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1.
Adv Exp Med Biol ; 1141: 1-12, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571163

RESUMO

Absorption, distribution, and excretion of drugs are involved in drug transport across plasma membrane, most of which are mediated by drug transporters. These drug transporters are generally divided into solute carrier (SLC) family and ATP-binding cassette (ABC) family. These transporters not only mediate transport of therapeutic drugs across membrane but also transport various kinds of endogenous compounds. Thus besides being participated in disposal of drug and its clinical efficacy/toxicity, these transporters also play vital roles in maintaining cell homeostasis via regulating transport of endogenous compounds. This chapter will outline classification of drug transporters, their roles in drug disposal/drug response, and remote communication between tissues/organs.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Proteínas Carreadoras de Solutos , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Transporte Biológico , Comunicação Celular , Membrana Celular/metabolismo , Humanos , Preparações Farmacêuticas/metabolismo , Proteínas Carreadoras de Solutos/metabolismo
2.
Adv Exp Med Biol ; 1141: 13-100, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571164

RESUMO

The transport of specific molecules across lipid membranes is an essential function of all living organisms. The processes are usually mediated by specific transporters. One of the largest transporter families is the ATP-binding cassette (ABC) family. More than 40 ABC transporters have been identified in human, which are divided into 7 subfamilies (ABCA to ABCG) based on their gene structure, amino acid sequence, domain organization, and phylogenetic analysis. Of them, at least 11 ABC transporters including P-glycoprotein (P-GP/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs), and breast cancer resistance protein (BCRP/ABCG2) are involved in multidrug resistance (MDR) development. These ABC transporters are expressed in various tissues such as the liver, intestine, kidney, and brain, playing important roles in absorption, distribution, and excretion of drugs. Some ABC transporters are also involved in diverse cellular processes such as maintenance of osmotic homeostasis, antigen processing, cell division, immunity, cholesterol, and lipid trafficking. Several human diseases such as cystic fibrosis, sitosterolemia, Tangier disease, intrahepatic cholestasis, and retinal degeneration are associated with mutations in corresponding transporters. This chapter will describe function and expression of several ABC transporters (such as P-GP, BCRP, and MRPs), their substrates and inhibitors, as well as their clinical significance.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Fenômenos Fisiológicos Celulares , Resistência a Múltiplos Medicamentos/genética , Regulação da Expressão Gênica , Humanos , Filogenia
3.
Adv Exp Med Biol ; 1141: 241-291, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571167

RESUMO

Drug transporters are considered to be determinants of drug disposition and effects/toxicities by affecting the absorption, distribution, and excretion of drugs. Drug transporters are generally divided into solute carrier (SLC) family and ATP binding cassette (ABC) family. Widely studied ABC family transporters include P-glycoprotein (P-GP), breast cancer resistance protein (BCRP), and multidrug resistance proteins (MRPs). SLC family transporters related to drug transport mainly include organic anion-transporting polypeptides (OATPs), organic anion transporters (OATs), organic cation transporters (OCTs), organic cation/carnitine transporters (OCTNs), peptide transporters (PEPTs), and multidrug/toxin extrusions (MATEs). These transporters are often expressed in tissues related to drug disposition, such as the small intestine, liver, and kidney, implicating intestinal absorption of drugs, uptake of drugs into hepatocytes, and renal/bile excretion of drugs. Most of therapeutic drugs are their substrates or inhibitors. When they are comedicated, serious drug-drug interactions (DDIs) may occur due to alterations in intestinal absorption, hepatic uptake, or renal/bile secretion of drugs, leading to enhancement of their activities or toxicities or therapeutic failure. This chapter will illustrate transporter-mediated DDIs (including food drug interaction) in human and their clinical significances.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Interações de Medicamentos , Preparações Farmacêuticas , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Transporte Biológico , Interações Alimento-Droga , Humanos , Proteínas de Neoplasias/metabolismo , Transportadores de Ânions Orgânicos , Preparações Farmacêuticas/metabolismo
4.
Adv Exp Med Biol ; 1141: 549-580, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571174

