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1.
BMC Pediatr ; 21(1): 237, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006251

RESUMO

BACKGROUND: Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a common form of neonatal jaundice. Histopathological examination of the liver in patients with NICCD typically shows fatty liver, steatohepatitis, and liver fibrosis. Jaundice and fatty liver often improve by 1 year of age. We herein describe a girl who was diagnosed with NICCD based on an SLC25A13 mutation, although no fatty deposits were found on pathologic examination of the liver. CASE PRESENTATION: The patient in this case was a 3-month-old girl. At 2 months of age, she presented with jaundice, discolored stools, and poor weight gain and was found to have hyperbilirubinemia. Cholangiography revealed that she did not have biliary atresia. A laparoscopic liver biopsy was performed, and liver histopathology showed no fatty deposits. Genetic analysis revealed a compound heterozygous mutation in SLC25A13, and she was diagnosed with NICCD. She was given medium-chain triglyceride milk and gained weight. She resumed consumption of normal milk and breast milk, and her stool color improved. She was discharged at 4 months of age with adequate weight gain and a lower total bilirubin concentration. She was in good condition after discharge and showed normal development at the time of outpatient follow-up. CONCLUSIONS: We experienced a case of NICCD in a patient without fatty liver. This case illustrates that the absence of hepatic steatosis in neonatal cholestasis does not rule out NICCD.


Assuntos
Colestase , Fígado Gorduroso , Transportadores de Ânions Orgânicos , Proteínas de Ligação ao Cálcio , Citrulinemia , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/etiologia , Feminino , Humanos , Lactente , Recém-Nascido , Proteínas de Transporte da Membrana Mitocondrial/genética , Mutação , Transportadores de Ânions Orgânicos/genética
2.
Int J Mol Sci ; 22(9)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33924853

RESUMO

Low phosphorus (P) availability is one of the major constraints to plant growth, particularly in acidic soils. A possible mechanism for enhancing the use of sparsely soluble P forms is the secretion of malate in plants by the aluminum-activated malate transporter (ALMT) gene family. Despite its significance in plant biology, the identification of the ALMT gene family in oilseed rape (Brassica napus; B. napus), an allotetraploid crop, is unveiled. Herein, we performed genome-wide identification and characterization of ALMTs in B. napus, determined their gene expression in different tissues and monitored transcriptional regulation of BnaALMTs in the roots and leaves at both a sufficient and a deficient P supply. Thirty-nine BnaALMT genes were identified and were clustered into five branches in the phylogenetic tree based on protein sequences. Collinearity analysis revealed that most of the BnaALMT genes shared syntenic relationships among BnaALMT members in B. napus, which suggested that whole-genome duplication (polyploidy) played a major driving force for BnaALMTs evolution in addition to segmental duplication. RNA-seq analyses showed that most BnaALMT genes were preferentially expressed in root and leaf tissues. Among them, the expression of BnaC08g13520D, BnaC08g15170D, BnaC08g15180D, BnaC08g13490D, BnaC08g13500D, BnaA08g26960D, BnaC05g14120D, BnaA06g12560D, BnaC05g20630D, BnaA07g02630D, BnaA04g15700D were significantly up-regulated in B. napus roots and leaf at a P deficient supply. The current study analyzes the evolution and the expression of the ALMT family in B. napus, which will help in further research on their role in the enhancement of soil P availability by secretion of organic acids.


Assuntos
Alumínio/metabolismo , Brassica napus/genética , Evolução Molecular , Malatos/metabolismo , Transportadores de Ânions Orgânicos/genética , Fosfatos/metabolismo , Proteínas de Arabidopsis/genética , Cromossomos de Plantas , Genoma de Planta , Família Multigênica , Transportadores de Ânions Orgânicos/metabolismo
3.
Int J Mol Sci ; 22(8)2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33917029

RESUMO

Endometrial cancer (EC) is associated with increased estrogen actions. Locally, estrogens can be formed from estrone-sulphate (E1-S) after cellular uptake by organic anion-transporting polypeptides (OATP) or organic anion transporters (OAT). Efflux of E1-S is enabled by ATP Binding Cassette transporters (ABC) and organic solute transporter (OST)αß. Currently, 19 E1-S transporters are known but their roles in EC are not yet understood. Here, we analysed levels of E1-S transporters in Ishikawa (premenopausal EC), HEC-1-A (postmenopausal EC), HIEEC (control) cell lines, in EC tissue, examined metabolism of steroid precursor E1-S, studied effects of OATPs' inhibition and gene-silencing on E1-S uptake, and assessed associations between transporters and histopathological data. Results revealed enhanced E1-S metabolism in HEC-1-A versus Ishikawa which could be explained by higher levels of OATPs in HEC-1-A versus Ishikawa, especially 6.3-fold up-regulation of OATP1B3 (SLCO1B3), as also confirmed by immunocytochemical staining and gene silencing studies, lower ABCG2 expression and higher levels of sulfatase (STS). In EC versus adjacent control tissue the highest differences were seen for ABCG2 and SLC51B (OSTß) which were 3.0-fold and 2.1-fold down-regulated, respectively. Immunohistochemistry confirmed lower levels of these two transporters in EC versus adjacent control tissue. Further analysis of histopathological data indicated that SLCO1B3 might be important for uptake of E1-S in tumours without lymphovascular invasion where it was 15.6-fold up-regulated as compared to adjacent control tissue. Our results clearly indicate the importance of E1-S transporters in EC pathophysiology and provide a base for further studies towards development of targeted treatment.


