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1.
Environ Pollut ; 276: 116717, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33640655

RESUMO

Genetic effects are suspected to influence cadmium internal dose. Our objective was to assess genetic determinants of urine cadmium in American Indian adults participating in the Strong Heart Family Study (SHFS). Urine cadmium levels and genotyped short tandem repeat (STR) markers were available on 1936 SHFS participants. We investigated heritability, including gene-by-sex and smoking interactions, and STR-based quantitative trait locus (QTL) linkage, using a variance-component decomposition approach, which incorporates the genetic information contained in the pedigrees. We also used available single nucleotide polymorphisms (SNPs) from Illumina's Metabochip and custom panel to assess whether promising QTLs associated regions could be attributed to SNPs annotated to specific genes. Median urine cadmium levels were 0.44 µg/g creatinine. The heritability of urine cadmium concentrations was 28%, with no evidence of gene-by-sex or -smoking interaction. We found strong statistical evidence for a genetic locus at chromosome 16 determining urine cadmium concentrations (Logarithm of odds score [LOD] = 3.8). Among the top 20 associated SNPs in this locus, 17 were annotated to ABCC1 (p-values from 0.0002 to 0.02), and attenuated the maximum linkage peak by a ∼40%. Suggestive QTL signals (LOD>1.9) in chromosomes 2, 6, 11, 14, and 19, showed associated SNPs in the genes NDUFA10, PDE10A, PLEKHA7, BAZ1A and CHAF1A, respectively. Our findings support that urinary cadmium levels are heritable and influenced by a QTL on chromosome 16, which was explained by genetic variation in ABCC1. Studies with extended sets of genome-wide markers are needed to confirm these findings and to identify additional metabolism and toxicity pathways for cadmium.


Assuntos
Cádmio , Locos de Características Quantitativas , Adulto , Cádmio/urina , Proteínas Cromossômicas não Histona , Ligação Genética , Genótipo , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Diester Fosfórico Hidrolases , Polimorfismo de Nucleotídeo Único
2.
J Pharmacol Exp Ther ; 376(1): 29-39, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33127749

RESUMO

Expression and functional changes in the organic anion transporting polypeptide (OATP)-multidrug resistance-associated protein (MRP) axis of transporters are well reported in patients with nonalcoholic steatohepatitis (NASH). These changes can impact plasma and tissue disposition of endo- and exogenous compounds. The transporter alterations are often assessed by administration of a xenobiotic or by transporter proteomic analysis from liver biopsies. Using gene expression, proteomics, and endogenous biomarkers, we show that the gene expression and activity of OATP and MRP transporters are associated with disease progression and recovery in humans and in preclinical animal models of NASH. Decreased OATP and increased MRP3/4 gene expression in two cohorts of patients with steatosis and NASH, as well as gene and protein expression in multiple NASH rodent models, have been established. Coproporphyrin I and III (CP I and III) were established as substrates of MRP4. CP I plasma concentration increased significantly in four animal models of NASH, indicating the transporter changes. Up to a 60-fold increase in CP I plasma concentration was observed in the mouse bile duct-ligated model compared with sham controls. In the choline-deficient amino acid-defined high-fat diet (CDAHFD) model, CP I plasma concentrations increased by >3-fold compared with chow diet-fed mice. In contrast, CP III plasma concentrations remain unaltered in the CDAHFD model, although they increased in the other three NASH models. These results suggest that tracking CP I plasma concentrations can provide transporter modulation information at a functional level in NASH animal models and in patients. SIGNIFICANCE STATEMENT: Our analysis demonstrates that multidrug resistance-associated protein 4 (MRP4) transporter gene expression tracks with nonalcoholic steatohepatitis (NASH) progression and intervention in patients. Additionally, we show that coproporphyrin I and III (CP I and III) are substrates of MRP4. CP I plasma and liver concentrations increase in different diet- and surgery-induced rodent NASH models, likely explained by both gene- and protein-level changes in transporters. CP I and III are therefore potential plasma-based biomarkers that can track NASH progression in preclinical models and in humans.


Assuntos
Coproporfirinas/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas Angiogênicas/genética , Proteínas Angiogênicas/metabolismo , Animais , Coproporfirinas/sangue , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Células Sf9 , Spodoptera
3.
BMC Res Notes ; 13(1): 497, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33109270

RESUMO

OBJECTIVE: Nigeria bears 25% of global malaria burden despite concerted efforts towards its control and elimination. The emergence of drug resistance to first line drugs, artemisinin combination therapies (ACTs), indicates an urgent need for continuous molecular surveillance of drug resistance especially in high burden countries where drug interventions are heavily relied on. This study describes mutations in Plasmodium falciparum genes associated with drug resistance in malaria; Pfk13, Pfmdr1, PfATPase6 and Pfcrt in isolates obtained from 83 symptomatic malaria patients collected in August 2014, aged 1-61 years old from South-west Nigeria. RESULTS: Two Pfmdr1, N86 and Y184 variants were present at a prevalence of 56% and 13.25% of isolates respectively. There was one synonymous (S679S) and two non-synonymous (M699V, S769M) mutations in the PATPase6 gene, while Pfcrt genotype (CVIET), had a prevalence of 45%. The Pfk13 C580Y mutant allele was suspected by allelic discrimination in two samples with mixed genotypes although this could not be validated with independent isolation or additional methods. Our findings call for robust molecular surveillance of antimalarial drug resistance markers in west Africa especially with increased use of antimalarial drugs as prophylaxis for Covid-19.