RESUMO

ATP-binding cassette (ABC) transporters are involved in active pumping of many diverse substrates through the cellular membrane. The transport mediated by these proteins modulates the pharmacokinetics of many drugs and xenobiotics. These transporters are involved in the pathogenesis of several human diseases. The overexpression of certain transporters by cancer cells has been identified as a key factor in the development of resistance to chemotherapeutic agents. In this chapter, the localization of ABC transporters in the human body, their physiological roles, and their roles in the development of multidrug resistance (MDR) are reviewed. Specifically, P-glycoprotein (P-GP), multidrug resistance-associated proteins (MRPs), and breast cancer resistance protein (BCRP/ABCG2) are described in more detail. The potential of ABC transporters as therapeutic targets to overcome MDR and strategies for this purpose are discussed as well as various explanations for the lack of efficacy of ABC drug transporter inhibitors to increase the efficiency of chemotherapy.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Neoplasias , Transportadores de Cassetes de Ligação de ATP/metabolismo , Resistência a Múltiplos Medicamentos/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Neoplasias/fisiopatologia , Distribuição Tecidual
5.
J Agric Food Chem ; 67(42): 11805-11814, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31566383

RESUMO

The impact of cross-breeding two low phytic acid (lpa) rice mutants on the content of phytic acid and the metabolite profile of the resulting double mutant was investigated. Progenies resulting from the cross of Os-lpa-XS110-1, a rice mutant carrying the myo-inositol kinase (OsMIK) mutated gene, and Os-lpa-XS110-2, with the multidrug resistance-associated protein ABC transporter gene 5 (OsMRP5) as the mutation target, were subjected to high-pressure ion chromatography. The reduction of the phytic acid content in the double mutant (-63%) was much more pronounced than in the single mutants (-26 and -47%). Gas chromatography-based metabolite profiling revealed a superimposition of the metabolite profiles inherited from the lpa progenitors in the double mutant progenies; the resulting metabolite signature was predominated by the OsMIK mutation effect. The study demonstrated that cross-breeding of two single lpa mutants can be employed to generate double lpa rice mutants showing both a significant reduction in the content of phytic acid and the imprinting of a specific mutation-induced metabolite signature.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Hibridização Genética , Oryza/química , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Ácido Fítico/análise , Proteínas de Plantas/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Mutação , Oryza/genética , Oryza/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Ácido Fítico/metabolismo , Proteínas de Plantas/metabolismo , Sementes/química , Sementes/genética , Sementes/metabolismo
6.
Cell Physiol Biochem ; 53(2): 400-412, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31403270

RESUMO

BACKGROUND/AIMS: Mutations in ABCA4 cause Stargardt macular degeneration, which invariably ends in legal blindness. We studied two common mutants, A1038V (in NBD1) and G1961E (in NBD2), with the purpose of exploring how they interact with the cell's quality control mechanism. The study was designed to determine how these mutants can be rescued. METHODS: We expressed wt and mutant ABCA4 in HEK293 cells and studied the effect of the mutations on trafficking and processing and the ability of correctors to rescue them. We used a combination of western blotting, confocal microscopy and surface biotinylation coupled with pulldown of plasma membrane proteins. RESULTS: G1961E is sensitive to inhibitors of the aggresome, tubacin and the lysosome, bafilomycin A. Both mutants cause a reduction in heat shock protein, Hsp27. Incubation of HEK293 cells expressing the mutants with VX-809, an FDA approved drug for the treatment of cystic fibrosis, increased the levels of A1038V and G1961E by 2- to 3-fold. Importantly, VX-809 increased the levels of both mutants at the plasma membrane suggesting that trafficking had been restored. Transfecting additional Hsp27 to the cells also increased the steady state levels of both mutants. However, in combination with VX-809 the addition of Hsp27 caused a dramatic increase in the protein expression particularly in the G1961 mutant which increased approximately 5-fold. CONCLUSION: Our results provide a new mechanism for the rescue of ABCA4 trafficking mutants based on the restoration of Hsp27. Our results provide a pathway for the treatment of Stargardt disease.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Aminopiridinas/farmacologia , Benzodioxóis/farmacologia , Transportadores de Cassetes de Ligação de ATP/genética , Aminopiridinas/uso terapêutico , Anilidas/farmacologia , Benzodioxóis/uso terapêutico , Membrana Celular/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Leupeptinas/farmacologia , Lisossomos/metabolismo , Degeneração Macular/congênito , Degeneração Macular/tratamento farmacológico , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Mutação , Transporte Proteico/efeitos dos fármacos
8.
Life Sci ; 231: 116548, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31181228

