Yuan Li

Second Military Medical University, Shanghai, Shanghai, Shanghai Shi, China

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Publications (9)37.37 Total impact

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    ABSTRACT: Context:Increasing body of evidence indicates that human labor, either term or preterm, is an inflammatory event. Corticotropin-releasing hormone (CRH) has been implicated to be a trigger of human parturition.Objective:To investigate whether CRH induces the cascades of inflammation in human pregnant myometrium, thereby leading to activation of uterus.Design:The myometrial tissues were obtained from pregnant women who were in labor (TL) or not in labor (TNL) at term. The output of cytokines and prostaglandins (PGs) was determined by Multiplex and ELISA. Western blot analysis was used to determine the levels of uterine activation proteins (UAPs).Results:The levels of chemokines and cytokines as well as activated NK-κB were increased in TL group than TNL group. CRH stimulated production of a number of chemokines and cytokines in cultured uterine smooth muscle cells (USMCs), which induced chemotaxis of monocytes. These effects were mediated by CRHR1 and dependent on adenylyl cyclase(AC) /PKA and NF-κB signaling. Cocultures of CRH-treated USMCs with monocytes greatly enhanced output of cytokines and chemokines as well as PGs in cultures and increased the expression of UAPs in USMCs. Interleukin-1β(IL-1β), IL-6 and tumor necrosis factor α stimulated the expression of UAPs and output of PGs in USMCs.Conclusions:CRH induces the production of chemokines and cytokines in myometrium at term, subsequently results in the cascades of inflammation in uterus. The inflammation induced by CRH can lead to activation of uterus.
    The Journal of Clinical Endocrinology and Metabolism 11/2013; · 6.31 Impact Factor
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    ABSTRACT: Placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is reduced in pregnancies complicated with preeclampsia (PE). Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) have been shown to suppress 11β-HSD2 expression in human placental cells. Our objectives were to investigate whether the reduced 11β-HSD2 expression is associated with the changes in PPARs in PE placentas, and whether PPARα and PPARγ affect 11β-HSD2 expression in placental cells. PPARα and PPARβ/δ mRNA and protein expression were increased whereas PPARγ mRNA and protein expression was decreased in PE placentas. 11β-HSD2 protein expression inversely correlated to PPARβ/δ in normal placentas whereas correlated positively to PPARγ and inversely to PPARα in PE placentas. In cultured placental cells, PPARα agonist inhibited whereas PPARγ agonist stimulated 11β-HSD2 mRNA and protein expression and activity in a dose-dependent manner. Knockdown of RXRα resulted in a loss of PPARγ effect but not PPARα effect on11β-HSD2. PPARα effect was remained whereas PPARγ effect was lost in the presence of the translational inhibitor, cycloheximide (CHX). PPARγ agonist dose-dependently stimulated specificity protein 1 (Sp-1) protein expression. Inhibition or Knockdown of Sp-1 resulted in a loss of the effects of PPARα and PPARγ. The protein level of Sp-1 did not correlated to 11β-HSD2 and PPARs in normal placentas, whereas Sp-1 expression correlated to 11β-HSD2, PPARγ and PPARβ/δ in PE placentas. Our data indicate that 11β-HSD2 expression can be modulated by PPARα and PPARγ in placental trophoblasts through Sp-1.Decreased 11β-HSD2 expression in PE placenta might be associated with decreased PPARγ whilst increased PPARα expression.
    Endocrinology 10/2013; · 4.72 Impact Factor
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    ABSTRACT: The chorion laeve controls the levels of active prostaglandins within the uterus by NAD-dependent 15-hydroxy prostaglandin dehydrogenase (PGDH). The expression of PGDH in chorion is modulated by glucocorticoids and progesterone. In this study, we investigated glucocorticoid receptor (GR) and progesterone receptors A and B (PRA and PRB) in the regulation of PGDH expression in chorion, and we determined whether reduced PGDH expression in chorion during labor is associated with the changes in GR and PR expression by real-time RT-PCR and Western blot analysis. Dexamethasone (DEX) inhibited PGDH expression whereas progesterone stimulated PGDH expression in chorionic trophoblasts. DEX suppressed PGDH expression in GR overexpression and PR knockdown cells. The inhibitory effect of DEX did not occur in GR knockdown cells. Progesterone inhibited PGDH in GR overexpression and PR knockdown cells and it stimulated PGDH in PRB overexpression cells whereas it suppressed PGDH in PRA overexpression cells. Knockdown of c-Jun resulted in a loss of progesterone- and DEX-induced effects. PGDH was down-regulated in chorion tissues during labor. PRB was decreased whereas PRA and GR were increased in chorion during labor. Glucocorticoids inhibit PGDH expression via GR in chorionic trophoblasts. Progesterone enhances PGDH expression through PRB, whereas it inhibits PGDH expression via GR and PRA. Decreased PGDH expression is associated with increased GR and PRA, although decreased PRB, in chorion during labor.
