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1.  Hyaluronic acid prevents immunosuppressive drug-induced ovarian damage via up-regulating PGRMC1 expression 
Scientific Reports  2015;5:7647.
Chemotherapy treatment in women can frequently cause damage to the ovaries, which may lead to primary ovarian insufficiency (POI). In this study, we assessed the preventative effects of hyaluronic acid (HA) in immunosuppressive drug-induced POI-like rat models and investigated the possible mechanisms. We found that HA, which was reduced in primary and immunosuppressant-induced POI patients, could protect the immunosuppressant-induced damage to granulosa cells (GCs) in vitro. Then we found that HA blocked the tripterygium glycosides (TG) induced POI-like presentations in rats, including delayed or irregular estrous cycles, reduced 17 beta-estradiol(E2) concentration, decreased number of follicles, destruction of follicle structure, and damage of reproductive ability. Furthermore, we investigated the mechanisms of HA prevention effects on POI, which was associated with promotion of GC proliferation and PGRMC1 expression. In conclusion, HA prevents chemotherapy-induced ovarian damage by promoting PGRMC1 in GCs. This study may provide a new strategy for prevention and treatment of POI.
PMCID: PMC4284510  PMID: 25558795
2.  Phosphoinositide-Dependent Kinase 1 and mTORC2 Synergistically Maintain Postnatal Heart Growth and Heart Function in Mice 
Molecular and Cellular Biology  2014;34(11):1966-1975.
The protein kinase Akt plays a critical role in heart function and is activated by phosphorylation of threonine 308 (T308) and serine 473 (S473). While phosphoinositide-dependent kinase 1 (PDK1) is responsible for Akt T308 phosphorylation, the identities of the kinases for Akt S473 phosphorylation in the heart remain controversial. Here, we disrupted mTOR complex 2 (mTORC2) through deletion of Rictor in the heart and found normal heart growth and function. Rictor deletion caused significant reduction of Akt S473 phosphorylation but enhanced Akt T308 phosphorylation, suggesting that a high level of Akt T308 phosphorylation maintains Akt activity and heart function. Deletion of Pdk1 in the heart caused significantly enhanced Akt S473 phosphorylation that was suppressed by removal of Rictor, leading to worsened dilated cardiomyopathy (DCM) and accelerated heart failure in Pdk1-deficient mice. In addition, we found that increasing Akt S473 phosphorylation through deletion of Pten or chemical inhibition of PTEN reversed DCM and heart failure in Pdk1-deficient mice. Investigation of heart samples from human DCM patients revealed changes similar to those in the mouse models. These results demonstrated that PDK1 and mTORC2 synergistically promote postnatal heart growth and maintain heart function in postnatal mice.
PMCID: PMC4019065  PMID: 24662050
3.  Rare Detection of Occult Hepatitis B Virus Infection in Children of Mothers with Positive Hepatitis B Surface Antigen 
PLoS ONE  2014;9(11):e112803.
The prevalence of occult Hepatitis B virus (HBV) infection in children was considerably varied from 0.1–64% in different reports. In this study we aimed to investigate the prevalence of occult HBV infection among the children born to mothers with positive hepatitis B surface antigen (HBsAg) in Jiangsu, China. Serum samples were collected from 210 children of 207 mothers with positive HBsAg. HBV serological markers were detected by ELISA and HBV DNA was detected by nested PCR. Homology comparison of HBV sequences recovered from the child and mother was used to define the infection. Three children (1.43%) were positive for HBsAg, in whom the HBV pre S and S gene sequence in each child was identical to that in her mother. Of the 207 HBsAg-negative children, nine displayed HBV DNA positive by two nested PCR assays using primers derived from S and C genes. However, the sequence alignment showed that the sequences in each child were considerably different from those in his/her mother. Therefore, the sequences amplified from the children were very likely resultant from the cross-contaminations. Furthermore, the nine children with ‘positive HBV DNA’ were all negative for anti-HBc, and one had anti-HBs 3.42 mIU/ml and eight others had anti-HBs from 72 to >1000 mIU/ml, indicating that the nine children were less likely infected with HBV. Therefore, none of the 207 HBsAg-negative children of HBV-infected mothers was found to have occult HBV infection. We conclude that the prevalence of occult HBV infection in vaccinated children born to HBsAg positive mothers should be extremely low. We recommend that homology comparison of sequences recovered from the child and mother be used to define the occult HBV infection in children born to HBV infected mothers.
