RESUMO
Type 1 diabetes mellitus (T1DM) and estrogen deficiency are associated with several alterations in bone turnover. Zinc (Zn) is required for growth, development, and overall health. Zinc has been used in complementary therapy against bone loss in several diseases. We hypothesized that Zn supplementation represents a potential therapy against severe bone loss induced by the combined effect of estrogen deficiency and T1DM. We evaluated the protective effect of Zn against bone alterations in a chronic model of these disorders. Female Wistar rats were ramdomized into 3 groups (5 rats each): control, OVX/T1DM (ovariectomized rats with streptozotocin-induced T1DM), and OVX/T1DM+Zn (OVX/T1DM plus daily Zn supplementation). Serum biochemical, bone histomorphometric, and molecular analyses were performed. Histomorphometric parameters were similar between the control and OVX/T1DM+Zn groups, suggesting that Zn prevents bone architecture alterations. In contrast, the OVX/T1DM group showed significantly lower trabecular width and bone area as well as greater trabecular separation than the control. The OVX/T1DM and OVX/T1DM+Zn groups had significantly higher serum alkaline phosphatase activity than the control. The supplemented group had higher levels of serum-ionized calcium and phosphorus than the nonsupplemented group. The RANKL/OPG ratio was similar between the control and OVX/T1DM+Zn groups, whereas it was higher in the OVX/T1DM group. In conclusion, Zn supplementation prevents bone alteration in chronic OVX/T1DM rats, as demonstrated by the reduced RANKL/OPG ratio and preservation of bone architecture. The findings may represent a novel therapeutic approach to preventing OVX/T1DM-induced bone alterations.
Assuntos
Densidade Óssea/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Suplementos Nutricionais , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Zinco/administração & dosagem , Fosfatase Alcalina/sangue , Animais , Glicemia/metabolismo , Osso e Ossos/efeitos dos fármacos , Cálcio/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Feminino , Osteoprotegerina/genética , Ovariectomia , Fósforo/sangue , Ligante RANK/genética , Ratos , Ratos WistarRESUMO
STUDY OBJECTIVE: To investigate the influence of single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP2C8, CYP2J2, and UGT2B7) and transporters (ABCC2 and ABCG2) on dose and dose-adjusted trough blood concentrations (C:D ratio), clinical outcomes, and occurrence of adverse events of tacrolimus and mycophenolate sodium in Brazilian kidney transplant recipients. DESIGN: Pharmacogenetic analysis of patients enrolled in a previously published study. PATIENTS: One hundred forty-eight adult kidney transplant recipients treated with tacrolimus, enteric-coated mycophenolate sodium, and prednisone for 90 days posttransplantation. MEASUREMENTS AND MAIN RESULTS: ABCC2 c.-24C>T and c.3972C>T, ABCG2 c.421C>A, CYP2C8*3, CYP2J2 c.-76G>T, and UGT2B7 c.372A>G SNPs were determined by real-time polymerase chain reaction. The CYP3A5*3C SNP data were used to eliminate the confounding effect of this variant on the results. ABCC2 c.3972T allele carriers showed higher tacrolimus C:D values than did carriers of the c.3972CC genotype. The CYP2C8*3 variant was also associated with slightly higher tacrolimus C:D values and higher estimated glomerular filtration rate but only in CYP3A5-nonexpressing patients (CYP3A5*3C/*3C carriers). None of the SNPs were associated with mycophenolate sodium dose or episodes of biopsy-confirmed acute rejection or delayed graft function. The CYP2J2 c.-76T allele was associated with increased risk for treatment-induced nausea and/or vomiting (OR: 5.30, 95% confidence interval 1.49-18.79, p<0.05). CONCLUSION: The ABCC2 c.3972C >T polymorphism affected tacrolimus C:D in Brazilian kidney transplant recipients. Further, CYP2C8*3 and CYP2J2 c.-76G>T SNPs influenced the renal function of these patients and the occurrence of adverse events during treatment with tacrolimus and mycophenolate sodium.