Assuntos
Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Estrona/análogos & derivados , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/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 , Fatores Etários , Transporte Biológico , Linhagem Celular Tumoral , Neoplasias do Endométrio/patologia , Estrona/metabolismo , Feminino , Imunofluorescência , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Família Multigênica , Gradação de Tumores , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Estadiamento de Neoplasias , Pós-Menopausa , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo
4.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33669292

RESUMO

The ABCG2 gene is a well-established hyperuricemia/gout risk locus encoding a urate transporter that plays a crucial role in renal and intestinal urate excretion. Hitherto, p.Q141K-a common variant of ABCG2 exhibiting approximately one half the cellular function compared to the wild-type-has been reportedly associated with early-onset gout in some populations. However, compared with adult-onset gout, little clinical information is available regarding the association of other uricemia-associated genetic variations with early-onset gout; the latent involvement of ABCG2 in the development of this disease requires further evidence. We describe a representative case of familial pediatric-onset hyperuricemia and early-onset gout associated with a dysfunctional ABCG2, i.e., a clinical history of three generations of one Czech family with biochemical and molecular genetic findings. Hyperuricemia was defined as serum uric acid (SUA) concentrations 420 µmol/L for men or 360 µmol/L for women and children under 15 years on two measurements, performed at least four weeks apart. The proband was a 12-year-old girl of Roma ethnicity, whose SUA concentrations were 397-405 µmol/L. Sequencing analyses focusing on the coding region of ABCG2 identified two rare mutations-c.393G>T (p.M131I) and c.706C>T (p.R236X). Segregation analysis revealed a plausible link between these mutations and hyperuricemia and the gout phenotype in family relatives. Functional studies revealed that p.M131I and p.R236X were functionally deficient and null, respectively. Our findings illustrate why genetic factors affecting ABCG2 function should be routinely considered in clinical practice as part of a hyperuricemia/gout diagnosis, especially in pediatric-onset patients with a strong family history.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Gota/complicações , Gota/genética , Hiperuricemia/complicações , Hiperuricemia/genética , Proteínas de Neoplasias/genética , Transportadores de Ânions Orgânicos/genética , Polimorfismo de Nucleotídeo Único , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Criança , República Tcheca , Feminino , Predisposição Genética para Doença , Células HEK293 , Humanos , Hiperuricemia/sangue , Masculino , Mutação , Proteínas de Neoplasias/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Linhagem , Fenótipo , Transfecção , Ácido Úrico/sangue
5.
Br J Anaesth ; 126(5): 949-957, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33676726

RESUMO

BACKGROUND: Rocuronium, a common neuromuscular blocking agent, is mainly excreted unchanged in urine (10-25%) and bile (>70%). Age, sex, liver blood flow, smoking, medical conditions, and ethnic background can affect its pharmacological actions. However, reasons for the wide variation in rocuronium requirements are mostly unknown. We hypothesised that pharmacogenetic factors might explain part of the variation. METHODS: One thousand women undergoing surgery for breast cancer were studied. Anaesthesia was maintained with propofol (50-100 µg kg-1 min-1) and remifentanil (0.05-0.25 µg kg-1 min-1). Neuromuscular block was maintained with rocuronium to keep the train-of-four ratio at 0-10%. DNA was extracted from peripheral blood and genotyped with a next-generation genotyping array. The genome-wide association study (GWAS) was conducted using an additive linear regression model with PLINK software. The FINEMAP tool and data from the Genotype-Tissue Expression project v8 were utilised to study the locus further. RESULTS: The final patient population comprised 918 individuals. Of the clinical variables tested, age, BMI, ASA physical status, and total dose of propofol correlated significantly (all P<0.001) with the rocuronium dose in a linear regression model. The GWAS highlighted one genome-wide significant locus in chromosome 12. The single-nucleotide polymorphisms (SNPs) with the most significant evidence of association were located in or near SLCO1A2. The two top SNPs, rs7967354 (P=5.3e-11) and rs11045995 (P=1.4e-10), and the clinical variables accounted for 41% of the variability in rocuronium dosage. CONCLUSIONS: Genetic variation in the gene SLCO1A2, encoding OATP1A2, an uptake transporter, accounted for 4% of the variability in rocuronium consumption. The underlying mechanism remains unknown.