PMCID: PMC4226608  PMID: 25383543
4.  miR-145 inhibits isoproterenol-induced cardiomyocyte hypertrophy by targeting the expression and localization of GATA6 
FEBS letters  2013;587(12):1754-1761.
Excessive βAR stimulation is an independent factor in inducing pathological cardiac hypertrophy. Here, we report miR-145 regulates both expression and localization of GATA6, thereby protecting the heart against cardiomyocyte hypertrophy induced by isoproterenol (ISO). The protective activity of miR-145 was associated with down-regulation of ANF, BNP and β-MHC expression, a decreased rate of protein synthesis and inhibited cell growth in NRCMs. These effects were reversed by exogenous over-expression of GATA6. In addition, GSK3β antagonists, LiCl and TDZD8, restored the nuclear accumulation of GATA6 in the presence of miR-145. Finally, we observed a dynamic pattern of miR-145 expression in ISO-treated NRCMs and in the hearts of mice that had undergone TAC. Together, our results identify miR-145 as an important regulator in cardiac hypertrophy.
PMCID: PMC4183134  PMID: 23624080
miR-145; GATA6; cardiomyocyte; hypertrophy
5.  Second trimester amniotic fluid cytokine concentrations, Ureaplasma sp. colonisation status and sexual activity as predictors of preterm birth in Chinese and Australian women 
This study tested if second trimester amniotic fluid cytokine levels, Ureaplasma sp. colonisation and sexual activity predict preterm birth and explain the differential preterm birth rates in Chinese compared to Australian women.
Amniotic fluid was collected by amniocentesis (Chinese 480, Australian 492). Cytokines were measured by multiplex assay and Ureaplasma sp. DNA was detected by PCR analysis. Lifestyle factors, including history of smoking and sexual activity during pregnancy, were obtained through completion of questionnaires upon recruitment to the study.
Inflammatory cytokine concentrations were poorly predictive of preterm birth. Ureaplasma sp. was detected in two of the Chinese pregnancies and none from Australia. Sexual activity was less frequent in Chinese, and was not associated with preterm birth or amniotic fluid findings in either population.
Second trimester amniocentesis for measurement of inflammatory markers and Ureaplasma sp. DNA was not indicative of risk of preterm birth, at least in these populations. The lower rate of preterm birth in China was not explained by differences in amniotic fluid inflammatory markers, Ureaplasma sp. colonisation, or sexual activity.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2393-14-340) contains supplementary material, which is available to authorized users.
PMCID: PMC4261245  PMID: 25273669
Ureaplasma sp; Preterm birth; Cytokines; Amniotic fluid; Sex in pregnancy
6.  Cytomegalovirus Seroprevalence in Pregnant Women and Association with Adverse Pregnancy/Neonatal Outcomes in Jiangsu Province, China 
PLoS ONE  2014;9(9):e107645.
In this study, we aimed to determine the provincial population-based seroprevalence in pregnant women and to further explore the association of maternal CMV infection status and adverse pregnancy/neonatal/growth outcomes in Jiangsu, China.
In this case-control study, the sera from 527 pregnant women with adverse pregnancy/neonatal outcomes and 496 mothers of healthy infants in Jiangsu Province, collected at gestation age of 15–20 weeks, were tested for anti-CMV IgG, IgM and IgG avidity. Adverse pregnancy/neonatal outcomes were identified based on pregnancy/neonatal outcomes.
The overall seroprevalence of anti-CMV IgG was 98.7%, with 99.4% and 98.0% in the case and control groups, respectively (P = 0.039). The prevalence of anti-CMV IgG+/IgM+, was higher in the case group than that in the control group (3.8% vs. 1.6%, P = 0.033). Anti-CMV IgG avidity assay showed that none in the control group were primarily infected, but five (0.9%) in the case group underwent primary infection (P = 0.084); all five infants of these women presented severe adverse neonatal/growth outcomes. Exact logistic regression analysis showed that anti-CMV IgG+/IgM+ was associated with adverse pregnancy/neonatal/growth outcomes (aOR = 2.44, 95% CI 1.01–6.48, P = 0.047). Maternal low education level and prior abnormal pregnancies also were risk factors for adverse pregnancy/neonatal outcomes.
In populations with very high prevalence of latent CMV infection, active maternal CMV infection during pregnancy might be a risk factor for adverse pregnancy/neonatal outcomes.
PMCID: PMC4161444  PMID: 25211647
7.  Gestational hypoxia induces preeclampsia-like symptoms via heightened endothelin-1 signaling in pregnant rats 
Hypertension  2013;62(3):10.1161/HYPERTENSIONAHA.113.01449.