RESUMO

AIMS: Multidrug resistance is a major obstacle in chemotherapy, which is mainly caused by the overexpression of ATP-binding cassette (ABC) transporters. Breast cancer resistance protein (BCRP) is one of the ABC transporters and is strongly associated with multidrug resistance. Results of studies on BCRP and multidrug resistance are always uncomparable and contradictory, which may be stem from the disadvantages of qualitative and semi-quantitative techniques. In addition, there are few literatures studying at low resistance level which is more similar to the clinical situation. Thus, it is imperative to develop a quantitative method to quantitate the expression of BCRP accurately and reveal its relationship with multidrug resistance. METHODS: SMMC-7721, MCF-7 and HepG-2 were induced by different concentrations of mitoxantrone, doxorubicin and methotrexate respectively to establish resistance cells. An advanced liquid chromatography linked to tandem mass spectrometry (LC-MS/MS) based method with surrogate peptide was developed and validated for determining BCRP at low resistant cells. The amount of BCRP was also evaluated by real-time-polymerase chain reaction (RT-PCR) and Western Blot (WB). KEY FINDINGS: The LC-MS/MS-based method we developed is more sensitive and stable than the similar methods and can monitor the slight variation of BCRP expression accurately and sensitively, while RT-PCR and WB cannot. SIGNIFICANCE: This study provides a solid foundation for understanding the development of drug resistance in cells and can be used to explain the conflicting results of published studies. Moreover, clinical multidrug resistances are mostly at low levels, which have not been discussed in current quantitative studies of BCRP.


Assuntos
Neoplasias da Mama/química , Neoplasias da Mama/metabolismo , Cromatografia Líquida/métodos , Proteínas de Membrana/análise , Proteínas de Membrana/biossíntese , Proteômica/métodos , Espectrometria de Massas em Tandem/métodos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Células Hep G2 , Humanos , Células MCF-7 , Proteínas de Neoplasias/metabolismo
9.
Expert Opin Drug Metab Toxicol ; 15(7): 577-593, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31185182

RESUMO

Introduction: Chemotherapy remains the only option for advanced cancer patients when other alternatives are not feasible. Nevertheless, the success rate of this type of therapy is often low due to intrinsic or acquired mechanisms of chemoresistance. Among them, drug extrusion from cancer cells through ATP-binding cassette (ABC) proteins plays an important role. ABC pumps are primary active transporters involved in the barrier and secretory functions of many healthy cells. Areas covered: In this review, we have used The Cancer Genome Atlas (TCGA) database to explore the relationship between the expression of the major ABC proteins involved in cancer chemoresistance in the most common types of cancer, and the drugs used in the treatment of these tumors that are substrates of these pumps. Expert opinion: From unicellular organisms to humans, several ABC proteins play a major role in detoxification processes. Cancer cells exploit this ability to protect themselves from cytostatic drugs. Among the ABC pumps, MDR1, MRPs and BCRP are able to export many antitumor drugs and are expressed in several types of cancer, and further up-regulated during treatment. This event results in the enhanced ability of tumor cells to reduce intracellular drug concentrations and hence the pharmacological effect of chemotherapy.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Transportadores de Cassetes de Ligação de ATP/metabolismo , Bases de Dados Genéticas , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/genética , Regulação para Cima
10.
Biol Pharm Bull ; 42(5): 649-665, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061307

RESUMO

Peroxisomes are indispensable organelles in mammals including humans. They are involved in the ß-oxidation of very long chain fatty acids, and the synthesis of ether phospholipids and bile acids. Pre-peroxisomes bud from endoplasmic reticulum and peroxisomal membrane and matrix proteins are imported to the pre-peroxisomes. Then, matured peroxisomes grow by division. Impairment of the biogenesis and function of peroxisomes results in severe diseases. Since I first undertook peroxisome research in Prof. de Duve's laboratory at Rockefeller University in 1985, I have continuously studied peroxisomes for more than 30 years, with a particular focus on the ATP-binding cassette (ABC) transporters. Here, I review the history of peroxisome research, the biogenesis and function of peroxisomes, and peroxisome disease including X-linked adrenoleukodystrophy. The review includes the targeting and function of the ABC transporter subfamily D.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Peroxissomos/metabolismo , Adrenoleucodistrofia/metabolismo , Animais , Humanos
11.
Acta Trop ; 196: 126-134, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31108084

