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1.
BMC Med Genet ; 21(1): 54, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32183743

RESUMO

BACKGROUND: The ABCG2 rs2231142 single nucleotide polymorphism (SNP) is one of the most significant genetic variants associated with hyperuricemia (HUA) in Asian populations. However, the risk of ABCG2 rs2231142 variants for HUA could interact with other important HUA risk variants and cardiovascular factors. This study investigated the effects of the combined association among ABCG2 rs2231142 and multiple HUA genetic variants or cardiovascular risk factors on HUA risk and serum uric acid (sUA) levels in an elderly Chinese population. METHODS: A total of 1206 participants over 65 years old were enrolled in this study. Physical and laboratory examinations were performed for all participants. The ABCG2 rs2231142, SLC2A9 rs3733591, and SLC22A12 rs893006 SNPs were assayed using a standardized protocol. Logistic regression analysis and liner regression were adjusted respectively to account for the association between ABCG2 rs2231142 and other genetic variants, as well as between cardiovascular risk factors and HUA risk and sUA levels. RESULTS: The prevalence of HUA was 14.71% in the elderly community-dwelling population. The ABCG2 rs2231142 risk T allele was associated with HUA risk (odds ratio (OR) = 1.63, 95% confidence interval (CI): 1.27-2.11; p = 1.65 × 10- 4) and with increased sUA levels (Beta = 0.16, p = 6.75 × 10- 9) in the whole study population. Linear regression analysis showed that the mean sUA level increased linearly with the number of risk alleles of the three candidate genetic variants (Beta = 0.18, p = 1.94 × 10- 12) The joint effect of the ABCG2 rs2231142 T allele and cardiovascular risk factors (obesity, hypertension and dyslipidemia) was also associated with increased HUA risk and sUA levels. Each copy of the risk T allele was significantly associated with enhanced HUA risk in patients with hypertriglyceridemia (OR = 2.52, 95% CI: 1.33-4.60; p = 0.003) compared to controls. CONCLUSION: Our findings reinforce the importance of the ABCG2 rs2231143 variant as a crucial genetic locus for HUA in Chinese populations and demonstrated the combined effects of multiple genetic risk variants and cardiovascular risk exposures on HUA risk and increased sUA level.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Doenças Cardiovasculares/etiologia , Genes Modificadores , Proteínas Facilitadoras de Transporte de Glucose/genética , Hiperuricemia/genética , Proteínas de Neoplasias/genética , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/fisiologia , Doenças Cardiovasculares/epidemiologia , China/epidemiologia , Estudos de Coortes , Modificador do Efeito Epidemiológico , Epistasia Genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Hiperuricemia/sangue , Hiperuricemia/epidemiologia , Vida Independente/estatística & dados numéricos , Masculino , Fatores de Risco , Ácido Úrico/sangue
2.
J Agric Food Chem ; 67(41): 11428-11435, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31589037

RESUMO

Diosgenin and diosgenyl saponins as the major bioactive compounds isolated from dietary fenugreek seeds, yam roots, etc. possessed strong antitumor effects. To understand their detailed antitumor mechanisms, a fluorophore-appended derivative of diosgenin [Glc/CNHphth-diosgenin (GND)] was synthesized, starting from diosgenin and glucosamine hydrochloride in overall yields of 7-12% over 7-10 steps. Co-localization of GND with organelle-specific stains, transmission electron microscopy, and relative protein analyses demonstrated that GND crossed the plasma membrane through organic anion-transporting polypeptide 1B1 and distributed in the endoplasmic reticulum (ER), lysosome, and mitochondria. In this process, GND induced ER swelling, mitochondrial damage, and autophagosome and upregulating IRE-1α to induce autophagy and apoptosis. Furthermore, autophagy inhibitor chloroquine delayed the appearance of cleaved poly(ADP-ribose) polymerase and inhibited cleaved caspase 8, which indicated that GND induced autophagy to activate caspase-8-dependent apoptosis. These observations suggested that diosgenyl saponin was a potent anticancer agent that elicited ER stress and mitochondria-mediated apoptotic pathways in liver cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Autofagia/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neoplasias Hepáticas/fisiopatologia , Extratos Vegetais/farmacologia , Saponinas/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/genética , Lisossomos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo
3.
Pregnancy Hypertens ; 17: 216-225, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31487644