Assuntos
Combinação Arteméter e Lumefantrina/uso terapêutico , ATPases Transportadoras de Cálcio/genética , Malária Falciparum/tratamento farmacológico , Proteínas de Membrana Transportadoras/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Mutação , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/genética , Adolescente , Adulto , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Criança , Pré-Escolar , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Resistência a Medicamentos/genética , Feminino , Expressão Gênica , Genótipo , Humanos , Lactente , Malária Falciparum/epidemiologia , Malária Falciparum/parasitologia , Pessoa de Meia-Idade , Epidemiologia Molecular , Nigéria/epidemiologia , Pandemias/prevenção & controle , Plasmodium falciparum/genética , Plasmodium falciparum/crescimento & desenvolvimento , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle
4.
Eur J Drug Metab Pharmacokinet ; 45(6): 761-770, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32930952

RESUMO

BACKGROUND AND OBJECTIVE: Deferasirox is an oral iron chelator used to reduce iron levels in iron-overloaded patients with transfusion-dependent anemia or non-transfusion-dependent thalassemia. This study investigated the effects of genetic polymorphisms on the pharmacokinetics of deferasirox in healthy Chinese subjects and constructed a pharmacokinetic prediction model based on physiologic factors and genetic polymorphism data. METHODS: Twenty-eight subjects were enrolled in a randomized, open-label, two-period crossover study, and they received a single dose of one of two formulations of deferasirox (20 mg/kg) with a 7-day washout interval between the two periods. The plasma defersirox concentration was determined using a validated liquid chromatography-tandem mass spectrometry method, and pharmacokinetic parameters were calculated using the noncompartmental method. The polymorphisms of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), UGT1A3, multidrug resistance protein 2 (MRP2), cytochrome P450 1A1 (CYP1A1), and breast cancer resistance protein 1 (BCRP1) were genotyped using Sanger sequencing. A back-propagation artificial neural network (BP-ANN) model was used to predict the pharmacokinetics. RESULTS: The UGT1A1 rs887829 C > T single-nucleotide polymorphism (SNP) significantly influenced the area under the plasma concentration-time curve and the terminal half-life. Neither the MRP2 rs2273697 G > A SNP nor BCRP1 rs2231142 G > T SNP altered the absorption, disposition, and excretion of the drug. The BP-ANN model had a high goodness-of-fit index and good coherence between the predicted and measured concentrations (R2 = 0.921). CONCLUSION: Metabolic enzyme-related genetic polymorphisms were more strongly associated with the pharmacokinetics of deferasirox than membrane transporter-related genetic polymorphisms in the Chinese population. TRIAL REGISTRATION: www.Chinadrugtrials.org.cn CTR20191164.


Assuntos
Deferasirox/farmacocinética , Quelantes de Ferro/farmacocinética , Redes Neurais de Computação , Adolescente , Adulto , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Estudos Cross-Over , Citocromo P-450 CYP1A1/genética , Composição de Medicamentos , Feminino , Glucuronosiltransferase/genética , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Polimorfismo Genético/genética , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Adulto Jovem
5.
BMC Infect Dis ; 20(1): 671, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32933490

RESUMO

BACKGROUND: The increasing antimalarial drug resistance is a significant hindrance to malaria control and elimination programs. For the last six decades, chloroquine (CQ) plus pyrimethamine remains the first-line treatment for P. vivax malaria. Regions where both P. falciparum and P. vivax co-exist, P. vivax is exposed to antifolate drugs due to either misdiagnosis or improper treatment that causes selective drug pressure to evolve. Therefore, the present study aims to estimate antimalarial drug resistance among the complicated and uncomplicated P. vivax patients. METHODS: A total of 143 P. vivax malaria positive patients were enrolled in this study, and DNA was isolated from their blood samples. Pvcrt-o, Pvmdr-1, Pvdhps, and Pvdhfr genes were PCRs amplified, and drug resistance-associated gene mutations were analyzed. Statistical analysis of the drug resistance genes and population diversity was performed using MEGA vs. 7.0.21 and DnaSP v software. RESULTS: Among the CQ resistance marker gene Pvcrt-o, the prevalence of K10 insertion was 17.5% (7/40) and 9.5% (7/73) of complicated and uncomplicated P vivax group isolates respectively. In Pvmdr-1, double mutant haplotype (M958/L1076) was found in 99% of the clinical isolates. Among the pyrimethamine resistance-associated gene Pvdhfr, the double mutant haplotype I13P33F57R58T61N117I173 was detected in 23% (11/48) in complicated and 20% (17/85) in uncomplicated group isolates. In the sulphadoxine resistance-associated Pvdhps gene, limited polymorphism was observed with the presence of a single mutant (D459A) among 16 and 5% of the clinical isolates in the complicated and uncomplicated group respectively. CONCLUSION: The study presents the situations of polymorphism in the antimalarial drug resistance-associated genes and emphasizes the need for regular surveillance. It is imperative for the development of suitable antimalarial drug policy in India.