RESUMO

The emergence of resistance to artemisinin-based combination therapies (ACT) was described in Southeast Asia. In this context, the identification of molecular markers of ACT resistance partner drugs is urgently needed for monitoring the emergence and spread of resistance. Polymorphisms in transporter genes, especially of the ATP-binding cassette (ABC) superfamily, have been involved in anti-malarial drug resistance. In this study, the association between the mutations in the P. falciparum multidrug resistance 1 gene (pfmdr1, N86Y, Y184 F, S1034C, N1042D and D1246Y) or repetitive amino acid motifs in pfmdr5 and the ex vivo susceptibility to anti-malarial drugs was evaluated. Susceptibility to chloroquine, quinine, monodesethylamodiaquine, lumefantrine, piperaquine, pyronaridine, mefloquine and dihydroartemisinin was assessed in 67 Senegalese isolates. The shorter DNNN motif ranged from to 2 to 11 copy repeats, and the longer DHHNDHNNDNNN motif ranged from 0 to 2 in pfmdr5. The present study showed the association between repetitive amino acid motifs (DNNN-DHHNDDHNNDNNN) in pfmdr5 and in vitro susceptibility to 4-aminoquinoline-based antimalarial drugs. The parasites with 8 and more copy repeats of DNNN in pfmdr5 were significantly more susceptible to piperaquine. There was a significant association between parasites whose DHHNDHNNDNNN motif was absent and replaced by DHHNDNNN, DHHNDHNNDHNNDNNN or DHHNDHNNDHNNDHNNDNNN and increased susceptibility to chloroquine, monodesethylamodiaquine and pyronaridine. A significant association between both the wild-type allele N86 in pfmdr1 and the N86-184 F haplotype and reduced susceptibility to lumefantrine was confirmed. Further studies with a large number of samples are required to validate the association between these pfmdr5 alleles and the modulation of 4-aminoquinoline-based antimalarial drug susceptibility.


Assuntos
Antimaláricos/farmacologia , Resistência a Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Plasmodium falciparum/efeitos dos fármacos , Polimorfismo Genético , Proteínas de Protozoários/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Haplótipos , Humanos , Malária Falciparum/parasitologia , Proteínas de Membrana Transportadoras/genética , Plasmodium falciparum/genética , Proteínas de Protozoários/genética
12.
Int J Mol Sci ; 20(10)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096671

RESUMO

ATP-binding cassette (ABC) transporters are a superfamily of proteins that transport nutrient substances and secondary metabolites through cell membranes. They also act as an uptake system for N,N'-diacetylchitobiose (GlcNAc)2 in Streptomyces coelicolor. (GlcNAc)2 is an important inducer of chitinase. However, whether the ABC transporter in Trichoderma spp. is also responsible for (GlcNAc)2 uptake and chitinase induction has not yet been confirmed. In this study, we applied RNA interference and overexpression technologies to alter the expression level of the ABC-B transporter in order to detect changes in its transportation ability and the expression level of inducible endo-chitinase ECH42-an important biocontrol enzyme in Trichoderma asperellum. The results revealed that, after interference with the expression of the ABC-B transporter, T. asperellum T4 was only able to grow normally when glucose was the only carbon source. Compared with the wild-type, the efficiency of (GlcNAc)2 by the overexpression strain evidently increased, along with the activity level of ECH42. In conclusion, one of the functions of the ABC-B transporter in T. asperellum is the uptake and transport of (GlcNAc)2 into cells, and chitobiose is a strong inducer of ECH42 in T. asperellum T4.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Quitinases/metabolismo , Dissacarídeos/metabolismo , Trichoderma/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transporte Biológico , Meios de Cultura/química , Escherichia coli/genética , Proteínas Fúngicas/genética , Regulação Fúngica da Expressão Gênica , Genes Fúngicos/genética , Polissacarídeos/metabolismo , Protoplastos , Trichoderma/genética , Trichoderma/crescimento & desenvolvimento
13.
Mar Drugs ; 17(5)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052268