Assuntos
Neoplasias da Mama/cirurgia , Fármacos Neuromusculares não Despolarizantes/administração & dosagem , Transportadores de Ânions Orgânicos/genética , Rocurônio/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Farmacogenética , Polimorfismo de Nucleotídeo Único , Propofol/administração & dosagem , Estudos Prospectivos , Remifentanil/administração & dosagem
6.
Life Sci ; 268: 118907, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33428880

RESUMO

The ATP-binding cassette (ABC) and solute carrier (SLC) transporter families consist of common drug transporters that mediate the efflux and uptake of drugs, respectively, and play an important role in the absorption, distribution, metabolism and excretion of drugs in vivo. Rheumatoid arthritis (RA) is an autoimmune disease characterized by erosive arthritis, and there are many RA patients worldwide. Methotrexate (MTX), the first-choice treatment for RA, can reduce the level of inflammation, prevent joint erosion and functional damage, and greatly reduce pain in RA patients. However, many patients show resistance to MTX, greatly affecting the efficacy of MTX. Many factors, such as irrational drug use and heredity, are associated with drug resistance. Considering the effect of drug transporters on drugs, many studies have compared the expression of drug transporters in drug-resistant and drug-sensitive patients, and abnormal transporter expression and transport activity have been found in patients with MTX resistance. Thus, drug transporters are involved in drug resistance. This article reviews the effects of transporters on the efficacy of MTX in the treatment of RA.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Metotrexato/farmacologia , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Anti-Inflamatórios não Esteroides/farmacologia , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacocinética , Artrite Reumatoide/metabolismo , Citocinas/genética , Citocinas/metabolismo , Humanos , Inativação Metabólica , Metotrexato/efeitos adversos , Metotrexato/farmacocinética , Transportadores de Ânions Orgânicos/genética , Distribuição Tecidual
7.
J Fish Dis ; 44(6): 837-845, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33400351

RESUMO

Bcl2 family proteins play a critical role in cell death or survival. BAX, the death-promoting protein of bcl2 family, mediated mitochondrial pathway inducing cells' apoptosis in mammal. MiRNAs have been implicated as negative regulators down-regulating genes' expression after post-transcriptional level. At present, little is known about the regulatory mechanism of miRNA on the Bcl2 family proteins during CyHV-2 infection in silver crucian carp (Carassius auratus gibelio). In this study, the ccBAX (silver crucian carp BAX) gene was cloned and expressed, and polyclonal antibodies were raised in mouse against the purified ccBAX-GST fusion protein. The structure analysis indicated that ccBAX protein included four conserve domains (BH1, BH2, BH3 and transmembrane domains) and the expression of ccBAX protein occurred throughout the cells. Furthermore, two miRNAs (miR-124 and miRNA-29b) were identified to negatively regulate ccBAX gene expression in GiCF cell. miR-124 was found to suppress the expression of WT-ccBAX (wild type), but not the MT-ccBAX (mutant). Overall, the results demonstrated that the expression of the ccBAX gene was significantly down-regulated by miR-124 in silver crucian carp (Carassius auratus gibelio) during CyHV-2 infection.


Assuntos
Doenças dos Peixes/imunologia , Regulação da Expressão Gênica/imunologia , Carpa Dourada/genética , Carpa Dourada/imunologia , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/imunologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Doenças dos Peixes/virologia , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/veterinária , Herpesviridae/fisiologia , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/veterinária , Infecções por Herpesviridae/virologia , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/imunologia , Filogenia , Alinhamento de Sequência/veterinária , Proteína X Associada a bcl-2/química
8.
Phytomedicine ; 80: 153374, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33075645

RESUMO

BACKGROUND: Insufficient renal urate excretion and/or overproduction of uric acid (UA) are the dominant causes of hyperuricemia. Baicalein (BAL) is widely distributed in dietary plants and has extensive biological activities, including antioxidative, anti-inflammatory and antihypertensive activities. PURPOSE: To investigate the anti-hyperuricemic effects of BAL and the underlying mechanisms in vitro and in vivo. METHODS: We investigated the inhibitory effects of BAL on GLUT9 and URAT1 in vitro through electrophysiological experiments and 14C-urate uptake assays. To evaluate the impact of BAL on serum and urine UA, the expression of GLUT9 and URAT1, and the activity of xanthine oxidase (XOD), we developed a mouse hyperuricemia model by potassium oxonate (PO) injection. Molecular docking analysis based on homology modeling was performed to explain the predominant efficacy of BAL compared with the other test compounds. RESULTS: BAL dose-dependently inhibited GLUT9 and URAT1 in a noncompetitive manner with IC50 values of 30.17 ± 8.68 µM and 31.56 ± 1.37 µM, respectively. BAL (200 mg/kg) significantly decreased serum UA and enhanced renal urate excretion in PO-induced hyperuricemic mice. Moreover, the expression of GLUT9 and URAT1 in the kidney was downregulated, and XOD activity in the serum and liver was suppressed. The docking analysis revealed that BAL potently interacted with Trp336, Asp462, Tyr71 and Gln328 of GLUT9 and Ser35 and Phe241 of URAT1. CONCLUSION: These results indicated that BAL exerts potent antihyperuricemic efects through renal UA excretal promotion and serum UA production. Thus, we propose that BAL may be a promising treatment for the prevention of hyperuricemia owing to its multitargeted inhibitory activity.