RESUMO

OBJECTIVES: To identify circRNA expression profiles in the placentae of severe preeclampsia (SPE) and normal pregnant (NP) women. METHODS: Placental samples were collected from six paired SPE and NP women. CircRNA expression profiles were identified by RNA-Seq and validated in another 30 SPE and NP samples by qRT-PCR. Several bioinformatic tools were utilised to analyse the potential function of differentially expressed circRNAs (DE-circRNAs) and to predict target microRNAs (miRNAs) and proteins. Furthermore, immunohistochemistry, Western blotting and RNA binding protein immunoprecipitation (RIP) were conducted to confirm the interaction between the circRNA and protein. RESULTS: In total, 18,631 circRNAs were detected. Among them, 180 circRNAs were differentially expressed, including 94 upregulated and 86 downregulated circRNAs. Seven DE-circRNAs were selected for validation, and the results of six circRNAs (hsa_circ_0007611, hsa_circ_0011460, hsa_circ_0002888, and hsa_circ_0007445, hsa_circ_0017068, hsa_circ_0012737) were consistent with the sequencing results. Bioinformatics analyses of DE-circRNAs revealed that most of them are involved in vasodilation, regulation of blood vessel size, protein transport and localization, and pathways in cancer. In addition to the mRNA expression profile, it was interesting to find that the hsa_circ_0011460 target gene solute carrier organic anion transporter family member 2A1 (SLCO2A1, PGT) was also significantly increased in SPE placentae. Immunohistochemistry, Western blotting and qRT-PCR validated the expression and distribution of PGT. Finally, RIP of HTR-8/SVneo cells confirmed that hsa_circ_0011460 targets PGT directly. CONCLUSIONS: A total of 180 DE-circRNAs were detected. One crucial circRNA, hsa_circ_0011460, was shown to interact directly with its host gene PGT. These findings indicated that hsa_circ_0011460 may serve as a potential therapeutic target for patients with SPE.


Assuntos
Transportadores de Ânions Orgânicos/genética , Pré-Eclâmpsia/genética , Diagnóstico Pré-Natal , /genética , Biomarcadores , Feminino , Humanos , Placenta/metabolismo , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/patologia , Gravidez , Índice de Gravidade de Doença
4.
Ecotoxicol Environ Saf ; 184: 109614, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31526925

RESUMO

Microcystin-leucine arginine (MC-LR) enters into gonadotropin-releasing hormone (GnRH) neurons and induces decline of serum GnRH levels resulting in male reproductive toxicity via hypothalamic-pituitary-testis axis. The organic anion transporting polypeptide 1a5 (Oatp1a5) is a critical transporter for the uptake of MC-LR by GnRH neurons. However, the underlying molecular mechanisms of the transport process are still elusive. In this study, we found that the transmembrane domains 2, 8, and 9 played important roles in transporting function of Oatp1a5. In addition, our data demonstrated that N-linked glycosylation was involved in the transport of MC-LR by Oatp1a5. Moreover, we showed that N-linked glycosylation sites Asn483 and Asn492 were vital for the transport function of Oatp1a5. In summary, the study furthered our understanding of mechanisms that the uptake of MC-LR by GnRH neurons and laid a theoretical foundation for preventing MC-LR from injuring male reproductive health.


Assuntos
Hormônio Liberador de Gonadotropina/metabolismo , Microcistinas/metabolismo , Neurônios/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Animais , Transporte Biológico Ativo , Linhagem Celular , Glicosilação , Mutação , Transportadores de Ânions Orgânicos/química , Transportadores de Ânions Orgânicos/genética , Domínios Proteicos
5.
Biomed Res Int ; 2019: 3617129, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467884

RESUMO

Background: Accumulating evidence from prospective epidemiological studies has showed that depression disorder (DD) is a risk factor for cancer. The aim of this study is to explore the association of DD and the overall occurrence risk of hepatocellular carcinoma (HCC) and the mechanism. Methods: In this study, 60 mice were randomly divided into four groups: Control group, DD group, HCC group, HCC-DD group. Mice received a chronic dose of reserpine to establish depression model, followed by Diethylnitrosamine and Carbon tetrachloride administration to establish HCC models. Behavioral depression was assessed by sucrose preference test (SPT) and the expression of Serotonin 1A (5-HT1A) receptor in the hippocampal. The expression of Oatp2a1 and Oatp2b1 in the digestive system tissues was detected by PCR and western blotting. Results: Reserpine-administrated mice had a reducing sucrose preference at Day 14 compared with blank mice (P<0.05). The expression of 5-HT1A receptor in the hippocampal was decreased in DD mice compared with blank mice. The survival analysis indicated that the HCC mice with DD have poorer survival rate compared with the HCC mice. Compared with HCC mice, the expression of Oatp2a1 and Oatp2b1 was lower in liver and stomach tissue and higher in hepatic carcinoma and colon tissue of HCC-DD mice (P<0.05), and the expression of Oatp2a1 was higher in the spleen tissue of HCC-DD mice while the expression of Oatp2b1 was lower (P<0.05). However, no difference was found in the expression of Oatp2a1 and Oatp2b1 in the small intestine tissue between HCC group and HCC-DD group. Conclusions: DD was the adverse factors for the overall occurrence risk of HCC. Mechanistically, be the downregulation of Oatp2a1 and Oatp2b1 in liver tissue induced by DD might be involved.


