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1.
Rev Environ Contam Toxicol ; 251: 131-184, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31129734

RESUMO

Maternal exposure to endocrine-disrupting chemicals (EDCs) is associated with long-term hormone-dependent effects that are sometimes not revealed until maturity, middle age, or adulthood. The aim of this study was to conduct descriptive reviews on animal experimental and human epidemiological evidence of the adverse health effects of in utero and lactational exposure to selected EDCs on the first generation and subsequent generation of the exposed offspring. PubMed, Web of Science, and Toxline databases were searched for relevant human and experimental animal studies on 29 October 29 2018. Search results were screened for relevance, and studies that met the inclusion criteria were evaluated and qualitative data extracted for analysis. The search yielded 73 relevant human and 113 animal studies. Results from studies show that in utero and lactational exposure to EDCs is associated with impairment of reproductive, immunologic, metabolic, neurobehavioral, and growth physiology of the exposed offspring up to the fourth generation without additional exposure. Little convergence is seen between animal experiments and human studies in terms of the reported adverse health effects which might be associated with methodologic challenges across the studies. Based on the available animal and human evidence, in utero and lactational exposure to EDCs is detrimental to the offspring. However, more human studies are necessary to clarify the toxicological and pathophysiological mechanisms underlying these effects.


Assuntos
Disruptores Endócrinos , Exposição Materna/estatística & dados numéricos , Animais , Feminino , Humanos , Gravidez
2.
Biol Reprod ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31566220

RESUMO

During pregnancy, there is increased expression of some cytokines at the fetal-maternal interface; and the clarification of their roles in trophoblast-endometrium interactions is crucial to understanding the mechanism of placentation. This review addresses the up-to-date reported mechanisms by which the members of the transforming growth factor beta superfamily regulate trophoblast proliferation, differentiation and invasion of the decidua, which are the main phases of placentation. The available information shows that these cytokines regulate placentation in somehow a synergistic and an antagonistic manner; and that dysregulation of their levels can lead to aberrant placentation. Nevertheless, prospective studies are needed to reconcile some conflicting reports; and identify some unknown mediators involved in the actions of these cytokines before their detailed mechanistic regulation of human placentation could be fully characterized.

3.
Biol Reprod ; 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31621835

RESUMO

Anti-androgenic endocrine-disrupting chemicals (EDCs) can cross the placenta to modify early offspring sexual dimorphic markers. These changes are linked to Anogenital Distance (AGD), which is an androgen sensitive anthropometric parameter used as a biomarker of perineal growth and caudal migration of the genital tubercle. This review aimed to summarize strength of evidence for associations of in utero exposure to EDCs with AGD and to identify gaps and limitations in the literature so as to inform future research. We performed an electronic search of English literature through September 2019 in MEDLINE, Web of Science and Toxline. We included epidemiological studies that examined in utero exposure to persistent and non-persistent EDCs, and considered AGD in offspring as an outcome. Our review contained 16 investigations examining exposure to persistent EDCs (9 studies) and non-persistent EDCs (7 studies). Some individual studies reported an inverse association between exposure to BPA, dioxins, perfluoroalkyl substances and organochlorides, and AGD in both male and female offspring. Meta-analysis of 3 studies found a small reduction of AGD in female offspring exposed to BPA. The number of studies per chemical is small and number of subjects examined is limited; so, replication of these results is needed. To achieve more specificity and better replication of results, future studies should establish the association of non-persistent EDCs using multiple urine samples, evaluate the cumulative impact of exposure to a mixture of anti-androgenic chemicals, and offer adequate consideration of more maternal- and children-related confounding factors.