Preeclampsia is a life-threatening pregnancy disorder. However, its pathogenesis remains unclear. We tested the hypothesis that gestational hypoxia induces preeclampsia-like symptoms via heightened endothelin-1 signaling. Time-dated pregnant and non-pregnant rats were divided into normoxic and hypoxic (10.5% O2 from the gestational day 6 to 21) groups. Chronic hypoxia had no significant effect on blood pressure or proteinuria in non-pregnant rats but significantly increased blood pressure in day 12 (systolic blood pressure: 111.7 ± 6.1 versus 138.5 ± 3.5 mmHg, P = 0.004) and day 20 (systolic blood pressure: 103.4 ± 4.6 versus 125.1 ± 6.1 mmHg, P = 0.02) in pregnant rats, as well as urine protein (μg/μL)/creatinine (nmol/μL) ratio in day 20 (0.10 ± 0.01 versus 0.20 ± 0.04, P = 0.04), as compared with the normoxic control group. This was accompanied with asymmetrical fetal growth restriction. Hypoxia resulted in impaired trophoblast invasion and uteroplacental vascular remodeling. In addition, plasma endothelin-1 levels, as well as the abundance of prepro-endothelin-1 mRNA, endothelin-1 type A receptor and angiotensin II type 1 receptor protein in the kidney and placenta were significantly increased in the chronic hypoxic group, as compared with the control animals. Treatment with the endothelin-1 type A receptor antagonist, BQ123 during the course of hypoxia exposure significantly attenuated the hypoxia-induced hypertension and other preeclampsia-like features. The results demonstrate that chronic hypoxia during gestation induces preeclamptic symptoms in pregnant rats via heightened endothelin-1 and endothelin-1 type A receptor-mediated signaling, providing a molecular mechanism linking gestational hypoxia and increased risk of preeclampsia.
PMCID: PMC3826959  PMID: 23817493
preeclampsia; hypoxia; hypertension; endothelin-1; ETAR; AT1R
8.  Differential expression of microRNAs in decidua-derived mesenchymal stem cells from patients with pre-eclampsia 
Mesenchymal stem cells (MSCs) at maternal-fetal interface are considered to play an important role in the pathogenesis of pre-eclampsia (PE). microRNAs (miRNAs) also have an important influence on differentiation, maturation, and functions of MSCs. Our aim in this study was to determine the differential expression of miRNAs in decidua-derived MSCs (dMSCs) from severe PE and normal pregnancies.
miRNA expression profiles in dMSCs from five patients with severe PE and five healthy pregnant women were screened using microarray. Then, bioinformatic analysis of the microarray results was performed. Out of 179 differentially expressed miRNAs, 49 miRNAs had significant (p < 0.05) differential expression of ≥ 2.0-fold changes, including 21 up-regulated and 28 down-regulated. miRNA-Gene-network and miRNA-Gene ontology (GO) -network analyses were performed. Overall, 21 up-regulated and 15 down-regulated miRNAs showed high degrees in these analyses. Moreover, the significantly enriched signaling pathways and GOs were identified. The analyses revealed that pathways associated with cell proliferation, angiogenesis, and immune functions were highly regulated by the differentially expressed miRNAs, including Wnt signaling pathway, mitogen-activated protein kinase signaling pathway, transforming growth factor beta signaling pathway, T-cell receptor signaling pathway, and B cell receptor signaling pathway. Four miRNA predicted target genes, vascular endothelial growth factor A (VEGFA), indoleamine 2,3-dioxygenase, suppression of cytokine signaling 3, and serine/threonine protein phosphatase 2A 55 kDa regulatory subunit B α isoform (PPP2R2A) were all decreased in dMSCs from patients with PE. Furthermore, the physiological roles of miR-16 and miR-136 in the down-regulation of VEGFA and PPP2R2A, respectively, were confirmed through reporter assays.
These findings suggest that miRNAs in dMSCs may be important regulatory molecules in the development of PE.
PMCID: PMC4237795  PMID: 25135655
Pre- eclampsia; Mesenchymal stem cells; miRNAs; Microarray
9.  Estrogen Regulates the Tumour Suppressor MiRNA-30c and Its Target Gene, MTA-1, in Endometrial Cancer 
PLoS ONE  2014;9(3):e90810.
