RESUMO
INTRODUCTION AND AIM: Matrix metalloproteinase (MMP)-2 and MMP-9 are reported to participate in several pregnancy-related diseases, including intrahepatic cholestasis of pregnancy (ICP), which is a severe liver disorder in pregnant women. Meanwhile, ample evidences have demonstrated that celastrol inhibits the activity and expression of MMPs. The present study aims to examine the effect of celastrol to alleviate symptoms of ICP in rat model. MATERIAL AND METHODS: By inducing ICP with 17 - ethinylestradiol in pregnant female rats, we assessed the impact of celastrol administration on symptoms of ICP, such as the rate of bile flow, the level of total bile acids (TBA), and the activities of MMP-2 and -9. Furthermore, the correlations between the levels of MMPs with the examined ICP symptoms were investigated. RESULTS: In rats with ICP, both MMP-2 and -9 exhibited significantly elevated activities, which were inhibited by the administration of celastrol. Furthermore, ICP symptoms such as bile flow rate and total TBA were restored by celastrol. Lastly, there were strong correlations between levels of the two MMPs and TBA. CONCLUSION: Our findings described for the first time the effects of celastrol to attenuate ICP symptoms through an inhibition of both MMP-2 and -9, providing evidence for a potential role of celastrol as a new drug for the treatment of ICP.
Assuntos
Colestase Intra-Hepática/tratamento farmacológico , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Complicações na Gravidez/tratamento farmacológico , Prenhez , Triterpenos/uso terapêutico , Animais , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/enzimologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Triterpenos Pentacíclicos , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/enzimologia , Ratos , Ratos Sprague-Dawley , TripterygiumRESUMO
ABSTRACT Intrahepatic cholestasis of pregnancy (ICP) is a severe liver disease uniquely occurring during pregnancy. In this study we aimed to identify novel biomarker for the diagnosis of ICP in Chinese population. 50 healthy pregnant women, 50 mild ICP patients and 48 severe ICP patients were enrolled for this study. Liver function tests, including serum total bilirubin, direct bilirubin, alanine transaminase, aspartate aminotransferase and cholyglycine, were performed in all participants. After an overnight fast serum levels of total bile acids (TBA), matrix metalloproteinase (MMP)-2 and MMP-9 were measured, and their correlation with liver function tests were analyzed. The observed increase in serum TBA in ICP patients was not statistically significant which made it unreliable for diagnosis of ICP in Chinese population. On the other hand, both MMP-2 and MMP-9 serum levels exhibited a progressive and significant elevation in mild and severe ICP patients compared with healthy pregnant women, which also positively correlated with liver function tests. Serum levels of both MMP-2 and MMP-9 could be reliably used as laboratory abnormalities for accurate diagnosis and sensitive grading of ICP in Chinese population.
Assuntos
Humanos , Feminino , Gravidez , Adulto , Complicações na Gravidez/sangue , Biomarcadores/sangue , Colestase Intra-Hepática/sangue , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/enzimologia , Índice de Gravidade de Doença , Estudos de Casos e Controles , Regulação para Cima , China , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/enzimologia , Reprodutibilidade dos Testes , Testes de Função HepáticaRESUMO
Intrahepatic cholestasis of pregnancy (ICP) is a severe liver disease uniquely occurring during pregnancy. In this study we aimed to identify novel biomarker for the diagnosis of ICP in Chinese population. 50 healthy pregnant women, 50 mild ICP patients and 48 severe ICP patients were enrolled for this study. Liver function tests, including serum total bilirubin, direct bilirubin, alanine transaminase, aspartate aminotransferase and cholyglycine, were performed in all participants. After an overnight fast serum levels of total bile acids (TBA), matrix metalloproteinase (MMP)-2 and MMP-9 were measured, and their correlation with liver function tests were analyzed. The observed increase in serum TBA in ICP patients was not statistically significant which made it unreliable for diagnosis of ICP in Chinese population. On the other hand, both MMP-2 and MMP-9 serum levels exhibited a progressive and significant elevation in mild and severe ICP patients compared with healthy pregnant women, which also positively correlated with liver function tests. Serum levels of both MMP-2 and MMP-9 could be reliably used as laboratory abnormalities for accurate diagnosis and sensitive grading of ICP in Chinese population.