4.
Biomark Med ; 13(15): 1321-1330, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31559841

RESUMO

The etiology of preeclampsia - an abnormal placentation-mediated disease - is not fully understood; and there are very few biomarkers with which to predict and diagnose it. Early prediction and diagnosis of this pathology can lead to a significant improvement in maternal and perinatal outcomes. Since members of the transforming growth factor ß superfamily influence placentation, and are released from the placenta into the maternal circulatory system, several studies have investigated the involvement of these cytokines in preeclampsia and the possibility of using their serum levels as biomarkers of the disease. In this review, we have summarized the reported relationships between the levels of this superfamily of cytokines and preeclampsia. The available information indicates that altered levels of some of these cytokines are involved in the pathogenesis and pathophysiology of preeclampsia, suggesting their likelihood of serving as predictive and diagnostic biomarkers of the disease.

5.
Biol Reprod ; 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31494673

RESUMO

Thyroid hormones regulate a number of metabolic processes during pregnancy. After implantation, the placenta forms and enhances embryonic growth and development. Dysregulated maternal thyroid hormone signaling has been observed in mal-placentation-mediated pregnancy complications like preeclampsia, miscarriage and intrauterine growth restriction, but the molecular mechanisms involved in this association have not been fully characterized. In this review, we have discussed thyroid hormone signaling and its roles in trophoblast proliferation, trophoblast differentiation, trophoblast invasion of the decidua and decidual angiogenesis. We have also explored the relationship between specific pregnancy complications and placental thyroid hormone transporters, deiodinases and thyroid hormone receptors. Additionally, we have examined the effects of specific endocrine-disruptors on placental thyroid hormone signaling. The available evidence indicates that thyroid hormone signaling is involved in the formation and functioning of the placenta, and serves as the basis for understanding the pathogenesis and pathophysiology of dysthyroidism-associated pregnancy complications like preeclampsia, miscarriage and intrauterine growth restriction.

6.
J Cell Physiol ; 2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30132880

RESUMO

Embryo implantation is essential for normal pregnancy, and the process of decidualization is critical for embryo implantation. However, the mechanism of decidualization during early pregnancy is still unknown. Forkhead box O3a (FOXO3a) is the most important functional transcription factor of the forkhead box family and is a highly conserved transcription factor of apoptosis-related genes. In the mouse uterus, FOXO3a was found to be expressed regularly from Days 1-7 of early pregnancy. Upon further exploration, it was found that FOXO3a was expressed at significantly higher levels at the implantation site than at the interimplantation site on Days 5-7 of pregnancy. Under artificial decidualization, FOXO3a was highly expressed in the first and second decidual zones. After decidualization, the expression of FOXO3a was significantly increased both in vivo and vitro. In primary stromal cells, apoptosis was reduced by decreased expression of FOXO3a after inducing decidualization. Moreover, when FOXO3a-small interfering RNA was transfected into the uteri of mice, the expression of decidualization- and apoptosis-related factors was impaired. Thus, FOXO3a might play an important role in decidualization during early pregnancy, and cell apoptosis might be one of pathways for FOXO3a-regulated decidualization.

7.
Molecules ; 22(10)2017 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-28991209

RESUMO

A series of linear furanocoumarins with different substituents have been designed and synthesized. Their structures were confirmed by ¹H-NMR spectroscopy, high resolution mass spectra (EI-MS), IR, and X-ray single-crystal diffraction. All of the target compounds were evaluated in vitro for their antifungal activity against Rhizoctorzia solani, Botrytis cinerea, Alternaria solani, Gibberella zeae, Cucumber anthrax, and Alternaria leaf spot at 100 µg/mL, and some of the designed compounds exhibited potential antifungal activities. Compound 3a (67.9%) exhibited higher activity than the control Osthole (66.1%) against Botrytis cinerea. Furthermore, compound 4b (62.4%) represented equivalent antifungal activity as Osthole (69.5%) against Rhizoctonia solani. The structure-activity relationship (SAR) study demonstrates that linear furanocoumarin moiety has an important effect on the antifungal activity, promoting the idea of the coumarin ring as a framework that might be exploited in the future.