Assuntos
Flavanonas/farmacologia , Hiperuricemia/tratamento farmacológico , Ácido Úrico/urina , Xantina Oxidase/antagonistas & inibidores , Animais , Antioxidantes/farmacologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Flavanonas/química , Flavanonas/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/química , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Células HEK293 , Humanos , Hiperuricemia/induzido quimicamente , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Transportadores de Ânions Orgânicos/química , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/química , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Ácido Oxônico/toxicidade , Ácido Úrico/sangue
9.
FASEB J ; 35(1): e21262, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33368618

RESUMO

The excretion and reabsorption of uric acid both to and from urine are tightly regulated by uric acid transporters. Metabolic syndrome conditions, such as obesity, hypercholesterolemia, and insulin resistance, are believed to regulate the expression of uric acid transporters and decrease the excretion of uric acid. However, the mechanisms driving cholesterol impacts on uric acid transporters have been unknown. Here, we show that cholesterol metabolite 27-hydroxycholesterol (27HC) upregulates the uric acid reabsorption transporter URAT1 encoded by SLC22A12 via estrogen receptors (ER). Transcriptional motif analysis showed that the SLC22A12 gene promoter has more estrogen response elements (EREs) than other uric acid reabsorption transporters such as SLC22A11 and SLC22A13, and 27HC-activated SLC22A12 gene promoter via ER through EREs. Furthermore, 27HC increased SLC22A12 gene expression in human kidney organoids. Our results suggest that in hypercholesterolemic conditions, elevated levels of 27HC derived from cholesterol induce URAT1/SLC22A12 expression to increase uric acid reabsorption, and thereby, could increase serum uric acid levels.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Hidroxicolesteróis/farmacologia , Rim/metabolismo , Transportadores de Ânions Orgânicos/biossíntese , Proteínas de Transporte de Cátions Orgânicos/biossíntese , Receptores de Estrogênio/metabolismo , Humanos , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Organoides/metabolismo , Receptores de Estrogênio/genética
10.
Intern Med ; 59(24): 3147-3154, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33328413

RESUMO

A 49-year-old man complained of chronic palpitation and shortness of breath, which had recently become exacerbated. A blood examination indicated severe refractory anemia and hypoproteinemia. Physical examinations revealed anemia, a systolic murmur, and spoon nails. Multiple nonspecific ileal ulcers were observed. A pathological examination indicated a small granuloma with CD68-positive histiocytes. He had a deeply wrinkled forehead, chiseled face, and clubbed fingers. Radiography revealed periostosis of the fingers and long bones in the limb. He was diagnosed with pachydermoperiostosis. SLCO2A1 demonstrated a c.1807C>T homo-mutation. He was also diagnosed with SLCO2A1-associated chronic enteropathy and thus was treated with 5-aminosalicylic acid, which temporarily improved the ileal ulcers, anemia, and hypoalbuminemia.


Assuntos
Doenças Inflamatórias Intestinais , Transportadores de Ânions Orgânicos , Osteoartropatia Hipertrófica Primária , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Transportadores de Ânions Orgânicos/genética , Osteoartropatia Hipertrófica Primária/diagnóstico , Osteoartropatia Hipertrófica Primária/genética , Úlcera
11.
PLoS One ; 15(8): e0237825, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822435

RESUMO

Cattle temperament is a complex and economically relevant trait. The objective of this study was to identify genomic regions and genes associated with cattle temperament. From a Brahman cattle population of 1,370 animals evaluated for temperament traits (Exit velocity-EV, Pen Score-PS, Temperament Score-TS), two groups of temperament-contrasting animals were identified based on their EV-average values ±1/2 standard deviation (SD). To be considered in the calm group, the EV of females ranged between 0.16-1.82 m/s (n = 50) and the EV of males ranged between 0.4-1.56 m/s (n = 48). Females were classified as temperamental if their EV ranged between 3.13-7.66 m/s (n = 46) and males were classified as temperamental if their EV ranged between 3.05-10.83 m/s (n = 45). Selected animals were genotyped using a total of 139,376 SNPs (GGP-HD-150K), evaluated for their association with EV. The Genome-Wide Association analysis (GWAS) identified fourteen SNPs: rs135340276, rs134895560, rs110190635, rs42949831, rs135982573, rs109393235, rs109531929, rs135087545, rs41839733, rs42486577, rs136661522, rs110882543, rs110864071, rs109722627, (P<8.1E-05), nine of them were located on intergenic regions, harboring seventeen genes, of which only ACER3, VRK2, FANCL and SLCO3A1 were considered candidate associated with bovine temperament due to their reported biological functions. Five SNPs were located at introns of the NRXN3, EXOC4, CACNG4 and SLC9A4 genes. The indicated candidate genes are implicated in a wide range of behavioural phenotypes and complex cognitive functions. The association of the fourteen SNPs on bovine temperament traits (EV, PS and TS) was evaluated; all these SNPs were significant for EV; only some were associated with PS and TS. Fourteen SNPs were associated with EV which allowed the identification of twenty-one candidate genes for Brahman temperament. From a functional point of view, the five intronic SNPs identified in this study, are candidates to address control of bovine temperament, further investigation will probe their role in expression of this trait.