RESUMO

Prorocentrum lima is a typical benthic toxic dinoflagellate, which can produce phycotoxins such as okadaic acid (OA). In this study, we identified three ABC transporter genes (ABCB1, ABCC1 and ABCG2) and characterized their expression patterns, as well as OA production under different environmental conditions in P. lima. We found that the three ABC transporters all showed high identity with related ABC proteins from other species, and contained classical features of ABC transport proteins. Among them, ABCG2 was a half size transporter. The three ABC transporter genes displayed various expression profiles under different conditions. The high concentration of Cu2+ could up-regulate ABCB1, ABCC1 and ABCG2 transcripts in P. lima, suggesting the potential defensive role of ABC transporters against metal ions in surrounding waters. Cu2+, in some concentration, could induce OA production; meanwhile, tributyltin inhibited OA accumulation. The grazer Artemia salina could induce OA production, and P. lima displayed some toxicity to the grazer, indicating the possibility of OA as an anti-grazing chemical. Collectively, our results revealed intriguing data about OA production and the expression patterns of three ABC transporter genes. However, we could not find any significant correlation between OA production and expression pattern of the three ABC transporters in P. lima. Our results might provide new molecular insights on the defensive responses of P. lima to the surrounding environment.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Dinoflagelados/metabolismo , Dinoflagelados/crescimento & desenvolvimento , Meio Ambiente , Toxinas Marinhas/química , Ácido Okadáico/metabolismo , RNA Mensageiro
14.
Cell Mol Life Sci ; 76(20): 4131-4144, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31053883

RESUMO

ABCB6 belongs to the family of ATP-binding cassette (ABC) transporters, which transport various molecules across extra- and intra-cellular membranes, bearing significant impact on human disease and pharmacology. Although mutations in the ABCB6 gene have been linked to a variety of pathophysiological conditions ranging from transfusion incompatibility to pigmentation defects, its precise cellular localization and function is not understood. In particular, the intracellular localization of ABCB6 has been a matter of debate, with conflicting reports suggesting mitochondrial or endolysosomal expression. ABCB6 shows significant sequence identity to HMT-1 (heavy metal tolerance factor 1) proteins, whose evolutionarily conserved role is to confer tolerance to heavy metals through the intracellular sequestration of metal complexes. Here, we show that the cadmium-sensitive phenotype of Schizosaccharomyces pombe and Caenorhabditis elegans strains defective for HMT-1 is rescued by the human ABCB6 protein. Overexpression of ABCB6 conferred tolerance to cadmium and As(III) (As2O3), but not to As(V) (Na2HAsO4), Sb(V), Hg(II), or Zn(II). Inactivating mutations of ABCB6 abolished vacuolar sequestration of cadmium, effectively suppressing the cadmium tolerance phenotype. Modulation of ABCB6 expression levels in human glioblastoma cells resulted in a concomitant change in cadmium sensitivity. Our findings reveal ABCB6 as a functional homologue of the HMT-1 proteins, linking endolysosomal ABCB6 to the highly conserved mechanism of intracellular cadmium detoxification.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Cádmio/toxicidade , Proteínas de Caenorhabditis elegans/genética , Inativação Metabólica/genética , Poluentes Químicos da Água/toxicidade , Transportadores de Cassetes de Ligação de ATP/deficiência , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Antimônio/toxicidade , Arseniatos/toxicidade , Trióxido de Arsênio/toxicidade , Cádmio/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Linhagem Celular Tumoral , Sequência Conservada , Expressão Gênica , Teste de Complementação Genética , Células HeLa , Humanos , Mercúrio/toxicidade , Mutação , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Schizosaccharomyces/efeitos dos fármacos , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismo , Vacúolos/efeitos dos fármacos , Vacúolos/metabolismo , Poluentes Químicos da Água/metabolismo , Zinco/toxicidade
16.
Medicine (Baltimore) ; 98(19): e15698, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083274