8.
Oncotarget ; 8(31): 51507-51521, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28881663

RESUMO

In this study, we investigated the effect of Bisphenol A (BPA), an endocrine-disrupting chemical, on the migration of human trophoblasts and mouse placentation by using the primary extravillous trophoblast (EVT) and its cell line HTR-8/SVneo, villous explant cultures, and pregnant mice. BPA increased EVT motility and the outgrowth of villous explants in a dose-dependent manner. BPA also increased the protein levels of integrin-ß1 and matrix metalloproteinase (MMP)-9 in human EVTs. Low-dose BPA (≤50 mg) increased the protein levels of MMP-9 and MMP-2 as well as integrin-ß1 and integrin-α5 in mouse placenta and decreased the proportion of the labyrinth and spongiotrophoblast layers. Inhibitors of mitogen-activated protein kinase (MAPK) U0126 and phosphatidylinositol-3-kinases (PI3K) LY294002 reversed the protein levels of integrin-ß1 and MMP-9 as well as the migratory ability induced by BPA. In conclusion, these results indicated that BPA can enhance trophoblast migration and impair placentation in mice by a mechanism involving upregulation of integrin(s) and MMP(s) as well as the stimulation of MAPK and PI3K/Akt (protein kinase B) signaling pathways.

9.
Reprod Fertil Dev ; 29(8): 1509-1520, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27439778

RESUMO

DNA cytosine-5 methylation plays a vital role in regulating the expression of E-cadherin, which is encoded by the CDH1 gene. In this study, we characterised the DNA methylation and expression pattern of CDH1 in an extravillous trophoblast cell line (HTR-8/SVneo) and two trophoblast cell lines -- JEG-3 and JAR. Promoter hypermethylation with reduced E-cadherin expression in HTR-8/SVneo cells and promoter hypomethylation with increased E-cadherin expression in JEG-3 and JAR cells were observed. Demethylation treatment significantly restored E-cadherin expression, contributing to decreases in the motility and invasiveness of HTR-8/SVneo cells. Sense-methylated oligonucleotides (MONs) labelled with Cy5 and complementary to a region of the human CDH1 promoter were designed, with the cytosines in 5'-cytosine-phosphate-guanine-3' (CpG) dinucleotides being replaced by methylated cytosines. Following MON transfection into JEG-3 cells, the level of CDH1 promoter DNA methylation as well as cell motility and invasiveness were increased and gene expression was significantly repressed. Our results indicate that MON-mediated DNA methylation of the CDH1 promoter and subsequent alterations in gene expression may contribute to trophoblast motility and invasion, suggesting a potential method for controlling the biological function of trophoblasts in vitro through epigenetic modification.


Assuntos
Caderinas/genética , Movimento Celular/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Oligonucleotídeos/farmacologia , Regiões Promotoras Genéticas/efeitos dos fármacos , Trofoblastos/citologia , Antígenos CD , Caderinas/metabolismo , Linhagem Celular , Feminino , Humanos , Trofoblastos/efeitos dos fármacos
10.
Reprod Biomed Online ; 34(2): 191-202, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27986413

RESUMO

The molecular mechanisms underlying endometrial stromal cell proliferation and differentiation (decidualization) are still not fully understood. This study revealed that increased Slp-2 expression is a significant factor modulating endometrial stromal cell proliferation and decidualization in both mice and humans. Our results showed a significant difference in the mRNA and protein levels between the implantation site and inter-implantation site on day 5 and day 6 of pregnancy in mice (all P < 0.05). Strong Slp-2 immunostaining was mainly localized within the decidual zone of mice through the post-implantation period. Mice with artificially induced deciduoma showed significantly higher expression of Slp-2 compared with uninduced controls (P < 0.005). Human stromal cells in the middle and late-secretory phases demonstrated significantly (all P < 0.05) upregulated SLP-2, compared with cells in the proliferative phase and early secretory phases. Further analyses of the SLP-2 gene knocked down revealed a significant (P < 0.005) repression of both the decidualization marker gene's expression (decidual/trophoblast prolactin-related protein in mice, insulin-like growth factor binding protein and prolactin in human) and the cell proliferation in in vitro-induced decidualized primary endometrial stromal cells in mice and humans.