Assuntos
Comportamento Animal , Bovinos/genética , Bovinos/psicologia , Emoções , Temperamento , Ceramidase Alcalina/genética , Animais , Proteína do Grupo de Complementação L da Anemia de Fanconi/genética , Feminino , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Genótipo , Masculino , Transportadores de Ânions Orgânicos/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Trocadores de Sódio-Hidrogênio/genética , Proteínas de Transporte Vesicular/genética
12.
J Stroke Cerebrovasc Dis ; 29(9): 105040, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32807452

RESUMO

BACKGROUND: Emotional disturbances, such as anxiety and depression are common after acute ischemic stroke (AIS). Individual variation in emotional outcome is strongly influenced by genetic factors. One of pituitary axis, is the hypothalamic-pituitary-thyroid axis, a critical regulator of post-stroke recovery, suggesting that allelic variants in thyroid hormone (TH) signaling regulation can influence stroke outcome. AIM: To determine associations between AIS emotional outcome and allelic variants of the TH metabolizing enzymes 1-3 type deiodinase (DIO1-3) and the membrane transporting organic anion polypeptide 1C1 (OATP1C1). METHODS: Eligible AIS patients from Lithuania (n=168) were genotyped for ten DIO1-3 and OATP1C1 single nucleotide polymorphisms (SNP): DIO1 rs12095080-A/G, rs11206244-C/T, and rs2235544-A/C; DIO2 rs225014-T/C and rs225015-G/A; DIO3 rs945006-T/G; OATP1C1 rs974453-G/A, rs10444412-T/C, rs10770704-C/T, and rs1515777-A/G. Emotional outcome was evaluated using the Hospital Anxiety and Depression Scale at discharge from the neurology department after experienced index AIS. RESULTS: After adjustment for potential confounders, the major allelic (wild-type) DIO1-rs12095080 genotype (AA) was associated with higher odds ratio of anxiety symptoms (OR = 5.16; 95% CI: 1.04-25.58; p = 0.045), conversely, DIO1-rs11206244 wild-type genotype (CC) and wild-type OATP1C1-rs1515777 allele containing the genotypes (AA + AG) were associated with lower odds ratio of symptoms of anxiety (OR = 0.37; 95% CI: 0.14-0.96; p = 0.041 and OR = 0.30; 95% CI: 0.12-0.76; p = 0.011, respectively). Wild-type OATP1C1-rs974453 genotype (GG) was associated with higher odds ratio of symptoms of depression (OR = 2.73; 95% CI: 1.04-7.12; p = 0.041). CONCLUSION: Allelic variants in thyroid axis genes may predict emotional outcomes of AIS.


Assuntos
Afeto , Ansiedade/genética , Proteínas de Ligação a DNA/genética , Depressão/genética , Transportadores de Ânions Orgânicos/genética , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Idoso , Ansiedade/diagnóstico , Ansiedade/epidemiologia , Ansiedade/psicologia , Depressão/diagnóstico , Depressão/epidemiologia , Depressão/psicologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Iodeto Peroxidase/genética , Lituânia/epidemiologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/psicologia
13.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(8): 828-832, 2020 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-32761588

RESUMO

OBJECTIVE: To explore the genetic basis for a child with concomitant spinal muscular atrophy (SMA) and Citrin protein deficiency. METHODS: The child was subjected to whole exome sequencing by using target sequence capture high-throughput sequencing. Candidate variants were verified by Sanger sequencing. The SMN genes of the patient were also analyzed through multiplex ligation-dependent probe amplification (MLPA). RESULTS: The patient was found to carry homozygous deletion of exons 7 and 8 of the SMN1 gene, for which his parents were both carriers. The patient also carried compound heterozygous variants c.1737G>A and IVS16ins3kbof the SLA25A13 gene, in addition with compound heterozygous variants c.948G>A and c.2693T>C of the POLG gene, for which his parents were carriers, too. CONCLUSION: Variants of the SLC25A13 gene probably underlay the deficiency of Citrin protein, which may lead to neonatal intrahepatic cholestasis (NICCD). The patient also had SMA. The compound heterozygous variants c.948G>A and c.2693T>C of the POLG gene are likely to cause mitochondrial DNA deletion syndrome type 4A, though other types of mitochondrial disease cannot be excluded.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Atrofia Muscular Espinal/genética , Transportadores de Ânions Orgânicos/genética , Deficiência de Proteína/genética , Proteínas de Ligação ao Cálcio/deficiência , Criança , DNA Polimerase gama/genética , Homozigoto , Humanos , Proteínas de Transporte da Membrana Mitocondrial/genética , Transportadores de Ânions Orgânicos/deficiência , Deleção de Sequência , Proteína 1 de Sobrevivência do Neurônio Motor/genética
14.
PLoS Genet ; 16(7): e1008856, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32614824

