biochemistry ,0302 clinical medicine ,Fluorescence Microscopy ,Neoplasms ,Fluorescence microscope ,Tumor Cells, Cultured ,Medicine and Health Sciences ,Membrane potential ,Membrane Potential, Mitochondrial ,Microscopy ,Multidisciplinary ,Chemistry ,Light Microscopy ,Drug Resistance, Multiple ,Electrophysiology ,Oncology ,030220 oncology & carcinogenesis ,Medicine ,Cell lines ,Cellular Structures and Organelles ,Biological cultures ,medicine.drug ,Research Article ,Technetium Tc 99m Sestamibi ,medicine.medical_specialty ,ATP Binding Cassette Transporter, Subfamily B ,Imaging Techniques ,Science ,Membrane Potential ,03 medical and health sciences ,HT29 Cells ,Internal medicine ,Fluorescence Imaging ,medicine ,Humans ,neoplasms ,P-Glycoproteins ,HT29 cells ,Glycoproteins ,Colorectal Cancer ,Cell Membrane ,Cancers and Neoplasms ,Biology and Life Sciences ,Biological Transport ,Cell Biology ,medicine.disease ,Research and analysis methods ,030104 developmental biology ,Endocrinology ,Verapamil ,Cancer cell ,Radiopharmaceuticals - Abstract
We investigated the relation of 99mTc-MIBI uptake to mitochondrial membrane potential (MMP) in cancer cell lines and patient-derived tumor cells (PDCs). In T47D and HT29 cells with low MDR1 expression, FCCP dose-dependently reduced MMP and 99mTc-MIBI accumulation in similar patterns with nearly perfect linear relationships. T47D and HT29 cells with high MDR1 expression had low 99mTc-MIBI accumulation that was minimally affected by FCCP dose. In these cells, verapamil markedly increased 99mTc-MIBI accumulation to magnitudes that were excessive compared to MMP increase. Decreased plasma membrane potential by verapamil and its recovery by FCCP suggested that enhanced 99mTc-MIBI transport through modified plasma membranes contributed to the excess accumulation. Evaluation of three different colon cancer PDCs with low to modest MDR1 expression verified that FCCP significantly suppressed MMP and similarly reduced 99mTc-MIBI accumulation. Verapamil partially recovered both MMP and 99mTc-MIBI accumulation that was lowered by FCCP. Importantly, a high linear correlation was found (r = 0.865) between 99mTc-MIBI accumulation and MMP in these cells. These findings indicate that low baseline 99mTc-MIBI uptake that is markedly increased by verapamil represents cancer cells with high levels of MDR1 expression. However, in cancer cells with low or modest levels of MDR1 expression that do not markedly increase 99mTc-MIBI uptake by verapamil, the magnitude of uptake is largely dependent on cellular MMP.
- Published
- 2019
126. Transport of Alzheimer’s associated amyloid-β catalyzed by P-glycoprotein
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Lauren Ammerman, Gang Chen, John G. Wise, James W. McCormick, and Pia D. Vogel
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Adenosine Triphosphatase ,0301 basic medicine ,Tariquidar ,Cancer Treatment ,Glycobiology ,Ligands ,Molecular Dynamics ,Alzheimer's Disease ,Biochemistry ,Substrate Specificity ,Adenosine Triphosphate ,Computational Chemistry ,Medical Conditions ,0302 clinical medicine ,ATP hydrolysis ,Medicine and Health Sciences ,DU145 cells ,P-glycoprotein ,Multidisciplinary ,biology ,Chemistry ,Hydrolysis ,Monomers ,In vitro toxicology ,Neurodegenerative Diseases ,Enzymes ,Cell biology ,Molecular Docking Simulation ,Protein Transport ,medicine.anatomical_structure ,Oncology ,Neurology ,Blood-Brain Barrier ,Physical Sciences ,Disease Progression ,Quinolines ,Cell lines ,Medicine ,Biological cultures ,Protein Binding ,Signal Transduction ,Research Article ,medicine.drug ,Imaging Techniques ,Science ,Molecular Dynamics Simulation ,Research and Analysis Methods ,Blood–brain barrier ,03 medical and health sciences ,Protein Domains ,Alzheimer Disease ,Cell Line, Tumor ,Fluorescence Imaging ,Mental Health and Psychiatry ,medicine ,Humans ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,P-Glycoproteins ,Glycoproteins ,Amyloid beta-Peptides ,Phosphatases ,Biology and Life Sciences ,Proteins ,Substrate (chemistry) ,Transporter ,Polymer Chemistry ,Peptide Fragments ,030104 developmental biology ,Catalytic cycle ,Biocatalysis ,Enzymology ,biology.protein ,Protein Conformation, beta-Strand ,Dementia ,030217 neurology & neurosurgery - Abstract
P-glycoprotein (P-gp) is a critical membrane transporter in the blood brain barrier (BBB) and is implicated in Alzheimer’s disease (AD). However, previous studies on the ability of P-gp to directly transport the Alzheimer’s associated amyloid-β (Aβ) protein have produced contradictory results. Here we use molecular dynamics (MD) simulations, transport substrate accumulation studies in cell culture, and biochemical activity assays to show that P-gp actively transports Aβ. We observed transport of Aβ40 and Aβ42 monomers by P-gp in explicit MD simulations of a putative catalytic cycle. In in vitro assays with P-gp overexpressing cells, we observed enhanced accumulation of fluorescently labeled Aβ42 in the presence of Tariquidar, a potent P-gp inhibitor. We also showed that Aβ42 stimulated the ATP hydrolysis activity of isolated P-gp in nanodiscs. Our findings expand the substrate profile of P-gp, and suggest that P-gp may contribute to the onset and progression of AD.
- Published
- 2021
127. Genetic and pharmacological relationship between P-glycoprotein and increased cardiovascular risk associated with clarithromycin prescription: An epidemiological and genomic population-based cohort study in Scotland, UK
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Ify R. Mordi, Chim C. Lang, N. David Yanez, James D. Chalmers, Colin N. A. Palmer, and Benjamin K. Chan
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Male ,Epidemiology ,Myocardial Infarction ,Glycobiology ,Type 2 diabetes ,Cardiovascular Medicine ,030204 cardiovascular system & hematology ,Biochemistry ,Cohort Studies ,Medical Conditions ,0302 clinical medicine ,Antibiotics ,Clarithromycin ,Medicine and Health Sciences ,Medicine ,Drug Interactions ,030212 general & internal medicine ,Young adult ,Aged, 80 and over ,education.field_of_study ,Antimicrobials ,Hazard ratio ,Drugs ,Genomics ,General Medicine ,Middle Aged ,Anti-Bacterial Agents ,3. Good health ,Prescriptions ,Cardiovascular Diseases ,Research Design ,Engineering and Technology ,Female ,Research Article ,Biotechnology ,medicine.drug ,Cohort study ,Adult ,medicine.medical_specialty ,Adolescent ,Population ,Cardiology ,Bioengineering ,Research and Analysis Methods ,Microbiology ,Young Adult ,03 medical and health sciences ,Genomic Medicine ,Microbial Control ,Internal medicine ,Genetics ,Humans ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,education ,P-Glycoproteins ,Glycoproteins ,Aged ,Pharmacology ,business.industry ,Biology and Life Sciences ,Cardiovascular Disease Risk ,Amoxicillin ,medicine.disease ,Diabetes Mellitus, Type 2 ,Scotland ,Heart Disease Risk Factors ,Medical Risk Factors ,Pharmacogenomics ,business - Abstract
Background There are conflicting reports regarding the association of the macrolide antibiotic clarithromycin with cardiovascular (CV) events. A possible explanation may be that this risk is partly mediated through drug–drug interactions and only evident in at-risk populations. To the best of our knowledge, no studies have examined whether this association might be mediated via P-glycoprotein (P-gp), a major pathway for clarithromycin metabolism. The aim of this study was to examine CV risk following prescription of clarithromycin versus amoxicillin and in particular, the association with P-gp, a major pathway for clarithromycin metabolism. Methods and findings We conducted an observational cohort study of patients prescribed clarithromycin or amoxicillin in the community in Tayside, Scotland (population approximately 400,000) between 1 January 2004 and 31 December 2014 and a genomic observational cohort study evaluating genotyped patients from the Genetics of Diabetes Audit and Research Tayside Scotland (GoDARTS) study, a longitudinal cohort study of 18,306 individuals with and without type 2 diabetes recruited between 1 December 1988 and 31 December 2015. Two single-nucleotide polymorphisms associated with P-gp activity were evaluated (rs1045642 and rs1128503 –AA genotype associated with lowest P-gp activity). The primary outcome for both analyses was CV hospitalization following prescription of clarithromycin versus amoxicillin at 0–14 days, 15–30 days, and 30 days to 1 year. In the observational cohort study, we calculated hazard ratios (HRs) adjusted for likelihood of receiving clarithromycin using inverse proportion of treatment weighting as a covariate, whereas in the pharmacogenomic study, HRs were adjusted for age, sex, history of myocardial infarction, and history of chronic obstructive pulmonary disease. The observational cohort study included 48,026 individuals with 205,227 discrete antibiotic prescribing episodes (34,074 clarithromycin, mean age 73 years, 42% male; 171,153 amoxicillin, mean age 74 years, 45% male). Clarithromycin use was significantly associated with increased risk of CV hospitalization compared with amoxicillin at both 0–14 days (HR 1.31; 95% CI 1.17–1.46, p < 0.001) and 30 days to 1 year (HR 1.13; 95% CI 1.06–1.19, p < 0.001), with the association at 0–14 days modified by use of P-gp inhibitors or substrates (interaction p-value: 0.029). In the pharmacogenomic study (13,544 individuals with 44,618 discrete prescribing episodes [37,497 amoxicillin, mean age 63 years, 56% male; 7,121 clarithromycin, mean age 66 years, 47% male]), when prescribed clarithromycin, individuals with genetically determined lower P-gp activity had a significantly increased risk of CV hospitalization at 30 days to 1 year compared with heterozygotes or those homozygous for the non-P-gp–lowering allele (rs1045642 AA: HR 1.39, 95% CI 1.20–1.60, p < 0.001, GG/GA: HR 0.99, 95% CI 0.89–1.10, p = 0.85, interaction p-value < 0.001 and rs1128503 AA 1.41, 95% CI 1.18–1.70, p < 0.001, GG/GA: HR 1.04, 95% CI 0.95–1.14, p = 0.43, interaction p-value < 0.001). The main limitation of our study is its observational nature, meaning that we are unable to definitively determine causality. Conclusions In this study, we observed that the increased risk of CV events with clarithromycin compared with amoxicillin was associated with an interaction with P-glycoprotein., In an observational cohort study and pharmacogenetic analysis, Ify Mordi and colleagues investigate risks of cardiovascular-related hospitalization in individuals prescribed clarithromycin versus amoxicillin., Author summary Why was this study done? Macrolide antibiotics such as clarithromycin are frequently used for treatment of lower respiratory tract infections. Several studies have reported increased cardiovascular risk associated with clarithromycin prescription, including the Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease (CLARICOR) randomized-controlled trial. The mechanism behind this increased risk is unclear; however, it would be important to identify patients who might be at higher risk when prescribed clarithromycin in whom alternative antibiotics such as amoxicillin could be used. What did the researchers do and find? We conducted an observational study in 2 parts to examine the association between clarithromycin prescription and cardiovascular outcome. First, we performed a propensity-weighted observational population cohort analysis comparing clarithromycin versus amoxicillin prescription and cardiovascular outcome in patients in Tayside, Scotland. In this analysis, we found that that patients prescribed clarithromycin were significantly more likely to have a cardiovascular hospitalization at 0–14 days and 30 days to 1 year after prescription than those prescribed amoxicillin and that individuals who were co-prescribed P-glycoprotein substrates or inhibitors and clarithromycin had a significantly higher risk of cardiovascular hospitalization. To explore these findings further, we performed a pharmacogenomic study involving patients with available genotype data from the Genetics of Diabetes Audit and Research Tayside Scotland (GoDARTS) study. Using 2 genetic variants associated with P-glycoprotein activity (rs1045642 and rs1128503), we found that patients with the AA genotype, which for both variants is associated with reduced P-glycoprotein activity, had a significantly increased risk of cardiovascular hospitalization between 30 days and 1 year. What do these findings mean? Our findings raise the possibility that the observed association between clarithromycin prescription and increased cardiovascular risk could be mediated by P-glycoprotein. These results may have implications for clarithromycin use in patients taking P-glycoprotein inhibitors or with low genetically predicted P-glycoprotein activity.