Assuntos
Antimaláricos/uso terapêutico , Resistência a Medicamentos/genética , Malária Vivax/tratamento farmacológico , Plasmodium vivax/genética , Proteínas de Protozoários/genética , Adolescente , Criança , Pré-Escolar , Cloroquina/uso terapêutico , DNA de Protozoário/genética , DNA de Protozoário/metabolismo , Feminino , Antagonistas do Ácido Fólico/uso terapêutico , Haplótipos , Humanos , Índia , Masculino , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Plasmodium vivax/isolamento & purificação , Polimorfismo de Nucleotídeo Único , Adulto Jovem
6.
Ecotoxicol Environ Saf ; 202: 110940, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800223

RESUMO

Recent evidence indicates that chronic, low-dose exposure to mixtures of pesticides can cause adverse responses in a variety of cells, tissues and organs, although interactions between pesticides circulating in the blood and cancer cells remain largely unexplored. The aim of this study was to investigate the potential of a mixture of four pesticides to induce multidrug resistance against the chemotherapeutic agents cisplatin, 5-fluorouracil and temozolomide in the human U87 glioblastoma cell line, and to explore the molecular mechanisms underlying this resistance. We found that the repeated administration of the pesticide mixture (containing the insecticides chlorpyrifos-ethyl and deltamethrin, the fungicide metiram, and the herbicide glyphosate) induced a strong drug resistance in U87 cells. The resistance was durable and transferred to subsequent cell generations. In addition, we detected a significant over-expression of the ATP-binding cassette (ABC) membrane transporters P-gp/ABCB1 and BRCP/ABCG2 as well as a glutathione-S-transferase (GST)/M1-type cellular detoxification function, known to have important roles in multidrug resistance, thus providing molecular support for the acquired multidrug resistance phenotype and shedding light on the mechanism of resistance. We further determined that there was lower mortality in the resistant brain tumor cells and that the mitochondrial apoptosis pathway was activated at a lower rate after chemotherapy compared to non-resistant control cells. In addition, multidrug-resistant cells were found to have both higher motility and wound-healing properties, suggesting a greater metastatic potential. Our results suggest that the investigation of P-gp, BRCP and GST/M1 multidrug resistance gene expression and/or protein levels in biopsy specimens of brain tumor patients who were at risk of pesticide exposure could be beneficial in determining chemotherapy dose and prolonging patient survival.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Praguicidas/toxicidade , Testes de Toxicidade Crônica , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/farmacologia
7.
BMC Infect Dis ; 20(1): 513, 2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32677899

RESUMO

BACKGROUND: Imported falciparum malaria from Africa has become a key public health challenge in Guizhou Province since 2012. Understanding the polymorphisms of molecular markers of drug resistance can guide selection of antimalarial drugs for the treatment of malaria. This study was aimed to analyze the polymorphisms of pfcrt, pfmdr1, and K13-propeller among imported falciparum malaria cases in Guizhou Province, China. METHOD: Fifty-five imported falciparum malaria cases in Guizhou Province during 2012-2016 were included in this study. Their demographic information and filter paper blood samples were collected. Genomic DNA of Plasmodium falciparum was extracted from the blood samples, and polymorphisms of pfcrt, pfmdr1, and K13-propeller were analyzed with nested PCR amplification followed by sequencing. Data were analyzed with the SPSS17.0 software. RESULTS: The prevalence of pfcrt K76T, pfmdr1 N86Y, and pfmdr1 Y184F mutation was 56.6, 22.2, and 72.2%, respectively, in imported falciparum malaria cases in Guizhou Province. We detected two mutant haplotypes of pfcrt, IET and MNT, with IET being more commonly found (54.7%), and five mutant haplotypes of pfmdr1, of which NFD was the most frequent (53.7%). There were totally 10 combined haplotypes of pfcrt and pfmdr1, of which the haplotype IETNFD possessed a predominance of 28.8%. In addition, three nonsynonymous mutations (S459T, C469F, and V692L) and two synonymous mutations (R471R and V589V) were detected in K13-propeller, all having prevalence less than 6.0%. In particular, a candidate K13 resistance mutation, C469F, was identified for the first time from Democratic Republic of the Congo with the prevalence of 2.0%. CONCLUSIONS: The high prevalence of IET haplotype of pfcrt and NFD haplotype of pfmdr1 suggests the presence of chloroquine, artemether/lumefantrine, and dihydroartemisinin/piperaquine resistance in these cases. Therefore cautions should be made to artemisinin therapy for P. falciparum in Africa. Continuous monitoring of anti-malarial drug efficacy in imported malaria cases is helpful for optimizing antimalarial drug therapy in Guizhou Province, China.


Assuntos
Doenças Transmissíveis Importadas/parasitologia , Resistência a Medicamentos/genética , Malária Falciparum/parasitologia , Plasmodium falciparum/genética , Polimorfismo Genético , Proteínas de Protozoários/genética , Adulto , África/epidemiologia , Substituição de Aminoácidos/genética , Antimaláricos/uso terapêutico , China/epidemiologia , Estudos de Coortes , Feminino , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Masculino , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Mutação , Plasmodium falciparum/isolamento & purificação , Doença Relacionada a Viagens
8.
Ann Hematol ; 99(9): 2173-2180, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32621177