Assuntos
Proteínas Sanguíneas/metabolismo , Endométrio/citologia , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Membrana/metabolismo , Células Estromais/citologia , Animais , Diferenciação Celular , Proliferação de Células , Decídua/metabolismo , Deciduoma/metabolismo , Implantação do Embrião , Feminino , Humanos , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Ciclo Menstrual , Camundongos , Gravidez , Prolactina/análogos & derivados , Prolactina/metabolismo , RNA Mensageiro/metabolismo , Células Estromais/metabolismo
11.
Placenta ; 46: 92-101, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27697227

RESUMO

INTRODUCTION: The invasion of extravillous cytotrophoblasts (EVTs) into the maternal uterine decidua and vasculature is critical for human placenta development and pregnancy maintenance. The imprinted gene MEST/PEG1 has been implicated in trophoblast development; however, the role of MEST in EVT invasion and the accompanying early pregnancy complications are not fully understood. METHODS: Western blot, immunofluorescence and immunohistochemistry were used to detect MEST protein expression and localization by using antibodies recognize 2 reported isoforms. Specific small interference RNA (siRNA) targeting both of the MEST isoforms was applied to silence MEST expression in extravillous explants and HTR8/SVneo cells. Cell invasion and migration were assessed using the Matrigel invasion, Transwell migration assay and the xCELLigence system. Promoter DNA methylation was examined using bisulfite-sequencing polymerase chain reaction (BSP). RESULTS: MEST protein was highly expressed in EVTs in the first trimester placenta and in the invasive EVT cell lines HTR-8/Svneo and HPT-8. Weak MEST expression was found in cytotrophoblasts (CTBs) and the choriocarcinoma-derived CTB cell line JEG-3. The specific siRNA knockdown of MEST expression significantly reduced HTR-8/Svneo cell invasion and migration as well as extravillous explant outgrowth, which were associated with the downregulation of Twist, N-cadherin and Vimentin. Decreased MEST protein expression with isoform 2 promoter hypermethylation was observed in the placentas of missed abortions, suggesting a possible pathological mechanism of missed abortion. CONCLUSIONS: Suppressed expression of MEST was associated with its isoform 2 promoter hypermethylation ex vivo placenta tissues and in vitro cultured EVT cell lines. The present results provide a possible pathological mechanism of missed abortion.


Assuntos
Aborto Retido/metabolismo , Proteínas/metabolismo , Trofoblastos/metabolismo , Sequência de Bases , Caderinas/metabolismo , Metilação de DNA , Feminino , Humanos , Gravidez , Primeiro Trimestre da Gravidez/metabolismo , Regiões Promotoras Genéticas , Vimentina/metabolismo
12.
Hum Reprod ; 31(10): 2339-51, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27604954

