Modulatory effect of iron chelators on adenosine deaminase activity and gene expression in Trichomonas vaginalis

Trichomonas vaginalis is a flagellate protozoan that parasitises the urogenital human tract and causes trichomoniasis. During the infection, the acquisition of nutrients, such as iron and purine and pyrimidine nucleosides, is essential for the survival of the parasite. The enzymes for purinergic signalling, including adenosine deaminase (ADA), which degrades adenosine to inosine, have been characterised in T. vaginalis. In the evaluation of the ADA profile in different T. vaginalisisolates treated with different iron sources or with limited iron availability, a decrease in activity and an increase in ADA gene expression after iron limitation by 2,2-bipyridyl and ferrozine chelators were observed. This supported the hypothesis that iron can modulate the activity of the enzymes involved in purinergic signalling. Under bovine serum limitation conditions, no significant differences were observed. The results obtained in this study allow for the assessment of important aspects of ADA and contribute to a better understanding of the purinergic system in T. vaginalis and the role of iron in establishing infection and parasite survival.

Modulatory effect of iron chelators on adenosine deaminase activity and gene expression in Trichomonas vaginalis.

Trichomonas vaginalis is a flagellate protozoan that parasitises the urogenital human tract and causes trichomoniasis. During the infection, the acquisition of nutrients, such as iron and purine and pyrimidine nucleosides, is essential for the survival of the parasite. The enzymes for purinergic signalling, including adenosine deaminase (ADA), which degrades adenosine to inosine, have been characterised in T. vaginalis. In the evaluation of the ADA profile in different T. vaginalis isolates treated with different iron sources or with limited iron availability, a decrease in activity and an increase in ADA gene expression after iron limitation by 2,2-bipyridyl and ferrozine chelators were observed. This supported the hypothesis that iron can modulate the activity of the enzymes involved in purinergic signalling. Under bovine serum limitation conditions, no significant differences were observed. The results obtained in this study allow for the assessment of important aspects of ADA and contribute to a better understanding of the purinergic system in T. vaginalis and the role of iron in establishing infection and parasite survival.

PON1 polymorphisms are predictors of ability to attain HDL-C goals in statin-treated patients.

OBJECTIVES: PON1 plays an important role in inhibiting LDL-C oxidation, which reduces atherosclerosis and cardiovascular disease. Elevated PON1 activity or levels may contribute to increased HDL-C levels, but controversy exists over the hypothesis that genetic variation in the PON1 gene locus modulates HDL-C levels and responses to statin treatment. Therefore, the objective of this study was to investigate the association between two polymorphisms in the PON1 gene and statin responses in a south Brazilian population. DESIGN AND METHODS: The study population included 433 dyslipidemic patients who were prescribed statins. Total cholesterol, triglyceride, HDL-C and LDL-C levels were measured in these patients both before and after approximately 6months of treatment with simvastatin/atorvastatin. Genotypes were assessed by real-time PCR for two PON1 polymorphisms, Q192R (rs662) and L55M (rs854560). RESULTS: Baseline lipid levels were not associated with Q192R or L55M polymorphisms. For the Q192R (rs662) polymorphism, we observed that HDL-C goals were attained less often in patients with RR homozygosity than in Q allele carriers (χ(2) P=0.009, adjusted residual analysis P=0.003). For the L55M (rs854560) polymorphism, LL homozygotes were underrepresented among subjects that achieved the HDL-C goal (χ(2) P=0.026, adjusted residual analysis P=0.008). Analysis by univariate logistic regression confirmed that QQ/QR and MM/ML carriers had an increased chance of attaining HDL-C goals (OR=2.41, CI95%=1.32-4.40, P=0.004 and OR=1.68, CI95%=1.15-2.45, P=0.008). In a multivariate logistic analysis used to assess predictors of attaining an HDL-C goal>1.55mmol/L, we observed that gender (OR=1.71, CI95%=1.04-2.83, P=0.036), baseline HDL-C levels (OR=1.13, CI95%=1.10-1.16, P<0.001) and the QQ/QR+MM/ML genotypes increased the chance of achieving HDL-C goals (OR=2.81, CI95%=1.35-5.85, P=0.006). CONCLUSIONS: The results of this study show that the Q192R (rs662) and L55M (rs854560) polymorphisms may play a role in interindividual variation in achievement of HDL-C goals in response to statins.

