Biological Role of Folic Acid in Pregnancy and Possible Therapeutic Application for the Prevention of Preeclampsia.

The rationale and importance of folic acid supplementation during pregnancy for fetal congenital defect prevention are accepted worldwide. Moreover, a sufficient plasma concentration of folates can reduce the incidence of spontaneous abortions, and support the normal expansion of placental blood vessels, ensuring physiological placental blood flow, thus promoting appropriate fetal growth and development. Furthermore, there is emerging evidence that long-term supplementation with folic acid can effectively prevent preeclampsia. Preeclampsia is unique to the human species in complications during pregnancy, which contributes to maternal and perinatal mortality worldwide. In the pathogenesis of preeclampsia abnormal placental invasion, the excess of antiangiogenic factors and maternal-placental syndrome play a key role. Increased blood levels of homocysteine during pregnancy are associated with the risk of preeclampsia. Moreover, hyperhomocysteinemia has been proposed to be an independent risk factor for preeclampsia. Folate supplementation helps to decrease elevated levels of homocysteine; thus, the role of folic acid supplementation in pregnancy is even more important. Multiple reports suggest that folate administration decreases the level of serum homocysteine and, therefore, reduce the risk and severity of preeclampsia. However, the association between folic acid supplementation and the decreased risk of preeclampsia has been investigated with controversial conclusions. Currently, the optimal dose of folic acid that is effective for preeclampsia prevention remains uncertain. In this review, we aim to summarize the accumulated knowledge on the role of folic acid in the pathogenesis of preeclampsia, and the possible impact of folate supplementation on the decreased risk of preeclampsia.

The Role of High Concentrations of Homocysteine for the Development of Fetal Growth Restriction / O papel de altas concentrações de homocisteína para o desenvolvimento da restrição de crescimento fetal

Abstract Objective To assess homocysteine (Hcy) levels in the three trimesters of pregnancy in women with fetal growth restriction (FGR) and to evaluate the role of Hcy as a possible predictor of FGR. Methods A total of 315 singleton pregnant women were included in the present prospective cohort study and were monitored since the 1st trimester of pregnancy before delivery. Newborns were monitored for the first 7 days of life. Patients who had risk factors for FGR were excluded. Fetal growth restriction was defined according to uterine fundal height (< 10 percentile), ultrasound fetometry (< 5 percentile), and anthropometry of newborns (<5 percentile). The concentrations of Hcy were detected at between 10 and 14, between 20 and 24, and between 30 and 34 weeks of pregnancy by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristics (ROC) curve test and diagnostic odds ratio (DOR) were performed to evaluate the results of ELISA. Results The concentration of Hcy in patients with FGR was 19.65 umol/L at between 10 and 14 weeks, compared with 9.28 umol/L in patients with normal fetal growth (p<0.0001). The optimal cut-off level for Hcy in the 1st trimester of pregnancy was>13.9 umol/L with AUC 0.788, sensitivity of 75%, specificity of 83.6%, and DOR of 15.2. Conclusion Assessment of serum Hcy concentration may be used as a predictor of FGR, with the highest diagnostic utility in the 1st trimester of pregnancy.

Resumo Objetivo Avaliar os níveis de homocisteína (Hcy) em três trimestres da gravidez em mulheres com restrição de crescimento fetal (FGR, na sigla em inglês) e avaliar o papel da Hcy como possível preditor de FGR. Métodos Um total de 315 gestantes solteiras foram incluídas no presente estudo de coorte prospectivo e monitoradas desde o 1° trimestre de gravidez antes do parto. Os recém-nascidos foram acompanhados durante os primeiros 7 dias de vida. Pacientes que apresentam fatores de risco para FGR foram excluídos. A FGR foi definida de acordo com a altura do fundo do útero (< percentil 10), ultrassonografia fetometria (< percentil 5) e antropometria dos recém-nascidos (< percentil 5). As concentrações de Hcy foram detectadas entre 10 e 14, entre 20 e 24 e entre 30 e 34 semanas de gravidez por ensaio de imunoabsorção enzimática (ELISA, na sigla em inglês). O teste da curva das características de operação do receptor (ROC, na sigla em inglês) e a razão de chances de diagnóstico (DOR, na sigla em inglês) foram realizados para avaliar os resultados do ELISA. Resultados A concentração de Hcy em pacientes com FGR foi de 19,65 umol/L entre 10 e 14 semanas, em comparação com 9,28 umol/L em pacientes com crescimento fetal normal (p<0,0001). O nível de corte ideal para Hcy no 1° trimestre da gravidez foi>13,9 umol/L com AUC 0,788, sensibilidade de 75%, especificidade de 83,6%, e DOR 15,2. Conclusão A avaliação da concentração sérica de Hcy pode ser usada como um preditor de FGR, com maior utilidade diagnóstica no 1° trimestre de gravidez.

The Role of High Concentrations of Homocysteine for the Development of Fetal Growth Restriction.

OBJECTIVE: To assess homocysteine (Hcy) levels in the three trimesters of pregnancy in women with fetal growth restriction (FGR) and to evaluate the role of Hcy as a possible predictor of FGR. METHODS: A total of 315 singleton pregnant women were included in the present prospective cohort study and were monitored since the 1st trimester of pregnancy before delivery. Newborns were monitored for the first 7 days of life. Patients who had risk factors for FGR were excluded. Fetal growth restriction was defined according to uterine fundal height (< 10 percentile), ultrasound fetometry (< 5 percentile), and anthropometry of newborns (< 5 percentile). The concentrations of Hcy were detected at between 10 and 14, between 20 and 24, and between 30 and 34 weeks of pregnancy by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristics (ROC) curve test and diagnostic odds ratio (DOR) were performed to evaluate the results of ELISA. RESULTS: The concentration of Hcy in patients with FGR was 19.65 umol/L at between 10 and 14 weeks, compared with 9.28 umol/L in patients with normal fetal growth (p < 0.0001). The optimal cut-off level for Hcy in the 1st trimester of pregnancy was > 13.9 umol/L with AUC 0.788, sensitivity of 75%, specificity of 83.6%, and DOR of 15.2. CONCLUSION: Assessment of serum Hcy concentration may be used as a predictor of FGR, with the highest diagnostic utility in the 1st trimester of pregnancy.