RESUMO

STUDY QUESTION: Does nm23 have functional significance in decidualization in mice and humans? SUMMARY ANSWER: nm23 affects decidualization via the phosphoinositide 3 kinase/mammalian target of rapamycin (PI3K-Akt-mTOR) signaling pathways in mouse endometrial stromal cells (ESCs; mESCs) and human ESCs. WHAT IS KNOWN ALREADY: The function of nm23 in suppressing metastasis has been demonstrated in a variety of cancer types. nm23 also participates in the control of DNA replication and cell proliferation and differentiation. STUDY DESIGN, SIZE AND DURATION: We first analyzed the expression profile of nm23 in mice during early pregnancy (n = 6/group), pseudopregnancy (n = 6/group) and artificial decidualization (n = 6/group) and in humans during the menstrual cycle phases and the first trimester. We then used primary cultured mESCs and a human ESC line, T-HESC, to explore the hormonal regulation of nm23 and the roles of nm23 in in vitro decidualization, and as a possible mediator of downstream PI3K-Akt-mTOR signaling pathways. PARTICIPANTS/MATERIALS, SETTINGS AND METHODS: We evaluated the dynamic expression of nm23 in mice and humans using immunohistochemistry, western blot and real-time quantitative RT-PCR (RT-qPCR). Regulation of nm23 by steroid hormones was investigated in isolated primary mESCs and T-HESCs by western blot. The effect of nm23 knockdown (using siRNA) on ESC proliferation was analyzed by 5-ethynyl-2'-deoxyuridine staining (EdU) and proliferating cell nuclear antigen protein (PCNA) expression. The influence of nm23 expression on the differentiation of ESCs was determined by RT-qPCR using the mouse differentiation markers decidual/trophoblast PRL-related protein (dtprp, also named prl8a2) and prolactin family 3 subfamily c member 1 (prl3c1) and the human differentiation markers insulin-like growth factor binding protein 1 (IGFBP1) and prolactin (PRL). The effects of nm23 siRNA (si-nm23) and the PI3K inhibitor LY294002 on the downstream effects of nm23 on the PI3K-Akt-mTOR signaling pathway were estimated by western blot. MAIN RESULTS AND THE ROLE OF CHANCE: NM23-M1 was specifically expressed in the decidual zone during early pregnancy and in artificially induced deciduoma, and NM23-H1 was strongly expressed in human first trimester decidua. The expression of nm23 was upregulated by oestradiol and progesterone (P < 0.05 versus control) in vitro in mESCs and T-HESC, and this was inhibited by their respective receptor antagonists, ICI 182,780 and RU486. Mouse and human nm23 knockdown decreased ESC proliferation and differentiation (P < 0.05 versus control). The PI3K-Akt-mTOR signaling pathways were downstream mediators of nm23 in mESCs and T-HESCs decidualization. LIMITATIONS AND REASONS FOR CAUTION: Whether the nm23 regulates decidualization via the activation of AMPK, RAS, PKA, STAT3 or other signaling molecules remains to be determined. The role of nm23 in decidualization was tested in vitro only. WIDER IMPLICATIONS OF THE FINDINGS: Results demonstrate that nm23 plays a vital role in decidualization in mice and humans and that nm23 gene expression is hormonally regulated. The downregulation of nm23 in decidua during the first trimester may be associated with infertility in women. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the National Natural Science Foundation of China (grant nos. 81370731, 31571551 and 31571190), the Science and Technology Project of Chongqing Education Committee (KJ130309), open funding by the Chongqing Institute for Family Planning (1201) and the Excellent Young Scholars of Chongqing Medical University (CQYQ201302). The authors have no conflicts of interest to declare.


Assuntos
Decídua/metabolismo , Regulação da Expressão Gênica , Nucleosídeo NM23 Difosfato Quinases/metabolismo , Transdução de Sinais/fisiologia , Animais , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Endométrio/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Camundongos , Nucleosídeo NM23 Difosfato Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Gravidez , Primeiro Trimestre da Gravidez , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Estromais/metabolismo , Serina-Treonina Quinases TOR/metabolismo
13.
Reprod Fertil Dev ; 2015 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-26014898