RESUMO

Resistant disease is still a main obstacle in acute myeloid leukemia (AML) treatment. Therefore, individual genetic variations affecting therapy response are gaining increasing importance. Both SNPs and ABC transporter genes could already be associated with drug resistance. Here, we report allelic variants of MRP1 (ABCC1) SNPs rs129081, rs212090, and rs212091 with significant influences on survival in AML patients. DNA was extracted from bone marrow samples (n = 160) at diagnosis. Genotyping 48 SNPs within seven different ABC transporter genes using real-time PCR revealed rs129081 GG variant with a significant higher OS (p = 0.035) and DFS (p = 0.01). Comparing TT and AA rs212090 variants showed significant influences on DFS (p = 0.021). SNP rs212091 GG expression was associated with worse OS (p = 0.006) and a significant difference in DFS between alleles GG and AA (p = 0.018). The multivariable models confirmed a significant influence on OS for rs212091 (AA HR = 0.296, 95% CI 0.113-0.774, p = 0.013 and GG p = 0.044). Rs129081 variant CG, TT of rs212090, AA, and AG of rs212091 demonstrated significant impact on DFS (p = 0.024, p = 0.029, p = 0.017, and p = 0.042, respectively). This analysis demonstrates a significant influence of MRP1 SNPs on survival in AML. As they were not associated to prognostic characteristics, we suggest these SNPs to be independent prognostic markers for AML.


Assuntos
Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Taxa de Sobrevida/tendências , Adulto Jovem
9.
BMC Infect Dis ; 20(1): 533, 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32698879

RESUMO

BACKGROUND: Plasmodium falciparum parasites, which could harbour anti-malaria drug resistance genes, are commonly detected in blood donors in malaria-endemic areas. Notwithstanding, anti-malaria drug resistant biomarkers have not been characterized in blood donors with asymptomatic P. falciparum infection. METHODS: A total of 771 blood donors were selected from five districts in the Greater Accra Region, Ghana. Each donor sample was screened with malaria rapid diagnostic test (RDT) kit and parasitaemia quantified microscopically. Dried blood spots from malaria positive samples were genotyped for P. falciparum chloroquine resistance transporter (Pfcrt), P. falciparum multi-drug resistance (Pfmdr1), P. falciparum dihydropteroate-synthetase (Pfdhps), P. falciparum dihydrofolate-reductase (Pfdhfr) and Kelch 13 propeller domain on chromosome 13 (Kelch 13) genes. RESULTS: Of the 771 blood donors, 91 (11.8%) were positive by RDT. Analysis of sequence reads indicated successful genotyping of Pfcrt, Pfmdr1, Pfdhfr, Pfdhps and Kelch 13 genes in 84.6, 81.3, 86.8, 86.9 and 92.3% of the isolates respectively. Overall, 21 different mutant haplotypes were identified in 69 isolates (75.8%). In Pfcrt, CVIET haplotype was observed in 11.6% samples while in Pfmdr1, triple mutation (resulting in YFN haplotype) was detected in 8.1% of isolates. In Pfdhfr gene, triple mutation resulting in IRNI haplotype and in Pfdhps gene, quintuple mutation resulting in AGESS haplotype was identified in 17.7% parasite isolates. Finally, five non-synonymous Kelch 13 alleles were detected; C580Y (3.6%), P615L (4.8%), A578S (4.8%), I543V (2.4%) and A676S (1.2%) were detected. CONCLUSION: Results obtained in this study indicated various frequencies of mutant alleles in Pfcrt, Pfmdr1, Pfdhfr, Pfdhps and Kelch 13 genes from P. falciparum infected blood donors. These alleles could reduce the efficacy of standard malaria treatment in transfusion-transmitted malaria cases. Incorporating malaria screening into donor screening protocol to defer infected donors is therefore recommended.


Assuntos
Doadores de Sangue , Resistência Microbiana a Medicamentos/genética , Resistência a Múltiplos Medicamentos/genética , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Plasmodium falciparum/genética , Adolescente , Adulto , Alelos , Antimaláricos/uso terapêutico , Doenças Assintomáticas , Biomarcadores , Cloroquina/uso terapêutico , Estudos Transversais , Di-Hidropteroato Sintase/genética , Feminino , Frequência do Gene , Gana/epidemiologia , Haplótipos , Humanos , Repetição Kelch/genética , Malária Falciparum/diagnóstico , Malária Falciparum/parasitologia , Masculino , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Mutação , Plasmodium falciparum/isolamento & purificação , Prevalência , Proteínas de Protozoários/genética , Tetra-Hidrofolato Desidrogenase/genética , Adulto Jovem
10.
PLoS Negl Trop Dis ; 14(6): e0008255, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32530913

RESUMO

BACKGROUND: Vivax malaria is an important public health problem in the Greater Mekong Subregion (GMS), including the China-Myanmar border. Previous studies have found that Plasmodium vivax has decreased sensitivity to antimalarial drugs in some areas of the GMS, but the sensitivity of P. vivax to antimalarial drugs is unclear in the China-Myanmar border. Here, we investigate the drug sensitivity profile and genetic variations for two drug resistance related genes in P. vivax isolates to provide baseline information for future drug studies in the China-Myanmar border. METHODOLOGY/PRINCIPAL FINDINGS: A total of 64 P. vivax clinical isolates collected from the China-Myanmar border area were assessed for ex vivo susceptibility to eight antimalarial drugs by the schizont maturation assay. The medians of IC50 (half-maximum inhibitory concentrations) for chloroquine, mefloquine, pyronaridine, piperaquine, quinine, artesunate, artemether, dihydroartemisinin were 84.2 nM, 34.9 nM, 4.0 nM, 22.3 nM, 41.4 nM, 2.8 nM, 2.1 nM and 2.0 nM, respectively. Twelve P. vivax clinical isolates were found over the cut-off IC50 value (220 nM) for chloroquine resistance. In addition, sequence polymorphisms in pvmdr1 (P. vivax multidrug resistance-1), pvcrt-o (P. vivax chloroquine resistance transporter-o), and difference in pvmdr1 copy number were studied. Sequencing of the pvmdr1 gene in 52 samples identified 12 amino acid substitutions, among which two (G698S and T958M) were fixed, M908L were present in 98.1% of the isolates, while Y976F and F1076L were present in 3.8% and 78.8% of the isolates, respectively. Amplification of the pvmdr1 gene was only detected in 4.8% of the samples. Sequencing of the pvcrt-o in 59 parasite isolates identified a single lysine insertion at position 10 in 32.2% of the isolates. The pvmdr1 M908L substitutions in pvmdr1 in our samples was associated with reduced sensitivity to chloroquine, mefloquine, pyronaridine, piperaquine, quinine, artesunate and dihydroartemisinin. CONCLUSIONS: Our findings depict a drug sensitivity profile and genetic variations of the P. vivax isolates from the China-Myanmar border area, and suggest possible emergence of chloroquine resistant P. vivax isolates in the region, which demands further efforts for resistance monitoring and mechanism studies.