- Published
- 2020
128. Effect of Pharmacological Modulation of Liver P-Glycoproteins on Cyclosporin A Biliary Excretion and Cholestasis A Study in Isolated Perfused Rat Liver.
- Author
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Monache, Marco, Gigliozzi, Alessandro, Benedetti, Antonio, Marucci, Luca, Bini, Adriano, Francia, Chiara, Papa, Emanuela, Cosimo, Emanuele, Fraioli, Flavia, Jezequel, Anne, and Alvaro, Domenico
- Abstract
In different cell types P-glycoproteins (P-gp)are involved in the transport of cyclosporin A (CyA).The aim of this study was to evaluate the effect of thepharmacological modulation of the hepatic P-gp on biliary secretion of CyA and on cholestasisinduced by acute administration of CyA in the isolatedperfused rat liver (IPRL). Verapamil was used as a P-gpspecific inhibitor and acetylaminofluorene (AAF) as a P-gp inducer. CyA biliary excretion wasdetermined by administering in the IPRL a tracer dose of[
3 H]CyA with or without verapamil or AAF. Theeffect on bile flow was evaluated by administering increasing doses of CyA (2.8, 8, and 20 mg/kgbody wt) in the IPRL. Morphological evidence of damagewas evaluated by optical and electron microscopy in theliver as well as in primary culture of rat hepatocytes exposed to CyA ± verapamil. Verapamilsignificantly inhibited the biliary excretion of atracer dose of [3 H]CyA (0.15 ± 0.04 vs0.33 ± 0.07%; P < 0.05). In contrast,pretreatment with AAF significantly increased the biliaryexcretion of [3 H]CyA, (0.61 ± 0.10 vs0.33 ± 0.07%; P < 0.05). CyA induced adose-dependent inhibition of bile flow with a maximaleffect at 20 mg/kg CyA (–49.3 ± 4.5% decreaseof basal bile flow). CyA cholestasis was significantlyworsened by the P-gp inhibitor, verapamil (–75.5± 7.5%; P < 0.05), but it was unaffected byinduction of P-gp via AAF pretreatment (–44.9 ±1.7%). During CyA cholestasis, the cumulative biliaryexcretion of [3 H]CyA was lower than in theabsence of cholestasis (0.22 ± 0.05 vs 0.33± 0.07%; P < 0.05), was inhibited by verapamil (0.08± 0.01%; P < 0.05), but was unaffected by AAF(0.23 ± 0.05%). No morphological evidence ofdamage was observed in the liver, and no evidence ofcytoskeleton derangement was seen in primary cultures of rathepatocytes exposed to CyA ± verapamil. Wedemonstrated that pharmacological modulation of P-gp mayinfluence the biliary excretion of CyA. The acutecholestatic effect of CyA is worsened by P-gp inhibitors,while it is unaffected by P-gp inducers. This indicatesCyA should not be given with other P-gp substrates orinhibitors. [ABSTRACT FROM AUTHOR]- Published
- 1999
- Full Text
- View/download PDF
129. Association betweenABCB1Polymorphisms and Antidepressant Treatment Response in Taiwanese Major Depressive Patients
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Hui Hua Chang, Chen Hsi Chou, I. Hui Lee, Yen Kuang Yang, and Po See Chen
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Oncology ,medicine.medical_specialty ,Treatment response ,Hydrocortisone ,Venlafaxine ,Major depressive disorder ,behavioral disciplines and activities ,Behavioral Neuroscience ,Antidepressive agents ,Rating scale ,Internal medicine ,mental disorders ,Genotype ,medicine ,Pharmacology (medical) ,Polymorphism ,P-Glycoproteins ,Fluoxetine ,business.industry ,medicine.disease ,Psychiatry and Mental health ,Endocrinology ,Antidepressant ,Original Article ,business ,medicine.drug - Abstract
Objective The multidrug resistance 1 (ABCB1, MDR1) gene, encoding P-glycoprotein, is extensively distributed and expressed in various tissues, such as a blood-brain barrier transporter. P-glycoprotein plays an important role in controlling the passage of substances between the blood and brain. The current study aimed to investigate possible associations of functional ABCB1polymorphisms (C3435T, G2677T and C1236T) with response to antidepressant treatment and serum cortisol levels in Taiwanese patients with major depressive disorder (MDD). Methods We recruited 112 MDD patients who were randomized to fluoxetine (n=58, mean dose: 21.4±4.5 mg/day) or venlafaxine (n=54, 80.2±34.7 mg/day) treatment for 6 weeks. The 21-item Hamilton Depression Rating Scale (HDRS) was administered initially and biweekly after treatment, and cortisol levels were assessed initially and after 6-week antidepressant treatment. Results The initial HDRS scores and the HDRS scores after six weeks of antidepressant treatment were not significantly different among the different genotypes in each polymorphism of ABCB1. The percentage changes of HDRS scores over time were significantly different in the polymorphisms of ABCB1G2677T (p=0.002). MDD patients with the G/G genotype of ABCB1G2677T had a worse antidepressant treatment response. However, the polymorphisms of ABCB1genotypes were not significantly associated with cortisol levels before and after antidepressant treatment in MDD patients. Conclusion The results suggested that the variants of ABCB1may influence the short-term antidepressant response in MDD patients. Further details of the underlying mechanisms of ABCB1in antidepressant treatment remain to be clarified.
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- 2015
130. Deficiency of multidrug resistance 2 contributes to cell transformation through oxidative stress
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Diego di Bernardo, Ali Tebbi, Annamaria Carissimo, Kosuke Hashimoto, Piero Carninci, Florence Levillayer, Nesrine Boudjadja, Yu Wei, Hugo Varet, Grégory Jouvion, Laurence Fiette, Guillaume Soubigou, Stefano Cairo, Ana Maria Suzuki, Pathogenèse des Virus de l'Hépatite B (PVHB), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hépacivirus et Immunité innée, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Histopathologie humaine et Modèles animaux, Institut Pasteur [Paris] (IP), Centre d'Informatique pour la Biologie, XenTech, RIKEN Center for Life Science Technologies (RIKEN CLST), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Telethon Institute of Genetics and Medicine, European Union’s Seventh Framework Program (FP7) under grant agreement No. 259743 (MODHEP consortium) to the Institut Pasteur (A.T., F.L., Y.W.), RIKEN Center (K.H., A.M.S., P.C.) and Telethon Institute of Genetics and Medicine (D.B.)., European Project: 259743,EC:FP7:HEALTH,FP7-HEALTH-2010-two-stage,MODHEP(2011), Wei, Yu, Systems biology of liver cancer: an integrative genomic-epigenomic approach - MODHEP - - EC:FP7:HEALTH2011-01-01 - 2016-06-30 - 259743 - VALID, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris], Tebbi, Ali, Levillayer, Florence, Jouvion, Grégory, Fiette, Laurence, Soubigou, Guillaume, Varet, Hugo, Boudjadja, Nesrine, Cairo, Stefano, Hashimoto, Kosuke, Suzuki, Ana Maria, Carninci, Piero, Carissimo, Annamaria, and DI BERNARDO, Diego
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0301 basic medicine ,Male ,Cancer Research ,Nude ,Apoptosis ,medicine.disease_cause ,Cell Transformation ,Lipid peroxidation ,chemistry.chemical_compound ,Mice ,Adenomatous Polyposis Coli ,Animals ,Cell Transformation, Neoplastic ,Cells, Cultured ,DNA Damage ,Female ,Fibroblasts ,Intestinal Neoplasms ,Lipid Peroxidation ,Liver ,Mice, Inbred BALB C ,Mice, Knockout ,Mice, Nude ,Oxidative Stress ,P-Glycoproteins ,Reactive Oxygen Species ,Inbred BALB C ,Cultured ,Bile acid ,General Medicine ,3. Good health ,Biochemistry ,ATP Binding Cassette Transporter, Subfamily B ,DNA damage ,medicine.drug_class ,Cells ,Knockout ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Original Manuscript ,Biology ,NO ,03 medical and health sciences ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Lipid biosynthesis ,medicine ,Neoplastic ,Fatty acid metabolism ,Microarray analysis techniques ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,HCCS ,Molecular biology ,[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,030104 developmental biology ,chemistry ,Carcinogenesis - Abstract
Summary The transporter of phosphatidylcholine Mdr2/MDR3 not only plays an essential role for bile formation but also is involved in the maintenance of lipid homeostasis. Deficiency of Mdr2 leads to accumulation of ROS, cell transformation and susceptibility to intestinal carcinogenesis., Multidrug resistance 2 (Mdr2), also called adenosine triphosphate-binding cassette B4 (ABCB4), is the transporter of phosphatidylcholine (PC) at the canalicular membrane of mouse hepatocytes, which plays an essential role for bile formation. Mutations in human homologue MDR3 are associated with several liver diseases. Knockout of Mdr2 results in hepatic inflammation, liver fibrosis and hepatocellular carcinoma (HCC). Whereas the pathogenesis in Mdr2 −/− mice has been largely attributed to the toxicity of bile acids due to the absence of PC in the bile, the question of whether Mdr2 deficiency per se perturbs biological functions in the cell has been poorly addressed. As Mdr2 is expressed in many cell types, we used mouse embryonic fibroblasts (MEF) derived from Mdr2 −/− embryos to show that deficiency of Mdr2 increases reactive oxygen species accumulation, lipid peroxidation and DNA damage. We found that Mdr2 −/− MEFs undergo spontaneous transformation and that Mdr2 −/− mice are more susceptible to chemical carcinogen-induced intestinal tumorigenesis. Microarray analysis in Mdr2−/− MEFs and cap analysis of gene expression in Mdr2 −/− HCCs revealed extensively deregulated genes involved in oxidation reduction, fatty acid metabolism and lipid biosynthesis. Our findings imply a close link between Mdr2 −/−-associated tumorigenesis and perturbation of these biological processes and suggest potential extrahepatic functions of Mdr2/MDR3.