Assuntos
Citocromo P-450 CYP2C8/genética , Sistema Enzimático do Citocromo P-450/genética , Rejeição de Enxerto/genética , Transplante de Rim , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Ácido Micofenólico/uso terapêutico , Tacrolimo/uso terapêutico , Adulto , Brasil/epidemiologia , Citocromo P-450 CYP2J2 , Feminino , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/sangue , Imunossupressores/uso terapêutico , Transplante de Rim/efeitos adversos , Masculino , Proteína 2 Associada à Farmacorresistência Múltipla , Ácido Micofenólico/sangue , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Tacrolimo/sangue , Resultado do TratamentoRESUMO
AIM: Atorvastatin, a HMG-CoA reductase inhibitor, used in the treatment of hypercholesterolemia, has been previously shown to regulate ABCB1 expression in vivo and in vitro. We hypothesized that the statin could regulate gene expression of ABCB1 transporter via microRNAs. METHODS: Expression of microRNAs and ABCB1 mRNA was examined in atorvastatin-treated and control cells using real-time PCR. miR-491-3P mimic and inhibitor were transfected in Caco-2 and ABCB1 expression was monitored by western blot and real-time PCR. RESULTS: In HepG2 cells, none of the microRNAs predicted to target ABCB1 3'UTR was regulated by atorvastatin treatment. In agreement with this, ABCB1 3'UTR activity was not modulated in HepG-2 cells after 48h-treatment as measured by luciferase assay. In Caco-2 cells, atorvastatin treatment provoked a decrease in luciferase activity and, accordingly, miR-491-3p was upregulated about 2.7 times after 48h-statin treatment. Luciferase analysis of miR-491-3p with a mimetic or inhibitor of miR-491-3p revealed that this microRNA could target ABCB1 3'UTR, as after miR-491-3p inhibition, ABCB1 levels were increased by two-fold, and miR-491-3p superexpression decreased ABCB1 3'UTR activity. Finally, functional analysis revealed that treatment with miR-491-3p inhibitor could reverses atorvastatin attenuation of ABCB1 (Pg-p) protein levels. CONCLUSION: Our results suggest atorvastatin control ABCB1 expression via miR-491-3p in Caco-2 cells. This finding may be an important mechanism of statin drug-drug interaction, since common concomitant drugs used in the prevention of cardiovascular diseases are ABCB1 substrates.
Assuntos
Atorvastatina/farmacologia , MicroRNAs/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , RNA Mensageiro/metabolismoRESUMO
BACKGROUND/AIMS: Berardinelli-Seip syndrome (BSS) is a recessive autosomal genetic disorder characterized by the near loss of adipose tissue with disturbance in lipid metabolism. METHODS: Biochemical and hormonal parameters and Pro12Ala, Pvull, Avall, Sstl and ADIPOQ polymorphisms in 22 patients with BSS were analyzed and examined for a possible association with lipid profiles. RESULTS: Parental consanguinity, insulin resistance and diabetes mellitus were observed in 63.6, 81.8 and 59.1% of patients, respectively. All individuals presented high triglyceride levels, and 68.1% of patients showed high cholesterol levels. The Pro/Pro genotype of the Pro12Ala polymorphism of the PPARγ2 gene was found in 86.3% of patients; the Ala/Ala variant was not observed in any patient. The PvuII polymorphism of the LPL gene showed a frequency of 50% for the P1P2 variant. The AvaII polymorphism of the LDLR gene showed a similar frequency of 40.9% for both CT and TT variants. The S1S1 genotype of the Sstl polymorphism of the APOC3 gene had a frequency of 86.3%. The CC allele of the ADIPOQ polymorphism of the adiponectin gene was found in 54.6% of patients. CONCLUSIONS: No association was found between lipid parameters and the relevant Pvull, Avall and Sstl polymorphisms. However, we did observe an association of the Pro12Ala and ADIPOQ polymorphisms with higher lipid levels, suggesting a close relationship between these factors.
Assuntos
Adiponectina/genética , Predisposição Genética para Doença , Lipodistrofia Generalizada Congênita/genética , PPAR gama/genética , Adulto , Brasil , Colesterol/sangue , Feminino , Humanos , Lipodistrofia Generalizada Congênita/sangue , Masculino , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangue , População BrancaRESUMO
BACKGROUND: The purpose of the present investigation is to compare the presence and number of periodontal pathogens in the subgingival microbiota of smokers versus never-smokers with chronic periodontitis and matched probing depths (PDs) using real-time polymerase chain reaction (RT-PCR). METHODS: Forty current smokers and 40 never-smokers, matched for age, sex, and mean PD of sampling site, were included in this investigation. A full-mouth periodontal examination was performed, and a pooled subgingival plaque sample was collected from the deepest site in each quadrant of each participant. To confirm smoking status, expired carbon monoxide (CO) concentrations were measured with a CO monitor. The presence and quantification of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola were determined using RT-PCR. RESULTS: Smokers had greater overall mean PD (P = 0.001) and attachment loss (P = 0.006) and fewer bleeding on probing sites (P = 0.001). An association was observed between smoking status and the presence of A. actinomycetemcomitans (P <0.001). The counts of A. actinomycetemcomitans (P <0.001), P. gingivalis (P = 0.042), and T. forsythia (P <0.001) were significantly higher in smokers. CONCLUSIONS: Smokers showed significantly greater amounts of P. gingivalis, A. actinomycetemcomitans, and T. forsythia than never-smokers. There was a significant association between smoking and the presence of A. actinomycetemcomitans.