RESUMO

Ovarian cancer (OC) is one of the most common gynecological malignancies and owns the highest mortality rate among all gynecological malignant tumors. ATP binding cassette subfamily B member 9 (ABCB9) is an antigen processing-like (TAPL) transporter that has been found to be involved in the development and progression of various malignant tumors in accumulating reports. However, the potential role of ABCB9 in OC has never been reported.In this study, ABCB9 expression was evaluated in normal ovarian tissues and ovarian cancer tissues using The Cancer Genome Atlas (TCGA) database. And the associations between ABCB9 expression and clinical parameters of patients of OC were evaluated by Chi-square tests. Kaplan-Meier analysis and Cox regression analysis were performed to evaluate the prognostic significance of ABCB9. GSEA was performed to explore related signaling pathway.ABCB9 expression levels were significantly decreased in OC compared with normal ovarian tissues (P < .001). Low ABCB9 expression was associated with survival status (P = .0148) in OC. Kaplan-Meier analysis showed that low ABCB9 expression was associated with poor overall survival in OC (P = .0032). Multivariable Cox regression analysis indicated that low ABCB9 expression was an independent prognostic factor (HR 0.64; P = .01) in OC patients. Besides, epithelial mesenchymal transition, UV response, and TGF-ß signaling were enriched in low ABCB9 expression phenotype, respectively, examined by gene set enrichment analysis.These results suggest that ABCB9 is an independent prognostic indicator in OC with certain clinical significance.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Neoplasias Ovarianas/metabolismo , Biomarcadores Tumorais/metabolismo , Feminino , Expressão Gênica , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Ovário/metabolismo , Ovário/patologia , Prognóstico , Transdução de Sinais , Análise de Sobrevida
17.
Appl Microbiol Biotechnol ; 103(10): 4167-4175, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30953120

RESUMO

Rhodococcus erythropolis N9T-4, which is an extremely oligotrophic bacterium, can survive in a completely inorganic medium with no additional carbon source. This bacterium utilizes atmospheric CO2, but does not require any additional energy source such as light and hydrogen gas, required by autotrophic microorganisms. However, its CO2 fixation and energy-acquisition systems in the oligotrophic growth remain unrevealed. We expected N9T-4 to have the transporter(s) that imports essential compound(s) for its oligotrophic growth. Three putative ATP-binding cassette (ABC) transporters were found to be highly upregulated under oligotrophic conditions. We constructed the gene-deletion mutants of a gene encoding the substrate-binding protein for each ABC transporter (∆sbp1, ∆sbp2, and ∆sbp3). Among these mutants, ∆sbp1 showed growth defects on oligotrophic medium without carbon source. We examined the growth of the mutants on the oligotrophic medium containing 1% trehalose as a sole carbon source. The results exhibited worse growth of ∆sbp3 than that of the control strain (∆ligD), whereas intracellular trehalose content of all mutants decreased compared with that of ∆ligD. It was reported that trehalose functions as the mycolate carrier to the arabinogalactan layer in the cell wall of Mycobacterium tuberculosis. Transmission electron microscopic analysis of ∆sbp1 cells showed that an outermost envelope of the ∆sbp1 cell diminished, which was expected to be mycolate layer. From these results, we suggest that the same trehalose-recycling system as that in a Mycobacterium cell functions in the oligotrophic growth of N9T-4, and the ABC transporter comprising Sbp1 as the substrate-binding protein is strongly involved in the oligotrophic growth of N9T-4.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Dióxido de Carbono/metabolismo , Rhodococcus/crescimento & desenvolvimento , Rhodococcus/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Membrana Celular/ultraestrutura , Meios de Cultura/química , Metabolismo Energético , Deleção de Genes , Regulação Bacteriana da Expressão Gênica , Microscopia Eletrônica de Transmissão , Ácidos Micólicos/metabolismo , Rhodococcus/genética , Rhodococcus/ultraestrutura
18.
Phytother Res ; 33(6): 1658-1669, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30945389

RESUMO

Doxorubicin (Dox) is a first-line drug for breast cancer chemotherapy. However, with the prolongation of chemotherapy cycle, breast cancer cells are increasingly tempt to resist Dox, and meanwhile, high cumulative dose of Dox brings enhancing toxic side effects, and these effects may lead to chemotherapy failure. Hence, it is necessary to search an agent in combination medication with Dox, which can not only enhance the chemosensitivity of Dox but also reduce the toxic side effects. Tanshinone IIA (Tan IIA) is reported to have antitumor activity in addition to its cardiovascular protective effects. We employed human breast cancer MCF-7 and MCF-7/dox cells in order to assess whether Tan IIA might perform such function. Our in vitro studies showed that Tan IIA could enhance the sensitivity of breast cancer cells to Dox through inhibiting the PTEN/AKT pathway and downregulating the expression of efflux ABC transporters including P-gp, BCRP, and MRP1. In addition, our in vivo studies showed Tan IIA enhanced the chemotherapeutic effect of Dox against breast cancer while reducing its toxic side effects including weight loss, myelosuppression, cardiotoxicity, and nephrotoxicity. Therefore, Tan IIA could be used as a novel agent combined with Dox in breast cancer therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Diterpenos de Abietano/administração & dosagem , Doxorrubicina/administração & dosagem , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Diterpenos de Abietano/farmacologia , Regulação para Baixo/efeitos dos fármacos , Doxorrubicina/farmacologia , Antagonismo de Drogas , Interações de Medicamentos , Sinergismo Farmacológico , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , PTEN Fosfo-Hidrolase/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Appl Microbiol Biotechnol ; 103(11): 4539-4548, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30997553