Assuntos
Carcinoma Hepatocelular/genética , Transtorno Depressivo/genética , Neoplasias Hepáticas/genética , Transportadores de Ânions Orgânicos/genética , Animais , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/patologia , Transtorno Depressivo/complicações , Transtorno Depressivo/patologia , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Camundongos , Fatores de Risco
6.
Chem Biol Interact ; 311: 108761, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31348918

RESUMO

Water contamination by cyanobacterial blooms is a worldwide health hazard to humans as well as livestock. Exposure to Microcystins (MCs), toxins produced by various cyanobacterial or blue green algae found in poorly treated drinking water or contaminated seafood such as fish or prawns are associated with hepatotoxicity, nephropathy and neurotoxicity and in extreme cases, death in humans. MC congeners, currently >240 known, differ dramatically in their uptake kinetics, i.e. their uptake via OATP1B1 and OATP1B3, in OATP overexpressing human HEK293 cells and primary human hepatocytes. It is thus likely that MC congeners will also differ with respect to the cellular efflux of the parent and conjugated congeners, e.g. via MRPs, MDRs, BCRP or BSEP. Consequently, the role and kinetics of different human efflux transporters - MRP, MDR, BCRP and BSEP in MC efflux was studied using insect membrane vesicles overexpressing the human transporters of interest. Of the efflux transporters investigated, MRP2 displayed MC transport. Michaelis-Menten kinetics displayed mild co-operativity and thus allosteric behavior of MRP2. MC transport by MRP2 was MC congener-specific, whereby MC-LF was transported more rapidly than MC-LR and -RR. Other human transporters (BCRP, BSEP, MRP1,3,5, MDR1) tested in this study did not exhibit interaction with MC. Although MRP2 showed specific MC transport, the MC-LR-GSH conjugate, was not transported suggesting the involvement of other transporters than MRP2 for the conjugate efflux.


Assuntos
Glutationa/química , Microcistinas/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Benzobromarona/química , Benzobromarona/metabolismo , Cromatografia Líquida de Alta Pressão , Células HEK293 , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Microcistinas/análise , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Espectrometria de Massas em Tandem
7.
J Nippon Med Sch ; 86(3): 149-158, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31292326

RESUMO

BACKGROUND: Methotrexate (MTX) is still the first-choice drug for the treatment of rheumatoid arthritis (RA). In Japan, MTX doses of up to 16 mg/week were approved in 2011. In this study, we aimed to identify the gene polymorphisms that can predict therapeutic effects of MTX in Japanese patients in current clinical settings. METHODS: This study involved 171 patients with RA (all Japanese nationals, age 63.5±10.0 years) who had been administered MTX. The analyzed polymorphisms included 82 single nucleotide polymorphisms (SNPs) involved in the MTX pharmacological pathway or in the pathogenesis of RA. Responders were patients who showed high sustained remission or low disease activity with MTX or conventional disease-modifying anti-rheumatic drugs (DMARDs) treatment beyond 6 months. Non-responders were patients who showed moderate or high disease activity, who were prescribed biological DMARDs. A logistic model was constructed with Responder/Non-responder as the target variable, and minor allele frequency was set as an explanatory variable. RESULTS: None of the 82 SNPs targeted for analysis met the Bonferroni significance threshold of 6.098×10-4. However, we identified SLCO1B1 rs11045879 as an SNP that might yield significant results if the number of patients were to be increased (P=0.015). CONCLUSIONS: The rs11045879 minor allele in the SLCO1B1 gene is a potential predictor of non-responders to MTX treatment among Japanese RA patients. In future collaborative research, we will investigate whether the association with SLCO1B1 polymorphism is significant by performing statistical analysis with a larger study population.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Estudos de Associação Genética , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Metotrexato/uso terapêutico , Transportadores de Ânions Orgânicos/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Alelos , Antirreumáticos/administração & dosagem , Grupo com Ancestrais do Continente Asiático , Feminino , Humanos , Modelos Logísticos , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Resultado do Tratamento
8.
Curr Drug Metab ; 20(7): 592-600, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31267867