RESUMO

The microRNAs (miRNAs) are important regulators of gene expression. In this study, we provide evidence for the first time to show that rickettsial pathogen Anaplasma phagocytophilum infection results in the down-regulation of tick microRNA-133 (miR-133), to induce Ixodes scapularis organic anion transporting polypeptide (isoatp4056) gene expression critical for this bacterial survival in the vector and for its transmission to the vertebrate host. Transfection studies with recombinant constructs containing transcriptional fusions confirmed binding of miR-133 to isoatp4056 mRNA. Treatment with miR-133 inhibitor resulted in increased bacterial burden and isoatp4056 expression in ticks and tick cells. In contrast, treatment with miR-133 mimic or pre-mir-133 resulted in dramatic reduction in isoatp4056 expression and bacterial burden in ticks and tick cells. Moreover, treatment of ticks with pre-mir-133 affected vector-mediated A. phagocytophilum infection of murine host. These results provide novel insights to understand impact of modulation of tick miRNAs on pathogen colonization in the vector and their transmission to infect the vertebrate host.


Assuntos
Anaplasma phagocytophilum/genética , Interações Hospedeiro-Patógeno/genética , Ixodes/genética , MicroRNAs/genética , Anaplasma phagocytophilum/patogenicidade , Animais , Apoptose , Vetores de Doenças , Regulação da Expressão Gênica/genética , Genes Essenciais/genética , Humanos , Insetos Vetores/genética , Ixodes/patogenicidade , Camundongos , Transportadores de Ânions Orgânicos/genética , Peptídeos/genética , Transcriptoma/genética
15.
BMC Neurol ; 20(1): 278, 2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32660532

RESUMO

BACKGROUND: Variants in the SLC25A1 gene are associated with a severe neurometabolic disease, D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA). A report in 2014 presented the first account of congenital myasthenic syndrome (CMS) with mild intellectual disability (ID) caused by SLC25A1. To date, only two missense variants in SLC25A1 have been linked to CMS. CASE PRESENTATIONS: A Chinese boy presented fatigable muscular weakness, myasthenic crisis, epilepsy and developmental delay along with mild elevation of urinary 2-ketoglutarate (2-KG) and lactic acid levels. He showed a partial response to pyridostigmine. Genetic analysis using trio whole-exome sequencing (WES), Sanger sequencing, and cosegregation analyses revealed two novel pathogenic variants of SLC25A1 (c.628C > T, p.R210X; c.145G > A, p.V49M). CONCLUSIONS: We report a boy who carries novel compound heterozygous variants of SLC25A1 and presents a phenotype intermediate between CMS and D/L-2-HGA. This case expands the range of known phenotypes and genotypes associated with SLC25A1.


Assuntos
Encefalopatias Metabólicas Congênitas , Proteínas Mitocondriais/genética , Mutação de Sentido Incorreto/genética , Síndromes Miastênicas Congênitas , Transportadores de Ânions Orgânicos/genética , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/fisiopatologia , Criança , Humanos , Masculino , Síndromes Miastênicas Congênitas/genética , Síndromes Miastênicas Congênitas/fisiopatologia , Fenótipo
16.
Mol Pharmacol ; 98(3): 234-242, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32587096

RESUMO

We previously established that androgen glucuronides are effluxed by multidrug resistance-associated proteins 2 and 3. However, no data exist on the mechanism of hepatic uptake of these metabolites. The first goal of this study was to explore the role of hepatic uptake transporters and characterize transport kinetics of glucuronides of testosterone (TG), dihydrotestosterone (DHTG), androsterone (AG), and etiocholanolone (EtioG) using cell lines overexpressing organic anion transporting polypeptides (OATP1B1, OATP1B3, and OATP2B1). Using a quantitative proteomics-guided approach, we then estimated the fractional contribution of individual OATPs in hepatic uptake of these glucuronides. The transport screening assays revealed that the glucuronides were primarily taken up by OATP1B1 and OATP1B3. The K m values for OATP1B1-mediated uptake were low for EtioG (6.2 µM) as compared with AG, TG, and DHTG (46.2, 56.7, and 71.3 µM, respectively), whereas the K m value for OATP1B3-mediated uptake for EtioG, AG, DHTG, and TG were 19.8, 29.3, 69.6, and 110.4 µM, respectively. Both OATP1B1 and OATP1B3 exhibited the highest transport rate toward AG as compared with other glucuronides. When adjusted for the transporter abundance in human livers, EtioG and DHTG were predicted to be transported by both OATP1B1 and OATP1B3, whereas TG and AG were preferentially (>68%) transported by OATP1B3. Collectively, this report elucidates the mechanisms of hepatic uptake of androgen glucuronides. Perturbation of these processes by genetic polymorphisms, disease conditions, or drug interactions can lead to changes in enterohepatic recycling of androgens. TG and AG can be further investigated as potential biomarkers of OATP1B3 inhibition. SIGNIFICANCE STATEMENT: This is the first study to elucidate the mechanism of hepatic uptake of androgen glucuronides and estimate the fractional contribution of individual OATPs using quantitative proteomics. Our results show that both OATP1B1 and OATP1B3 are responsible for the hepatic uptake of major circulating testosterone glucuronides. The apparent higher selectivity of OATP1B3 toward testosterone glucuronide and androsterone glucuronide can be leveraged for establishing these metabolites as clinical biomarkers of OATP1B3 activity.