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- 2015
131. The reliability of molecular dynamics simulations of the multidrug transporter P-glycoprotein in a membrane environment
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Nandhitha Subramanian, Karmen Condic-Jurkic, Alan E. Mark, and Megan L. O'Mara
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Models, Molecular ,Protein Conformation, alpha-Helical ,0301 basic medicine ,Computer science ,Glycobiology ,lcsh:Medicine ,ATP-binding cassette transporter ,Crystal structure ,Crystallography, X-Ray ,Biochemistry ,01 natural sciences ,Protein Structure, Secondary ,Mice ,chemistry.chemical_compound ,Molecular dynamics ,Adenosine Triphosphate ,Protein structure ,Biochemical Simulations ,Macromolecular Structure Analysis ,Nucleotide ,lcsh:Science ,Protein secondary structure ,P-glycoprotein ,chemistry.chemical_classification ,Crystallography ,Multidisciplinary ,010304 chemical physics ,biology ,Physics ,Simulation and Modeling ,Replicate ,Condensed Matter Physics ,Lipids ,Transmembrane domain ,Cholesterol ,Membrane ,Order (biology) ,Physical Sciences ,Crystal Structure ,medicine.symptom ,Biological system ,Research Article ,Protein Structure ,Crystal Lattices ,Protein domain ,Molecular Dynamics Simulation ,Research and Analysis Methods ,03 medical and health sciences ,Protein Domains ,0103 physical sciences ,medicine ,Solid State Physics ,Animals ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Sensitivity (control systems) ,Binding site ,P-Glycoproteins ,Molecular Biology ,Glycoproteins ,Binding Sites ,Membranes ,lcsh:R ,Biology and Life Sciences ,Computational Biology ,Proteins ,030104 developmental biology ,Mechanism of action ,chemistry ,biology.protein ,lcsh:Q ,Adenosine triphosphate ,Multidrug transporter - Abstract
Despite decades of research, the mechanism of action of the ABC multidrug transporter P-glycoprotein (P-gp) remains elusive. Due to experimental limitations, many researchers have turned to molecular dynamics simulation studies in order to investigate different aspects of P-gp function. However, such studies are challenging and caution is required when interpreting the results. P-gp is highly flexible and the time scale on which it can be simulated is limited. There is also uncertainty regarding the accuracy of the various crystal structures available, let alone the structure of the protein in a physiologically relevant environment. In this study, three alternative structural models of mouse P-gp (3G5U, 4KSB, 4M1M), all resolved to 3.8 Å, were used to initiate sets of simulations of P-gp in a membrane environment in order to determine: a) the sensitivity of the results to differences in the starting configuration; and b) the extent to which converged results could be expected on the times scales commonly simulated for this system. The simulations suggest that the arrangement of the nucleotide binding domains (NBDs) observed in the crystal structures is not stable in a membrane environment. In all simulations, the NBDs rapidly associated (within 10 ns) and changes within the transmembrane helices were observed. The secondary structure within the transmembrane domain was best preserved in the 4M1M model under the simulation conditions used. However, the extent to which replicate simulations diverged on a 100 to 200 ns timescale meant that it was not possible to draw definitive conclusions as to which structure overall was most stable, or to obtain converged and reliable results for any of the properties examined. The work brings into question the reliability of conclusions made in regard to the nature of specific interactions inferred from previous simulation studies on this system involving similar sampling times. It also highlights the need to demonstrate the statistical significance of any results obtained in simulations of large flexible proteins, especially where the initial structure is uncertain.
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- 2018
132. Entinostat reverses P-glycoprotein activation in snail-overexpressing adenocarcinoma HCC827 cells
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Yumi Shibasaki, Takuo Ogihara, Takumi Tomono, Tatsuya Machida, Kentaro Yano, and Hiroki Kamioka
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Adenosine Triphosphatase ,0301 basic medicine ,Pyridines ,Cytotoxicity ,Cancer Treatment ,Glycobiology ,lcsh:Medicine ,Vimentin ,Toxicology ,Pathology and Laboratory Medicine ,Biochemistry ,Lung and Intrathoracic Tumors ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Movement ,Medicine and Health Sciences ,lcsh:Science ,P-glycoprotein ,Multidisciplinary ,biology ,Chemistry ,Entinostat ,Enzymes ,Gene Expression Regulation, Neoplastic ,Protein Transport ,Oncology ,030220 oncology & carcinogenesis ,Benzamides ,Cellular Structures and Organelles ,Research Article ,Epithelial-Mesenchymal Transition ,Antineoplastic Agents ,Adenocarcinoma ,03 medical and health sciences ,Extraction techniques ,Downregulation and upregulation ,Cell Line, Tumor ,otorhinolaryngologic diseases ,Humans ,Vesicles ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,P-Glycoproteins ,Glycoproteins ,Dose-Response Relationship, Drug ,lcsh:R ,Phosphatases ,Biology and Life Sciences ,Proteins ,Cancers and Neoplasms ,Cell Biology ,RNA extraction ,Non-Small Cell Lung Cancer ,Research and analysis methods ,Cytoskeletal Proteins ,030104 developmental biology ,Tumor progression ,Cell culture ,Cancer cell ,Enzymology ,Cancer research ,biology.protein ,lcsh:Q ,Snail Family Transcription Factors ,Histone deacetylase - Abstract
Epithelial-to-mesenchymal transition (EMT) in cancer cells facilitates tumor progression by promoting invasion and metastasis. Snail is a transcriptional factor that induces EMT, while P-glycoprotein (P-gp) is an efflux transporter involved in anticancer drug resistance, and P-gp efflux activity is stimulated in Snail-overexpressing lung cancer cells with EMT characteristics. Since the histone deacetylase (HDAC) inhibitor entinostat (Ent) reverses EMT features, our aim in this study was to determine whether Ent also suppresses P-gp activation in Snail-induced cells. First, we confirmed that Ent treatment reduced migration activity, downregulated E-cadherin and upregulated vimentin at the mRNA level in Snail-overexpressing cells, thus inhibiting EMT. Efflux and uptake assays using rhodamine123 (Rho123), a fluorescent P-gp substrate, showed that Ent also inhibited Snail-induced activation of P-gp. Moreover, P-gp activity was more strongly inhibited by Ent in Snail-overexpressing cells than in Mock cells. When we evaluated the uptakes of Rho123 by LLC-PK1 cells and P-gp-overexpressing LLC-GA5COL150 cells, Rho123 accumulation in LLC-GA5COL150 cells was significantly decreased compared with that in LLC-PK1 cells. Coincubation with Ent had no effect on Rho123 accumulation in either of the cell lines. Thus, Ent appears to be an inhibitor, but not a substrate, of P-gp at low concentration. Our results suggest that Ent treatment might suppress not only Snail-induced cancer malignant alteration, but also P-gp-mediated multidrug resistance.
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- 2018
133. Phytotherapeutics: The Emerging Role of Intestinal and Hepatocellular Transporters in Drug Interactions with Botanical Supplements
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Saiqa Muneer, Farah Mukhtar, Shamyla Nawazish, Ghulam Murtaza, Mariam, and Naveed Ullah
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Drug ,Carcinoma, Hepatocellular ,media_common.quotation_subject ,Herbalism ,Herb-Drug Interactions ,Pharmaceutical Science ,drug transporters ,Review ,Pharmacology ,Biology ,030226 pharmacology & pharmacy ,Analytical Chemistry ,law.invention ,lcsh:QD241-441 ,Efficacy ,03 medical and health sciences ,0302 clinical medicine ,P-glycoproteins ,lcsh:Organic chemistry ,law ,Drug Discovery ,Humans ,Physical and Theoretical Chemistry ,Drug transport ,media_common ,organic anion transporting polypeptides ,Drug disposition ,Organic Chemistry ,Liver Neoplasms ,Transporter ,Intestines ,Chemistry (miscellaneous) ,030220 oncology & carcinogenesis ,Dietary Supplements ,Molecular Medicine ,Phytotherapy ,botanical supplements ,metabolism ,Drug metabolism - Abstract
In herbalism, botanical supplements are commonly believed to be safe remedies, however, botanical supplements and dietary ingredients interact with transport and metabolic processes, affecting drug disposition. Although a large number of studies have described that botanical supplements interfere with drug metabolism, the mode of their interaction with drug transport processes is not well described. Such interactions may result in serious undesired effects and changed drug efficacy, therefore, some studies on interaction between botanical supplement ingredients and drug transporters such as P-gp and OATPs are described here, suggesting that the interaction between botanical supplements and the drug transporters is clinically significant.