RESUMO

BACKGROUND: The Pharmacokinetics of Methotrexate (MTX) has been reported to show significant intersubject variability. MTX is metabolized by SHMT1 and transported by OATP1B1 and OATP1B3 both of which show genetic polymorphisms. The non-genetic and genetic factors may influence the pharmacokinetics of MTX. OBJECTIVE: This study aimed to determine the pharmacokinetic parameters of MTX in Chinese patients and to investigate the effect of various non-genetic factors and genetic variants of OATP1B1, OATP1B3 on MTX's pharmacokinetics. METHODS: MTX concentration and clinical characteristics data were collected from 71 rheumatoid arthritis patients. For each patient, SLC19A1, SHMT1, OATP1B1, and OATP1B3 genotyping were tested. Population pharmacokinetic analysis was performed by Nonlinear Mixed-Effect Modeling (NONMEM). MTX pharmacokinetic properties analysis was executed using the one-compartment pharmacokinetic model which incorporated first-order conditional estimation methods with interaction. Besides, the impact of genetic factors and demographic factors on MTX disposition were explored. RESULTS: All the genotypes of steady-state plasma concentrations and OATP1B1 rs4149056, OATP1B1 rs2306283, and OATP1B3 rs7311358 were determined. The detected blood drug concentration reached the standard. Genotypes were all measured. At the same time, the population pharmacokinetic model of methotrexate was obtained CL(L·h-1) =8.25× e0.167× SNP (SNP: SLCO1B1 388A/A=3; SLCO1B1 388A/G=2; SLCO1B1 388G/G=1); V(L)= 32.8; Ka(h- 1)=1.69. CONCLUSION: In our study, it was showed that OATP1B1-388 G>A SNP had a significant effect on CL/F. The factor should be considered when determining MTX dosing. However, prospective studies with a large number of participants are needed to validate the results of this study.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Metotrexato/farmacocinética , Transportadores de Ânions Orgânicos/genética , Polimorfismo Genético/genética , Transporte Biológico/genética , Feminino , Genótipo , Glicina Hidroximetiltransferase/genética , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Masculino , Pessoa de Meia-Idade , Proteína Carregadora de Folato Reduzido/genética , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética
9.
Int J Mol Sci ; 20(13)2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31269743

RESUMO

To characterize effects of type 2 diabetes (T2D) on mRNA expression levels for 10 Cytochromes P450 (CYP450s), two carboxylesterases, and three drug transporters (ABCB1, ABCG2, SLCO2B1) in human duodenal biopsies. To compare drug metabolizing enzyme activities of four CYP450 isoenzymes in duodenal biopsies from patients with or without T2D. mRNA levels were quantified (RT-qPCR) in human duodenal biopsies obtained from patients with (n = 20) or without (n = 16) T2D undergoing a scheduled gastro-intestinal endoscopy. CYP450 activities were determined following incubation of biopsy homogenates with probe substrates for CYP2B6 (bupropion), CYP2C9 (tolbutamide), CYP2J2 (ebastine), and CYP3A4/5 (midazolam). Covariables related to inflammation, T2D, demographic, and genetics were investigated. T2D had no major effects on mRNA levels of all enzymes and transporters assessed. Formation rates of metabolites (pmoles mg protein-1 min-1) determined by LC-MS/MS for CYP2C9 (0.48 ± 0.26 vs. 0.41 ± 0.12), CYP2J2 (2.16 ± 1.70 vs. 1.69 ± 0.93), and CYP3A (5.25 ± 3.72 vs. 5.02 ± 4.76) were not different between biopsies obtained from individuals with or without T2D (p > 0.05). No CYP2B6 specific activity was measured. TNF-α levels were higher in T2D patients but did not correlate with any changes in mRNA expression levels for drug metabolizing enzymes or transporters in the duodenum. T2D did not modulate expression or activity of tested drug metabolizing enzymes and transporters in the human duodenum. Previously reported changes in drug oral clearances in patients with T2D could be due to a tissue-specific disease modulation occurring in the liver and/or in other parts of the intestines.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Hidrolases de Éster Carboxílico/genética , Sistema Enzimático do Citocromo P-450/genética , Diabetes Mellitus Tipo 2/genética , Duodeno/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Idoso , Hidrolases de Éster Carboxílico/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Projetos Piloto , RNA Mensageiro/genética
10.
BMC Urol ; 19(1): 62, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288793

RESUMO

BACKGROUND: Porcine urinary bladders are widely used for uro-pharmacological examinations due to their resemblance to the human organ. However, characterisations of the porcine urothelium at the molecular level are scarce up to now. As it has become clear over the last years that this tissue plays an important role in the signaling-pathways of the bladder, we examined whether the transporter and receptor pattern (with focus on the transmitter acetylcholine) is comparable to the human urothelium. With regard to in vitro studies, we also investigated if there is a difference between the native tissue and cultivated primary urothelial cells in culture. METHODS: Urothelium from German Landrace and Göttingen Minipig bladders was collected. One part of the German Landrace tissue was used for cultivation, and different passages of the urothelial cells were collected. The actual mRNA expression of different transporters and receptors was examined via quantitative real-time PCR. These included the vesicular acetylcholine transporter (VAChT), the choline acetyl transferase (ChAT), organic cation transporters 1-3 (OCT1-3), organic anion transporting polypeptide 1A2 (OATP1A2), P-glycoprotein (ABCB1), the carnitine acetyl-transferase (CarAT), as well as the muscarinic receptors 1-5 (M1-5). RESULTS: There is a strong qualitative resemblance between the human and the porcine urothelium with regard to the investigated cholinergic receptors, enzymes and transporters. CarAT, OCT1-3, OATP1A2 and ABCB1 could be detected in the urothelium of both pig races. Moreover, all 5 M-receptors were prominent with an emphasis on M2 and M3. VAChT and ChAT could not be detected at all. Cultures of the derived urothelial cells showed decreased expression of all targets apart from ABCB1 and CarAT. CONCLUSIONS: Based on the expression pattern of receptors, transporters and enzymes of the cholinergic system, the porcine urinary bladder can be regarded as a good model for pharmacological studies. However, cultivation of primary urothelial cells resulted in a significant drop in mRNA expression of the targets. Therefore, it can be concluded that the intact porcine urothelium, or the whole pig bladder, may be appropriate models for studies with anticholinergic drugs, whereas cultivated urothelial cells have some limitation due to significant changes in the expression levels of relevant targets.