Assuntos
Bactérias/classificação , Periodontite Crônica/microbiologia , Fumar , Adulto , Idoso , Aggregatibacter actinomycetemcomitans/isolamento & purificação , Carga Bacteriana , Bacteroides/isolamento & purificação , Monóxido de Carbono/análise , Estudos de Casos e Controles , Estudos Transversais , Placa Dentária/microbiologia , Feminino , Gengiva/microbiologia , Hemorragia Gengival/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Perda da Inserção Periodontal/microbiologia , Bolsa Periodontal/microbiologia , Porphyromonas gingivalis/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real/métodos , Treponema denticola/isolamento & purificaçãoRESUMO
AIMS: To investigate early alterations on bone mineral density (BMD) and RANK, RANKL and OPG mRNA expression in peripheral blood leukocytes (PBL) in children and adolescents with type 1 diabetes (T1D) and the relationship with glycemic control and bone biomarkers. METHODS: This cross-sectional study included 75 children and adolescents with T1D and 100 individuals without diabetes (normoglycemic-NG) aged 6-20 years old. T1D individuals were considered to have good (T1DG) or poor (T1DP) glycemic control according to the values of HbA1c. Phosphorus, magnesium, total and ionized calcium, osteocalcin, alkaline phosphatase and tartaric-resistant acid phosphatase (TRAP) values were determined in blood samples. BMD was measured by DEXA. RANK, RANKL and OPG mRNA expression was measured in PBL by real-time PCR. RESULTS: Osteocalcin values were decreased in diabetic groups in comparison to NG group (p<0.05), and a negative correlation with both serum glucose (r=-0.265, p<0.01) and Hb1Ac (r=-0.252, p<0.01) in T1D group was found. BMD was lower in diabetic groups in comparison with NG group (p<0.05) and a negative correlation was observed between BMD and both serum glucose (r=-0.357, p<0.01) and HbA1c (r=-0.351, p<0.01) in T1D group. OPG mRNA expression was significantly increased in T1D and T1DP groups in comparison with NG group (p<0.05). In conclusion, children and adolescents with early onset T1D presented low bone mineral density associated to unsatisfactory glycemic control, increased OPG mRNA expression and low osteocalcin concentration.
Assuntos
Biomarcadores/sangue , Densidade Óssea , Diabetes Mellitus Tipo 1/fisiopatologia , Hiperglicemia/etiologia , Hipoglicemia/etiologia , Osteoprotegerina/genética , Adolescente , Adulto , Fosfatase Alcalina/sangue , Cálcio/sangue , Estudos de Casos e Controles , Criança , Estudos Transversais , Feminino , Humanos , Hiperglicemia/diagnóstico , Hipoglicemia/diagnóstico , Leucócitos Mononucleares , Masculino , Osteocalcina/sangue , Osteoprotegerina/sangue , Fósforo/sangue , Ligante RANK/sangue , Ligante RANK/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor Ativador de Fator Nuclear kappa-B/sangue , Receptor Ativador de Fator Nuclear kappa-B/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto JovemRESUMO
Imatinib mesylate (IM) has become a standard of care in chronic myeloid leukemia (CML) therapy. Single nucleotide polymorphisms (SNPs) and altered expression in drug transporter genes may influence IM response. In order to investigate whether mRNA expression and SNPs in drug transporters are associated with IM resistance, we studied 118 chronic-phase CML patients receiving the standard dose of IM (400 mg/day). They were assigned as responders and non-responders according to European LeukemiaNet criteria (2009). mRNA expression in samples at diagnosis (without IM therapy) and outcomes after IM failure were also evaluated in subgroups of patients. Major molecular response (MMR), complete molecular response and primary and secondary resistance were all assessed. BCR-ABL1, ABCB1, ABCG2, SLC22A1 and SLCO1A2 mRNA expression and SNPs in ABCG2 and SLC22A1 genes were analyzed. ABCG2 mRNA expression in the non-responders was higher before and during IM therapy. Furthermore, ABCG2 was overexpressed in those who did not achieve MMR (P=0.027). In a subgroup of patients who switched to second-generation tyrosine kinase inhibitors, high mRNA expression of ABCG2 was associated with a risk of 24 times that of not achieving complete cytogenetic response (OR 24.00, 95% CI 1.74-330.80; P=0.018). In the responder group, patients who achieved MMR (P=0.009) presented higher mRNA levels of SLC22A1. The SNPs were not associated with mRNA expression of ABCG2 and SLC22A1. Our data suggest that elevated ABCG2 expression (an efflux transporter) could be associated with IM resistance and could impact on second-generation TKI response, whereas high SLC22A1 expression (an influx transporter) may be associated with a successful IM therapy in CML patients.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Proteínas de Neoplasias/genética , Transportador 1 de Cátions Orgânicos/genética , Piperazinas/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Pirimidinas/uso terapêutico , RNA Mensageiro/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Prognóstico , Indução de RemissãoRESUMO
BACKGROUND: Reverse cholesterol transport (RCT) has been inversely related to atherosclerosis and cardiovascular risk. The influence of menopause in the RCT process is poorly understood and the effects of cholesterol-lowering interventions, including statins and hormone therapy (HT), on genes controlling the RCT in postmenopausal women are also unknown. METHODS: The effects on serum lipids and expression profile of genes involved in RCT - APOA1, ABCA1, ABCG1, SCARB1 and LXRA - were evaluated by TaqMan(®) quantitative PCR in peripheral blood mononuclear cells (PBMC) from 87 postmenopausal hypercholesterolemic women treated with atorvastatin (AT, n=17), estrogen or estrogen plus progestin (HT, n=34) and estrogen or estrogen plus progestin associated with atorvastatin (HT+AT, n=36). RESULTS: Atorvastatin and HT treatments reduced the mRNA levels of APOA1 and SCARB1, respectively, whereas ABCA1 expression was reduced after all treatments. Although the expression of LXRA, an important transcription factor controlling the expression of genes involved in RCT, was not modified after any treatment, it was correlated with ABCA1, APOA1 and SCARB1 RNAm values before and after treatments, however no correlation with ABCG1 was observed. In a linear regression analysis, HT was related to an increase in apoAI levels after treatment when compared to atorvastatin and, moreover, higher SCARB1 and ABCA1 basal expression were also associated with decreased apoAI levels after treatments. CONCLUSION: ABCA1 mRNA levels are decreased by atorvastatin and HT, however these treatments have a differential effect on APOA1 and SCARB1 expression in PBMC from postmenopausal women. Basal ABCA1 and SCARB1 expression profile could be helpful markers in predicting the effect of atorvastatin and HT on RCT, according to the changes in apoAI levels in this sample population.
Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Anticolesterolemiantes/uso terapêutico , Apolipoproteína A-I/metabolismo , Ácidos Heptanoicos/uso terapêutico , Leucócitos Mononucleares/metabolismo , Pirróis/uso terapêutico , Receptores Depuradores Classe B/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Anticolesterolemiantes/administração & dosagem , Apolipoproteína A-I/genética , Atorvastatina , Células Cultivadas , Estradiol/uso terapêutico , Feminino , Ácidos Heptanoicos/administração & dosagem , Compostos Heterocíclicos/uso terapêutico , Humanos , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Pessoa de Meia-Idade , Pós-Menopausa , Pirróis/administração & dosagem , Receptores Depuradores Classe B/genética , TranscriptomaAssuntos
Angioedema/induzido quimicamente , Angioedema/genética , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Isoenzimas/genética , Neprilisina/genética , Proteína Quinase C/genética , Proteínas Proto-Oncogênicas c-ets/genética , Ramipril/efeitos adversos , Proteínas Repressoras/genética , HumanosRESUMO
BACKGROUND: This study examined the association between estrogen receptor α gene (ESR1) polymorphisms and blood pressure (BP), heart rate (HR) and autonomic modulation of HR in a sample population. STUDY DESIGN: Two hundred thirty-two young healthy women were selected, and those using oral contraceptives (OC) were compared with nonusers (control group). Short-term HR variability (HRV) was evaluated in both the supine and sitting positions using temporal indices rMSSD [square root of the mean squared differences of successive R-R intervals (RRi) divided by the number of RRi minus one], SDNN (root mean square of differences from mean RRi, divided by the number of RRi) and frequency domain methods. Power spectral components were reported at low frequency (LF) and high frequency (HF) and as LF/HF ratio. ESR1 c.454-397T>C (rs2234693) and c.454-351A>G (rs9340799) polymorphisms were determined by polymerase chain reaction and fragment restriction analysis. RESULTS: The ESR1 T>C and A>G polymorphisms had no effect on HR, rMSSD, SDNN, LF, HF or LF/HF ratio (supine or sitting), independently of OC use. The ESR1 T-A, T-G, C-A and C-G haplotypes were not associated with HR, BP or HRV. CONCLUSIONS: ESR1 variants had no effect on the autonomic modulation of HR in young women users and nonusers of OC and may not be implicated in cardiovascular risk in young women.
Assuntos
Sistema Nervoso Autônomo/efeitos dos fármacos , Anticoncepcionais Orais Combinados/efeitos adversos , Receptor alfa de Estrogênio/genética , Estrogênios/efeitos adversos , Frequência Cardíaca/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único , Progestinas/efeitos adversos , Adulto , Pressão Sanguínea/efeitos dos fármacos , Brasil/epidemiologia , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Desogestrel/efeitos adversos , Receptor alfa de Estrogênio/metabolismo , Etinilestradiol/efeitos adversos , Feminino , Estudos de Associação Genética , Humanos , Íntrons , Levanogestrel/efeitos adversos , Norpregnenos/efeitos adversos , Fatores de RiscoRESUMO
OBJECTIVE: To investigate the relationship of short tandem repeats (STR) near genes involved in the leptin-melanocortin pathway with body mass index (BMI) and leptinemia. SUBJECTS AND METHODS: Anthropometric variables and leptinemia were measured in 100 obese and 110 nonobese individuals. D1S200, D2S1788, DS11912, and D18S858 loci were analyzed by PCR and high-resolution electrophoresis. RESULTS: Overall STR allele frequencies were similar between the obese and non-obese group (p > 0.05). Individual alleles D1S200 (17), D11S912 (43), D18S858 (11/12) were associated with obesity (p < 0.05). Individuals carrying these alleles showed higher BMI than non-carriers (p < 0.05). Moreover, a relationship between D18S858 11/12 alleles and increased waist circumference was found (p = 0.040). On the other hand, leptinemia was not influenced by the studied STRs (p > 0.05). CONCLUSIONS: D1S200, D11S912, and D18S858 loci are associated with increased BMI and risk for obesity in this sample.