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- 2017
134. Dominance of P-glycoprotein 12 in phenotypic resistance conversion against ivermectin in Caenorhabditis elegans
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Ricardo Nascimento Araújo, Rodrigo Miranda, Ricardo Toshio Fujiwara, Gabriela F. Rodrigues-Luiz, Luiza Almeida Figueiredo, Sebastião Rodrigo Ferreira, and Thais Fuscaldi Rebouças
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0301 basic medicine ,Life Cycles ,Nematoda ,Drug Resistance ,Glycobiology ,lcsh:Medicine ,Gene Expression ,ATP-binding cassette transporter ,Drug resistance ,Biochemistry ,Ivermectin ,RNA interference ,Larvae ,Gene expression ,Medicine and Health Sciences ,lcsh:Science ,Nematode Infections ,Caenorhabditis elegans ,Phylogeny ,P-glycoprotein ,Genetics ,Multidisciplinary ,biology ,Antiparasitic Agents ,Eukaryota ,Animal Models ,Nucleic acids ,Phenotypes ,Phenotype ,Experimental Organism Systems ,Genetic interference ,Epigenetics ,medicine.drug ,Research Article ,ATP Binding Cassette Transporter, Subfamily B ,Research and Analysis Methods ,03 medical and health sciences ,Model Organisms ,Species Specificity ,parasitic diseases ,medicine ,Parasitic Diseases ,Gene silencing ,Animals ,Gene Regulation ,Gene Silencing ,Caenorhabditis elegans Proteins ,P-Glycoproteins ,Glycoproteins ,lcsh:R ,Organisms ,Biology and Life Sciences ,biology.organism_classification ,Invertebrates ,030104 developmental biology ,biology.protein ,Caenorhabditis ,RNA ,lcsh:Q ,Developmental Biology - Abstract
While diseases caused by nematodes remains a considerable drawback for the livestock, agriculture and public health, anthelmintics drug resistance has been observed over the past years and is a major concern for parasite control. Ivermectin, initially considered as a highly potent drug, currently presents a reduced anti-helminthic efficacy, which is influenced by expression of several ATP-binding cassette transporters (ABC), among them the P-glycoproteins (Pgps). Here we present some evidences of Pgps dominance during Ivermectin resistance/susceptibility using Pgps double silencing in C. elegans and the phylogenetic relationship of Pgps among nematodes, which strengthen the use of this model for study of drug resistance in nematodes. Firstly, we evaluated the quantitative gene expression of 12 out the 15 known Pgps from resistant and WT strains of C. elegans, we demonstrated the upregulation of Pgps 12 and 13 and downregulation of all remaining Pgps in ivermectin resistant strain. By using an RNAi loss-of-function approach we observed that Pgp 12 gene silencing reverts the resistance phenotype to ivermectin, while Pgp 4 gene silencing does not alter the resistance phenotype but induces a resistance in wild type strain. Interestingly, the dual silencing of Pgp 12 and Pgp 4 expression demonstrates the dominance of phenotype promoted by Pgp 12 silencing. Finally, in silico analysis reveals a close relationship between Pgps from C. elegans and several nematodes parasites. Taken together, our results indicate that Pgp 12 is crucial for the resistance to ivermectin and thus a good candidate for further studies aiming to develop specific inhibitors to this transporter, allowing the continuous use of ivermectin to control the burden on animal and human health inflicted by nematode parasites globally.
- Published
- 2017
135. Anti-leukemic activity of bortezomib and carfilzomib on B-cell precursor ALL cell lines
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Takeshi Inukai, Atsushi Nemoto, Kanji Sugita, Hiroki Sato, Masayoshi Minegishi, Hiroko Oshiro, Keiko Kagami, Meixian Huang, Shotaro Iwamoto, Shinpei Somazu, Kazuya Takahashi, Hiroaki Goto, Yusuke Furukawa, Toshihiko Imamura, Mio Yano, Jiro Kikuchi, Chihiro Tomoyasu, Koshi Akahane, David M. Lucas, Atsushi Watanabe, Tamao Shinohara, Kumiko Goi, and Masako Abe
- Subjects
0301 basic medicine ,Glycobiology ,Cancer Treatment ,lcsh:Medicine ,Apoptosis ,Biochemistry ,Bortezomib ,Hematologic Cancers and Related Disorders ,chemistry.chemical_compound ,0302 clinical medicine ,Spectrum Analysis Techniques ,Medicine and Health Sciences ,lcsh:Science ,Chemotherapeutic Agents ,Cell Analysis ,Staining ,B-Lymphocytes ,Multidisciplinary ,Cell Death ,Chemistry ,Pharmaceutics ,Drugs ,Cell Staining ,Combination chemotherapy ,Hematology ,Acute Lymphoblastic Leukemia ,Flow Cytometry ,Leukemia ,medicine.anatomical_structure ,Bioassays and Physiological Analysis ,Oncology ,Spectrophotometry ,Cell Processes ,030220 oncology & carcinogenesis ,Lymphoblastic Leukemia ,Oncology Agents ,Cytophotometry ,Oligopeptides ,medicine.drug ,Research Article ,Clinical Oncology ,Vincristine ,Cell Viability Testing ,Daunorubicin ,Antineoplastic Agents ,Research and Analysis Methods ,03 medical and health sciences ,Cancer Chemotherapy ,Drug Therapy ,Cell Line, Tumor ,Leukemias ,medicine ,Humans ,Chemotherapy ,P-Glycoproteins ,B cell ,Glycoproteins ,Pharmacology ,lcsh:R ,Biology and Life Sciences ,Cancers and Neoplasms ,Cell Biology ,medicine.disease ,Carfilzomib ,030104 developmental biology ,Specimen Preparation and Treatment ,Proteasome inhibitor ,Cancer research ,lcsh:Q ,Clinical Medicine ,Combination Chemotherapy - Abstract
Prognosis of childhood acute lymphoblastic leukemia (ALL) has been dramatically improved. However, prognosis of the cases refractory to primary therapy is still poor. Recent phase 2 study on the efficacy of combination chemotherapy with bortezomib (BTZ), a proteasome inhibitor, for refractory childhood ALL demonstrated favorable clinical outcomes. However, septic death was observed in over 10% of patients, indicating the necessity of biomarkers that could predict BTZ sensitivity. We investigated in vitro BTZ sensitivity in a large panel of ALL cell lines that acted as a model system for refractory ALL, and found that Philadelphia chromosome-positive (Ph+) ALL, IKZF1 deletion, and biallelic loss of CDKN2A were associated with favorable response. Even in Ph-negative ALL cell lines, IKZF1 deletion and bilallelic loss of CDKN2A were independently associated with higher BTZ sensitivity. BTZ showed only marginal cross-resistance to four representative chemotherapeutic agents (vincristine, dexamethasone, l-asparaginase, and daunorubicin) in B-cell precursor-ALL cell lines. To improve the efficacy and safety of proteasome inhibitor combination chemotherapy, we also analyzed the anti-leukemic activity of carfilzomib (CFZ), a second-generation proteasome inhibitor, as a substitute for BTZ. CFZ showed significantly higher activity than BTZ in the majority of ALL cell lines except for the P-glycoprotein-positive t(17;19) ALL cell lines, and IKZF1 deletion was also associated with a favorable response to CFZ treatment. P-glycoprotein inhibitors effectively restored the sensitivity to CFZ, but not BTZ, in P-glycoprotein-positive t(17;19) ALL cell lines. P-glycoprotein overexpressing ALL cell line showed a CFZ-specific resistance, while knockout of P-glycoprotein by genome editing with a CRISPR/Cas9 system sensitized P-glycoprotein-positive t(17;19) ALL cell line to CFZ. These observations suggested that IKZF1 deletion could be a useful biomarker to predict good sensitivity to CFZ and BTZ, and that CFZ combination chemotherapy may be a new therapeutic option with higher anti-leukemic activity for refractory ALL that contain P-glycoprotein-negative leukemia cells.