Assuntos
Neurônios Colinérgicos/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Receptores Muscarínicos/metabolismo , Bexiga Urinária/metabolismo , Urotélio/metabolismo , Animais , Células Cultivadas , Transportadores de Ânions Orgânicos/genética , Receptores Muscarínicos/genética , Especificidade da Espécie , Suínos , Porco Miniatura , Bexiga Urinária/citologia , Urotélio/citologia
11.
Cytogenet Genome Res ; 158(3): 126-132, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31203270

RESUMO

Primary hypertrophic osteoarthropathy (PHO), also known as pachydermoperiostosis, is a rare, multisystemic, autosomal recessive condition typically presenting with digital clubbing, osteoarthropathy, and various skin manifestations. Radiographs show distinctive periosteal reaction and thickening along the long bones. PHO is caused by homozygous mutations in the HPGD gene in chromosome 4q34.1 or the SLCO2A1 gene in 3q22.1q22.2. Here, we report on a 20-year-old male with enlarged and swollen joints with arthralgia, palmoplantar hyperhidrosis, and large hands and feet with marked digital clubbing. We also present radiographic, MRI, and ultrasonographic features of the case. These clinical and imaging findings were compatible with the diagnosis of PHO, and a novel homozygous mutation, c.576C>G, p.Ile192Met, was found in SLCO2A1.


Assuntos
Artrite Juvenil/diagnóstico , Mutação , Transportadores de Ânions Orgânicos/genética , Osteoartropatia Hipertrófica Primária/diagnóstico por imagem , Osteoartropatia Hipertrófica Primária/genética , Artrite Juvenil/genética , Diagnóstico Diferencial , Humanos , Masculino , Osteoartropatia Hipertrófica Primária/diagnóstico , Adulto Jovem
12.
J Endocrinol Invest ; 42(10): 1245-1252, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31004291

RESUMO

PURPOSE: Primary hypertrophic osteoarthropathy (PHO) is an inherited disease characterized by digital clubbing, periostosis and pachydermia with defects in the degradation of prostaglandin E2 (PGE2). Mutations in SLCO2A1 gene-encoding prostaglandin transporter (PGT) resulted in PHO, autosomal recessive 2 (PHOAR2). The spectrum of mutations and variable clinical complications of PHOAR2 has been delineated. In this study, we investigated a Chinese PHO family with a manifestation of Bartter-like hypokalemia. METHODS: Clinical manifestations were collected and genetic analyses were performed in the PHO family. RESULTS: The 33-year-old male proband had severe hypokalemia due to potassium loss from the kidney, while his brother had mild hypokalemia. After being treated with etoricoxib, the serum potassium level of the patient increased rapidly to the normal range which corresponded with the reduction in his serum PGE2 and PE2 metabolite (PGEM) levels. A novel SLCO2A1 compound heterozygous mutation of p.I284V and p.C459R was identified in two PHO patients in this family. CONCLUSIONS: The present findings supported that the Bartter-like hypokalemia is a new complication of PHOAR2 caused by the high level of PGE2. Etoricoxib was demonstrated to be effective for the renal hypokalemia in PHO patients.


Assuntos
Síndrome de Bartter/genética , Hipopotassemia/genética , Mutação de Sentido Incorreto , Transportadores de Ânions Orgânicos/genética , Osteoartropatia Hipertrófica Primária/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Síndrome de Bartter/complicações , China , Análise Mutacional de DNA , Família , Heterozigoto , Humanos , Hipopotassemia/etiologia , Masculino , Osteoartropatia Hipertrófica Primária/complicações , Linhagem
13.
Phytomedicine ; 61: 152841, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31035043