Evaluation of sexual dimorphism in the efficacy and safety of simvastatin/atorvastatin therapy in a southern Brazilian cohort.

BACKGROUND: Dyslipidemia is the primary risk factor for cardiovascular disease, and statins have been effective in controlling lipid levels. Sex differences in the pharmacokinetics and pharmacodynamics of statins contribute to interindividual variations in drug efficacy and toxicity. OBJECTIVE: To evaluate the presence of sexual dimorphism in the efficacy and safety of simvastatin/atorvastatin treatment. METHODS: Lipid levels of 495 patients (331 women and 164 men) were measured at baseline and after 6 ± 3 months of simvastatin/atorvastatin treatment to assess the efficacy and safety profiles of both drugs. RESULTS: Women had higher baseline levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) compared with men (p < 0.0001). After treatment, women exhibited a greater decrease in plasma TC and LDL-C levels compared with men. After adjustment for covariates, baseline levels of TC and LDL-C influenced more than 30% of the efficacy of lipid-lowering therapy (p < 0.001), regardless of sex. Myalgia [with or without changes in creatine phosphokinase (CPK) levels] occurred more frequently in women (25.9%; p = 0.002), whereas an increase in CPK and/or abnormal liver function was more frequent in in men (17.9%; p = 0.017). CONCLUSIONS: Our results show that baseline TC and LDL-C levels are the main predictors of simvastatin/atorvastatin therapy efficacy, regardless of sex. In addition, they suggest the presence of sexual dimorphism in the safety of simvastatin/atorvastatin. The effect of sex differences on receptors, transporter proteins, and gene expression pathways needs to be better evaluated and characterized to confirm these observations.

Evaluation of Sexual Dimorphism in the Efficacy and Safety of Simvastatin/Atorvastatin Therapy in a Southern Brazilian Cohort / Papel do Dimorfismo Sexual na Eficácia e Segurança da Terapia com Sinvastatina ou Atorvastatina em uma Coorte no Sul do Brasil

Background: Dyslipidemia is the primary risk factor for cardiovascular disease, and statins have been effective in controlling lipid levels. Sex differences in the pharmacokinetics and pharmacodynamics of statins contribute to interindividual variations in drug efficacy and toxicity. Objective: To evaluate the presence of sexual dimorphism in the efficacy and safety of simvastatin/atorvastatin treatment. Methods: Lipid levels of 495 patients (331 women and 164 men) were measured at baseline and after 6 ± 3 months of simvastatin/atorvastatin treatment to assess the efficacy and safety profiles of both drugs. Results: Women had higher baseline levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) compared with men (p < 0.0001). After treatment, women exhibited a greater decrease in plasma TC and LDL-C levels compared with men. After adjustment for covariates, baseline levels of TC and LDL-C influenced more than 30% of the efficacy of lipid-lowering therapy (p < 0.001), regardless of sex. Myalgia [with or without changes in creatine phosphokinase (CPK) levels] occurred more frequently in women (25.9%; p = 0.002), whereas an increase in CPK and/or abnormal liver function was more frequent in in men (17.9%; p = 0.017). Conclusions: Our results show that baseline TC and LDL-C levels are the main predictors of simvastatin/atorvastatin therapy efficacy, regardless of sex. In addition, they suggest the presence of sexual dimorphism in the safety of simvastatin/atorvastatin. The effect of sex differences on receptors, transporter proteins, and gene expression pathways needs to be better evaluated and characterized to confirm these observations. .