MicroRNA-30c (miR-30c) has been reported to be a tumour suppressor in endometrial cancer (EC). We demonstrate that miR-30c is down-regulated in EC tissue and is highly expressed in estrogen receptor (ER)-negative HEC-1-B cells. MiR-30c directly inhibits MTA-1 expression and functions as a tumour suppressor via the miR-30c-MTA-1 signalling pathway. Furthermore, miR-30c is decreased upon E2 treatment in both ER-positive Ishikawa and ER-negative HEC-1-B cells. Taken together, our results suggest that miR-30c is an important deregulated miRNA in EC and might serve as a potential biomarker and novel therapeutic target for EC.
PMCID: PMC3940948  PMID: 24595016
10.  Mesenchymal Stem Cells Ameliorate Th1-Induced Pre-Eclampsia-Like Symptoms in Mice via the Suppression of TNF-α Expression 
PLoS ONE  2014;9(2):e88036.
Pre-eclampsia (PE) is thought to be a pregnancy-induced autoimmune disease. Despite several strategies carried out for targeting specific factors relevant to its pathogenesis, PE remains potentially fatal to some patients. Here, we reported a way to isolate mesenchymal stem cells (MSCs) from decidua. The MSCs not only exhibited differentiation and self-renewal capacities, they also possessed immunomodulatory functions and secreted some soluble mediators including IL-6, TGF-β, IDO, VEGF and COX-2. Most importantly, the MSCs were specifically provided with the ability to suppress T cells proliferation by IDO in response to inflammatory cytokine IFN-γ. Moreover, we developed a Th1 cell-induced PE mouse model which displayed a high level of pathogenesis factor TNF-α. Strikingly, MSCs-based therapy significantly ameliorated both clinical and histopathological severity of PE symptoms including decreasing the blood pressure and proteinuria, suppressing glomerulonephritis, protecting the feto-placental development. The therapy also reversed abnormal TNF-α expression in uterine and splenic lymphocytes. These data suggest that MSCs may ameliorate Th1-induced PE-like symptoms in mice via the suppression of TNF-α and MSCs-based therapy may provide a potential novel method for PE.
PMCID: PMC3928118  PMID: 24558374
11.  CAPN 7 promotes the migration and invasion of human endometrial stromal cell by regulating matrix metalloproteinase 2 activity 
Matrix metalloproteinase 2 (MMP-2) has been reported to be an important regulator of cell migration and invasion through degradation of the extracellular matrix (ECM) in many diseases, such as cancer and endometriosis. Here, we found calcium-activated neutral protease 7 (CAPN 7) expression was markedly upregulated in the eutopic endometrium and endometrial stromal cells of women diagnosed with endometriosis. Our studies were carried out to detect the effects of CAPN 7 on human endometrial stromal cell (hESC) migration and invasion.
Western blotting and quantitative real-time PCR were used to detect the expression of CAPN 7 in endometriosis patients and normal fertile women. Scratch-wound-healing and invasion chamber assay were used to investigate the role of CAPN 7 in hESC migration and invasion. Western blotting, quantitative real-time PCR and zymography were carried out to detect the effect of CAPN 7 on the expressions and activity of MMP-2.
CAPN 7 was markedly up-regulated in endometriosis, thereby promoting the migration and invasion of hESC. CAPN 7 overexpression led to increased expression of MMP-2 and tissue inhibitor of metalloproteinases 2 (TIMP-2); CAPN 7 knockdown reversed these changes. CAPN 7 increased MMP-2 activity by increasing the ratio of MMP-2 to TIMP-2. We also found that OA-Hy (an MMP-2 inhibitor) decreased the effects of CAPN 7 overexpression on hESC migration and invasion by approximately 50% and 55%, respectively. Additionally, a coimmunoprecipitation assay demonstrated that CAPN 7 interacted with activator protein 2α (AP-2α): an important transcription factor of MMP-2.
CAPN 7 promotes hESC migration and invasion by increasing the activity of MMP-2 via an increased ratio of MMP-2 to TIMP-2.
PMCID: PMC3717291  PMID: 23855590
CAPN 7; Endometrial stromal cell; Migration; Invasion
12.  Diagnostic challenges in minimal deviation adenocarcinoma of the uterine cervix: A report of two cases and review of the literature 
Molecular and Clinical Oncology  2013;1(5):833-838.
Minimal deviation adenocarcinoma (MDA) of the uterine cervix, otherwise known as adenoma malignum, is a rare variant of cervical adenocarcinoma, which represents a diagnostic challenge in the field of gynecologic oncology, due to its benign-resembling histological characteristics. To achieve a better understanding of this disease, we present two cases of MDA: one case presented with profuse watery discharge and cervical enlargement, accompanied by retention cysts and hardening; the other presented with a history of myoma cervicis uteri. Both patients underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy and our follow-up indicated that the patients were still free of any disease. Subsequently, a literature review was performed and the results demonstrated that early diagnosis, clinical stage and surgical protocols are the main factors affecting the prognosis of MDA. Close follow-up of the cases may provide more information regarding this disease and the efficacy of the available therapeutic methods.