- Published
- 2017
136. CAC1 knockdown reverses drug resistance through the downregulation of P-gp and MRP-1 expression in colorectal cancer
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Nanzheng Chen, Xuejun Sun, Qi Gao, Yunhua Wu, Junke Fu, Qianqian Geng, and Ying Kong
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Male ,0301 basic medicine ,Protein Expression ,Glycobiology ,Apoptosis ,Drug resistance ,Biochemistry ,Metastasis ,Mice ,0302 clinical medicine ,Basic Cancer Research ,Medicine and Health Sciences ,Cell Cycle and Cell Division ,Gene knockdown ,Multidisciplinary ,Cell Death ,medicine.diagnostic_test ,Animal Models ,Middle Aged ,Cullin Proteins ,Oncology ,Experimental Organism Systems ,Cell Processes ,030220 oncology & carcinogenesis ,Medicine ,Cell lines ,Female ,Fluorouracil ,Multidrug Resistance-Associated Proteins ,Colorectal Neoplasms ,Biological cultures ,Research Article ,Adult ,ATP Binding Cassette Transporter, Subfamily B ,Science ,Down-Regulation ,Mice, Nude ,Antineoplastic Agents ,Mouse Models ,Biology ,Flow cytometry ,03 medical and health sciences ,Model Organisms ,Downregulation and upregulation ,In vivo ,Gene Expression and Vector Techniques ,medicine ,Animals ,Humans ,Molecular Biology Techniques ,Molecular Biology ,P-Glycoproteins ,Aged ,Glycoproteins ,Colorectal Cancer ,Molecular Biology Assays and Analysis Techniques ,Cancers and Neoplasms ,Biology and Life Sciences ,Cell Biology ,HCT116 Cells ,digestive system diseases ,In vitro ,Research and analysis methods ,SW480 cells ,030104 developmental biology ,Drug Resistance, Neoplasm ,Caco-2 ,Animal Studies ,Cancer research ,Caco-2 Cells - Abstract
CDK2-associated cullin domain 1 (CAC1) is as a novel cell cycle regulator widely expressed in colorectal cancer (CRC). However, its expression and function in drug resistant CRC cells remains elusive. Therefore, the present study aimed to assess the biochemical function and relevance of CAC1 in drug resistant CRC cells, and detect the potential mechanism. For this purpose, a total of 83 CRC cases were collected for the immunohistochemical analysis of CAC1 expression. Functional studies (stable transfection, flow cytometry, colony formation, and invasion and migration assays) were performed in SW480, LoVo and their corresponding 5-FU resistant cells. In addition, a nude mice xenograft model was established for further observation in vivo. In the present study, CAC1 protein expression was higher in CRC tissues than that in normal tissues (P
- Published
- 2019
137. Potential contribution of P-glycoproteins to macrocyclic lactone resistance in the cattle parasitic nematode Cooperia oncophora
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Jessie De Graef, W.E. Pomroy, Peter Geldhof, Georg von Samson-Himmelstjerna, Salha AlGusbi, Jürgen Krücken, Dominique Kerboeuf, Sabrina Ramünke, Janina Demeler, Institute for Parasitology and Tropical Veterinary Medicine, Freie Universität Berlin, Universiteit Gent = Ghent University [Belgium] (UGENT), Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT), Institute of Veterinary, Animal and Biomedical Sciences, and Institut National de la Recherche Agronomique (INRA)-Université de Tours
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ATP Binding Cassette Transporter, Subfamily B ,Nematodes ,Molecular Sequence Data ,Resistance ,Drug Resistance ,Drug resistance ,Cooperia ,Polymerase Chain Reaction ,030308 mycology & parasitology ,Microbiology ,Lactones ,03 medical and health sciences ,P-glycoproteins ,Ivermectin ,parasitic diseases ,Botany ,Anthelmintic ,medicine ,Animals ,Helminths ,Enzyme Inhibitors ,Molecular Biology ,030304 developmental biology ,Anthelmintics ,0303 health sciences ,Trichostrongyloidea ,biology ,Sequence Analysis, DNA ,DNA, Helminth ,biology.organism_classification ,Teladorsagia circumcincta ,[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology ,Nematode ,Verapamil ,Larva ,Protozoa ,Parasitology ,medicine.drug ,Haemonchus contortus - Abstract
International audience; Resistance against macrocyclic lactones such as ivermectin is widespread among parasitic gastrointestinal nematodes of small ruminants and is rapidly increasing in cattle parasites. ABC transporters of the subfamily B, the so-called P-glycoproteins (Pgps) have been frequently implicated in ivermectin resistance and are a major cause of multi-drug resistance in protozoa and helminths. The Pgp inhibitor verapamil (VPL) dramatically enhanced susceptibility of the cattle parasitic nematode Cooperia oncophora to ivermectin in vitro as measured in a larval developmental assay and a larval migration inhibition assay using third stage larvae. Moreover, VPL completely restored susceptibility to ivermectin in a resistant isolate resulting in virtually identical dose-response curves of susceptible and resistant isolates in the presence of VPL. Further characterisation of the molecular mechanisms resulting in Pgp-mediated ivermectin resistance is still hampered by the lack of molecular and biochemical information for Pgps of parasitic nematodes. Using PCR with degenerate primers, fragments of four different C. oncophora Pgps could be amplified and the Conpgp-2, previously implicated in macrocyclic lactone resistance in Haemonchus contortus, and Conpgp-3 full-length cDNAs were obtained by RACE PCR. The pgp sequences presented here contribute important data required to systematically screen resistant C. oncophora isolates for up- or down-regulation of Pgps and for the detection of single nucleotide polymorphisms in Pgps to detect selection of specific Pgp alleles by anthelmintics as early as possible.
- Published
- 2013
138. Arabidopsis TWISTED DWARF1 Functionally Interacts with Auxin Exporter ABCB1 on the Root Plasma Membrane
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Masayoshi Maeshima, Stefano Mancuso, Marta Zwiewka, Aurélien Bailly, Alexander Schulz, Elisa Azzarello, Jiří Friml, Sina Henrichs, Markus Geisler, and Bangjun Wang
- Subjects
0106 biological sciences ,Auxin efflux ,EFFLUX ,Arabidopsis ,ATP-binding cassette transporter ,Plant Science ,Plasma protein binding ,Endoplasmic Reticulum ,Plant Roots ,01 natural sciences ,Plant Epidermis ,Cell membrane ,Gene Expression Regulation, Plant ,BINDING CASSETTE TRANSPORTER ,Protein Interaction Mapping ,heterocyclic compounds ,Research Articles ,chemistry.chemical_classification ,0303 health sciences ,Microscopy, Confocal ,PLANT DEVELOPMENT ,food and beverages ,LOCALIZATION ,Apoplast ,Cell biology ,Phenotype ,medicine.anatomical_structure ,Biochemistry ,Plant Shoots ,Protein Binding ,animal structures ,Recombinant Fusion Proteins ,Gravitropism ,Biology ,IMMUNOPHILIN ,LATERAL ROOT ,Tacrolimus Binding Proteins ,03 medical and health sciences ,Auxin ,medicine ,030304 developmental biology ,Indoleacetic Acids ,Arabidopsis Proteins ,fungi ,Cell Membrane ,Lateral root ,Biology and Life Sciences ,PIN ,Biological Transport ,Cell Biology ,Protein Structure, Tertiary ,chemistry ,Mutation ,CELLS ,ATP-Binding Cassette Transporters ,P-GLYCOPROTEINS ,RESISTANCE ,010606 plant biology & botany - Abstract
Plant architecture is influenced by the polar, cell-to-cell transport of auxin that is primarily provided and regulated by plasma membrane efflux catalysts of the PIN-FORMED and B family of ABC transporter (ABCB) classes. The latter were shown to require the functionality of the FK506 binding protein42 TWISTED DWARF1 (TWD1), although underlying mechanisms are unclear. By genetic manipulation of TWD1 expression, we show here that TWD1 affects shootward root auxin reflux and, thus, downstream developmental traits, such as epidermal twisting and gravitropism of the root. Using immunological assays, we demonstrate a predominant lateral, mainly outward-facing, plasma membrane location for TWD1 in the root epidermis characterized by the lateral marker ABC transporter G36/PLEIOTROPIC DRUG-RESISTANCE8/PENETRATION3. At these epidermal plasma membrane domains, TWD1 colocalizes with nonpolar ABCB1. In planta bioluminescence resonance energy transfer analysis was used to verify specific ABC transporter B1 (ABCB1)–TWD1 interaction. Our data support a model in which TWD1 promotes lateral ABCB-mediated auxin efflux via protein–protein interaction at the plasma membrane, minimizing reflux from the root apoplast into the cytoplasm.
- Published
- 2013
139. Molecular Mimics of Classic P-Glycoprotein Inhibitors as Multidrug Resistance Suppressors and Their Synergistic Effect on Paclitaxel
- Author
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Abdelsattar M. Omar, Moustafa E. El-Araby, Hanan A. Assiri, Maan T. Khayat, and Ahmed M. Al-Abd
- Subjects
0301 basic medicine ,Adenosine Triphosphatase ,ATPase ,Cytotoxicity ,Glycobiology ,Cancer Treatment ,lcsh:Medicine ,Pharmacology ,Toxicology ,Pathology and Laboratory Medicine ,Biochemistry ,Mass Spectrometry ,Analytical Chemistry ,Oxazolone ,chemistry.chemical_compound ,Spectrum Analysis Techniques ,Medicine and Health Sciences ,Drug Interactions ,lcsh:Science ,Liquid Chromatography ,Multidisciplinary ,biology ,Pharmaceutics ,Chromatographic Techniques ,Drug Synergism ,Drug Resistance, Multiple ,Enzymes ,Chemistry ,Oncology ,Physical Sciences ,Efflux ,Intracellular ,Research Article ,Clinical Oncology ,ATP Binding Cassette Transporter, Subfamily B ,Curcumin ,Paclitaxel ,Liquid Chromatography-Mass Spectrometry ,Drug-Drug Interactions ,Research and Analysis Methods ,03 medical and health sciences ,Cancer Chemotherapy ,Drug Therapy ,Cell Line, Tumor ,Humans ,Chemotherapy ,IC50 ,P-Glycoproteins ,Glycoproteins ,Colorectal Cancer ,lcsh:R ,Molecular Mimicry ,Phosphatases ,Biology and Life Sciences ,Proteins ,Cancers and Neoplasms ,Antineoplastic Agents, Phytogenic ,Multiple drug resistance ,030104 developmental biology ,chemistry ,Cell culture ,Drug Design ,biology.protein ,Enzymology ,lcsh:Q ,Drug Screening Assays, Antitumor ,Clinical Medicine - Abstract
P-glycoprotein (Pgp) is a membrane bound efflux pump spread in a variety of tumor cells and considered as a main component of multidrug resistance (MDR) to chemotherapies. In this work, three groups of compounds (imidazolone, oxazolone and vinyl dipeptide derivatives) were synthesized aiming to develop a molecular framework that effectively suppresses MDR. When tested for their influence on Pgp activity, four compounds coded Cur1-01, Cur1-12V, Curox-1 and Curox-3 significantly decreased remaining ATP concentration indicating Pgp substrate site blocking. On the other hand, Cur-3 and Cur-10 significantly increased remaining ATP concentration, which is indicative of Pgp ATPase inhibition. The cytotoxicity of synthesized compounds was examined against Pgp expressing/highly resistant colorectal cancer cell lines (LS-174T). Compounds Cur-1 and Cur-3 showed considerable cytotoxicity with IC50 values of 7.6 and 8.9 μM, respectively. Equitoxic combination (at IC50 concentrations) of PTX and Cur-3 greatly diminished resistant cell clone from 45.7% to 2.5%, albeit with some drop in potency from IC50 of 7.9 nM to IC50 of 23.8 nM. On the other hand, combination of PTX and the non-cytotoxic Cur1-12V (10 μM) significantly decreased the IC50 of PTX to 3.8 nM as well as the resistant fraction to 16.2%. The combination test was confirmed using the same protocol but on another resistant CRC cell line (HCT-116) as we obtained similar results. Both Cur-3 and Cur1-12V (10 μM) significantly increased the cellular entrapment of Pgp probe (doxorubicin) elevating its intracellular concentration from 1.9 pmole/cell to 3.0 and 2.9 pmole/cell, respectively.
