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Feng Y.,Shanghai JiaoTong University | Zhao L.-Z.,Shanghai JiaoTong University | Hong L.,Shanghai JiaoTong University | Shan C.,Shanghai JiaoTong University | And 3 more authors.
Journal of Nutritional Biochemistry | Year: 2013

Epigenetics might explain correlations between lifestyle and risk of disease. Maternal diet has been shown to dynamically alter epigenetic regulation, including affecting DNA methylation status. This study was designed to test the hypothesis that GATA-4 gene methylation would lead to congenital heart defects in vitamin A-deficient offspring. Ten weaning female rats (VAN group) were fed with a diet which contents 4 IU vitamin A/g diet, while 20 rats (VAD group) were maintained on a diet without vitamin A. After 10 weeks of feeding, all the female rats were mated with normal male rats. The VAN group and a portion of VAD group rats were still given the same diet as before mating, while the rest of the rats from the VAD group (VADS group) were transferred to a diet with enough added vitamin A (10 IU/g diet) for the pregnancy cycle. The embryo hearts were dissected out at embryonic day 13.5 (E13.5) for observation of cardiac development, GATA-4 gene methylation status and the expression of DNA methyltransferases (DNMTs). Embryos from vitamin A-deficient group exhibited a high incidence of cardiac defects. High methylation was present in the CpG loci of GATA-4 gene with a low expression of GATA-4 mRNA from vitamin A-deficient group embryos. Moreover, up-regulation of DNMT1 and down-regulation of DNMT3a and DNMT3b expression were found in this group embryo. These findings show that aberrant methylation is one of key mechanisms to heart defects in vitamin A-deficient offspring. DNMTs play a critical role in this process. © 2013 Elsevier Inc.


Xiao Y.,Shanghai Institute of Pediatric Research | Chen Y.,Shanghai Institute of Pediatric Research | Chen Y.,Shanghai JiaoTong University | Wen J.,Shanghai Institute of Pediatric Research | And 4 more authors.
Critical Reviews in Eukaryotic Gene Expression | Year: 2012

Thymosin β4 (Tβ4), a 5 kDa protein, has been demonstrated to play an important role in a variety of biological activities, such as actin sequestering, cellular motility, migration, inflammation, and damage repair. Recently, several novel findings provided compelling evidence that Tβ4 played a key role in facilitating tumor metastasis and angiogenesis. It has been found that Tβ4 expressed increasingly in a number of metastatic tumors, which was associated with an increased expression of a known angiogenic factor, vascular endothelial growth factor. Thus, Tβ4 provided a potential target of opportunity for cancer management, especially for cancer metastasis therapy. © 2012 Begell House, Inc.


Chen Y.,Shanghai JiaoTong University | Chen Y.,Shanghai Institute of Pediatric Research | Chen Y.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition | Jie W.,Shanghai Institute of Pediatric Research | And 6 more authors.
Critical Reviews in Eukaryotic Gene Expression | Year: 2012

Lysine-specific demethylase 1 (LSD1), the first identified histone demethylase, was belonged to the superfamily of the flavin adenine dinucleotide (FAD)-dependent amine oxidases. LSD1 specifically demethylates mono or dimethylated dimethylated histone H3 lysine4 (H3K4) and H3 lysine 9 (H3K9) via a redox process. Recently evidences showed that LSD1 played an important role in a broad spectrum of biological processes, including cell proliferation, adipogenesis, spermatogenesis, chromosome segregation and embryonic development. Furthermore, LSD1 also could promote progress of tumor by inhibiting the tumor suppressor activity of p53. To date, as a potential drug for discovering anti-tumor drugs, the medical significance of LSD1 inhibitors have been greatly appreciated. Here, we reviewed the remarkable progress being made in understanding of LSD1, mainly on its structure, basic function and medical application in tumor therapy. © 2011 Begell House, Inc.


Feng Y.,Shanghai JiaoTong University | Yu Y.-M.,Shanghai JiaoTong University | Yin M.-Z.,Shanghai JiaoTong University | Hong L.,Shanghai JiaoTong University | And 2 more authors.
Journal of Nutritional Science and Vitaminology | Year: 2012

Vitamin A is a key micronutrient required during crucial stages of embryonic development and vitamin A deficiency (VAD) results in embryonic heart malformation. The pleiotropic functions of vitamin A are mediated by specific nuclear receptors: the retinoic acid receptors (RARα, -β, and -γ) and the retinoic X receptors (RXRα, -β, and -γ). The action of nuclear receptors has been implicated in controlling of cell proliferation, differentiation and apoptosis, and the expressions of these receptor genes are regulated by retinoic acid levels during the early stages of embryonic development. GATA-4 is one of the earliest transcription factors expressed in developing cardiac cells. However, the functional links of specific nuclear receptors to heart development in VAD embryos are not clearly understood. In our study, weaning female Sprague-Dawley rats were fed a modified diet containing different concentrations of vitamin A according to the American Institute of Nutrition 93 Growth Purified Diet. After 10-wk feeding, the female rats were mated with normal male rats, and a portion of them were transferred to a diet with enough added vitamin A for the pregnancy cycle. The embryo hearts were dissected out at embryonic day 13.5 (E13.5) to study the expression of RARs, RXRs and GATA-4. The embryo hearts from E18.5 were for observation of ultrastructural changes. In comparison to vitamin A supplemented groups, the embryo hearts from vitamin A insufficient groups exhibited ultrastructural changes and significantly lower expression of GATA-4, RARα, and -β, and higher expression of RXRα and - γ. Our findings suggest that the down-regulation of RARs and the up-regulation of RXRs resulted from VAD affected GATA-4 gene expression, which resulted in ultrastructural changes in embryo hearts due to maternal insufficiency of vitamin A during pregnancy.