PMCID: PMC3916131  PMID: 24649256
minimal deviation adenocarcinoma; uterine cervix; case report; literature
13.  Effect of elective cesarean section on the risk of mother-to-child transmission of hepatitis B virus 
Many clinicians and hepatitis B virus (HBV)-infected pregnant women prefer elective caesarean section (ECS) to prevent mother-to-child transmission of HBV, since some studies found higher transmission of HBV in infants born by vaginal delivery (VD) than by cesarean section. However, other studies showed that ECS does not reduce the risk of being infected with HBV in infants. In this study, we aimed to clarify whether ECS may reduce the risk of mother-to-child transmission of HBV.
Totally 546 children (1–7-year-old) born to 544 HBsAg-positive mothers from 15 cities and rural areas across Jiangsu Province, China, were enrolled. Of these children, 137 (2 pairs of twins) were born to HBeAg-positive mothers; 285 were delivered by ECS and 261 others by VD (one pair of twin in each group). HBV serologic markers were tested by enzyme or microparticle immunoassay.
The maternal and gestational ages, maternal HBeAg-positive rates, and children’s ages, gender ratios, hepatitis B vaccine coverage and administrations of HBIG were comparable between ECS and VD groups (all p >0.05). The overall prevalence of HBsAg in the 546 children was 2.4%, with 2.5% (7/285) and 2.3% (6/261) in those born by ECS and VD respectively (p = 0.904). Further comparison of chronic HBV infection in the 137 children of HBeAg-positive mothers showed that the HBsAg-positive rates in ECS and VD groups were 10.3% (7/68) and 8.7% (6/69) respectively (p = 0.750), while the mothers had similar HBV DNA levels (2.38 × 106 vs. 2.35 × 106 IU/ml, p = 0.586). Additionally, the overall rate of anti-HBs ≥10 mIU/ml in the children was 71.6%, with 72.3% and 70.9% in those born by ECS and VD respectively (p = 0.717).
With the recommended immunoprophylaxis against hepatitis B, ECS does not reduce the risk of mother-to-child transmission of HBV. Therefore, ECS should not be used in HBsAg-positive pregnant women to prevent mother-to-child transmission of HBV.
PMCID: PMC3664615  PMID: 23706093
Hepatitis B virus; Mother-to-child transmission; Vaginal delivery; Caesarean section
14.  MicroRNA-181a Suppresses Mouse Granulosa Cell Proliferation by Targeting Activin Receptor IIA 
PLoS ONE  2013;8(3):e59667.
Activin, a member of the transforming growth factor-β superfamily, promotes the growth of preantral follicles and the proliferation of granulosa cells. However, little is known about the role of microRNAs in activin-mediated granulosa cell proliferation. Here, we reported a dose- and time-dependent suppression of microRNA-181a (miR-181a) expression by activin A in mouse granulosa cells (mGC). Overexpression of miR-181a in mGC suppressed activin receptor IIA (acvr2a) expression by binding to its 3′-untranslated region (3′-UTR), resulting in down-regulation of cyclin D2 and proliferating cell nuclear antigen expression, leading to inhibition of the cellular proliferation, while overexpression of acvr2a attenuated the suppressive effect of miR-181a on mGC proliferation. Consistent with the inhibition of acvr2a expression, miR-181a prevented the phosphorylation of the activin intracellular signal transducer, mothers against decapentaplegic homolog 2 (Smad2), leading to the inactivation of activin signaling pathway. Interestingly, we found that miR-181a expression decreased in ovaries of mice at age of 8, 12, and 21 days, as compared with that in ovaries of 3-day old mice, and its level was reduced in preantral and antral follicles of mice compared with that in primary ones. Moreover, the level of miR-181a in the blood of patients with premature ovarian failure was significantly increased compared with that in normal females. This study identifies an interplay between miR-181a and acvr2a, and reveals an important role of miR-181a in regulating granulosa cell proliferation and ovarian follicle development.
PMCID: PMC3604175  PMID: 23527246
15.  Breastfeeding Is Not a Risk Factor for Mother-to-Child Transmission of Hepatitis B Virus 
PLoS ONE  2013;8(1):e55303.
Many clinicians do not encourage breastfeeding in hepatitis B virus (HBV) carriers, since HBV DNA can be detected in breast milk and breast lesions may increase exposure of infants to HBV. The aim of this study was to determine whether breastfeeding may add risk for perinatal HBV transmission.