- Published
- 2016
140. Association of MDR1, CYP2D6, and CYP2C19 gene polymorphisms with prophylactic migraine treatment response
- Author
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Gulcin Tezcan, Oznur Yildirim, Berrin Tunca, Isil Ezgi Eryilmaz, Unal Egeli, Necdet Karli, Ozlem Taskapilioglu, Gulsah Cecener, Gülfer Atasayar, Mehmet Zarifoglu, Secil Ak, Fatma Ezgi Can, Uludağ Üniversitesi/Tıp Fakültesi/Nöroloji Anabilim Dalı., Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Biyoloji Anabilim Dalı., Uludağ Üniversitesi/Tıp Fakültesi/Biyoistatistik Anabilim Dalı., Atasayar, Gülfer, Eryılmaz, Işıl Ezgi, Karlı, Necdet, Egeli, Ünal, Zarifoğlu, Mehmet, Çeçener, Gülşah, Taşkapılıoğlu, Özlem, Tunca, Berrin, Yıldırım, Öznur, Ak, Seçil, Tezcan, Gülçin, Can, Fatma Ezgi, ABI-6078-2020, AAP-9988-2020, AAH-1656-2021, GWV-3548-2022, AAH-3843-2020, F-8554-2017, and AAH-1420-2021
- Subjects
Male ,Central nervous system agents ,Genetic association studies ,Genomic DNA ,Pharmacology ,ABCB1 protein, human ,Treatment response ,030226 pharmacology & pharmacy ,0302 clinical medicine ,P-glycoproteins ,Valproic acid ,Medicine ,Amitriptyline ,Treatment outcome ,2D6 ,Priority journal ,Valproic Acid ,Analogs and derivatives ,CYP2C19 protein, human ,Prophylactic therapy response ,2C19 ,Propranolol ,Phenotype ,Neurology ,Cytochrome P-450 CYP2D6 ,Migraine with aura ,Clinical neurology ,Migraine without aura ,Migraine disorders ,Female ,medicine.drug ,Human ,Topiramate ,Adult ,CYP2D6 ,ATP Binding Cassette Transporter, Subfamily B ,Genotype ,MDR1 ,Multidrug-resistance ,CYP2C19 ,Fructose ,Major clinical study ,Polymorphism, genetic ,Neurosciences & neurology ,Article ,03 medical and health sciences ,Drug Resistant Epilepsy ,Epilepsy ,Carbamazepine ,Cytochrome P450 2C19 ,Multidrug resistance protein 1 ,Genetics ,Humans ,Migraine treatment ,Polymorphism ,Migraine ,Alleles ,Aged ,Genetic association study ,Cytochrome-P450 ,C3435t polymorphism ,Genetic polymorphism ,business.industry ,Prophylaxis ,Neurosciences ,Multidrug resistance protein ,Frequency ,Cytochrome P450 2D6 ,medicine.disease ,Monotherapy ,Gene frequency ,Cytochrome P-450 CYP2C19 ,Risk factors ,Pharmacogenetics ,DNA polymorphism ,Drug resistance ,Genetic association ,Neurology (clinical) ,Risk factor ,business ,030217 neurology & neurosurgery - Abstract
Prophylactic therapy response varies in migraine patients. The present study investigated the relationship between the resistance to the drugs commonly used in prophylactic therapy and the possible polymorphic variants of proteins involved in the metabolism of these drugs. Migraine patients with the MDR1 3435TT genotype exhibited a better treatment response to topiramate than migraine patients with the CC and CT genotypes ( p =0.020). The MDR1 C3435T polymorphism was also found to be a higher risk factor for topiramate treatment failure in a comparison of the number of days with migraine ( β 2 =1.152, p =0.015). However, there was no significant relationship between the treatment response to topiramate and either the CYP2D6 or CYP2C19 polymorphism, and there were no significant correlations between the treatment responses to amitriptyline, propranolol, and valproic acid and the MDR1 , CYP2D6 and CYP2C19 gene polymorphisms. This is the first study to investigate the effect of the polymorphic variants on prophylactic therapy response in migraine patients.
- Published
- 2016
141. Global marine pollutants inhibit P-glycoprotein: Environmental levels, inhibitory effects, and cocrystal structure
- Author
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Lydia M. Vermeer, Amro Hamdoun, Lindsay T. Bonito, Stuart A. Sandin, Greg Loewen, Cristina Cregger, Sascha C.T. Nicklisch, Steven D. Rees, Geoffrey Chang, Aaron P. McGrath, and Tufan Gökirmak
- Subjects
0301 basic medicine ,Protein Conformation ,010501 environmental sciences ,Crystallography, X-Ray ,01 natural sciences ,Toxicology ,chemistry.chemical_compound ,Mice ,Polybrominated diphenyl ethers ,Hydrocarbons, Chlorinated ,Water Pollution, Chemical ,Halogenated Diphenyl Ethers ,Water pollution ,Research Articles ,P-glycoprotein ,Multidisciplinary ,Crystallography ,integumentary system ,biology ,food and beverages ,SciAdv r-articles ,6. Clean water ,Chlorinated ,Subfamily B ,Environmental chemistry ,Research Article ,Environmental Monitoring ,ATP Binding Cassette Transporter, Subfamily B ,Oceans and Seas ,ATP Binding Cassette Transporter ,Chemical ,03 medical and health sciences ,Marine Pollutants ,Animals ,Humans ,Climate-Related Exposures and Conditions ,14. Life underwater ,Pesticides ,Mexico ,P-Glycoproteins ,0105 earth and related environmental sciences ,Pollutant ,Binding Sites ,Tuna ,Prevention ,Diphenyl ether ,Water Pollution ,Transporter ,Pesticide ,Hydrocarbons ,030104 developmental biology ,chemistry ,13. Climate action ,biology.protein ,X-Ray - Abstract
Common seafood pollutants inhibit a crucial cellular defense protein., The world’s oceans are a global reservoir of persistent organic pollutants to which humans and other animals are exposed. Although it is well known that these pollutants are potentially hazardous to human and environmental health, their impacts remain incompletely understood. We examined how persistent organic pollutants interact with the drug efflux transporter P-glycoprotein (P-gp), an evolutionarily conserved defense protein that is essential for protection against environmental toxicants. We identified specific congeners of organochlorine pesticides, polychlorinated biphenyls, and polybrominated diphenyl ethers that inhibit mouse and human P-gp, and determined their environmental levels in yellowfin tuna from the Gulf of Mexico. In addition, we solved the cocrystal structure of P-gp bound to one of these inhibitory pollutants, PBDE (polybrominated diphenyl ether)–100, providing the first view of pollutant binding to a drug transporter. The results demonstrate the potential for specific binding and inhibition of mammalian P-gp by ubiquitous congeners of persistent organic pollutants present in fish and other foods, and argue for further consideration of transporter inhibition in the assessment of the risk of exposure to these chemicals.