RESUMO

The MtrA-MtrB two-component regulatory system is highly conserved in Actinobacteria and plays crucial roles in cell cycle progression, cell morphology, antibiotic resistance, and osmoprotection. Previously, we revealed that the MtrA protein of Saccharopolyspora erythraea E3 strain (a high erythromycin-producing strain) had a two amino acid (H197 and V198) deletion in the DNA recognition helices of the C-terminal domain compared to the wild type S. erythraea strain NRRL2338. Here, we identified mepA (encoding a membrane protein related to metalloendopeptidases) as an MtrA target gene, and found that deleting the two amino acids in MtrA (MtrAdel) resulted in the loss of its DNA-binding activity for the mepA gene. The mutant MtrAdel lost its regulatory activity and affected various physiological functions consistent with mtrA deletion, including increased erythromycin biosynthesis, enhanced antibiotic resistance, deregulated osmoprotection, and improved transport of substances. The introduction of the wild type mtrA gene into the S. erythraea E3 strain with the mtrAdel gene decreased the erythromycin yield by approximately 50%, confirming that MtrA repressed erythromycin production. These findings demonstrate that MtrA is an important pleiotropic regulator of erythromycin biosynthesis, antibiotic resistance, osmoprotection, and substance transport in S. erythraea and provide new insights for improving erythromycin production. Future studies linking the molecular effects of MtrA to these phenotypes will improve our understanding of the MtrA-MtrB two-component regulatory system in Actinobacteria.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antibacterianos/biossíntese , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Eritromicina/biossíntese , Saccharopolyspora/enzimologia , Saccharopolyspora/metabolismo , Deleção de Sequência , Transporte Biológico , Farmacorresistência Bacteriana , Regulação Bacteriana da Expressão Gênica , Teste de Complementação Genética , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Fenótipo , Saccharopolyspora/crescimento & desenvolvimento
20.
Curr Top Med Chem ; 19(10): 795-811, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30977450

RESUMO

Neurodegeneration is a distinguishing feature of many age related disorders and other vector borne neuroinflammatory diseases. There are a number of factors that can modulate the pathology of these disorders. ATP-binding cassette (ABC) transporters are primarily involved in the maintenance of normal brain homeostasis by eliminating toxic peptides and compounds from the brain. Also, ABC transporters protect the brain from the unwanted effects of endogenous and exogenous toxins that can enter the brain parenchyma. Therefore, these transporters have the ability to determine the pathological outcomes of several neurological disorders. For instance, ABC transporters like P-glycoprotein (ABCB1), and BCRP (ABCG2) have been reported to facilitate the clearance of peptides such as amyloid-ß (Aß) that accumulate in the brain during Alzheimer's disease (AD) progression. Other members such as ABCA1, ABCA2, ABCC8, ABCC9, ABCG1 and ABCG4 also have been reported to be involved in the progression of various brain disorders such as HIV-associated dementia, Multiple sclerosis (MS), Ischemic stroke, Japanese encephalitis (JE) and Epilepsy. However, these defective transporters can be targeted by numerous botanical compounds such as Verapamil, Berberine and Fascalpsyn as a therapeutic target to treat these neurological outcomes. These compounds are already reported to modulate ABC transporter activity in the CNS. Nonetheless, the exact mechanisms involving the ABC transporters role in normal brain functioning, their role in neuronal dysfunction and how these botanical compounds ensure and facilitate their therapeutic action in association with defective transporters still remain elusive. This review therefore, summarizes the role of ABC transporters in neurological disorders, with a special emphasis on its role in AD brains. The prospect of using botanical/natural compounds as modulators of ABC transporters in neurological disorders is discussed in the latter half of the article.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Doenças do Sistema Nervoso/metabolismo , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Animais , Humanos , Doenças do Sistema Nervoso/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia
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