Assuntos
Antimaláricos/farmacologia , Resistência a Medicamentos , Malária Vivax/parasitologia , Proteínas de Membrana Transportadoras/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Plasmodium vivax/efeitos dos fármacos , Polimorfismo Genético , Proteínas de Protozoários/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , China , Feminino , Genótipo , Humanos , Lactente , Concentração Inibidora 50 , Masculino , Pessoa de Meia-Idade , Mianmar , Testes de Sensibilidade Parasitária , Plasmodium vivax/isolamento & purificação , Análise de Sequência de DNA , Adulto Jovem
11.
Am J Ophthalmol ; 218: 255-260, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32442430

RESUMO

PURPOSE: To describe patients with late-onset pseudoxanthoma elasticum (PXE) associated with a likely hypomorphic ABCC6 variant. DESIGN: Retrospective observational case series. METHODS: Clinical evaluation, multimodal retinal imaging, genetic testing, and molecular modeling. RESULTS: Three patients, in whom vision symptoms first arose at 80 years of age or later, showed age-related macular degeneration (AMD)-like fundus changes. However, features characteristic of PXE, including discrete angioid streaks and reduced fluorescence on late-phase indocyanine green angiography, prompted genetic testing which revealed the c.1171A>G variant in combination with a large deletion in the ABCC6 gene in each case. None of the patients had obvious skin changes or cardiovascular disease atypical for their age. Comparative molecular modeling supported the hypothesis that the c.1171A>GABCC6 variant acted as a hypomorphic variant. CONCLUSIONS: Late-onset PXE extends the spectrum of ectopic calcification disorders caused by mutations in ABCC6 and may clinically be limited to the eye, mimicking AMD. Patients may be identified based on specific ocular changes, whereas skin and cardiovascular changes may remain ambiguous. The study provides evidence for a role for hypomorphic ABCC6 variants in the pathogenesis of PXE.


Assuntos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Pseudoxantoma Elástico/genética , Idoso de 80 Anos ou mais , Estrias Angioides/diagnóstico , Corantes/administração & dosagem , Angiofluoresceinografia , Testes Genéticos , Humanos , Verde de Indocianina/administração & dosagem , Masculino , Reação em Cadeia da Polimerase Multiplex , Mutação , Pseudoxantoma Elástico/diagnóstico , Estudos Retrospectivos , Tomografia de Coerência Óptica
12.
BMC Infect Dis ; 20(1): 307, 2020 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-32334523

RESUMO

BACKGROUND: Plasmodium vivax is the most widely distributed malaria parasite, and its drug resistance poses unique challenges to malaria elimination. The Greater Mekong Subregion (GMS) is known as the global epicenter of multidrug resistance. Surveillance of molecular markers associated with drug resistance in this area will help to inform drug policy. METHODS: Dry blood spots from 58 patients out of 109 with P. vivax infection between 2017, December and 2019, March were obtained from Yingjiang County, Yunnan Province, along the China-Myanmar border. Pvdhfr, Pvdhps, Pvmdr1 and Pvcrt-o were amplified and sequenced to assess gene mutations. The polymorphism and prevalence of these molecular markers were analyzed. RESULTS: Mutations in Pvdhfr at codons 57, 58, 61, 99 and 117 were detected in 27.59, 48.28, 27.59, 32.76 and 48.28% of the isolates, respectively. Single mutant haplotype (I13F57S58T61S99S117I173) was the most frequent (29.31%, 17/58), followed by double mutant haplotype (20.69%, 12/58). Of three types of tandem repeat variations of Pvdhfr, deletion type was the most common. Pvdhps showed a lower prevalence among mutation genotypes. Single mutant was dominant and accounted for 34.48% (20/58). Prevalence of Pvmdr1 mutations at codons 958 and 1076 were 100.00% and 84.48%, respectively. The proportion of double and single mutant types was 84.48% (49/58) and 15.52% (9/58), respectively. Eleven samples (18.97%, 11/58) showed K10 "AAG" insertion in chloroquine resistance transporter gene Pvcrt-o. CONCLUSIONS: There was moderate diversity of molecular patterns of resistance markers of Pvdhfr, Pvdhps, Pvmdr1 and Pvcrt-o in imported P. vivax cases to Yingjiang county in Western Yunnan, along the China-Myanmar border. Prevalence and molecular pattern of candidate drug resistance markers Pvdhfr, Pvdhps, Pvmdr1 and Pvcrt-o were demonstrated in this current study, which would help to update drug policy.