- Published
- 2016
142. Effects of TNFα, NOS3, MDR1 Gene Polymorphisms on Clinical Parameters, Prognosis and Survival of Multiple Myeloma Cases
- Author
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Ayse Gaye Tomatir, Tugce Sever, C Basmaci, Sibel Oguzkan-Balci, Mehmet Yilmaz, Okan, Sacide Pehlivan, and Mustafa Pehlivan
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Epidemiology ,very elderly ,ABCB1 protein, human ,Gastroenterology ,Pathogenesis ,0302 clinical medicine ,Multiple myeloma ,single nucleotide polymorphism ,middle aged ,Genotype ,genetics ,antineoplastic agent ,Aged, 80 and over ,allele ,Middle Aged ,Prognosis ,female ,Oncology ,030220 oncology & carcinogenesis ,Tumor necrosis factor alpha ,Female ,Multiple Myeloma ,Adult ,medicine.medical_specialty ,ATP Binding Cassette Transporter, Subfamily B ,Nitric Oxide Synthase Type III ,tumor necrosis factor ,MDR1 ,NOS3 (+894, VNTR) ,Antineoplastic Agents ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Young Adult ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,human ,TNFalpha (-308, -238 and -857) ,P-Glycoproteins ,Gene ,Genotyping ,Alleles ,Aged ,endothelial nitric oxide synthase ,business.industry ,Tumor Necrosis Factor-alpha ,Public Health, Environmental and Occupational Health ,multidrug resistance protein ,case control study ,medicine.disease ,Transplantation ,030104 developmental biology ,Case-Control Studies ,Immunology ,Gene polymorphism ,NOS3 protein, human ,business ,genetic predisposition - Abstract
It is not clear how gene polymorphisms affecting drugs can contributes totheir efficacy in multiple myeloma (MM). We here aimed to explore associations among gene polymorphisms of tumor necrosis factor alpha (TNFalpha), nitric oxide synthesis 3 (NOS3) and multi-drug resistance 1 (MDR1), clinical parameters, prognosis and survival in MM patients treated with VAD (vincristine-adriamycine-dexamethasone), MP (mephalane-prednisolone), autolougus stem cell transplantation (ASCT), BODEC (bortezomib-dexamethasone-cyclophosphamide) and TD (thalidomide-dexamethasone). We analyzed TNFalpha, NOS 3 and MDR1 in 77 patients with MM and 77 healthy controls. The genotyping was performed with PCR and/or PCR-RFLP. There was no clinically significant difference between MM and control groups when TNFalpha (-238) and (-857) and MDR1 gene polymorphisms were studied. However, the TNFalpha gene polymorphism (-308) GG genotype (p=0.012) and NOS3 (+894) TT genotype (p=0.008) were more common in the MM group compared to healthy controls. NOS3 (VNTR) AA (p=0.007) and NOS3 (+894) GG genotypes (p=0.004) were decreased in the MM group in contrast. In conclusion, the NOS3 (+894) TT and TNFalpha (-308) GG genotypes may have roles in myeloma pathogenesis. Keywords
- Published
- 2016
143. An in vitro model for the development of acquired tamoxifen resistance
- Author
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Unal Egeli, Berrin Tunca, Gulsah Cecener, Gamze Guney Eskiler, Eskiler, GG, Cecener, G, Tunca, B, Egeli, U, Sakarya Üniversitesi/Tıp Fakültesi/Temel Tıp Bilimleri Bölümü, Güney Eskiler, Gamze, Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Biyoloji Anabilim Dalı., Eskiler, Gamze Güney, Çeçener, Gülşah, Tunca, Berrin, Egeli, Ünal, AAP-9988-2020, AAH-1420-2021, AAB-6011-2022, and ABI-6078-2020
- Subjects
0301 basic medicine ,MCF7 cells ,Abcg2 ,Health, Toxicology and Mutagenesis ,Expression ,Apoptosis ,Drug resistance ,ABCB1 protein, human ,MCF-7 cell line ,Toxicology ,Induction ,Breast cancer ,P-glycoproteins ,0302 clinical medicine ,Annexin ,Mechanisms ,Cell structure ,skin and connective tissue diseases ,Transporter associated with antigen processing 1 ,Gene expression regulation ,Cancer resistance ,Lipocortin 5 ,biology ,Estradiol ,Messenger RNA ,Afimoxifene ,Multidrug resistance-associated protein 1 ,Breast Neoplasms ,Aromatase Inhibitors ,Estrogen Receptors ,Breast cancer resistance protein ,Gene expression profiling ,Gene Expression Regulation, Neoplastic ,ABCG1 ,030220 oncology & carcinogenesis ,Reverse transcription polymerase chain reaction ,ABCC1 ,MCF-7 Cells ,Multidrug Resistance-Associated Proteins ,Receptor ,Human ,medicine.drug ,ATP Binding Cassette Transporter, Subfamily B ,Priority jourbiological modelnal ,Cell Survival ,Breast-cancer cells ,TAP1 protein, human ,Concentration response ,Models, Biological ,Article ,Treatment duration ,03 medical and health sciences ,E2f1 ,Genetics ,medicine ,Cancer model ,Humans ,RNA, Messenger ,ATP Binding Cassette Transporter, Subfamily B, Member 2 ,Antigen peptide transporter-1 ,Cell Shape ,Drug-resistance ,ABC transporter G1 ,Analysis of Variance ,Drug effects ,business.industry ,In vitro study ,Multidrug resistance protein ,Cell Biology ,Line ,medicine.disease ,Estrogen ,In vitro ,Tamoxifen ,Metabolism ,030104 developmental biology ,Human cell ,Drug Resistance, Neoplasm ,Immunology ,Biological model ,Cancer research ,biology.protein ,Protein expression ,business ,Controlled study ,Multidrug resistance associated protein 1 - Abstract
The development of resistance to tamoxifen (Tam) remains a challenging clinical problem for ER+ breast cancer patients. To understand the mechanisms underlying of resistance, previous studies have driven the acquisition of Tam resistance by exposing cells to varying concentration of drug for varying lengths of time. However, a detailed protocol for the establishment of Tam-resistant cells remains to be clarified. In the present study, we aimed to determine and compare the effect of different in vitro protocols on the degree of resistance to 4-hydroxytamoxifen (4-OH Tam) for MCF7 cells. For this purpose, MCF7-Tam resistance (MCF7-TamR) cells were developed by treated with different concentrations (100, 200, 400, 600, 800 and 1000 nM) of 4-OH Tam over 3 months. The relative resistance was measured by WST-1 analysis. Studies characterizing of the 4-OH Tam resistance of MCF7-TamR cells were performed by 17 beta-oestradiol (E2) and Annexin V/PI analysis. In addition, the expression levels of ABCC1, ABCG2 and ABCG1 were detected by RT-PCR, any changes in morphological of each resistance group were observed at the end of each month and compared with parental MCF7 cells. Consequently, exposure time and concentration can affect the degree of resistance to 4-OH Tam; thus, dose and treatment duration should be chosen according to the desired degree of resistance. This work presents a novel procedure for the generation of MCF7-TamR cells, thus enabling the identification and characterization of MCF7-TamR cells.
- Published
- 2016
144. The Protein Kinase CK2 Mediates Cross-Talk between Auxin- and Salicylic Acid-Signaling Pathways in the Regulation of PINOID Transcription
- Author
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Eleonora Caldarella, Laia Armengot, M. Carmen Martínez, Maria Mar Marquès-Bueno, Universitat Autònoma de Barcelona (UAB), Reproduction et développement des plantes (RDP), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-École normale supérieure - Lyon (ENS Lyon), Ministerio de Educacion, Cultura y Deporte, Fondos FEDER [BFU2010-15090, BFU2013-42695-P], Ministerio de Economia y Competitividad, Departament d'Universitats, Recerca i Societat de la Informacio [2009SGR-795], École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Transcription, Genetic ,[SDV]Life Sciences [q-bio] ,Cell Membranes ,Arabidopsis ,Gene Expression ,lcsh:Medicine ,Plant Science ,Biochemistry ,Mixed Function Oxygenases ,dominant-negative mutant ,Transcription (biology) ,Gene Expression Regulation, Plant ,Transcriptional regulation ,polarity ,Plant Hormones ,Casein Kinase II ,lcsh:Science ,Regulation of gene expression ,chemistry.chemical_classification ,Multidisciplinary ,Plant Biochemistry ,phosphorylation ,Nuclear Proteins ,food and beverages ,Plants ,Plants, Genetically Modified ,efflux ,Up-Regulation ,Enzymes ,embryonic structures ,plant development ,Casein kinase 2 ,Signal transduction ,Cellular Structures and Organelles ,Salicylic Acid ,Signal Transduction ,Research Article ,animal structures ,Arabidopsis Thaliana ,DNA transcription ,arabidopsis-thaliana ,p-glycoproteins ,transport ,resistance ,expression ,Brassica ,Biology ,Protein Serine-Threonine Kinases ,Research and Analysis Methods ,Gene Expression Regulation, Enzymologic ,03 medical and health sciences ,Model Organisms ,Auxin ,Plant and Algal Models ,Gene Types ,Genetics ,Gene Regulation ,Protein kinase A ,Indoleacetic Acids ,Arabidopsis Proteins ,fungi ,lcsh:R ,Organisms ,Biology and Life Sciences ,Proteins ,Membrane Proteins ,Cell Biology ,biology.organism_classification ,Hormones ,030104 developmental biology ,chemistry ,Enzymology ,Auxins ,Regulator Genes ,lcsh:Q ,Protein Kinases ,Transcription Factors - Abstract
International audience; The protein kinase CK2 is a ubiquitous and highly conserved enzyme, the activity of which is vital for eukaryotic cells. We recently demonstrated that CK2 modulates salicylic acid (SA) homeostasis in Arabidopsis thaliana, and that functional interplay between CK2 and SA sustains transcriptional expression of PIN-FORMED (PIN) genes. In this work, we show that CK2 also plays a key role in the transcriptional regulation of PINOID (PID), an AGC protein kinase that modulates the apical/basal localization of auxin-efflux transporters. We show that PID transcription is up-regulated by auxin and by SA and that CK2 is involved in both pathways. On the one hand, CK2 activity is required for proteosome-dependent degradation of AXR3, a member of the AUX/IAA family of auxin transcriptional repressors that must be degraded to activate auxin-responsive gene expression. On the other hand, the role of CK2 in SA homeostasis and, indirectly, in SA-driven PID transcription, was confirmed by using Arabidopsis NahG transgenic plants, which cannot accumulate SA. In conclusion, our results evidence a role for CK2 as a functional link in the negative cross-talk between auxin- and SA-signaling.
- Published
- 2016
145. Global marine pollutants inhibit P-glycoprotein: Environmental levels, inhibitory effects, and cocrystal structure.
- Author
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Nicklisch, Sascha CT, Nicklisch, Sascha CT, Rees, Steven D, McGrath, Aaron P, Gökirmak, Tufan, Bonito, Lindsay T, Vermeer, Lydia M, Cregger, Cristina, Loewen, Greg, Sandin, Stuart, Chang, Geoffrey, Hamdoun, Amro, Nicklisch, Sascha CT, Nicklisch, Sascha CT, Rees, Steven D, McGrath, Aaron P, Gökirmak, Tufan, Bonito, Lindsay T, Vermeer, Lydia M, Cregger, Cristina, Loewen, Greg, Sandin, Stuart, Chang, Geoffrey, and Hamdoun, Amro
- Abstract
The world's oceans are a global reservoir of persistent organic pollutants to which humans and other animals are exposed. Although it is well known that these pollutants are potentially hazardous to human and environmental health, their impacts remain incompletely understood. We examined how persistent organic pollutants interact with the drug efflux transporter P-glycoprotein (P-gp), an evolutionarily conserved defense protein that is essential for protection against environmental toxicants. We identified specific congeners of organochlorine pesticides, polychlorinated biphenyls, and polybrominated diphenyl ethers that inhibit mouse and human P-gp, and determined their environmental levels in yellowfin tuna from the Gulf of Mexico. In addition, we solved the cocrystal structure of P-gp bound to one of these inhibitory pollutants, PBDE (polybrominated diphenyl ether)-100, providing the first view of pollutant binding to a drug transporter. The results demonstrate the potential for specific binding and inhibition of mammalian P-gp by ubiquitous congeners of persistent organic pollutants present in fish and other foods, and argue for further consideration of transporter inhibition in the assessment of the risk of exposure to these chemicals.
- Published
- 2016
146. Effects of cholesterol content on activity of P-glycoproteins and membrane physical state, and consequences for anthelmintic resistance in the nematode Haemonchus contortus.