RESUMO

BACKGROUND: 14-Deoxy-11,12-didehydroandrographolide (deAND) is the second most abundant diterpenoid in Andrographis paniculata (Burm. f.) Nees, a traditional medicine used in Asia. To date, the biological activity of deAND has not been clearly investigated. PURPOSE: In this study, we intended to examine the modulatory effect of deAND on hepatic drug metabolism as well as its bioavailability. STUDY DESIGN: deAND prepared from A. paniculata was orally given to Sprague-Dawley rats and changes in plasma deNAD were determined by HPLC-MS. Modulation of deAND on drug-metabolizing enzyme and drug transporter expression as well as the possible mechanism involved was examined in primary rat hepatocytes. RESULTS: After a single oral administration of 50 mg/kg deAND to rats, the maximum plasma concentration (Cmax), time to reach the Cmax, area under the curve (AUC0-24h), mean retention time, and half-life (t1/2) of deAND were 2.65 ± 0.68 µg/ml, 0.29 ± 0.15 h, 6.30 ± 1.66 µg/ml•h, 5.55 ± 2.52 h, and 3.56 ± 1.05 h, respectively. The oral bioavailability was 3.42%. In primary rat hepatocytes treated with up to 10 µM deAND, a dose-dependent increase was noted in the expression of cytochrome P450 (CYP) 1A1/2, CYP2C6, and CYP3A1/2; UDP-glucuronosyltransferase (UGT) 1A1, NAD(P)H:quinone oxidoreductase (NQO1), π form of GSH S-transferase (GSTP), multidrug resistance-associated protein 2, p-glycoprotein, and organic anion transporter protein 2B1. Immunoblotting assay and EMSA revealed that deAND increases the nuclear translocation and DNA binding activity of aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and nuclear factor erythroid-derived 2-related factor 2 (Nrf2). Knockdown of AhR and Nrf2 expression abolished deAND induction of CYP isozymes and UGT1A1, NQO1, and GSTP expression, respectively. CONCLUSION: These results indicate that deAND quickly passes through enterocytes in rats and effectively up-regulates hepatic drug-metabolizing enzyme and drug transporter expression in an AhR-, PXR-, and Nrf2-dependent manner.


Assuntos
Diterpenos/farmacocinética , Enzimas/metabolismo , Hepatócitos/efeitos dos fármacos , Administração Oral , Andrographis/química , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Disponibilidade Biológica , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Diterpenos/administração & dosagem , Diterpenos/sangue , Enzimas/genética , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Hepatócitos/fisiologia , Inativação Metabólica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Masculino , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Ratos Sprague-Dawley , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Regulação para Cima/efeitos dos fármacos
14.
Curr Pharm Des ; 25(6): 627-634, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30931851

RESUMO

BACKGROUND: Methotrexate (MTX) is one of the leading chemotherapeutic agents with the bestdemonstrated efficacies against childhood acute lymphoblastic leukemia (ALL). Due to the narrow therapeutic range, significant inter- and intra-patient variabilities of MTX, non-effectiveness and/or toxicity occur abruptly to cause chemotherapeutic interruption or discontinuation. The relationship between clinical outcome and the systemic concentration of MTX has been well established, making the monitoring of plasma MTX levels critical in the treatment of ALL. Besides metabolizing enzymes, multiple transporters are also involved in determining the intracellular drug levels. In this mini-review, we focused on the genetic polymorphisms of MTX-disposition related transporters and the potential association between the discussed genetic variants and MTX pharmacokinetics, efficacy, and toxicity in the context of MTX treatment. METHODS: We searched PubMed for citations published in English using the terms "methotrexate", "transporter", "acute lymphoblastic leukemia", "polymorphisms", and "therapeutic drug monitoring". The retrieval papers were critically reviewed and summarized according to the aims of this mini-review. RESULTS: Solute carrier (SLC) transporters (SLC19A1, SLCO1A2, SLCO1B1, and SLC22A8) and ATP-binding cassette (ABC) transporters (ABCB1, ABCC2, ABCC3, ABCC4, ABCC5, and ABCG2) mediate MTX disposition. Of note, the influences of polymorphisms of SLC19A1, SLCO1B1 and ABCB1 genes on the clinical outcome of MTX have been extensively studied. CONCLUSION: Overall, the data critically reviewed in this mini-review article confirmed that polymorphisms in the genes encoding SLC and ABC transporters confer higher sensitivity to altered plasma levels, MTX-induced toxicity, and therapeutic response in pediatric patients with ALL. Pre-emptive determination may be helpful in individualizing treatment.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Metotrexato/farmacologia , Transportadores de Ânions Orgânicos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/uso terapêutico , Criança , Humanos , Metotrexato/uso terapêutico , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
15.
World J Gastroenterol ; 25(14): 1753-1763, 2019 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-31011259