Assuntos
Malária Vivax/parasitologia , Mutação , Plasmodium vivax/efeitos dos fármacos , Plasmodium vivax/genética , Adolescente , Adulto , Idoso , Antimaláricos/uso terapêutico , Biomarcadores , Criança , Pré-Escolar , China , Cloroquina/uso terapêutico , Resistência Microbiana a Medicamentos/genética , Resistência a Múltiplos Medicamentos/genética , Feminino , Haplótipos , Humanos , Malária Vivax/tratamento farmacológico , Malária Vivax/epidemiologia , Masculino , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Plasmodium vivax/isolamento & purificação , Polimorfismo Genético , Prevalência , Proteínas de Protozoários/genética , Adulto Jovem
13.
PLoS Pathog ; 16(3): e1008427, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32191775

RESUMO

Evolution of pest resistance reduces the efficacy of insecticidal proteins from the gram-positive bacterium Bacillus thuringiensis (Bt) used widely in sprays and transgenic crops. Better understanding of the genetic basis of resistance is needed to more effectively monitor, manage, and counter pest resistance to Bt toxins. Here we used CRISPR/Cas9 gene editing to clarify the genetics of Bt resistance and the associated effects on susceptibility to other microbial insecticides in one of the world's most damaging pests, the cotton bollworm (Helicoverpa armigera). We discovered that CRISPR-mediated knockouts of ATP-binding cassette (ABC) transporter genes HaABCC2 and HaABCC3 together caused >15,000-fold resistance to Bt toxin Cry1Ac, whereas knocking out either HaABCC2 or HaABCC3 alone had little or no effect. Inheritance of resistance was autosomal and recessive. Bioassays of progeny from interstrain crosses revealed that one wild type allele of either HaABCC2 or HaABCC3 is sufficient to sustain substantial susceptibility to Cry1Ac. In contrast with previous results, susceptibility to two insecticides derived from bacteria other than Bt (abamectin and spinetoram), was not affected by knocking out HaABCC2, HaABCC3, or both. The results here provide the first evidence that either HaABCC2 or HaABCC3 protein is sufficient to confer substantial susceptibility to Cry1Ac. The functional redundancy of these two proteins in toxicity of Cry1Ac to H. armigera is expected to reduce the likelihood of field-evolved resistance relative to disruption of a toxic process where mutations affecting a single protein can confer resistance.


Assuntos
Bacillus thuringiensis , Proteínas de Bactérias , Endotoxinas , Proteínas Hemolisinas , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Animais , Bacillus thuringiensis/genética , Bacillus thuringiensis/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Endotoxinas/genética , Endotoxinas/metabolismo , Proteínas Hemolisinas/genética , Proteínas Hemolisinas/metabolismo , Mariposas , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Controle Biológico de Vetores
14.
Toxicol Lett ; 327: 9-18, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32201199

RESUMO

Superoxide dismutase 2 (SOD2) is a key enzyme for scavenging reactive oxygen species produced by mitochondria, which plays an important role in maintaining cellular homeostasis. However, its effects on the detoxification capability of liver cells have not been reported. In this study, we found that change in SOD2 expression affects the proliferation of liver cells. Genome-wide microarray analysis showed that SOD2 positively regulates the drug transporter ABCC2, and co-expression analysis suggested that lncRNA CLCA3P participates in the process. Further experiments showed that SOD2 can promote the expression of CLCA3P, which increases the transcription of ABCC2 by interacting with the transcription factor IRF1. By increasing ABCC2 expression SOD2 facilitates drugs efflux of liver cells and thus promotes their survival under a drug-toxic environment. This study elucidates the improvement of the detoxification of liver cells by a regulatory axis, SOD2-CLCA3P-IRF1-ABCC2, and provides novel insight into the modification of human liver cells that can be applied to bioartificial liver system or the study of SOD2 in drug metabolism.


Assuntos
Fígado/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Paclitaxel/metabolismo , RNA Longo não Codificante , Superóxido Dismutase/metabolismo , Animais , Antineoplásicos Fitogênicos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Análise de Sequência com Séries de Oligonucleotídeos , Interferência de RNA , Superóxido Dismutase/genética
15.
PLoS One ; 15(2): e0228938, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32074140

RESUMO

Calcifications can disrupt organ function in the cardiovascular system and the kidney, and are particularly common in patients with chronic kidney disease (CKD). Fetuin-A deficient mice maintained against the genetic background DBA/2 exhibit particularly severe soft tissue calcifications, while fetuin-A deficient C57BL/6 mice remain healthy. We employed molecular genetic analysis to identify risk factors of calcification in fetuin-A deficient mice. We sought to identify pharmaceutical therapeutic targets that could be influenced by dietary of parenteral supplementation. We studied the progeny of an intercross of fetuin-A deficient DBA/2 and C57BL/6 mice to identify candidate risk genes involved in calcification. We determined that a hypomorphic mutation of the Abcc6 gene, a liver ATP transporter supplying systemic pyrophosphate, and failure to regulate the Trpm6 magnesium transporter in kidney were associated with severity of calcification. Calcification prone fetuin-A deficient mice were alternatively treated with parenteral administration of fetuin-A dietary magnesium supplementation, phosphate restriction, or by or parenteral pyrophosphate. All treatments markedly reduced soft tissue calcification, demonstrated by computed tomography, histology and tissue calcium measurement. We show that pathological ectopic calcification in fetuin-A deficient DBA/2 mice is caused by a compound deficiency of three major extracellular and systemic inhibitors of calcification, namely fetuin-A, magnesium, and pyrophosphate. All three of these are individually known to contribute to stabilize protein-mineral complexes and thus inhibit mineral precipitation from extracellular fluid. We show for the first time a compound triple deficiency that can be treated by simple dietary or parenteral supplementation. This is of special importance in patients with advanced CKD, who commonly exhibit reduced serum fetuin-A, magnesium and pyrophosphate levels.