RESUMO

We characterised DNA methylation and gene expression of four tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors DR4, DR5, DcR1 and DcR2 in three choriocarcinoma (JAR, JEG-3, BeWo) and two transformed (HTR-8/SVneo and HPT-8) cell lines. DR4 mRNA was detected in JAR, JEG-3, BeWo and HTR-8/SVneo cells, whereas DR5 was present in all detected cells. DcR1 transcripts were expressed only in JAR, JEG-3 and BeWo cells, whereas DcR2 transcripts were detected only in HTR-8/SVneo and HPT-8 cells. Hypermethylated DR4 promoter was observed in JAR, JEG-3, BeWo and HTR-8/SVneo cells, hypermethylated DcR1 promoter in HTR-8/SVneo and HPT-8 cells and hypermethylated DcR2 promoter in JAR, JEG-3 and BeWo cells. Restoration of DR4, DcR1 and DcR2 expression with decreased DNA methylation of these genes was induced by the DNA demethylation agent 5-aza-2'-deoxycytidine (5-aza-CdR) in trophoblast cells, whereas DR5 expression did not exhibit any change. Significant negative correlation between the expression and DNA methylation of these genes was also observed. In all tested cell lines, only HPT-8 demonstrated sensitivity to TRAIL-induced apoptosis. Combined treatment with 5-aza-CdR and TRAIL resulted in apoptosis in JAR, JEG-3, BeWo and HTR-8/SVneo cells but not in HPT-8 cells. The results indicate that DNA methylation is associated with TRAIL receptor expression and might be involved in trophoblast apoptosis.

14.
Nutrients ; 7(3): 1916-32, 2015 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-25781218

RESUMO

It is well known that maternal folate deficiency results in adverse pregnancy outcomes. In addition to aspects in embryonic development, maternal uterine receptivity and the decidualization of stromal cells is also very important for a successful pregnancy. In this study, we focused on endometrium decidualization and investigated whether apoptosis, which is essential for decidualization, was impaired. Flow cytometry and TUNEL detection revealed that apoptosis of mouse endometrium decidual cells was suppressed in the dietary folate-deficient group on Days 7 and 8 of pregnancy (Day 1 = vaginal plug) when decidua regression is initiated. The endometrium decidual tissue of the folate deficiency group expressed less Bax compared to the normal diet group while they had nearly equal expression of Bcl2 protein. Further examination revealed that the mitochondrial transmembrane potential (ΔΨm) decreased, and the fluorescence of diffuse cytoplasmic cytochrome c protein was detected using laser confocal microscopy in normal decidual cells. However, no corresponding changes were observed in the folate-deficient group. Western blotting analyses confirmed that more cytochrome c was released from mitochondria in normal decidual cells. Taken together, these results demonstrated that folate deficiency could inhibit apoptosis of decidual cells via the mitochondrial apoptosis pathway, thereby restraining decidualization of the endometrium and further impairing pregnancy.


Assuntos
Apoptose , Decídua/fisiopatologia , Implantação do Embrião/fisiologia , Deficiência de Ácido Fólico/fisiopatologia , Ácido Fólico/sangue , Mitocôndrias/fisiologia , Complicações na Gravidez/sangue , Animais , Citocromos c/metabolismo , Endométrio , Feminino , Deficiência de Ácido Fólico/sangue , Potencial da Membrana Mitocondrial , Camundongos , Gravidez , Complicações na Gravidez/fisiopatologia , Prenhez , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Células Estromais , Proteína X Associada a bcl-2/metabolismo
15.
Int J Endocrinol ; 2014: 620165, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25389438

RESUMO

DNA (cytosine-5-) methylation silencing of GSTP1 function occurs in prostate adenocarcinoma (PCa). Previous studies have shown that there is an inverse relationship between dietary lycopene intake and the risk of PCa. However, it is unknown whether lycopene reactivates the tumor suppressor gene glutathioneS-transferase-π (GSTP1) by demethylation of the hypermethylated CpGs that act to silence the GSTP1 promoter. Here, we demonstrated that lycopene treatment significantly decreased the methylation levels of the GSTP1 promoter and increased the mRNA and protein levels of GSTP1 in an androgen-independent PC-3 cell line. In contrast, lycopene treatment did not demethylate the GSTP1 promoter or increase GSTP1 expression in the androgen-dependent LNCaP cell line. DNA methyltransferase (DNMT) 3A protein levels were downregulated in PC-3 cells following lycopene treatment; however, DNMT1 and DNMT3B levels were unchanged. Furthermore, the long interspersed element (LINE-1) and short interspersed element ALU were not demethylated when treated by lycopene. In LNCaP cells, lycopene treatment did not affect any detected DNMT protein expression, and the methylation levels of LINE-1 and ALU were decreased. These results indicated that the protective effect of lycopene on the prostate is different between androgen-dependent and androgen-independent derived PCa cells. Further, in vivo studies should be conducted to confirm these promising results and to evaluate the potential role of lycopene in the protection of the prostate.