OBJETIVO: Investigar a relação de short tandem repeats (STR) em genes envolvidos na via da leptina-melanocortina com índice de massa corporal (IMC) e leptinemia. SUJEITOS E MÉTODOS: Variáveis antropométricas e leptinemia foram medidas em 100 indivíduos obesos e 110 não obesos. Os loci D1S200, D2S1788, DS11912 e D18S858 foram analisados por PCR e eletroforese de alta resolução. RESULTADOS: As frequências globais dos alelos da STR foram similares entre os grupos obeso e não obeso (p > 0,05). Alelos individuais de D1S200 (17), D11S912 (43), D18S858 (11/12) foram associados com obesidade (p < 0,05). Indivíduos portadores desses alelos apresentaram valores de IMC maiores que os dos não portadores (p < 0,05). Além disso, a presença dos alelos D18S858 11/12 foi relacionada com circunferência abdominal elevada (p = 0,040). Por outro lado, a leptinemia não foi influenciada pelos STRs estudados (p > 0,05). CONCLUSÕES: Os loci D1S200, D11S912 e D18S858 são associados com IMC aumentado e risco de obesidade nesta amostra populacional.
Assuntos
Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Frequência do Gene/genética , Leptina/genética , Melanocortinas/genética , Repetições de Microssatélites/genética , Obesidade/genética , Alelos , Brasil , Estudos de Casos e Controles , Leptina/sangue , Obesidade/sangue , Proteínas/genética , Estatísticas não Paramétricas , Circunferência da Cintura , Relação Cintura-QuadrilRESUMO
BACKGROUND: Imatinib mesylate (IM) is a selective tyrosine kinase inhibitor used for treating chronic myeloid leukemia (CML). IM has high efficacy, however some individuals develop a resistance due to impaired bioavailability. Polymorphisms in genes encoding membrane transporters such as ABCB1 have been associated with differences in protein expression and function that influence the response to several drugs. AIM: To investigate the relationship of ABCB1 polymorphisms with markers of response to IM in patients with CML. METHODS: One hundred eighteen CML patients initially treated with a standard dose of IM (400mg/day) for 18months were selected at two health centers in Sao Paulo City, Brazil. The response criteria were based on the European LeukemiaNet recommendations. ABCB1 polymorphisms c.1236C>T (rs1128503), c.3435C>T (rs1045642) and c.2677G>T/A (rs2032582) were evaluated by PCR-RFLP. RESULTS: ABCB1 polymorphisms were not related with a risk for CML in this sample population (p<0.05). In the CML group, frequencies of ABCB1 SNPs were similar between responder and non-responder patients (p>0.05). In the responder group, the frequency of ABCB11236CT/2677GT/3435CT haplotype was higher in patients with major molecular response (MMR) (51.7%) than in patients without MMR (8.3%, p=0.010). Furthermore, carriers of this haplotype had increased the probability of reaching the MMR compared with the non-carriers (OR: 11.8; 95% CI: 1.43-97.3, p=0.022). CONCLUSIONS: The ABCB1 1236CT/2677GT/3435CT haplotype is positively associated with the major molecular response to IM in CML patients.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Antineoplásicos/uso terapêutico , Haplótipos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Subfamília B de Transportador de Cassetes de Ligação de ATP , Alelos , Antineoplásicos/administração & dosagem , Benzamidas , Frequência do Gene , Humanos , Mesilato de Imatinib , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Polimorfismo de Nucleotídeo Único , Pirimidinas/administração & dosagem , Resultado do TratamentoRESUMO
Menopause is associated with changes in lipid levels resulting in increased risk of atherosclerosis and cardiovascular events. Hormone therapy (HT) and atorvastatin have been used to improve lipid profile in postmenopausal women. Effects of HT, atorvastatin and APOE polymorphisms on serum lipids and APOE and LXRA expression were evaluated in 87 hypercholesterolemic postmenopausal women, randomly selected for treatment with atorvastatin (AT, n=17), estrogen or estrogen plus progestagen (HT, n=34) and estrogen or estrogen plus progestagen associated with atorvastatin (HT+AT, n=36). RNA was extracted from peripheral blood mononuclear cells (PBMC) and mRNA expression was measured by TaqMan(®) PCR. APOE É2/É3/É4 genotyping was performed using PCR-RFLP. Total cholesterol (TC), LDL-c and apoB were reduced after each treatment (p<0.001). Triglycerides, VLDL-c and apoAI were reduced only after atorvastatin (p<0.05), whereas triglycerides and VLDL-c were increased after HT (p=0.01). HT women had lower reduction on TC, LDL-c and apoB than AT and HT+AT groups (p<0.05). APOE mRNA expression was reduced after atorvastatin treatment (p=0.03). Although LXRA gene expression was not modified by atorvastatin, it was correlated with APOE mRNA before and after treatments. Basal APOE mRNA expression was not influenced by gene polymorphisms, however the reduction on APOE expression was more pronounced in É3É3 than in É3É4 carriers. Atorvastatin down-regulates APOE mRNA expression and it is modified by APOE genotypes in PBMC from postmenopausal women.