Assuntos
Calcinose/patologia , Microvasos/fisiologia , alfa-2-Glicoproteína-HS/metabolismo , Animais , Calcinose/genética , Difosfatos/metabolismo , Modelos Animais de Doenças , Feminino , Rim/patologia , Fígado/patologia , Magnésio/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Microvasos/metabolismo , Minerais , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Insuficiência Renal Crônica/complicações , Canais de Cátion TRPM/genética , Canais de Cátion TRPM/metabolismo , alfa-2-Glicoproteína-HS/fisiologia , alfa-Fetoproteínas
16.
Parasit Vectors ; 13(1): 67, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051017

RESUMO

BACKGROUND: The malaria elimination plan of the Greater Mekong Subregion (GMS) is jeopardized by the increasing number of Plasmodium vivax infections and emergence of parasite strains with reduced susceptibility to the frontline drug treatment chloroquine/primaquine. This study aimed to determine the evolution of the P. vivax multidrug resistance 1 (Pvmdr1) gene in P. vivax parasites isolated from the China-Myanmar border area during the major phase of elimination. METHODS: Clinical isolates were collected from 275 P. vivax patients in 2008, 2012-2013 and 2015 in the China-Myanmar border area and from 55 patients in central China. Comparison was made with parasites from three border regions of Thailand. RESULTS: Overall, genetic diversity of the Pvmdr1 was relatively high in all border regions, and over the seven years in the China-Myanmar border, though slight temporal fluctuation was observed. Single nucleotide polymorphisms previously implicated in reduced chloroquine sensitivity were detected. In particular, M908L approached fixation in the China-Myanmar border area. The Y976F mutation sharply decreased from 18.5% in 2008 to 1.5% in 2012-2013 and disappeared in 2015, whereas F1076L steadily increased from 33.3% in 2008 to 77.8% in 2015. While neutrality tests suggested the action of purifying selection on the pvmdr1 gene, several likelihood-based algorithms detected positive as well as purifying selections operating on specific amino acids including M908L, T958M and F1076L. Fixation and selection of the nonsynonymous mutations are differently distributed across the three border regions and central China. Comparison with the global P. vivax populations clearly indicated clustering of haplotypes according to geographic locations. It is noteworthy that the temperate-zone parasites from central China were completely separated from the parasites from other parts of the GMS. CONCLUSIONS: This study showed that P. vivax populations in the China-Myanmar border has experienced major changes in the Pvmdr1 residues proposed to be associated with chloroquine resistance, suggesting that drug selection may play an important role in the evolution of this gene in the parasite populations.


Assuntos
Antimaláricos/farmacologia , Variação Genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Plasmodium vivax/genética , Proteínas de Protozoários/genética , China , Cloroquina/farmacologia , Erradicação de Doenças , Evolução Molecular , Haplótipos , Humanos , Malária Vivax/epidemiologia , Malária Vivax/parasitologia , Mutação , Mianmar , Plasmodium vivax/efeitos dos fármacos , Análise de Sequência de DNA , Tailândia
17.
Int J Med Microbiol ; 310(2): 151400, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32001143

RESUMO

A plethora of toxin-antitoxin systems exist in bacteria and has multilateral roles in bacterial pathogenesis and virulence. Toxin-antitoxin systems have been involved in persister cell formation in Escherichia coli and Mycobacterium but have not been reported to be associated with Staphylococcus aureus persistence. Persistence is the ability of bacterial cells to tolerate unfavorable conditions and multiple stresses. There are less known and more unknown factors that either alleviate or aggravate bacterial persistence phenomenon. For the first time, we reported a new chromosomally encoded tripartite toxin-antitoxin system and its role in S. aureus persister cell formation. The toxin gene is bacteriostatic in action and counterbalanced by antitoxin RNA that could basepair with the toxin mRNA and formed a duplex. The transcriptional regulator positively regulates the toxin expression under certain stress conditions. The toxin ectopic induction increased S. aureus susceptibility to norfloxacin, ciprofloxacin, and ofloxacin. Whole-genome RNA sequencing revealed that MDR efflux pump norA is significantly down-regulated by toxin ectopic induction. The deletion of norA from S. aureus genome reduced resistance toward ciprofloxacin, norfloxacin, and ofloxacin, as well as resulted in a decrease in minimal inhibitory concentration while complementation of norA successfully restored the phenotypes. The persistence assay of the norA mutant revealed that deletion of norA increased persister cell survival in S. aureus. Altogether, we have provided insight into the first tripartite type-I TA system and revealed the role of MDR NorA in the persister cell formation of S. aureus.