Zhong Y.,Shanghai JiaoTong University | Zhong Y.,Shanghai Institute of Pediatric Research | Huang J.,Shanghai JiaoTong University | Tang W.,Shanghai JiaoTong University | And 4 more authors.
FEMS Immunology and Medical Microbiology | Year: 2012

The aim of the study was to investigate the effect of living probiotics, probiotic DNA and the synthetic oligodeoxynucleotides containing CpG motifs (CpG-ODN) on both immune response and intestinal barrier function in ovalbumin-sensitized rat and the underlying mechanisms. Brown-Norway rats were orally sensitized with ovalbumin, and living probiotics, probiotic DNA extraction, synthetic CpG-ODN or non-CpG ODN control was administered. In the living probiotics, probiotic DNA and CpG-ODN groups, the allergic response was significantly inhibited, the Th1/Th2 cytokine balance was shifted away from Th2 side, the percentage of CD4+CD25+high Treg cells was increased, and the intestinal barrier function was improved. The levels of toll-like receptor (TLR) 9 mRNA and nuclear factor (NF)-κB activity, as well as the IκB-α phosphorylation (p-IκB-α) was significantly increased in these three intervention groups compared with the OVA-positive group, whereas no such effects were found in the non-CpG ODN control group. These data show that the probiotic genomic DNA and the synthetic CpG-ODN was comparable with living probiotics in preventing food allergic response by immune modulation and intestinal barrier function enhancement, and the activation of TLR9/NF-κB signal pathway might be involved in this process. © 2012 Federation of European Microbiological Societies.


Xiao Y.,Shanghai JiaoTong University | Xiao Y.,Shanghai Institute of Pediatric Research | Xiao Y.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition | Wang J.,Shanghai JiaoTong University | And 16 more authors.
Cellular Signalling | Year: 2014

An increasing body of evidence suggests that miRNAs are involved in fibrotic process of several organs including heart, lung and kidney. It has been observed recently that aberrant expression of miR-200s are associated with hepatic fibrosis. However, the role and underlying mechanism of miR-200s in hepatic fibrogenesis remains unknown. Here, we investigate the role of miR-200b in the activation of immortalized human hepatic stallate cells (HSCs), LX-2 cells. We firstly found that miR-200b significantly enhanced proliferation and migration of LX-2 cells. Secondly, our findings showed that miR-200b enhanced the phosphorylation of Akt, a downstream effector of phosphatidyl-inositol 3-Kinase (PI3K). FOG2, as the targets of fly miR-8 and human miR-200s, directly binds to p85α and inhibits the activation of the PI3K/Akt pathway. Here, we showed that FOG2 protein levels in LX-2 cells were suppressed significantly by miR-200b mimics. FOG2 knockdown by siRNAs activated the PI3K/Akt signaling, which increased cell growth and migration that mimicked the effect of miR-200b. Conversely, LY294002, a highly selective inhibitor of PI3K, could block phosphorylation of Akt and effect of miR-200b. In addition, we showed that miR-200b enhanced the expression of matrix metalloproteinase-2 (MMP-2), which may increase the migration of LX-2 cells. Finally, our results indicated that the expression of miR-200b was unregulated in the biliary atresia (BA) and associated with liver fibrotic progression. These data suggest a potential mechanism for Akt activation through FOG2 down-regulation by miR-200b that can lead to HSC growth and migration. In view of the putative pathogenic role of miR-200b in HSCs, miR-200b may constitute a potential marker for HSC activation and liver fibrosis progression. © 2014 Elsevier Inc.


Chen Y.,Shanghai JiaoTong University | Chen Y.,Shanghai Institute of Pediatric Research | Chen Y.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition | Ge W.,Shanghai JiaoTong University | And 6 more authors.
International Journal of Molecular Medicine | Year: 2012

Intestinal fibrosis is one of the major serious complications of Crohn's disease (CD). However, there are no effective antifibrotic drugs to treat intestinal fibrosis in CD. Therefore, it is important to understand the pathogenesis of fibrosis in CD. It has been reported that members of the miR-200 family are essential in the regulation of renal fibro-genesis. In this study, we analyzed the function of miR-200a and miR-200b in intestinal fibrosis, which was induced by transforming growth factor β1 (TGF-β1) in vitro. Furthermore, we detected the expression of miR-200a and miR-200b in CD specimens, which were divided into groups of fibrosis and no-fibrosis. The results of this study showed that administration of miR-200b could partially protect intestinal epithelial cells from fibrogenesis invitro. Furthermore, we found that miR-200b was overexpressed in the serum of the fibrosis group. The results suggest that miR-200b has potential value for diagnostic and therapeutic applications for CD patients with fibrosis complications.