Methodology/Principal Findings
Totally 546 children (1–7-year-old) of 544 HBV-infected mothers were investigated, with 397 breastfed and 149 formula-fed; 137 were born to HBeAg-positive mothers. All children had been vaccinated against hepatitis B but only 53.3% received hepatitis B immune globulin (HBIG). The overall prevalence of HBsAg+, HBsAg−/anti-HBc+, and anti-HBs (≥10 mIU/ml) in children was 2.4%, 3.1%, and 71.6% respectively. The HBsAg prevalence in breast- and formula-fed children was 1.5% and 4.7% respectively (P = 0.063); the difference was likely due to the higher mothers' HBeAg-positive rate in formula-fed group (formula-fed 49.0% vs. breastfed 15.9%, P<0.001). Further logistic regression analyses showed that breastfeeding was not associated with the HBV infection in the children, adjusting for the effect of maternal HBeAg status and other factors different between the two groups.
Under the recommended prophylaxis, breastfeeding is not a risk factor for mother-to-child transmission of HBV. Therefore, clinicians should encourage HBV-infected mothers to breastfeed their infants.
PMCID: PMC3557270  PMID: 23383145
16.  Kinetics of IgG antibody to cytomegalovirus (CMV) after birth and seroprevalence of anti-CMV IgG in Chinese children 
Virology Journal  2012;9:304.
Prevalence of cytomegalovirus (CMV) infection is 90–100% in developing countries; however, the kinetics of anti-CMV IgG in infants remains elusive.
Sera from 112 mother-newborn pairs and longitudinal samples from 41 infants up to 2-year old were tested for anti-CMV IgG and IgM. Additionally, samples from 837 healthy children were included.
Of 112 mothers, 108 (96.4%) were anti-CMV IgG positive; their 108 newborns were also seropositive. In a 2-year follow-up among 40 infants of positive mothers, anti-CMV IgG level in 8 individuals decreased with time and became undetectable by age of 3.5–8 months, and that in 32 others decreased at 1- and 3.5-month old, and then increased. Based on the positive IgM, rising IgG levels, and low anti-CMV IgG avidity index, 76.7% of the primary infections were demonstrated to occur during 1–3.5 months of age. The overall seroprevalence of anti-CMV in 837 children was 82.4%, which was generally constant from 2 to 8 years old (χ2 = 3.150, p = 0.790).
The maternally acquired anti-CMV IgG in infants disappears before 8-month old. Primary CMV infection in Chinese children mostly occurs during 1–3.5 months of age. Whether the relatively lower seroprevalence of anti-CMV in Chinese children found in this survey may reflect the positive rate in child-bearing age women in the future remains to be further studied.
PMCID: PMC3544651  PMID: 23228149
Cytomegalovirus; Anti-CMV IgG; Kinetics; Primary infection; Children
17.  MicroRNA-145 Protects Cardiomyocytes against Hydrogen Peroxide (H2O2)-Induced Apoptosis through Targeting the Mitochondria Apoptotic Pathway 
PLoS ONE  2012;7(9):e44907.
MicroRNAs, a class of small and non-encoding RNAs that transcriptionally or post-transcriptionally modulate the expression of their target genes, has been implicated as critical regulatory molecules in many cardiovascular diseases, including ischemia/reperfusion induced cardiac injury. Here, we report microRNA-145, a tumor suppressor miRNA, can protect cardiomyocytes from hydrogen peroxide (H2O2)-induced apoptosis through targeting the mitochondrial pathway. Quantitative real-time PCR (qPCR) demonstrated that the expression of miR-145 in either ischemia/reperfused mice myocardial tissues or H2O2-treated neonatal rat ventricle myocytes (NRVMs) was markedly down-regulated. Over-expression of miR-145 significantly inhibited the H2O2-induced cellular apoptosis, ROS production, mitochondrial structure disruption as well as the activation of key signaling proteins in mitochondrial apoptotic pathway. These protective effects of miR-145 were abrogated by over-expression of Bnip3, an initiation factor of the mitochondrial apoptotic pathway in cardiomyocytes. Finally, we utilized both luciferase reporter assay and western blot analysis to identify Bnip3 as a direct target of miR-145. Our results suggest miR-145 plays an important role in regulating mitochondrial apoptotic pathway in heart challenged with oxidative stress. MiR-145 may represent a potential therapeutic target for treatment of oxidative stress-associated cardiovascular diseases, such as myocardial ischemia/reperfusion injury.