RESUMO

BACKGROUND: We recently reported on a hereditary enteropathy associated with a gene encoding a prostaglandin transporter and referred to as chronic enteropathy associated with SLCO2A1 gene (CEAS). Crohn's disease (CD) is a major differential diagnosis of CEAS, because these diseases share some clinical features. Therefore, there is a need to develop a convenient screening test to distinguish CEAS from CD. AIM: To examine whether prostaglandin E major urinary metabolites (PGE-MUM) can serve as a biomarker to distinguish CEAS from CD. METHODS: This was a transactional study of 20 patients with CEAS and 98 patients with CD. CEAS was diagnosed by the confirmation of homozygous or compound heterozygous mutation of SLCO2A1. We measured the concentration of PGE-MUM in spot urine by radioimmunoassay, and the concentration was compared between the two groups of patients. We also determined the optimal cut-off value of PGE-MUM to distinguish CEAS from CD by receiver operating characteristic (ROC) curve analysis. RESULTS: Twenty Japanese patients with CEAS and 98 patients with CD were enrolled. PGE-MUM concentration in patients with CEAS was significantly higher than that in patients with CD (median 102.7 vs 27.9 µg/g × Cre, P < 0.0001). One log unit increase in PGE-MUM contributed to 7.3 increase in the likelihood for the diagnosis of CEAS [95% confidence interval (CI) 3.2-16.7]. A logistic regression analysis revealed that the association was significant even after adjusting confounding factors (adjusted odds ratio 29.6, 95%CI 4.7-185.7). ROC curve analysis revealed the optimal PGE-MUM cut-off value for the distinction of CEAS from CD to be 48.9 µg/g × Cre with 95.0% sensitivity and 79.6% specificity. CONCLUSION: PGE-MUM measurement is a convenient, non-invasive and useful test for the distinction of CEAS from CD.


Assuntos
Enteropatias/diagnóstico , Transportadores de Ânions Orgânicos/genética , Ácidos Prostanoicos/urina , Úlcera/diagnóstico , Adulto , Colo/patologia , Doença de Crohn/diagnóstico , Doença de Crohn/urina , Diagnóstico Diferencial , Feminino , Humanos , Íleo/patologia , Enteropatias/genética , Enteropatias/patologia , Enteropatias/urina , Masculino , Pessoa de Meia-Idade , Mutação , Transportadores de Ânions Orgânicos/metabolismo , Prostaglandinas E/metabolismo , Ácidos Prostanoicos/metabolismo , Úlcera/genética , Úlcera/patologia , Úlcera/urina
16.
Nat Commun ; 10(1): 1835, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015435

RESUMO

Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease.


Assuntos
Albuminúria/etiologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/sangue , Microbioma Gastrointestinal/fisiologia , Ésteres do Ácido Sulfúrico/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminúria/sangue , Albuminúria/tratamento farmacológico , Albuminúria/patologia , Animais , Animais Geneticamente Modificados , Estudos de Coortes , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/urina , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Cães , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Células Madin Darby de Rim Canino , Masculino , Metabolômica/métodos , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos/genética , Podócitos/metabolismo , Podócitos/patologia , Ratos , Estreptozocina/toxicidade , Ésteres do Ácido Sulfúrico/sangue , Tirosina Fenol-Liase/antagonistas & inibidores , Tirosina Fenol-Liase/metabolismo , Adulto Jovem
17.
Oncol Rep ; 41(4): 2558-2566, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816509

RESUMO

Curcumin is a natural polyphenolic compound with pronounced anticancer properties, despite its low bioavailability caused by extensive glucuronidation and sulfation. Information on the cellular uptake mechanisms and their contribution to the anticancer effects of curcumin and its biotransformation products is limited. The present study, therefore, investigated the role of organic anion­transporting polypeptides (OATPs) in the cellular uptake of curcumin and its major metabolites in OATP­expressing Chinese hamster ovary (CHO) and human ZR­75­1 breast cancer cells. The uptake rates for curcumin in OATP1B1­, OATP1B3­ and OATP2B1­transfected CHO cells were 2­ to 3­fold higher than wild­type cells. Curcumin sulfate was transported by all three OATPs, although to a much lesser extent, while uptake of tetrahydrocurcumin was the highest but only via OATP1B1 and OATP1B3. Notably, curcumin glucuronide did not exhibit any affinity for these OATPs. The increased mRNA levels of OATP1B1 in wild­type human breast cancer ZR­75­1 cells compared with OATP1B1 knockdown cells was associated with a higher initial uptake of curcumin and tetrahydrocurcumin leading to decreased IC50 values. In conclusion, our data revealed that OATPs act as cellular uptake transporters for curcumin and its major metabolites, and this may also be applicable to patients undergoing cancer therapy.


Assuntos
Antineoplásicos/metabolismo , Neoplasias da Mama/tratamento farmacológico , Curcumina/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/patologia , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Cricetulus , Curcumina/farmacologia , Curcumina/uso terapêutico , Técnicas de Silenciamento de Genes , Humanos , Transportadores de Ânions Orgânicos/genética
18.
J Int Med Res ; 47(5): 1927-1935, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30832523