16.
Mol Biol Rep ; 41(4): 1977-84, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24413994

RESUMO

Abnormal cell proliferation is a main driver of tumor formation and development, which involves the deletion, mutation, and downregulation of tumor suppressor genes. One study recently demonstrated that miR-200a plays an oncogenic role by inhibiting phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression. In the human endometrial adenocarcinoma cell line HEC-1B, suppression of miR-200a expression inhibited cell proliferation and promoted apoptosis, whereas its over-expression had no effect on proliferation and apoptosis. Furthermore, inhibition or over-expression of miR-200a increased or reduced the expression of PTEN, respectively, with no change in PTEN mRNA levels. These effects were achieved by directly targeting miR-200a to the 3' untranslated region of the PTEN mRNA to inhibit its translation. Taken together, we propose that in HEC-1B cells, miR-200a functions as an oncogene, affecting proliferation and apoptosis by regulating the expression of the tumor suppressor PTEN at the translational level.


Assuntos
Adenocarcinoma/genética , Apoptose/genética , Neoplasias do Endométrio/genética , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , Regiões 3' não Traduzidas , Pareamento de Bases , Sequência de Bases , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/química , PTEN Fosfo-Hidrolase/química , Interferência de RNA , RNA Mensageiro/genética , Transfecção
17.
Reprod Sci ; 21(6): 733-42, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24336674

RESUMO

Embryo implantation is a complicated process involving a series of endometrial changes that depend on differential gene expression. MicroRNAs (miRNAs) are important for regulation of gene expression. Previous studies have shown that miRNAs may participate in the regulation of gene expression during embryo implantation. To explore the role of endometrial miRNAs in early murine pregnancy, we used microarrays to investigate whether miRNAs were differentially expressed in the mouse endometrium on pregnancy day 4 (D4) and day 6 (D6). The results demonstrated that 17 miRNAs were upregulated and 18 were downregulated (>2-fold) in D6 endometria compared to D4. We identified that mmu-miR-193 exhibited the highest upregulation on D6, and the upregulation of mmu-miR-193 before embryo implantation could reduce the embryo implantation rate. Further, we demonstrated that mmu-miR-193 influenced embryo implantation by regulating growth factor receptor-bound protein 7 expression. In summary, our study suggests that mmu-miR-193 plays an important role in embryo implantation.


Assuntos
Implantação do Embrião/fisiologia , Proteína Adaptadora GRB7/biossíntese , MicroRNAs/fisiologia , Útero/metabolismo , Animais , Células Cultivadas , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Gravidez , Distribuição Aleatória
18.
Environ Toxicol Pharmacol ; 36(2): 648-58, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23892282

RESUMO

Benzo(a)pyrene (B[a]P) is an environmental carcinogen that induces tumors in many animal species, but the neurotoxic effects of B[a]P have not been well studied. In the present study, we investigated the effects of subacute exposure to B[a]P in Sprague-Dawley (SD) rats. Male rats received daily injections of either B[a]P (0, 1, 2.5, or 6.25mg/kg, i.p.) or vehicle for 45 days. Exposure to B[a]P affected the behavior of rats in the Morris water maze test. Gene microarray and real-time PCR analyses revealed that exposure to B[a]P affected signal transduction in the rat hippocampus. Protein microarray analysis revealed that altered protein expression played a role in cell death in the functional annotation cluster analysis. Finally, major vault protein was found to display low cDNA and protein expression levels. The present study explored some of the possible mechanisms underlying B[a]P neurotoxicity and provided evidence that B[a]P plays a neurotoxic role in rats.