Assuntos
Proteínas de Bactérias/genética , Farmacorresistência Bacteriana Múltipla/genética , Regulação Bacteriana da Expressão Gênica , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Staphylococcus aureus/genética , Staphylococcus aureus/fisiologia , Sistemas Toxina-Antitoxina/genética , Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Testes de Sensibilidade Microbiana , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Sequenciamento Completo do Genoma
18.
Phytomedicine ; 68: 153148, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32028185

RESUMO

BACKGROUND: Aloe-emodin (AE) is among the primary bioactive anthraquinones present in traditional Chinese medicinal plants such as Rheum palmatum L. Multidrug resistance protein 2 (ABCC2/ MRP2) is an important efflux transporter of substances associated with cellular oxidative stress. However, the effects of traditional Chinese medicine on this protein remain unclear. PURPOSE: The aim of this research is to study the role of ABCC2 in AE-induced hepatotoxicity. METHODS: The expression of ABCC2 protein and mRNA levels were analyzed by Western-Blotting and qRT-PCR, respectively. The intracellular oxidative stress caused by AE was evaluated by quantifying the levels of intracellular reactive oxygen species, malondialdehyde, glutathione reduced and oxidized glutathione. The levels of adenosine triphosphate, mitochondrial membrane potential and mitochondrial DNA were explored to evaluate the effects of AE on mitochondrial function. The effects of AE on cell apoptosis and cell cycle were detected by flow cytometry. To further clarify the key role of ABCC2 in AE induced cytotoxicity, we used pCI-neo-ABCC2 plasmid to over express ABCC2 protein, and small interfering RNA was used to knockdown ABCC2 in HepG2 cells. Additionally, we investigated the impact of AE on ABCC2 degradation pathway and the hepatotoxic effects of AE in mice. RESULTS: AE was found to inhibit ABCC2 transport activity, downregulate ABCC2 expression and altered intracellular redox balance. Induction of oxidative stress resulted in depletion of intracellular glutathione reduced, mitochondria dysfunction and activation of apoptosis. ABCC2 overexpression significantly reduced AE-induced intracellular oxidative stress and cell death, which was enhanced by ABCC2 knockdown. Furthermore, AE was observed to promote ABCC2 degradation through induction of autophagy and hepatotoxicity was induced in mice by promoting ABCC2 degradation. CONCLUSIONS: The inhibition of ABCC2 is a novel effect of AE that triggers oxidative stress and apoptosis. These findings are helpful in understanding the toxicological effects of AE-containing medicinal plants.


Assuntos
Antraquinonas/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Feminino , Células Hep G2 , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
19.
Int J Cancer ; 146(9): 2475-2487, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32010961

RESUMO

Multidrug resistance due to facilitated drug efflux mediated by ATP-binding cassette (ABC) transporters is a main cause for failure of cancer therapy. Genetic polymorphisms in ABC genes affect the disposition of chemotherapeutics and constitute important biomarkers for therapeutic response and toxicity. Here we correlated germline variability in ABC transporters with disease-specific survival (DSS) in 960 breast cancer (BRCA), 314 clear cell renal cell carcinoma and 325 hepatocellular carcinoma patients. We find that variant burden in ABCC1 is a strong predictor of DSS in BRCA patients, whereas candidate polymorphisms are not associated with DSS. This association is highly drug-specific for subgroups treated with the MRP1 substrates cyclophosphamide (log-rank p = 0.0011) and doxorubicin (log-rank p = 0.0088) independent of age and tumor stage, whereas no association was found in individuals treated with tamoxifen (log-rank p = 0.13). Structural mapping of significant variants revealed multiple variants at residues involved in protein stability, cofactor stabilization or substrate binding. Our results demonstrate that BRCA patients with high variant burden in ABCC1 are less prone to respond appropriately to pharmacological therapy with MRP1 substrates, thus incentivizing the consideration of genomic germline data for precision cancer medicine.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias da Mama/mortalidade , Resistencia a Medicamentos Antineoplásicos/genética , Mutação em Linhagem Germinativa , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida
20.
Cells ; 9(2)2020 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-31991926

RESUMO

: The efficiency of chemotherapy drugs can be affected by ATP-binding cassette (ABC) transporter expression or by their mutation status. Multidrug resistance is linked with ABC transporter overexpression. In the present study, we performed rare mutation analyses for 12 ABC transporters related to drug resistance (ABCA2, -A3, -B1, -B2, -B5, -C1, -C2, -C3, -C4, -C5, -C6, -G2) in a dataset of 18 cancer patients. We focused on rare mutations resembling tumor heterogeneity of ABC transporters in small tumor subpopulations. Novel rare mutations were found in ABCC1, but not in the other ABC transporters investigated. Diverse ABCC1 mutations were found, including nonsense mutations causing premature stop codons, and compared with the wild-type protein in terms of their protein structure. Nonsense mutations lead to truncated protein structures. Molecular docking and heat map analyses of ABCC1/MRP1 pointed out that Lys498* appeared in a separate cluster branch due to the large deletion, leading to a massive disruption in the protein conformation. The resulting proteins, which are nonfunctional due to nonsense mutations in tumors, offer a promising chemotherapy strategy since tumors with nonsense mutations may be more sensitive to anticancer drugs than wild-type ABCC1-expressing tumors. This could provide a novel tumor-specific toxicity strategy and a way to overcome drug resistance.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Neoplasias/genética , Transportadores de Cassetes de Ligação de ATP/química , Transportadores de Cassetes de Ligação de ATP/metabolismo , Códon sem Sentido , Feminino , Humanos , Masculino , Simulação de Acoplamento Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/química , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Neoplasias/metabolismo , Polimorfismo de Nucleotídeo Único
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