    American Journal Of Pathology 03/2013; · 4.60 Impact Factor
  • Yuan Li, Hang Gu
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    ABSTRACT: To observe the selective regulation of peroxisome proliferator-activated receptors (PPAR) on fatty acid binding protein-4 (FABP4) in human syncytiotrophoblasts. Cultivate normal human syncytiotrophoblast cells, and put in the specific antagonists and agonists of PPAR each subtypes receptors, then observe the different expression of FABP4 mRNA and protein. Pretreated the human syncytiotrophoblast cells with the agonists (GW7647, GW0742) and antagonists (GW6471, GSK0660) of PPARα and PPARβ receptors, the expression of the FABP4 was not significantly change (P > 0.05). However pretreated with PPAR γ agonists (rosiglitazone, 1×10(-9), 1×10(-8), 1×10(-7) and 1×10(-6) mol/L), the expression of FABP4 mRNA and protein could be dose dependent-promoted significantly (mRNA: 1.27 ± 0.12, 1.45 ± 0.14, 1.57 ± 0.14, 1.72 ± 0.12, protein:1.10 ± 0.08, 1.37 ± 0.09, 1.60 ± 0.13, 1.79 ± 0.14; P < 0.05), furthermore, the promotion can be dose dependent-reversed by specific antagonists GW9662 (mRNA:0.92 ± 0.06, 0.77 ± 0.06, 0.64 ± 0.05, 0.55 ± 0.05, protein:0.91 ± 0.03, 0.78 ± 0.06, 0.70 ± 0.07, 0.55 ± 0.06; P < 0.05). In normal human syncytiotrophoblast cells, FABP4 is a target factor of PPARγ. PPARγ regulated the expression of FABP4 mRNA and protein selectively. And the regulation will not be influenced by the other two PPAR subtypes.
    Zhonghua fu chan ke za zhi 10/2012; 47(10):726-9.
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    ABSTRACT: Context: Our previous study has demonstrated that CRH has differential effects on human uterine contractility before and after onset of labor. Intracellular Ca(2+) concentration ([Ca(2+)]i) mobilization plays an important role in the control of uterine contraction. Objective: Our objective was to investigate the effects of CRH on [Ca(2+)]i homeostasis in laboring and nonlaboring myometrial cells and determine subsequent signaling involved in [Ca(2+)]i regulation by CRH. Design: The myometrial tissues were obtained from pregnant women who were undergoing or not undergoing labor at term. [Ca(2+)]i was determined by Ca(2+) imaging system using the fluorescent dye fura-2-acetoxymethyl ester. Western blot analysis, ELISA, and RIA were used to determine the signaling pathways induced by CRH. Results: CRH induced Ca(2+) transient in laboring cells, which was blocked by CRH receptor type 1 (CRHR1) antagonist antalarmin. CRHR1 knockdown impaired this effect of CRH. CRH activated Gi protein, decreased cAMP production, and induced phosphorylated phospholipase C-β3 and inositol-1,4,5-triphosphate production. Phospholipase C and inositol-1,4,5-triphosphate receptor inhibitors blocked the CRH-induced Ca(2+) transient in laboring cells. CRH did not induce whereas antalarmin induced the Ca(2+) transient in nonlaboring cells. Knockdown of CRHR1 impaired the effect of antalarmin. CRH acted on CRHR1 to activate Gs in nonlaboring cells. Forskolin blocked antalarmin-induced Ca(2+) transient. Conclusions: CRH acts on CRHR1 to activate different signaling pathways before and after onset of labor, thereby resulting in differential calcium signaling in response to CRH. The signaling pathways of CRHR1 might serve as a target for the development of new therapeutic strategies for preterm birth.
    The Journal of Clinical Endocrinology and Metabolism 08/2012; 97(10):E1851-61. · 6.31 Impact Factor
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    ABSTRACT: Glucose transport across the placenta is mediated by glucose transporters (GLUT), which is critical for normal development and survival of the fetus. Regulatory mechanisms of GLUT in placenta have not been elucidated. Placental CRH has been implicated to play a key role in the control of fetal growth and development. We hypothesized that CRH, produced locally in placenta, could act to modulate GLUT in placenta. To investigate this, we obtained human placentas from uncomplicated term pregnancies and isolated and cultured trophoblast cells. GLUT1 and GLUT3 expressions in placenta were determined, and effects of CRH on GLUT1 and GLUT3 were examined. GLUT1 and GLUT3 were identified in placental villous syncytiotrophoblasts and the endothelium of vessels. Treatment of cultured placental trophoblasts with CRH resulted in an increase in GLUT1 expression while a decrease in GLUT3 expression in a dose-dependent manner. Cells treated with either CRH antibody or nonselective CRH receptor (CRH-R) antagonist astressin showed a decrease in GLUT1 and an increase in GLUT3 expression. CRH-R1 antagonist antalarmin decreased GLUT1 expression while increased GLUT3 expression. CRH-R2 antagonist astressin2b increased the expression of both GLUT1 and GLUT3. Knockdown of CRH-R1 decreased GLUT1 expression while increased GLUT3 expression. CRH-R2 knockdown caused an increase in both GLUT1 and GLUT3 expression. Our data suggest that, in placenta, CRH produced locally regulates GLUT1 and GLUT3 expression, CRHR1 and CRHR2-mediated differential regulation of GLUT1 and GLUT3 expression. Placental CRH may regulate the growth of fetus and placenta by modulating the expression of GLUT in placenta during pregnancy.