Assuntos
Glucuronídeos/química , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Fígado/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Androgênios/química , Transporte Biológico , Linhagem Celular , Células HEK293 , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportadores de Ânions Orgânicos/genética , Proteômica/métodos , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética
17.
BMC Med Genet ; 21(1): 91, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32375679

RESUMO

BACKGROUND: Renal hypouricemia (RHUC) is a hereditary disorder where mutations in SLC22A12 gene and SLC2A9 gene cause RHUC type 1 (RHUC1) and RHUC type 2 (RHUC2), respectively. These genes regulate renal tubular reabsorption of urates while there exist other genes counterbalancing the net excretion of urates including ABCG2 and SLC17A1. Urate metabolism is tightly interconnected with glucose metabolism, and SLC2A9 gene may be involved in insulin secretion from pancreatic ß-cells. On the other hand, a myriad of genes are responsible for the impaired insulin secretion independently of urate metabolism. CASE PRESENTATION: We describe a 67 year-old Japanese man who manifested severe hypouricemia (0.7 mg/dl (3.8-7.0 mg/dl), 41.6 µmol/l (226-416 µmol/l)) and diabetes with impaired insulin secretion. His high urinary fractional excretion of urate (65.5%) and low urinary C-peptide excretion (25.7 µg/day) were compatible with the diagnosis of RHUC and impaired insulin secretion, respectively. Considering the fact that metabolic pathways regulating urates and glucose are closely interconnected, we attempted to delineate the genetic basis of the hypouricemia and the insulin secretion defect observed in this patient using whole exome sequencing. Intriguingly, we found homozygous Trp258* mutations in SLC22A12 gene causing RHUC1 while concurrent mutations reported to be associated with hyperuricemia were also discovered including ABCG2 (Gln141Lys) and SLC17A1 (Thr269Ile). SLC2A9, that also facilitates glucose transport, has been implicated to enhance insulin secretion, however, the non-synonymous mutations found in SLC2A9 gene of this patient were not dysfunctional variants. Therefore, we embarked on a search for causal mutations for his impaired insulin secretion, resulting in identification of multiple mutations in HNF1A gene (MODY3) as well as other genes that play roles in pancreatic ß-cells. Among them, the Leu80fs in the homeobox gene NKX6.1 was an unreported mutation. CONCLUSION: We found a case of RHUC1 carrying mutations in SLC22A12 gene accompanied with compensatory mutations associated with hyperuricemia, representing the first report showing coexistence of the mutations with opposed potential to regulate urate concentrations. On the other hand, independent gene mutations may be responsible for his impaired insulin secretion, which contains novel mutations in key genes in the pancreatic ß-cell functions that deserve further scrutiny.


Assuntos
Complicações do Diabetes/genética , Proteínas Facilitadoras de Transporte de Glucose/genética , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Erros Inatos do Transporte Tubular Renal/genética , Cálculos Urinários/genética , Idoso , Complicações do Diabetes/complicações , Complicações do Diabetes/patologia , Glucose/metabolismo , Fator 1-alfa Nuclear de Hepatócito/genética , Heterozigoto , Proteínas de Homeodomínio/genética , Homozigoto , Humanos , Insulina/biossíntese , Insulina/genética , Secreção de Insulina/genética , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Mutação/genética , Erros Inatos do Transporte Tubular Renal/complicações , Erros Inatos do Transporte Tubular Renal/patologia , Ácido Úrico/metabolismo , Cálculos Urinários/complicações , Cálculos Urinários/patologia , Sequenciamento Completo do Exoma
18.
PLoS One ; 15(4): e0231336, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32271837

RESUMO

Prolonged hyperuricemia is a cause of gout and an independent risk factor for chronic health conditions including diabetes and chronic kidney diseases. Genome-wide association studies (GWASs) for serum uric acid (SUA) concentrations have repeatedly confirmed genetic loci including those encoding uric acid transporters such as ABCG2 and SLC9A2. However, many single nucleotide polymorphisms (SNPs) found in GWASs have been common variants with small effects and unknown functions. In addition, there is still much heritability to be explained. To identify the causative genetic variants for SUA concentrations in Korean subjects, we conducted a GWAS (1902 males) and validation study (2912 males and females) and found four genetic loci reaching genome-wide significance on chromosomes 4 (ABCG2) and 11 (FRMD8, EIF1AD and SLC22A12-NRXN2). Three loci on chromosome 11 were distributed within a distance of 1.3 megabases and they were in weak or moderate linkage disequilibrium (LD) states (r2 = 0.02-0.68). In a subsequent association analysis on the GWAS loci of chromosome 11 using closely positioned markers derived from whole genome sequencing data, the most significant variant to be linked with the nearby GWAS signal was rs121907892 (c.774G>A, p.W258*) of the SLC22A12 gene. This variant, and each of the three GWAS SNPs, were in LD (r2 = 0.06-0.32). The strength of association of SNPs with SUA concentration (negative logarithm of P-values) and the genetic distance (r2 of LD) between rs121907892 and the surrounding SNPs showed a quantitative correlation. This variant has been found only in Korean and Japanese subjects and is known to lower the SUA concentration in the general population. Thus, this low-frequency variant, rs121907892, known to regulate SUA concentrations in previous studies, is responsible for the nearby GWAS signals.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Estudo de Associação Genômica Ampla , Hiperuricemia/patologia , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Ácido Úrico/sangue , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Alelos , Cromossomos Humanos Par 11/genética , Proteínas do Citoesqueleto/genética , Feminino , Frequência do Gene , Loci Gênicos , Genótipo , Humanos , Hiperuricemia/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Desequilíbrio de Ligação , Masculino , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , República da Coreia
19.
Sci Rep ; 10(1): 4883, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32184453

