RESUMEN
The paper contains short information concerning the role of folate-related processes in cell metabolism and multiple diseases which are characterized by hyperhomocysteinemia. The authors represent more detailed information about the folate-related processes in human placenta, namely about the content of aminothiols at different allelic variants of placental methylenetetrahydrofolate reductase during the course of physiological pregnancy and preeclampsia. The existing data concerning the expression and catalytic activity of corresponding enzymes are corroborated by the authors' own results that proved for the first time the functional activity of transsulfuration pathway in human placenta. This pathway is activated in placental explants in parallel with down-regulation of proliferation and up-regulation of apoptosis when hyperhomocysteinemia is imitated by high concentration of homocysteine in culture medium. On the whole the presented data point to the importance of placental folate-related processes for its normal function.
Asunto(s)
Apoptosis , Ácido Fólico/metabolismo , Expresión Génica , Homocisteína , Placenta/metabolismo , Compuestos de Sulfhidrilo/metabolismo , Femenino , Ácido Fólico/farmacología , Homocisteína/genética , Homocisteína/metabolismo , Humanos , Hiperhomocisteinemia/genética , Hiperhomocisteinemia/metabolismo , Hiperhomocisteinemia/patología , Placenta/enzimología , Placenta/patología , Preeclampsia/genética , Preeclampsia/metabolismo , Preeclampsia/patología , EmbarazoRESUMEN
Human placenta is an active metabolic organ. It defines a final set of quantitative and qualitative substances, transferred to the fetus. In view of high level of obstetric complications in Ukraine, in particular, preeclampsia, anemia, etc., we have undertaken a study of folate-dependent metabolism in human placenta. Disturbances of folate-dependent metabolism are considered as causes of pregnancy complications. Investigations carried out on 38 samples of term placenta, obtained after physiological pregnancy, and 58 samples obtained after pregnancy with wide-spread complications typical of Ukraine. We have estimated the level of folate, components of methionine cycle--methionine and homocysteine, and related with methionine cycle cysteine and glutathione and polymorphism of methylentetrahydrofolate reductase (MTHFR) catalyzes the irreversible conversion of 5,10-methyl-enetetrahydrofolate to 5-methyltetrahydrofolate, which serves as supplier of methyl group for methionine cycle. We have revealed, that C677T and T677T genotypes of MTHFR are represented more frequently in the samples from complicated pregnancies. In the samples-carriers of C/T genotype of MTHFR and in the group with complicated pregnancies the content of aminothiols and folates correlate in different directions with homocysteine level which serves as a marker of folate-dependent methionine cycle and related processes. On the basis of possitive correlation between homocysteine and cysteine in all investigated groups with different genotypes and the presence/absence of obstetrical complication we suggest the existence of transsulfuration pathway of homocysteine in the human placenta.
Asunto(s)
Ácido Fólico/metabolismo , Placenta/metabolismo , Complicaciones del Embarazo/metabolismo , Compuestos de Sulfhidrilo/metabolismo , Adulto , Femenino , Genotipo , Edad Gestacional , Humanos , Recién Nacido , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Mutación , Placenta/enzimología , Polimorfismo Genético , Embarazo , Complicaciones del Embarazo/enzimología , Complicaciones del Embarazo/epidemiología , Complicaciones del Embarazo/genética , Resultado del EmbarazoRESUMEN
Elevated level of homocysteine in blood serum of pregnant women is the risk factor for placental malfunction and fetal abnormalities. Our study has shown the activation of apoptosis, inhibition of proliferation, destruction of placental trophoblast and activation of the transsulfuration pathway under elevated homocysteine level in the incubation medium in the range of 20-80 microM. The activation of the transsulfuration pathway indicates that placenta may to some extent withstand elevated homocysteine level.
Asunto(s)
Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Homocisteína/farmacología , Trofoblastos/efectos de los fármacos , Cistationina betasintasa/genética , Cistationina betasintasa/metabolismo , Femenino , Expresión Génica/efectos de los fármacos , Homocisteína/metabolismo , Humanos , Microscopía Fluorescente , Técnicas de Cultivo de Órganos , Placenta/efectos de los fármacos , Placenta/enzimología , Placenta/metabolismo , Placenta/ultraestructura , Embarazo , Trimestres del Embarazo , Azufre/metabolismo , Trofoblastos/enzimología , Trofoblastos/metabolismo , Trofoblastos/ultraestructuraRESUMEN
Glutathione S-transferase P1-1 is the main phase II xenobiotic metabolism enzyme in human placenta. Low level of its gene expression and corresponding ineffective protection of fetus from toxic compounds is associated with pregnancy disorders such as preeclampsia and abnormalities of fetus development. It was previously reported that environmental radioactive contamination caused down-regulation of GSTP1 transcription in human placenta, but mechanisms responsible for such changes were unclear. In the present study we have found that observed changes in transcription of this gene are not caused by promoter methylation because GSTP1 promoter was not methylated in any of analyzed 91 placental samples. Regulation of GSTP1 by methylation or transcription factors was not previously studied in human placenta. Using "Gene Expression Atlas" online software the placental expression profile of transcription factors known to interact with GSTP1 promoter in other cell types, was identified. According to computer analysis the genes coding for GATA2, GATA3, Fos-B, Nrf3 and MafK transcription factors are highly expressed in human placenta, while genes coding for c-Fos, Juns, Mafs, ERbeta, RARalpha and NF-kappaB factors have moderate level of expression. Competitive EMSA provided the evidence that ARE and NF-kappaB-like sites specifically interacted with placental nuclear proteins. Among these proteins transcription factors AP-1 and NF-kappaB were identified using corresponding consensus oligonucleotides as competitors in EMSA.
Asunto(s)
Regulación Enzimológica de la Expresión Génica , Gutatión-S-Transferasa pi/genética , Placenta/enzimología , Transcripción Genética , Femenino , Humanos , Metilación , Regiones Promotoras Genéticas , Factores de Transcripción/genéticaRESUMEN
The influence of irradiation and NSE on the microsomal lipid composition of the rat liver and heart was studied. It was shown, that radiation treatment in a dose of 2 Gy had not a significant affect on the heart phospholipid composition, whereas in the liver the amounts of the phosphatidylethnolamine and phosphatidylinositol were increased and the amounts of the phosphatidylcholine and sphyngomieline were decreased. NSE did not impact on these characteristics. The alterations of the plasmalogen/diacyl forms ratio of the PC and PE also took place only in the liver microsome. The analysis of the fatty acids esterified to phospholipids showed similar situation: the fatty acids of the heart microsome less were changed than those of the liver microsome undergo irradiation. The amount of arachidonic acid rise after the adding of NSE to rats. Investigation of the important component of biological membranes--cholesterol and its esters also showed that the liver tissue is more vulnerable to irradiation than the heart. NSE led to insignificant increase of the not esterified cholesterol in the liver. As a result of the present work we may conclude that the liver microsome is more vulnerable than the heart under X-ray radiation and NSE has protective effect in these conditions.