Assuntos
Colestase Intra-Hepática/sangue , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Complicações na Gravidez/sangue , Adulto , Ácidos e Sais Biliares/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , China , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/enzimologia , Feminino , Humanos , Testes de Função Hepática , Valor Preditivo dos Testes , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/enzimologia , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Regulação para CimaRESUMO
OBJECTIVES: To compare the circulating levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitors of metalloproteinase (TIMP)-1, TIMP-2, and the MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios in preeclampsia and gestational hypertension with those found in normotensive pregnancies. DESIGN AND METHODS: We studied 83 pregnant women (30 healthy pregnant women with uncomplicated pregnancies, 26 with gestational hypertension, and 27 with preeclampsia) and 30 healthy nonpregnant women in a cross-sectional study. MMP and TIMP concentrations were measured in plasma samples by gelatin zymography and ELISA, respectively. RESULTS: We found higher plasma pro-MMP-9 levels, and higher pro-MMP-9/TIMP-1 ratios in women with gestational hypertension (95%-CI: 1.031 to 2.357, and 0.012 to 0.031, respectively), but not with preeclampsia, compared with those found in normotensive pregnant women (95%-CI: 0.810 to 1.350, and 0.006 to 0.013, respectively; both P<0.05). We found no significant differences in pro-MMP-2 levels (P>0.05). CONCLUSIONS: The higher net MMP-9 (but not MMP-2) activity in gestational hypertension compared with normotensive pregnancy suggests that MMP-9 plays a role in the pathophysiology of gestational hypertension. Conversely, the lack of such alterations in preeclampsia is consistent with the notion that different pathophysiological mechanisms are involved in these hypertensive disorders.
Assuntos
Hipertensão/enzimologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Pré-Eclâmpsia/enzimologia , Complicações na Gravidez/enzimologia , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Adulto , Biomarcadores/sangue , Pressão Sanguínea , Índice de Massa Corporal , Feminino , Frequência Cardíaca , Humanos , Obesidade/enzimologia , Gravidez , Valores de ReferênciaRESUMO
This work was designed to study the expression of the vasodilator peptide angiotensin-(1-7) [Ang-(1-7)] and its generating enzyme (ACE2) in the uteroplacental interface. Placentas were obtained from 11 early pregnancy failures (5 miscarriages and 6 ectopic pregnancies), 15 normotensive, and 10 preeclamptic gestations. In placental villi, the main sites of immunocytochemical expression of Ang-(1-7) and ACE2 were the syncytiotrophoblast, cytotrophoblast, endothelium and vascular smooth muscle of primary and secondary villi. Syncitial Ang-(1-7) expression in samples obtained from miscarriages and ectopic pregnancies was increased compared to normal term pregnancy [2.0 (2.0-2.25 for the 25 and 75% interquartile range) vs 1.3 (1.0-1.9), p<0.01]. In the maternal stroma, Ang-(1-7) and ACE2 were expressed in the invading and intravascular trophoblast and in decidual cells in all 3 groups. Ang-(1-7) and ACE2 staining was also found in arterial and venous endothelium and smooth muscle of the umbilical cord. The expression of Ang-(1-7) and ACE2 was similar in samples obtained from normal term or preeclamptic pregnancies, except for increased expression of ACE2 in umbilical arterial endothelium in preeclampsia [0.5 (0.5-0.8) vs 0.0 (0.0-0.0), p<0.01]. The uteroplacental location of Ang-(1-7) and ACE2 in pregnancy suggests an autocrine function of Ang-(1-7) in the vasoactive regulation that characterizes placentation and established pregnancy.