PMCID: PMC3445575  PMID: 23028672
18.  Gaps in the prevention of perinatal transmission of hepatitis B virus between recommendations and routine practices in a highly endemic region: a provincial population-based study in China 
BMC Infectious Diseases  2012;12:221.
Hepatitis B virus (HBV) infection is endemic in China; perinatal transmission is the main source of chronic HBV infection. Simultaneous administration of hepatitis B immune globulin (HBIG) and hepatitis B vaccine is highly effective to prevent perinatal transmission of HBV; however, the effectiveness also depends on full adherence to the recommended protocols in daily practice. In the present investigation, we aimed to identify gaps in immunoprophylaxis of perinatal transmission of HBV between recommendations and routine practices in Jiangsu Province, China.
Totally 626 children from 6 cities and 8 rural areas across Jiangsu Province, China, born from February 2003 to December 2004, were enrolled; 298 were born to mothers with positive hepatitis B surface antigen (HBsAg) and 328 were born to HBsAg-negative mothers. Immunoprophylactic measures against hepatitis B were retrospectively reviewed for about half of the children by checking medical records or vaccination cards and the vaccine status was validated for most of children.
Of 298 children born to HBV carrier mothers, 11 (3.7%) were HBsAg positive, while none of 328 children born to non-carrier mothers was HBsAg positive (P < 0.01). The rates of anti-HBs ≥ 10 mIU/ml in children of carrier and non-carrier mothers were 69.5% and 69.2% respectively (P = 0.95). The hepatitis B vaccine coverage in two groups was 100% and 99.4% respectively (P = 0.50), but 15.1% of HBV-exposed infants did not receive the timely birth dose. Prenatal HBsAg screening was performed only in 156 (52.3%) of the carrier mothers. Consequently, only 112 (37.6%) of HBV-exposed infants received HBIG after birth. Furthermore, of the 11 HBV-infected children, only one received both HBIG and hepatitis B vaccine timely, seven missed HBIG, two received delayed vaccination, and one missed HBIG and received delayed vaccination.
There are substantial gaps in the prevention of perinatal HBV infection between the recommendations and routine practices in China, which highlights the importance of full adherence to the recommendations to eliminate perinatal HBV infection in the endemic regions.
PMCID: PMC3462156  PMID: 22984924
Hepatitis B virus; Perinatal infection; Immunoprophylaxis; Gaps
19.  Interstitial magnetic resonance lymphography is an effective diagnostic tool for the detection of lymph node metastases in patients with cervical cancer 
BMC Cancer  2012;12:360.
The aim of the present study was to determine the feasibility of detecting sentinel lymph node (SLN) metastases using interstitial magnetic resonance (MR) lymphography in patients with cervical cancer. MR data were compared to pathological results from the lymph nodes excised during surgery.
Twenty-eight patients with cervical cancer were enrolled and studied from January 2006 to December 2010. All patients underwent interstitial MR lymphography to determine the presence of sentinel lymph nodes and visualize lymphatic vessel drainage in the pelvis. Radical hysterectomy and excision of pelvic lymph nodes was performed according to their lesion grade. Gadodiamide was injected either intradermally into the bipedal toe web, into the labia majora or into the cervical tissue. MR results were compared with pathological reports.
In 28 patients, lymphatic vessel drainage and lymph node groups were clearly visualized. Of these, 5 were MR lymphography positive and 23 were MR lymphography negative. Six had pathologically proven metastasis, five had true positives and 1 had a false negative in the obturator lymph node.
Interstitial MR lymphography can be used to determine the extent and shape of pelvic lymphatic vessel drainage and lymph node metastases in patients with cervical cancer.
PMCID: PMC3492153  PMID: 22900495
Cervical cancer; Magnetic resonance (MR); Lymphography
20.  Orphan Nuclear Receptor Nur77 Regulates Androgen Receptor Gene Expression in Mouse Ovary 
PLoS ONE  2012;7(6):e39950.