    Endocrinology 03/2012; 153(3):1464-71. · 4.72 Impact Factor
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    ABSTRACT: CRH has been implicated to play a key role in the control of human pregnancy and parturition. Large-conductance potassium channels (BKCa) play a pivotal role in the modulation of uterine contractility during pregnancy. The objectives of the present study were to investigate the effect of CRH on BKCa expression in human pregnant myometrial cells. Myometrial tissues were collected at cesarean section from pregnant women not-in-labor (TNL) or in-labor (TL) at term, and myocytes were isolated and cultured. CRH was identified in human pregnant myometrium and mainly expressed in myometrial myocytes. Cultured myometrial cells were able to secrete CRH. In TNL myometrial cells, CRH treatment increased the expression of BKCa α- and β-subunits. CRH receptor type 1 (CRH-R1) antagonist, antalarmin, decreased whereas CRH receptor type 2 (CRH-R2) antagonist, astressin2b, increased the expression of BKCa. CRH-R2 small interfering RNA (siRNA) caused an increase, but CRH-R1 siRNA resulted in a decrease, in BKCa expression. In contrast to TNL cells, CRH exhibited an opposite effect on BKCa expression in TL myometrial cells, i.e. decreased BKCa expression. Antalarmin enhanced but astressin2b reduced BKCa expression. CRH-R2 siRNA decreased whereas CRH-R1 siRNA increased BKCa expression. 1,3-Dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one significantly inhibited the frequency of spontaneous contractions of myometrial strips, and this effect was significantly decreased in TL strips compared with TNL ones. Our data suggest that CRH-R1 and CRH-R2 show differential regulation of BKCa expression. These effects mediated by CRH-R1 and CRH-R2 are changed after the onset of labor. This leads us to suggest that CRH may fine-tune myometrial contractility by modulating the expression of BKCa during pregnancy and labor.
    Endocrinology 08/2011; 152(11):4406-17. · 4.72 Impact Factor
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    ABSTRACT: Sustained high concentration of glucose has been verified toxic to β-cells. Glucose augments Ca(2+)-stimulated insulin release in pancreatic β-cells, but chronic high concentration of glucose could induce a sustained level of Ca(2+) in β-cells, which leads to cell apoptosis. However, the mechanism of high glucose-induced β-cell apoptosis remains unclear. In this study, we use a calcium channel blocker, nifedipine, to investigate whether the inhibition of intracellular Ca(2+) concentration could protect β-cells from chronic high glucose-induced apoptosis. It was found that in a concentration of 33.3 mM, chronic stimulation of glucose could induce INS-1 β-cells apoptosis at least through the endoplasmic reticulum stress pathway and 10 μM nifedipine inhibited Ca(2+) release to protect β-cells from high glucose-induced endoplasmic reticulum stress and apoptosis. These results indicated that inhibition of Ca(2+) over-accumulation might provide benefit to attenuate islet β-cell decompensation in a high glucose environment.
    International Journal of Molecular Sciences 01/2011; 12(11):7569-80. · 2.46 Impact Factor
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    ABSTRACT: Human uterus undergoes distinct molecular and functional changes during pregnancy and parturition. Hydrogen sulfide (H(2)S) has recently been shown to play a key role in the control of smooth muscle tension. The role of endogenous H(2)S produced locally in the control of uterine contractility during labour is unknown. Human myometrium biopsies were obtained from pregnant women undergoing cesarean section at term. Immunohistochemistry analysis showed that cystathionine-γ-lyase (CSE) and cystathionine-β-synthetase (CBS), the principle enzymes responsible for H(2)S generation, were mainly localized to smooth muscle cells of human pregnant myometrium. The mRNA and protein expression of CBS as well as H(2)S production rate were down-regulated in labouring tissues compared to nonlabouring tissues. Cumulative administration of L-cysteine (10(-7)-10(-2) mol/L), a precursor of H(2)S, caused a dose-dependent decrease in the amplitude of spontaneous contractions in nonlabouring and labouring myometrium strips. L-cysteine at high concentration (10(-3) mol/L) increased the frequency of spontaneous contractions and induced tonic contraction. These effects of L-cysteine were blocked by the inhibitors of CBS and CSE. Pre-treatment of myometrium strips with glibenclamide, an inhibitor of ATP-sensitive potassium (K(ATP)) channels, abolished the inhibitory effect of L-cysteine on spontaneous contraction amplitude. The effects of L-cysteine on the amplitude of spontaneous contractions and baseline muscle tone were less potent in labouring tissues than that in nonlabouring strips. H(2)S generated by CSE and CBS locally exerts dual effects on the contractility of pregnant myometrium. Expression of H(2)S synthetic enzymes is down-regulated during labour, suggesting that H(2)S is one of the factors involved in the transition of pregnant uterus from quiescence to contractile state after onset of parturition.
    PLoS ONE 01/2011; 6(8):e23788. · 3.53 Impact Factor