Assuntos
Apolipoproteínas E/metabolismo , Regulação para Baixo/efeitos dos fármacos , Terapia de Reposição de Estrogênios , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Pós-Menopausa , Pirróis/uso terapêutico , Idoso , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Apolipoproteínas/sangue , Apolipoproteínas E/genética , Atorvastatina , Brasil , LDL-Colesterol/sangue , Quimioterapia Combinada/efeitos adversos , Terapia de Reposição de Estrogênios/efeitos adversos , Terapia de Reposição de Estrogênios/métodos , Feminino , Ácidos Heptanoicos/efeitos adversos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hipercolesterolemia/sangue , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Receptores X do Fígado , Pessoa de Meia-Idade , Receptores Nucleares Órfãos/genética , Receptores Nucleares Órfãos/metabolismo , Polimorfismo de Nucleotídeo Único , Pirróis/efeitos adversos , RNA Mensageiro/metabolismoRESUMO
AIMS: The relationship between variants in SLCO1B1 and SLCO2B1 genes and lipid-lowering response to atorvastatin was investigated. MATERIAL AND METHODS: One-hundred-thirty-six unrelated individuals with hypercholesterolemia were selected and treated with atorvastatin (10 mg/day/4 weeks). They were genotyped with a panel of ancestry informative markers for individual African component of ancestry (ACA) estimation by SNaPshot(®) and SLCO1B1 (c.388A>G, c.463C>A and c.521T>C) and SLCO2B1 (-71T>C) gene polymorphisms were identified by TaqMan(®) Real-time PCR. RESULTS: Subjects carrying SLCO1B1 c.388GG genotype exhibited significantly high low-density lipoprotein (LDL) cholesterol reduction relative to c.388AA+c.388AG carriers (41 vs. 37%, p = 0.034). Haplotype analysis revealed that homozygous of SLCO1B1*15 (c.521C and c.388G) variant had similar response to statin relative to heterozygous and non-carriers. A multivariate logistic regression analysis confirmed that c.388GG genotype was associated with higher LDL cholesterol reduction in the study population (OR: 3.2, CI95%:1.3-8.0, p < 0.05). CONCLUSION: SLCO1B1 c.388A>G polymorphism causes significant increase in atorvastatin response and may be an important marker for predicting efficacy of lipid-lowering therapy.
Assuntos
Ácidos Heptanoicos/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/genética , Transportadores de Ânions Orgânicos/genética , Polimorfismo de Nucleotídeo Único , Pirróis/uso terapêutico , Idoso , Anticolesterolemiantes/uso terapêutico , Atorvastatina , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Transportador 1 de Ânion Orgânico Específico do Fígado , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Farmacogenética/métodos , Resultado do TratamentoRESUMO
BACKGROUND: Pioglitazone is a peroxisome proliferator-activated receptor gamma (PPARγ) activator used in the treatment of type 2 diabetes (DM2) patients and it has been suggested that can induce bone loss. Tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) mRNA expression in blood leukocytes and the relationship with polymorphisms and bone markers in DM2 treated with pioglitazone were investigated. METHODS: DM2 (n=53) and normoglycemic (NG, n=52) individuals were included. DM2 patients were treated with pioglitazone (45 mg/day/16 weeks). mRNA expression was evaluated by real-time polymerase chain reaction (PCR). TNFA -308G>A and IL6 -174G>C polymorphisms were detected by PCR-RFLP and high resolution melting polymerase chain reaction (HRM-PCR). RESULTS: Pioglitazone reduced bone specific alkaline phosphatase (bALP) and increased TNFα in DM2 group (p<0.001). DM2 or pioglitazone did not influence TNFα and IL-6 expression (p>0.05). TNFA -308A allele was associated with reduced basal TNFα mRNA levels in NG and DM2 and reduced alkaline phosphatase (tALP) after treatment (p<0.05). IL6 -174C allele was associated with decreased oral glucose tolerance test (OGTT)-2 h in DM2 individuals (p<0.05). CONCLUSIONS: TNFA -308G >A polymorphism appear to be involved in regulation of gene expression independently of hyperglycemia and its interaction with pioglitazone may modify tALP, a important bone marker. IL6 -174G>C variant is related with reduced risk of postprandial hyperglycemia but not with mRNA expression or bone markers.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Tiazolidinedionas/farmacologia , Adulto , Idoso , Fosfatase Alcalina/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Interleucina-6/genética , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Pioglitazona , Reação em Cadeia da Polimerase , Polimorfismo Genético , Fator de Necrose Tumoral alfa/genéticaRESUMO