Xiao Y.,Shanghai JiaoTong University | Xiao Y.,Shanghai Institute of Pediatric Research | Xiao Y.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition | Wang J.,Shanghai JiaoTong University | And 16 more authors.
Journal of Hepatology | Year: 2015

Background & Aims Cholestatic liver disease is associated with dysregulated expression of microRNAs (miRNAs). However, it remains unknown whether miRNAs are involved in the cholestasis-induced proliferation of cholangiocytes. In this study, we tested the hypothesis that miRNAs modulate cholangiocyte proliferation through effects on the IL-6 pathway, a known regulator of cholangiocyte proliferation. Methods Expression of IL-6, Foxa2, and phosphorylated signal transducer activator of transcription 3 (STAT3) was investigated in patients with biliary atresia (BA) and in rats subjected to bile duct ligation (BDL). miRNA expression was determined in BA patients and BDL rats, with miRNA array and quantitative real-time PCR. Biological functions of miRNAs were studied using immunoblot, immunohistochemical and proliferation assays. Luciferase reporter assays and Western blots were performed to identify miRNA targets. Results Hepatic interleukin-6 (IL-6) expression was significantly elevated in BA patients and BDL rats, while the expression of miR-124 was dramatically decreased in comparison to controls. Moreover, mRNA levels of STAT3 and IL-6 receptor (IL-6R) were inversely correlated with those of miR-124. Ectopic expression of miR-124 inhibited IL-6-mediated cholangiocyte proliferation in vitro and cholangiocyte hyperplasia in vivo, through a mechanism involving direct targeting of the 3'-untranslated region of STAT3 and IL-6R. We further demonstrated that miR-200 family members were significantly upregulated in cholestasis and inhibited FOXA2 expression in cholangiocytes, which further enhanced the expression of IL-6. Conclusions Our findings suggest that downregulation of miR-124 and upregulation of miR-200 collaboratively promote bile duct proliferation through the IL-6/STAT3 pathway.


Xiao Y.,Shanghai JiaoTong University | Xiao Y.,Shanghai Institute of Pediatric Research | Xiao Y.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition | Yan W.,Shanghai JiaoTong University | And 12 more authors.
Cell Cycle | Year: 2015

Although our previous studies have provided evidence that oxidative stress has an essential role in total parenteral nutrition (TPN)-associated liver injury, the mechanisms involved are incompletely understood. Here, we show the existence of crosstalk between the miR-200 family of microRNAs and oxidative stress. The members of the miR-200 family are markedly enhanced in hepatic cells by hydrogen peroxide (H2O2) treatment. The upregulation of miR-200-3p in turn modulates the H2O2-mediated oxidative stress response by targeting p38α. The enhanced expression of miR-200-3p mimics p38α deficiency and promotes H2O2-induced cell death. Members of the miR-200 family that are known to inhibit the epithelial to mesenchymal transition (EMT) are induced by the tumor suppressor p53. Here, we show that p53 phosphorylation at Ser 33 contributes to H2O2-induced miR-200s transcription. In addition, we show that p38α can directly phosphorylate p53 at serine 33 upon H2O2 exposure. Thus, we suggest that in liver cells, the oxidative stress-induced, p38α-mediated phosphorylation of p53 at Ser33 is essential for the functional regulation of oxidative stress-induced miR-200 transcription by p53. Collectively, our data indicate that the p53-dependent expression of miR-200a-3p promotes cell death by inhibiting a p38/p53/miR-200 feedback loop. © 2015 Taylor & Francis Group, LLC.


PubMed | Shanghai Institute of Pediatric Research and Bengbu Medical College
Type: Journal Article | Journal: Molecular medicine reports | Year: 2015

Hepatoblastoma (HB) is the most common malignant hepatic tumor in children and complete surgical resection offers the highest possibility for cure in this disease. Tumor metastasis is the principle obstacle to the development of efficient treatments for patients with HB. The present study aimed to measure the expression levels of thymosin 4 (T4) in liver samples from patients with HB and to investigate the involvement of T4 in HB metastasis. The expression of T4 was significantly higher in liver samples from patients with metastatic HB and in the HepG2 metastatic HB cell line, compared with that in adjacent healthy liver samples and in the L02 healthy hepatic cell line. By contrast, the expression levels of epithelial-cadherin (E-cadherin) and cytosolic accumulation of -catenin, the two most prominent markers involved in epithelial-mesenchymal transition (EMT), were reduced in liver specimens from patients with metastatic HB compared with that of healthy adjacent control tissue. HepG2 cells were transfected with small interfering-RNA in order to downregulate T4 gene expression. This resulted in a reduced cell migratory capacity compared with control cells. T4 gene expression knockdown significantly inhibited transforming growth factor 1-mediated-EMT in vitro by upregulating the expression of E-cadherin. The results of the present study suggested that T4 may promote HB metastasis via the induction of EMT, and that T4 may therefore be a target for the development of novel treatments for patients with HB.

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