Assuntos
Angiotensina I/análise , Carboxipeptidases/análise , Fragmentos de Peptídeos/análise , Placenta/química , Complicações na Gravidez/metabolismo , Gravidez/metabolismo , Angiotensina I/metabolismo , Enzima de Conversão de Angiotensina 2 , Carboxipeptidases/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A , Placenta/enzimologia , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Complicações na Gravidez/enzimologiaRESUMO
BACKGROUND: Neural tube defects (NTDs) have been associated with biochemical factors involved in the conversion of homocysteine to methionine as folate deficiency and the mutation 677T in the N(5),N(10)-methylenetetrahydrofolate reductase gene (MTHFR). METHODS: A case-control study was performed to detect this mutation in 38 unrelated women with NTD deceased products and 31 mothers without antecedents of NTD offspring. All products were born in Nuevo León (northeastern Mexico) during 1997. Erythrocyte and plasmatic folate levels and the genotype of the 677 polymorphism at the MTHFR locus were analyzed in both groups. RESULTS: Although no significant differences were found in mean blood folate levels, the percentage of women in the case group with erythrocyte folate levels <160 ng/mL was significantly higher than in the control group (75 vs. 51.2%, p <0.05). The proportion of women with plasma folate levels <3.5 ng/mL was higher in the case group (16.2 vs. 0%, p <0.01). Genotype analysis demonstrated a significantly higher proportion of 677T homozygous mothers with NTD products (39.6 vs. 9.1%, p <0.05). Allele frequencies for the 677T mutation were 0.55 and 0.36 for cases and controls, respectively. The odds ratio (OR) for having a NTD product was 6.1 (95%, CI 1.56-23.6) for homozygous 677T mothers vs. homozygous 677C and heterozygous mothers. Significantly low levels of erythrocyte folate were found in the 677C homozygous case group and in plasma folate in the 677C/677T heterozygous case mothers. CONCLUSIONS: Our study suggests that folate deficiency and MTHFR unfavorable genotype in mothers are important risk factors for severe NTD phenotype in our population.
Assuntos
Deficiência de Ácido Fólico/genética , Ácido Fólico/sangue , Defeitos do Tubo Neural/etiologia , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Complicações na Gravidez/enzimologia , Adulto , Alelos , Substituição de Aminoácidos , Anencefalia/etiologia , Anencefalia/mortalidade , Estudos de Casos e Controles , Códon/genética , Análise Mutacional de DNA , Eritrócitos/química , Feminino , Deficiência de Ácido Fólico/enzimologia , Deficiência de Ácido Fólico/epidemiologia , Deficiência de Ácido Fólico/metabolismo , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Homocisteína/metabolismo , Humanos , Recém-Nascido , Masculino , Troca Materno-Fetal , Metilenotetra-Hidrofolato Redutase (NADPH2) , México/epidemiologia , Mutação de Sentido Incorreto , Defeitos do Tubo Neural/mortalidade , Gravidez , Resultado da Gravidez , Fatores de Risco , Disrafismo Espinal/etiologia , Disrafismo Espinal/mortalidadeRESUMO
A esteatose Hepatica Aguda na gestacao e uma patologia que ocorre no terceiro trimestre, que acarreta prejuizo ao figado materno podendo gerar graves complicacoes. Acreditava-se que fosse uma patologia rara, porem trabalhos realizados nas decadas de 80 e 90 tem constatado o seu diagnostico mais frequente. A etiopatogenia permanece desconhecida. Varios estudiosos tem correlacionado com alteracao da beta-oxidacao dos acidos graxos por deficiencia na cadeia longa da 3-hidroxiacyl coenzima A dehidrogenase. O tratamento desta patologia consiste na antecipacao do parto, conduta que vem reduzindo a mortalidade materna e fetal
Assuntos
Humanos , Feminino , Complicações na Gravidez/enzimologia , Hepatopatias/diagnóstico , Necrose , 3-Hidroxiesteroide Desidrogenases/análise , Doença Aguda , Mortalidade Fetal , Fígado/química , Mortalidade Infantil , Hepatopatias/complicações , Mortalidade MaternaRESUMO
Pregnancies were compared in 18 Ecuadorian women of low socioeconomic status and 11 of high socioeconomic status. Objective evidence of malnutrition was demonstrable in virtually all of the women from the low socioeconomic group and in none from the high socioeconomic group. Birth weight and placental weight were significantly lower in the malnourished group. Nucleic acid and protein content of placentas were slightly lower and activity of alkaline ribonuclease was markedly elevated. The data reinforce animal studies and demonstrate for the first time in human subjects that alkaline RNase activity is increased in placentas from malnourished women. We suggest that activity of this enzyme in placenta may prove to be a useful marker of maternal and fetal nutritional status.