Assuntos
Benzo(a)pireno/toxicidade , Carcinógenos Ambientais/toxicidade , Hipocampo/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Animais , Comportamento Animal/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Imuno-Histoquímica , Masculino , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/fisiopatologia , Síndromes Neurotóxicas/psicologia , Análise de Sequência com Séries de Oligonucleotídeos , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fatores de Tempo , Partículas de Ribonucleoproteínas em Forma de Abóbada/genética , Partículas de Ribonucleoproteínas em Forma de Abóbada/metabolismo
19.
Reprod Sci ; 20(12): 1518-28, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23690337

RESUMO

Successful mouse embryo implantation requires a receptive uterus and an activated blastocyst. A large number of genes, cytokines, and other factors are involved in the process. MicroRNAs (miRNAs) regulate the expression of many genes, and previous studies have investigated the relationship between miRNA expression and embryo implantation. In this study, we show that mmu-microRNA-200a (mmu-miR-200a) is expressed in a spatiatemporal manner during implantation in mouse uterus and found that phosphatase and tensin homolog (PTEN), SON, and programmed cell death 4 (Pdcd4) are the target genes of mmu-miR-200a by bioinformatics analysis. In vitro gain and loss of function experiments confirm that PTEN, a critical gene for cell proliferation and apoptosis, is the target gene of mmu-miR-200a. Our experiments also show that injection of the uterine horn with mmu-miR-200a lentivirus leads to a decreased implantation rate. Collectively, our results suggest that mmu-miR-200a affects embryo implantation by regulating PTEN protein expression. Thus, clarifying the physiological functions of uterine miRNAs will help to elucidate the embryo implantation process and may even contribute to curing infertility and inventing new contraceptives.


Assuntos
Implantação do Embrião , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Útero/enzimologia , Animais , Apoptose , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proliferação de Células , Células Cultivadas , Biologia Computacional , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Vetores Genéticos , Lentivirus/genética , Camundongos , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Transfecção , Regulação para Cima , Útero/fisiopatologia
20.
Mol Biol Rep ; 40(1): 651-63, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23065227

RESUMO

Full development of a receptive uterus is necessary for embryo implantation; however, many genes that are required for the endometrial modifications that occur during this process remain unidentified. To identify novel genes that control endometrial modifications during this period, we investigated the differential gene expression profile in the endometrium of mice on days 2 (D2) (pre-implantation) and 4 (D4) of pregnancy (i.e., the implantation window) using 17-bp long serial analysis of gene expression (LongSAGE). One hundred fifty-six tags were annotated as unique transcripts. Of these, 101 tags were significantly upregulated, and 55 tags were downregulated in the D4 library relative to the D2 library. These differentially expressed genes should therefore be of increased importance in the establishment of uterine receptivity. The differential expressions of certain of the identified genes, namely, Hspa8, Tctp, Sparc, Ifitm1, Ik, serbp1 and Dnmt1, were validated by semi-quantitative RT-PCR and/or immunohistochemistry. Functional grouping analysis classified 86 of the mapped tags into 17 categories, which are closely associated with morphological modifications of the endometrium during pregnancy. Ingenuity pathways analysis revealed that the identified differentially expressed genes fell into six primary networks, which themselves contain numerous factors that are related to key modulators of signaling pathways that are vital for endometrial modifications. These findings will aid in the further understanding of the molecular events that underlie the implantation physiology in mice.


Assuntos
Implantação do Embrião/genética , Endométrio/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Animais , Feminino , Biblioteca Gênica , Redes Reguladoras de Genes , Camundongos , Anotação de Sequência Molecular , Gravidez , Reprodutibilidade dos Testes
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