Fundamento: A dislipidemia é o principal fator de risco para doenças cardiovasculares e as estatinas são efetivas no controle do perfil lipídico. Diferenças sexuais na farmacocinética e farmacodinâmica contribuem para a variação interindividual na eficácia e toxicidade de fármacos. Objetivo: Avaliar a existência de dimorfismo sexual na eficácia e segurança do tratamento com sinvastatina/atorvastatina. Métodos: 495 sujeitos (331 mulheres e 164 homens) tiveram seus níveis lipídicos mensurados antes e após 6±3 meses de tratamento com sinvastatina/atorvastatina para avaliação dos perfis de eficácia e segurança. Resultados: As mulheres apresentaram maiores níveis basais de colesterol total, LDL-C e HDL-C quando comparadas aos homens (p < 0,0001). Após o tratamento, mulheres tiveram uma maior redução dos níveis de colesterol total e de LDL-C que homens. Após ajuste para covariáveis, foi observado que os níveis basais de colesterol total e de LDL-C são responsáveis por cerca de 30% da eficácia (p < 0,001), independentemente do sexo. Mialgia (com ou sem alteração de creatina fosfoquinase - CPK) ocorreu mais frequentemente em mulheres (25,9%) (p = 0,002), enquanto o aumento isolado de CPK e alterações de função hepática foram mais frequentemente observados em homens (17,9%) (p = 0,017). Conclusões: Nossos resultados demonstram que os níveis basais de colesterol total e LDL-C são os maiores preditores da eficácia do tratamento, independente do sexo. Adicionalmente, sugerimos que existe dimorfismo sexual na segurança do tratamento com sinvastatina/atorvastatina. O efeito das diferenças sexuais em receptores, proteínas transportadoras e rotas de expressão gênica devem ser avaliados ...

Are polymorphisms in oestrogen receptors genes associated with lipid levels in response to hormone therapy?

BACKGROUND: Polymorphisms in the oestrogen receptor 1 (ESR1) and oestrogen receptor 2 (ESR2) genes are associated with intermediate or endpoint markers of cardiovascular disease and with the efficacy of postmenopausal hormone therapy (HT). Contradictory findings have been described in the past and the role of these genetics variants remains unclear. METHODS: A cross-sectional study was carried out with 266 postmenopausal women, of whom 115 received oral HT (HT+) and 151 did not receive any HT (HT-). We analysed three single-nucleotide polymorphisms (SNPs) in ESR1 (rs1801132, rs7757956 and rs2813544) and two in ESR2 (rs3020450 and rs7154455) and derived haplotypes with three additional polymorphisms that had been previously investigated by our group (ESR1 rs2234693 and ESR2 rs1256049 and rs4986938). RESULTS: The ESR1 rs2813544 polymorphism was associated with low-density lipoprotein cholesterol (LDL-C) in HT+ postmenopausal women (p = 0.044; pC = 0.388), while one ESR2 gene haplotype was associated with total cholesterol (T-chol) (p = 0.015; pC = 0.090) and LDL-C in HT+ postmenopausal women (p = 0.021; pC = 0.126). CONCLUSION: Our findings suggest that, in HT+ postmenopausal women, the rs2813544 polymorphism may influence LDL-C levels and, as previously described, ESR2 rs1256049 is associated with T-chol and LDL-C. No previous study has investigated the association of this SNP set with lipoprotein levels in women while taking into account the hormonal status of the patients.

Evaluation of UGT1A1 and SULT1A1 polymorphisms with lipid levels in women with different hormonal status.

BACKGROUND: Estrogens influence many physiological processes including cardiovascular health. Polymorphisms in phase I and II estrogen metabolism enzymes are associated with lipid levels in women. METHODS: A cross-sectional study was carried out with 269 postmenopausal women, 116 who received oral hormonal therapy (HT) (39-75 years) with estrogens or estrogens plus progestagen, 153 that did not receive any HT (38-85 years), and 155 premenopausal women (18-52 years). Polymorphisms in UGT1A1 (rs5839491) and SULT1A1 (rs1042028) were analysed by PCR-based methods. Adjusted lipid levels means were compared among genotypes by one-way analysis of variance, with corrections for multiple testing. RESULTS: The UGT1A1*28 polymorphism was associated with total cholesterol (T-chol) (p = 0.030; corrected p = 0.060) and low-density lipoprotein cholesterol (LDL-C) levels (p = 0.011, corrected p = 0.022) in premenopausal women. The premenopausal and postmenopausal women, both carriers of SULT1A1*2/*2, had lower levels of T-chol and LDL-C means than carriers of the SULT1A1*1/*1 (p = 0.004, corrected p = 0.008 and 0.009, corrected p = 0.018, respectively). CONCLUSION: The data showed the presence of an association between the UGT1A1*28/*28 and SULT1A1*2/*2 and T-chol and LDL-C levels in women with different hormonal status. No previous studies investigated the association of the polymorphisms examined in this study with lipoprotein levels in women separately by hormonal status.