BACKGROUND: p.C282Y mutation and rare variants in the HFE gene have been associated with hereditary hemochromatosis (HH). HH is also caused by mutations in other genes, such as the hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin (SLC40A1). The low rate homozygous p.C282Y mutation in Brazil is suggestive that mutations in non-HFE genes may be linked to HH phenotype. AIM: To screen exon-by-exon DNA sequences of HFE, HJV, HAMP, TFR2 and SLC40A1 genes to characterize the molecular basis of HH in a sample of the Brazilian population. MATERIALS AND METHODS: Fifty-one patients with primary iron overload (transferrin saturation ≥50% in females and ≥60% in males) were selected. Subsequent bidirectional DNA sequencing of HFE, HJV, HAMP, TFR2 and SLC40A1 exons was performed. RESULTS: Thirty-seven (72.5%) out of the 51 patients presented at least one HFE mutation. The most frequent genotype associated with HH was the homozygous p.C282Y mutation (n=11, 21.6%). In addition, heterozygous HFE p.S65C mutation was found in combination with p.H63D in two patients and homozygous HFE p.H63D was found in two patients as well. Sequencing in the HJV and HAMP genes revealed HJV p.E302K, HJV p.A310G, HJV p.G320V and HAMP p.R59G alterations. Molecular and clinical diagnosis of juvenile hemochromatosis (homozygous form for the HJV p.G320V) was described for the first time in Brazil. Three TFR2 polymorphisms (p.A75V, p.A617A and p.R752H) and six SLC40A1 polymorphisms (rs13008848, rs11568351, rs11568345, rs11568344, rs2304704, rs11568346) and the novel mutation SLC40A1 p.G204S were also found. CONCLUSIONS: The HFE p.C282Y in homozygosity or in heterozygosity with p.H63D was the most frequent mutation associated with HH in this sample. The HJV p.E302K and HAMP p.R59G variants, and the novel SLC40A1 p.G204S mutation may also be linked to primary iron overload but their role in the pathophysiology of HH remain to be elucidated.
Assuntos
Hemocromatose/congênito , Antígenos de Histocompatibilidade Classe I/genética , Homeostase/genética , Ferro/metabolismo , Proteínas de Membrana/genética , Mutação , Adolescente , Adulto , Brasil/epidemiologia , Criança , Pré-Escolar , Feminino , Frequência do Gene , Genótipo , Hemocromatose/genética , Proteína da Hemocromatose , Humanos , Sobrecarga de Ferro/genética , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: most hereditary hemochromatosis (HH) patients are homozygous for the p.C282Y mutation in the HFE gene. Some studies reported that HH phenotypic expression could be modulated by genetic factors such as HJV and HAMP gene mutations. AIMS: the aims of this study were to identify HJV and HAMP mutations and to analyze their impact on HH phenotype in non-p.C282Y homozygous individuals. METHODS: Twenty-four Brazilian patients with primary iron overload and non-p.C282Y homozygous genotype (transferrin saturation >50% in women and >60% in men and absence of secondary causes) were selected. Subsequent bidirectional sequencing of the HJV and HAMP exons was performed. RESULTS: sequencing revealed a substitution in heterozygosis, c.929C > G, which corresponds to p.A310G polymorphism in HJV exon 4 (rs7540883). In the same gene, in another individual, an IVS1-36C > G intronic variant was detected in heterozygosis. In the HAMP gene, an IVS3 + 42G > A intronic variant was identified. There were six (25.0%) patients carrying a heterozygous genotype for the HFE p.C282Y and nine (37.5%) patients carrying a heterozygous genotype for the HFE p.H63D. CONCLUSION: HJV p.A310G polymorphism and two intronic variants were found, but none of these alterations were associated with digenic inheritance with the HFE gene. Our data indicate that HJV and HAMP functional mutations are not frequent in these patients.
Assuntos
Peptídeos Catiônicos Antimicrobianos/genética , Proteínas Ligadas por GPI/genética , Sobrecarga de Ferro/genética , Polimorfismo Genético , Adulto , Idoso , Brasil , Éxons/genética , Feminino , Proteína da Hemocromatose , Hepcidinas , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Sequência de DNARESUMO
Rare HFE variants have been shown to be associated with hereditary hemochromatosis (HH), an iron overload disease. The low frequency of the HFE p.C282Y mutation in HH-affected Brazilian patients may suggest that other HFE-related mutations may also be implicated in the pathogenesis of HH in this population. The main aim was to screen for new HFE mutations in Brazilian individuals with primary iron overload and to investigate their relationship with HH. Fifty Brazilian patients with primary iron overload (transferrin saturation>50% in females and 60% in males) were selected. Subsequent bidirectional sequencing for each HFE exon was performed. The effect of HFE mutations on protein structure were analyzed by molecular dynamics simulation and free binding energy calculations. p.C282Y in homozygosis or in heterozygosis with p.H63D were the most frequent genotypic combinations associated with HH in our sample population (present in 17 individuals, 34%). Thirty-six (72.0%) out of the 50 individuals presented at least one HFE mutation. The most frequent genotype associated with HH was the homozygous p.C282Y mutation (n=11, 22.0%). One novel mutation (p.V256I) was indentified in heterozygosis with the p.H63D mutation. In silico modeling analysis of protein behavior indicated that the p.V256I mutation does not reduce the binding affinity between HFE and ß2-microglobulin (ß2M) in the same way the p.C282Y mutation does compared with the native HFE protein. In conclusion, screening of HFE through direct sequencing, as compared to p.C282Y/p.H63D genotyping, was not able to increase the molecular diagnosis yield of HH. The novel p.V256I mutation could not be implicated in the molecular basis of the HH phenotype, although its role cannot be completely excluded in HH-phenotype development. Our molecular modeling analysis can help in the analysis of novel, previously undescribed, HFE mutations.