- Author
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Riou M, Guégnard F, Le Vern Y, Grasseau I, Koch C, Blesbois E, and Kerboeuf D
- Subjects
- Animals, Anthelmintics pharmacology, Cell Membrane drug effects, Membrane Fluidity, Xenobiotics pharmacology, ATP Binding Cassette Transporter, Subfamily B metabolism, Animal Shells chemistry, Cell Membrane chemistry, Cholesterol chemistry, Drug Resistance, Haemonchus chemistry, Haemonchus drug effects
- Abstract
Eukaryote plasma membranes protect cells from chemical attack. Xenobiotics, taken up through passive diffusion, accumulate in the membranes, where they are captured by transporters, among which P-glycoproteins (Pgps). In nematodes such as Haemonchus contortus, eggshells and cuticles provide additional protective barriers against xenobiotics. Little is known about the role of these structures in the transport of chemical molecules. Pgps, members of the ABC transporter family, are present in eggshells and cuticles. Changes in the activity of these proteins have also been correlated with alterations in lipids, such as cholesterol content, in eggshells. However, the cellular mechanisms underlying these effects remain unclear. We show here that an experimental decrease in the cholesterol content of eggshells of Haemonchus contortus, with Methyl-beta-CycloDextrin (MβCD), results in an increase in membrane fluidity, favouring Pgp activity and leading to an increase in resistance to anthelmintics. This effect is modulated by the initial degree of anthelminthic resistance of the eggs. These results suggest that eggshell fluidity plays a major role in the modulation of Pgp activity. They confirm that Pgp activity is highly influenced by the local microenvironment, in particular sterols, as observed in some vertebrate models. Thus, eggshell barriers could play an active role in the transport of xenobiotics., (© M. Riou et al., published by EDP Sciences, 2020.)
- Published
- 2020
- Full Text
- View/download PDF
147. Are pharmacogenomic biomarkers an effective tool to predict taxane toxicity and outcome in breast cancer patients? Literature review
- Author
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Ludovica Taglieri, Susanna Scarpa, Gerardo Salerno, and Francesca De Iuliis
- Subjects
Bridged-Ring Compounds ,Cancer Research ,ATP Binding Cassette Transporter, Subfamily B ,Population ,SNP ,Antineoplastic Agents ,Breast Neoplasms ,Disease ,Taxane ,Bioinformatics ,Toxicology ,Polymorphism, Single Nucleotide ,Pharmacogenomic Variants ,Breast cancer ,Medicine ,Humans ,Pharmacology (medical) ,Polymorphism ,Adverse effect ,education ,P-Glycoproteins ,Pharmacology ,education.field_of_study ,Evidence-Based Medicine ,business.industry ,Medicine (all) ,ABCB1 ,Single Nucleotide ,medicine.disease ,Clinical trial ,Oncology ,Pharmacogenetics ,Pharmacogenomics ,Cytochrome P-450 CYP1B1 ,CYP1B1 ,Female ,Taxoids ,Biomarkers ,Bridged Compounds ,business - Abstract
Breast cancer is a heterogeneous disease, characterized by various molecular phenotypes that correlate with different prognosis and response to treatments. Taxanes are some of the most active chemotherapeutic agents for breast cancer; however, their utilization is limited, due to hematologic and cumulative neurotoxicity on treated patients. To understand why only some patients experience severe adverse effects and why patients respond and develop resistance with different rates to taxane therapy, the metabolic pathways of these drugs should be completely unraveled. The variant forms of several genes, related to taxane pharmacokinetics, can be indicative markers of clinical parameters, such as toxicity or outcome. The search of the data has been conducted through PubMed database, presenting clinical data, clinical trials and basic research restricted to English language until June 2015. We studied the literature in order to find any possible association between the major pharmacogenomic variants and specific taxane-related toxicity and patient outcome. We found that the data of these studies are sometimes discordant, due to both the small number of enrolled patients and the heterogeneity of the examined population. Among all analyzed genes, only CYP1B1 and ABCB1 resulted the strongest candidates to become biomarkers of clinical response to taxane therapy in breast cancer, although their utilization still remains an experimental procedure. In the future, greater studies on genetic polymorphisms should be performed in order to identify differentiating signatures for patients with higher toxicity and with resistant or responsive outcome, before the administration of taxanes.
- Published
- 2015
148. Genome-wide association data suggest ABCB1 and immune-related gene sets may be involved in adult antisocial behavior
- Author
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Salvatore, JE, Edwards, AC, McClintick, JN, Bigdeli, TB, Adkins, A, Aliev, F, Edenberg, HJ, Foroud, T, Hesselbrock, V, Kramer, J, Nurnberger, JI, Schuckit, M, Tischfield, JA, Xuei, X, and Dick, DM
- Subjects
Adult ,Male ,ATP Binding Cassette Transporter ,Clinical Sciences ,Cocaine-Related Disorders ,Substance Misuse ,Genetics ,Humans ,Psychology ,Genetic Predisposition to Disease ,Polymorphism ,P-Glycoproteins ,Violence Research ,Human Genome ,Substance Abuse ,Brain ,Antisocial Personality Disorder ,Single Nucleotide ,Brain Disorders ,Alcoholism ,Mental Health ,Good Health and Well Being ,Subfamily B ,Case-Control Studies ,Interferon Type I ,Public Health and Health Services ,Female ,Genome-Wide Association Study - Abstract
Adult antisocial behavior (AAB) is moderately heritable, relatively common and has adverse consequences for individuals and society. We examined the molecular genetic basis of AAB in 1379 participants from a case-control study in which the cases met criteria for alcohol dependence. We also examined whether genes of interest were expressed in human brain. AAB was measured using a count of the number of Antisocial Personality Disorder criteria endorsed under criterion A from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). Participants were genotyped on the Illumina Human 1M BeadChip. In total, all single-nucleotide polymorphisms (SNPs) accounted for 25% of the variance in AAB, although this estimate was not significant (P=0.09). Enrichment tests indicated that more significantly associated genes were over-represented in seven gene sets, and most were immune related. Our most highly associated SNP (rs4728702, P=5.77 × 10(-7)) was located in the protein-coding adenosine triphosphate-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1). In a gene-based test, ABCB1 was genome-wide significant (q=0.03). Expression analyses indicated that ABCB1 was robustly expressed in the brain. ABCB1 has been implicated in substance use, and in post hoc tests we found that variation in ABCB1 was associated with DSM-IV alcohol and cocaine dependence criterion counts. These results suggest that ABCB1 may confer risk across externalizing behaviors, and are consistent with previous suggestions that immune pathways are associated with externalizing behaviors. The results should be tempered by the fact that we did not replicate the associations for ABCB1 or the gene sets in a less-affected independent sample.
- Published
- 2015
149. Analysis of functional variants reveals new candidate genes associated with alexithymia
- Author
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Massimo Mezzavilla, Sheila Ulivi, Antonietta Robino, Martina La Bianca, Paolo Gasparini, Davide Carlino, Mezzavilla, Massimo, Ulivi, Sheila, La Bianca, Martina, Carlino, Davide, Gasparini, Paolo, and Robino, Antonietta
- Subjects
Alexithymia ,Male ,Candidate gene ,Personality Inventory ,Emotions ,ABCB4 ,Functional variants ,Adolescent ,Adult ,Affective Symptoms ,Aged ,Case-Control Studies ,DNA-Binding Proteins ,Female ,Humans ,Membrane Proteins ,Middle Aged ,P-Glycoproteins ,Phenotype ,Tumor Suppressor Proteins ,Young Adult ,Psychiatry and Mental Health ,Biological Psychiatry ,Medicine (all) ,Developmental psychology ,Membrane Protein ,media_common ,Genetics ,Affective Symptom ,Trait ,Biological psychiatry ,Personality Assessment Inventory ,Case-Control Studie ,Psychology ,Human ,ATP Binding Cassette Transporter, Subfamily B ,DNA-Binding Protein ,media_common.quotation_subject ,Functional variant ,medicine ,Personality ,Gene ,Emotion ,Tumor Suppressor Protein ,P-Glycoprotein ,medicine.disease - Abstract
In this study we explored the possible association between 36,915 functional variants and alexithymia, a personality trait characterized by the inability to identify and describe emotions and feelings. From our analysis, variants in the genes ABCB4, TP53AIP1, ARHGAP32 and TMEM88B were identified linked to the alexithymia phenotype.
- Published
- 2015
150. Direct genotyping of C3435T single nucleotide polymorphism in unamplified human MDR1 gene using a surface plasmon resonance imaging DNA sensor
- Author
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Stefano Mariani, Maria Minunni, Roberto Barale, Maura Carrai, and Simona Scarano
- Subjects
ATP Binding Cassette Transporter, Subfamily B ,Optical Phenomena ,Genotype ,Surface plasmon resonance imaging (SPRi) DNA sensor ,Molecular Inversion Probe ,Polymorphism, Single Nucleotide ,Sensitivity and Specificity ,Biochemistry ,law.invention ,Analytical Chemistry ,chemistry.chemical_compound ,law ,C3435T single nucleotide polymorphisms (SNPs) ,Direct optical genotyping ,Human genomic DNA (hDNA) ,MDR1 gene ,DNA ,Humans ,P-Glycoproteins ,Surface Plasmon Resonance ,Surface plasmon resonance ,Polymorphism ,Genotyping ,Gene ,Polymerase chain reaction ,Hybridization probe ,Single Nucleotide ,Molecular biology ,genomic DNA ,chemistry - Abstract
Optical genotyping of C3435T single nucleotide polymorphisms (SNPs) in unamplified human multidrug resistance (MDR1) gene was here performed by a surface plasmon resonance imaging (SPRi) dual-targeting DNA assay, allowing its selective detection down to 0.18 fM of the whole genomic DNA. The result was achieved by the combination of the rational selection of the DNA probe and an optimized sample pretreatment (i.e., ultrasound fragmentation and thermal denaturation). Some assay developments and tunings were reported in a previously published research, but here, for the first time, the biosensor reliability and its analytical performance were directly tested on the unamplified human DNA extracted from lymphocytes. The assay resulted to be able to differentiate among all the possible genotypes of C3435T (homozygote and heterozygote) in the diluted genomic samples using a label-free approach and by bypassing the classical PCR amplification of the target sequences. Moreover, the reusability of the DNA-based chip allowed up to 40 subsequent measuring cycles, opening new horizons in multi-SNP genotyping based on cheap and daily routine clinical monitoring by optical biosensing.
- Published
- 2015
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