OBJETIVO: Avaliar os níveis de homocisteína (Hcy) em três trimestres da gravidez em mulheres com restrição de crescimento fetal (FGR, na sigla em inglês) e avaliar o papel da Hcy como possível preditor de FGR. MéTODOS: Um total de 315 gestantes solteiras foram incluídas no presente estudo de coorte prospectivo e monitoradas desde o 1° trimestre de gravidez antes do parto. Os recém-nascidos foram acompanhados durante os primeiros 7 dias de vida. Pacientes que apresentam fatores de risco para FGR foram excluídos. A FGR foi definida de acordo com a altura do fundo do útero (< percentil 10), ultrassonografia fetometria (< percentil 5) e antropometria dos recém-nascidos (< percentil 5). As concentrações de Hcy foram detectadas entre 10 e 14, entre 20 e 24 e entre 30 e 34 semanas de gravidez por ensaio de imunoabsorção enzimática (ELISA, na sigla em inglês). O teste da curva das características de operação do receptor (ROC, na sigla em inglês) e a razão de chances de diagnóstico (DOR, na sigla em inglês) foram realizados para avaliar os resultados do ELISA. RESULTADOS: A concentração de Hcy em pacientes com FGR foi de 19,65 umol/L entre 10 e 14 semanas, em comparação com 9,28 umol/L em pacientes com crescimento fetal normal (p < 0,0001). O nível de corte ideal para Hcy no 1° trimestre da gravidez foi > 13,9 umol/L com AUC 0,788, sensibilidade de 75%, especificidade de 83,6%, e DOR 15,2. CONCLUSãO: A avaliação da concentração sérica de Hcy pode ser usada como um preditor de FGR, com maior utilidade diagnóstica no 1° trimestre de gravidez.

Primary high-grade serous ovarian cancer cells are sensitive to senescence induced by carboplatin and paclitaxel in vitro.

BACKGROUND: Various types of normal and cancer cells undergo senescence in response to carboplatin and paclitaxel, which are considered the gold standard treatments in ovarian cancer management. Surprisingly, the effect of these drugs on ovarian cancer cell senescence remained unknown. METHODS: The experiments were conducted on primary high-grade serous ovarian cancer cells. Molecular markers of senescence were evaluated using cytochemistry and immunofluorescence. Cell cycle distribution was analyzed using flow cytometry. Expression of cyclins and signaling pathways was tested using western blot. Telomere length and telomerase activity were measured using qPCR, and the colocalization of telomeres with DNA damage foci using immuno-FISH. Oxidative stress-related parameters were quantified using appropriate fluorescence probes. Production of cancerogenic agents was analyzed using qPCR and ELISA. RESULTS: Carboplatin applied with paclitaxel induces senescence of ovarian cancer cells in vitro. This activity was reflected by permanent G2/M growth arrest, a high fraction of cells expressing senescence biomarkers (SA-ß-Gal and γ-H2A.X), upregulated expression of p16, p21, and p53 cell cycle inhibitors, and decreased expression of cyclin B1. Neither telomere length nor telomerase activity changed in the senescent cells, and the majority of DNA damage was localized outside telomeres. Moreover, drug-treated cancer cells exhibited increased production of STAT3 protein, overproduced superoxide and peroxides, and increased mitochondrial mass. They were also characterized by upregulated ANG1, CCL11, IL-6, PDGF-D, TIMP-3, TSP-1, and TGF-ß1 at the mRNA and/or protein level. CONCLUSIONS: Our findings imply that conventional chemotherapy may elicit senescence in ovarian cancer cells, which may translate to the development of a cancer-promoting phenotype, despite the inability of these cells to divide.

Prognostic role of increased serum homocysteine concentration in preeclampsia.

Objective: To assess homocysteine (Hcy) concentration in women with preeclampsia (PE).Methods: Hcy concentrations were detected by ELISA in 305 pregnancies.Results: Hcy concentration in patients with PE was 16.07 umol/L at 10-14 weeks as compared to 7.19 umol/L in normotensive pregnancies (p < 0.0001). Optimal cutoff level for Hcy in the first trimester of pregnancy was >9.55 umol/L with area under curve of 0.859, sensitivity of 91.67%, specificity of 72.24%.Conclusion: Assessment of serum Hcy concentration may be used as a predictor of PE, with the highest diagnostic utility in the first trimester of pregnancy.

Effect of homocysteine on pregnancy: A systematic review.

Research purpose was to put together the available pieces of present scientific data and to close the gap in the knowledge of Hcy levels in pregnancy and its association with some pregnancy complications. Scientific data were taken from research papers published between January 1990 and December 2017, and found on the Internet (PubMed, ClinicalKey and Embase databases) by the following tags entered in English, Russian, French and German languages: pregnancy, homocysteine, pregnancy complications, pregnancy loss, preeclampsia, intrauterine growth restriction, and placental abruption. The review showed that Hcy levels range in uncomplicated pregnancy. Upon that, Hcy level tends to decrease during the second and third trimesters. Some studies have revealed a link between polymorphism and abortion. Sufficient data were obtained indicating the relationship between HHcy and PE. Placental abruption was also associated with high Hcy levels increasing the risk 5.3-fold, but still there are data not supporting the hypothesis that Hcy levels correlate with placental abruption.