RESUMO

OBJECTIVE: Acute gout is a painful, inflammatory arthritis that features a rapidly escalating inflammatory response resulting from the formation of monosodium urate crystals in the affected joint space. Previously, we found that Chuanhu anti-gout mixture (CAGM) had similar effects as colchicine against gout in the clinic. Subsequently, to improve its effectiveness and efficacy, we modified the original formulation of CAGM. The current study evaluated the effectiveness of the modified formulation in mice. METHODS: Potassium oxonate (PO) was used to establish a mouse model of hyperuricemia. Plasma levels of uric acid and creatine were determined using the respective test kits. Hepatic xanthine oxidase (XOD) expression was examined by enzyme-linked immunosorbent assay. To explore the underlying mechanism, renal urate transporter 1 (URAT1) mRNA levels were evaluated by quantitative real-time PCR. Allopurinol and benzbromarone were used as reference drugs. RESULTS: The original CAGM and its modified high-dose formulation significantly reduced serum uric acid and creatine levels in hyperuricemic mice. In addition, the CAGM-treated groups displayed lower mRNA levels of hepatic XOD and renal URAT1. CONCLUSIONS: CAGM and its modified formulation significantly ameliorated PO-induced hyperuricemia in mice, which might be partially attributable to reductions of hepatic XOD and renal URAT1 levels.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Hiperuricemia/tratamento farmacológico , Rim/fisiopatologia , Substâncias Protetoras/uso terapêutico , Animais , Creatinina/sangue , Hiperuricemia/sangue , Hiperuricemia/induzido quimicamente , Hiperuricemia/genética , Masculino , Camundongos , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Ácido Oxônico , Substâncias Protetoras/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ácido Úrico/sangue , Xantina Oxidase/metabolismo
19.
Science ; 363(6432)2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30872492

RESUMO

Macrophages are a heterogeneous cell population involved in tissue homeostasis, inflammation, and various pathologies. Although the major tissue-resident macrophage populations have been extensively studied, interstitial macrophages (IMs) residing within the tissue parenchyma remain poorly defined. Here we studied IMs from murine lung, fat, heart, and dermis. We identified two independent IM subpopulations that are conserved across tissues: Lyve1loMHCIIhiCX3CR1hi (Lyve1loMHCIIhi) and Lyve1hiMHCIIloCX3CR1lo (Lyve1hiMHCIIlo) monocyte-derived IMs, with distinct gene expression profiles, phenotypes, functions, and localizations. Using a new mouse model of inducible macrophage depletion (Slco2b1 flox/DTR), we found that the absence of Lyve1hiMHCIIlo IMs exacerbated experimental lung fibrosis. Thus, we demonstrate that two independent populations of IMs coexist across tissues and exhibit conserved niche-dependent functional programming.


Assuntos
Pulmão/imunologia , Pulmão/patologia , Macrófagos/imunologia , Animais , Antígenos Ly , Receptor 1 de Quimiocina CX3C/genética , Linhagem da Célula , Derme/imunologia , Modelos Animais de Doenças , Fibrose , Glicoproteínas/análise , Antígenos de Histocompatibilidade Classe II/genética , Proteínas de Membrana Transportadoras , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Miocárdio/imunologia , Transportadores de Ânions Orgânicos/genética , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Transcriptoma
20.
PLoS One ; 14(3): e0213747, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30865704

RESUMO

Elevated plasma concentrations of the uremic toxin asymmetrical dimethylarginine (ADMA) and low plasma concentrations of L-homoarginine are independently associated with cardiovascular events and total mortality. Enzymes degrading ADMA [dimethylaminohydrolase 1 (DDAH1)] and synthesizing L-homoarginine [L-arginine:glycine amidinotransferase (AGAT)] are expressed in human proximal tubule cells. So far, it is not known which transport protein in the basolateral membrane of proximal tubule cells is mediating the uptake of ADMA into the cells for subsequent degradation or the export of intracellularly synthesized L-homoarginine. One study suggested that the uptake transporter OATP4C1 (gene symbol SLCO4C1) may be involved in the transport of ADMA and other uremic toxins. OATP4C1 is a member of the SLCO/SLC21 family of solute carriers, localized in the basolateral membrane of human proximal tubule cells. By using stably-transfected HEK cells overexpressing human OATP4C1, we demonstrate that ADMA and L-homoarginine are substrates of OATP4C1 with Km values of 232.1 µM and 49.9 µM, respectively. ADMA and the structurally related uremic toxin SDMA (100 µM) inhibited OATP4C1-mediated L-homoarginine uptake (P < 0.01), whereas other tested uremic toxins such as urea and p-cresyl sulfate have no effect on OATP4C1-mediated transport. Preloading experiments (300 µM for 60 min) with subsequent efflux studies revealed that OATP4C1 also facilitates efflux e.g. of L-homoarginine. Both ADMA and L-homoarginine are substrates of human OATP4C1. Because proximal tubule cells are one site of ADMA metabolism and L-homoarginine synthesis, we postulate a protective role of OATP4C1 by mediating uptake of ADMA from and export of L-homoarginine into the systemic circulation.


Assuntos
Arginina/análogos & derivados , Homoarginina/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Arginina/metabolismo , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/patologia , Células HEK293 , Humanos , Concentração Inibidora 50 , Rim/metabolismo , Cinética , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Transportadores de Ânions Orgânicos/genética , Toxinas Biológicas/química , Toxinas Biológicas/metabolismo
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