Assuntos
Antígenos de Histocompatibilidade Classe I/genética , Sobrecarga de Ferro/genética , Proteínas de Membrana/genética , Mutação , Patologia Molecular/métodos , Brasil/epidemiologia , Testes Genéticos , Proteína da Hemocromatose , Antígenos de Histocompatibilidade Classe I/química , Humanos , Proteínas de Membrana/química , Modelos Moleculares , Mutação de Sentido Incorreto , Conformação Proteica , Análise de Sequência de DNARESUMO
OBJECTIVE: The relationship between variants of the leptin gene (LEP) and obesity and metabolic biomarkers was investigated in Brazilian individuals. SUBJECTS AND METHODS: One-hundred-ten obese (BMI > 30 kg/m²) and 100 non-obese individuals (145 women and 65 men, aged 49 ± 14 years) were randomly selected. Plasma leptin, glycemia, serum lipid measurements and LEP -2548G>A and 3'HVR polymorphisms were analyzed. RESULTS: The LEP -2548GG genotype was associated with a 2.2 percent and 2.0 percent increase in BMI (p = 0.009) and plasma leptin (p = 0.031), respectively. 3'HVR I/II (classes I/I+I/II) genotypes contributed with 1.8 percent of BMI values (p = 0.046). LEP I/G combined genotypes (I/IGG, I/IGA and I/IIGG) were associated with obesity, and increased BMI, waist circumference, leptin and triglycerides (p < 0.05). These relationships were found in women (p < 0.05) but not in men. LEP I/G combined genotypes were not associated with hypertension, hyperglycemia, dyslipidemia and coronary artery disease. CONCLUSIONS: LEP I/G combined genotypes are associated with obesity-related metabolic biomarkers and phenotype in a gender-dependent manner.
OBJETIVO: A relação entre as variantes do gene da leptina (LEP) e obesidade e biomarcadores metabólicos foi investigada em indivíduos brasileiros. SUJEITOS E MÉTOODS: Cento e dez indivíduos obesos (IMC > 30 kg/m²) e 100 não obesos (145 mulheres e 65 homens, idade 49 ± 14 anos) foram selecionados aleatoriamente. Leptina plasmática, glicemia, lípides séricos e polimorfismos LEP -2548G>A e 3'HVR foram analisados. RESULTADOS: O genótipo -2548GG foi associado com aumento de 2,2 por cento e 2,0 por cento no IMC (p = 0,009) e leptina plasmática (p = 0,031), respectivamente, enquanto os genótipos 3´HVR I/II (classes I/I+I/II) contribuíram com 1,8 por cento dos valores de IMC (p = 0,046). Os genótipos combinados LEP I/G (I/IGG, I/IGA e I/IIGG) foram associados com obesidade e IMC aumentado, circunferência abdominal, leptina e triglicérides aumentados (p < 0,05). Essas relações foram encontradas em mulheres (p < 0,05), mas não em homens. Os genótipos LEP I/G combinados não foram associados com hipertensão, hiperglicemia, dislipidemia e doença arterial coronariana. CONCLUSÕES: Genótipos combinados LEP I/G são associados com biomarcadores metabólicos e fenótipo de obesidade de forma gênero-dependente.
Assuntos
Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variação Genética/genética , Leptina/genética , Obesidade/genética , Índice de Massa Corporal , Brasil , Biomarcadores/sangue , Métodos Epidemiológicos , Leptina/sangue , Obesidade/sangueRESUMO
Bacteriophages have been researched as a new alternative to antibiotics. These viruses inject their genetic material into bacteria and use their host machinery to multiply themselves. The research of bacteriophages in Brazil will certainly provide low-cost treatment of multidrug resistant bacteria, new microbiological diagnosis and advantages for the Brazilian food industry.
Bacteriófagos têm sido pesquisados como uma alternativa ao uso de antibióticos. Estes vírus infectam as bactérias e utilizam a maquinaria celular para multiplicar o próprio material genético. O estudo de bacteriófagos no Brasil levará ao desenvolvimento de tratamentos de baixo custo, novos testes diagnósticos e vantagens para a industria alimentícia.