RESUMO

Loss-of-function mutations in the solute carrier organic anion transporter family, member 2a1 gene (SLCO2A1), which encodes a prostaglandin (PG) transporter, have been identified as causes of chronic nonspecific multiple ulcers in the small intestine; however, the underlying mechanisms have not been revealed. We, therefore, evaluated the effects of systemic knockout of Slco2a1 (Slco2a1-/-) and conditional knockout in intestinal epithelial cells (Slco2a1ΔIEC) and macrophages (Slco2a1ΔMP) in mice with dextran sodium sulphate (DSS)-induced acute colitis. Slco2a-/- mice were more susceptible to DSS-induced colitis than wild-type (WT) mice, but did not spontaneously develop enteritis or colitis. The nucleotide-binding domain, leucine-rich repeats containing family, pyrin domain-containing-3 (NLRP3) inflammasome was more strongly upregulated in colon tissues of Slco2a-/- mice administered DSS and in macrophages isolated from Slco2a1-/- mice than in the WT counterparts. Slco2a1ΔMP, but not Slco2a1ΔIEC mice, were more susceptible to DSS-induced colitis than WT mice, partly phenocopying Slco2a-/- mice. Concentrations of PGE2 in colon tissues and macrophages from Slco2a1-/- mice were significantly higher than those of WT mice. Blockade of inflammasome activation suppressed the exacerbation of colitis. These results indicated that Slco2a1-deficiency increases the PGE2 concentration, resulting in NLRP3 inflammasome activation in macrophages, thus exacerbating intestinal inflammation.


Assuntos
Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Transportadores de Ânions Orgânicos/deficiência , Transportadores de Ânions Orgânicos/metabolismo , Animais , Western Blotting , Células Cultivadas , Colite/genética , Sulfato de Dextrana/toxicidade , Enterocolite/induzido quimicamente , Enterocolite/genética , Enterocolite/metabolismo , Enterocolite/patologia , Ensaio de Imunoadsorção Enzimática , Inflamassomos/imunologia , Inflamassomos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Modelos Teóricos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transportadores de Ânions Orgânicos/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
J Steroid Biochem Mol Biol ; 200: 105652, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32147459

RESUMO

Human OATP2B1 encoded by the SLCO2B1 gene is a multispecific transporter mediating the cellular uptake of large, organic molecules, including hormones, prostaglandins and bile acids. OATP2B1 is ubiquitously expressed in the human body, with highest expression levels in pharmacologically relevant barriers, like enterocytes, hepatocytes and endothelial cells of the blood-brain-barrier. In addition to its endogenous substrates, OATP2B1 also recognizes clinically applied drugs, such as statins, antivirals, antihistamines and chemotherapeutic agents and influences their pharmacokinetics. On the other hand, OATP2B1 is also overexpressed in various tumors. Considering that elevated hormone uptake by OATP2B1 results in increased cell proliferation of hormone dependent tumors (e.g. breast or prostate), inhibition of OATP2B1 can be a good strategy to inhibit the growth of these tumors. 13-epiestrones represent a potential novel strategy in the treatment of hormone dependent cancers by the suppression of local estrogen production due to the inhibition of the key enzyme of estrone metabolism, 17ß-hydroxysteroid-dehydrogenase type 1 (HSD17ß1). Recently, we have demonstrated that various phosphonated 13-epiestrones are dual inhibitors also suppressing OATP2B1 function. In order to gain better insights into the molecular determinants of OATP2B1 13-epiestrone interaction we investigated the effect of C-2 and C-4 halogen or phenylalkynyl modified epiestrones on OATP2B1 transport function. Potent inhibitors (with EC50 values in the low micromolar range) as well as non-inhibitors of OATP2B1 function were identified. Based on the structure-activity relationship (SAR) of the various 13-epiestrone derivatives we could define structural elements important for OATP2B1 inhibition. Our results may help to understand the drug/inhibitor interaction profile of OATP2B1, and also may be a useful strategy to block steroid hormone entry into tumors.


Assuntos
Estrona/farmacologia , Transportadores de Ânions Orgânicos/metabolismo , Linhagem Celular Tumoral , Estrona/análogos & derivados , Estrona/química , Humanos , Transportadores de Ânions Orgânicos/química , Transportadores de Ânions Orgânicos/genética , Relação Estrutura-Atividade
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