The androgen receptor (AR) is a nuclear receptor that is expressed in growing follicles and involved in folliculogenesis and follicle growth. The orphan nuclear receptor, Nur77, also has an important role in steroid signaling and follicle maturation. We hypothesized that AR levels and androgen signaling through AR are regulated by Nur77 in the ovary. In the ovaries of Nur77 knockout mice (n = 5), real-time PCR results showed that the mRNA levels of AR and an androgen signaling target gene, Kitl, were decreased by 35% and 24%, respectively, relative to wild-type mice (n = 5), which suggested transcriptional regulation of AR by Nur77 in vivo. In cultured mouse granulosa cells and a steroidogenic human ovarian granulosa-like tumor cell line, KGN, mRNA and protein expression levels of AR were increased by overexpressing Nur77 but decreased by knocking down endogenous Nur77. Consistent with increased AR expression, chromatin immunoprecipitation showed that Nur77 bound to the NGFI-B response element (NBRE) in the AR promoter sequence. AR promoter activity was stimulated by Nur77 in HEK293T cells and attenuated in Nur77 knockout mouse granulosa cells (luciferase assay). Overexpression of Nur77 enhanced the androgenic induction of Kitl (200 nM; 48h), while knockout of Nur77 attenuated this induction. These results demonstrate that AR is regulated by Nur77 in the ovaries, and they suggest that the participation of Nur77 in androgen signaling may be essential for normal follicular development.
PMCID: PMC3386274  PMID: 22761936
21.  microRNA-103 regulates the growth and invasion of endometrial cancer cells through the downregulation of tissue inhibitor of metalloproteinase 3 
Oncology Letters  2012;3(6):1221-1226.
Despite improvements in treatment over the past few decades, endometrial cancer remains one of the most common causes of mortality in women and there is an urgent need for the development of targeted therapies. The aim of this study was to confirm the target gene of miR-103 in human endometrial cancer and investigate the biological functions in which miR-103 is involved through the regulation of the expression of its target gene. This study may provide useful data to gain a better understanding of the effect of miR-103 in tumor formation. miR-103 expression levels were measured using real-time quantitative PCR. The effect of miR-103 on tissue inhibitor of metalloproteinase 3 (TIMP-3) expression was assessed in endometrial cancer cell lines with a miR-103 inhibitor to decrease the level of miR-103 expression. Furthermore, the roles of miR-103 in cell growth and invasion were analyzed using miR-103 inhibitor-transfected cells. The level of expression of miR-103 decreased following transfection with the miR-103 inhibitor. miR-103 inhibitor transfection increased the activity of the luciferase reporter assay containing the TIMP-3 3’-untranslated region (UTR) construct and increased the levels of the TIMP-3 protein but not its mRNA in endometrial cancer cell lines. Finally, miR-103 inhibitor-transfected cells exhibited reduced cell growth and invasive characteristics. Our data suggested that miR-103 post-transcriptionally downregulates the expression of the tumor suppressor TIMP-3 and stimulates growth and invasion in endometrial cancer cell lines. This provides a possible therapeutic target that may upregulate TIMP-3 in endometrial cancer.
PMCID: PMC3392565  PMID: 22783422
miR-103; endometrial cancer; tissue inhibitor of metalloproteinase 3; Ishikawa cells; HEC-1B cells
22.  Transplacentally Acquired Maternal Antibody against Hepatitis B Surface Antigen in Infants and its Influence on the Response to Hepatitis B Vaccine 
PLoS ONE  2011;6(9):e25130.
Passively acquired maternal antibodies in infants may inhibit active immune responses to vaccines. Whether maternal antibody against hepatitis B surface antigen (anti-HBs) in infants may influence the long-term immunogenicity of hepatitis B vaccine remains unknown.
Methodology/Principal Findings
Totally 338 pairs of mothers and children were enrolled. All infants were routinely vaccinated against hepatitis B based on 0-, 1- and 6-month schedule. We characterized the transplacental transfer of maternal anti-HBs, and compared anti-HBs response in children of mothers with or without anti-HBs. In a prospective observation, all 63 anti-HBs positive mothers transferred anti-HBs to their infants; 84.1% of the infants had higher anti-HBs concentrations than their mothers. One and half years after vaccination with three doses of hepatitis B vaccine, the positive rate and geometric mean concentration (GMC) of anti-HBs in 32 infants with maternal anti-HBs were comparable with those in 32 infants without maternal antibody (90.6% vs 87.5%, P = 0.688, and 74.5 vs 73.5 mIU/ml, P = 0.742, respectively). In a retrospective analysis, five and half years after vaccination with three doses vaccine, the positive rates of anti-HBs in 88 children of mothers with anti-HBs ≥1000 mIU/ml, 94 children of mothers with anti-HBs 10–999 mIU/ml, and 61 children of mothers with anti-HBs <10 mIU/ml were 72.7%, 69.2%, and 63.9% (P = 0.521), respectively; anti-HBs GMC in these three groups were 38.9, 43.9, and 31.7 mIU/ml (P = 0.726), respectively.
The data demonstrate that maternal anti-HBs in infants, even at high concentrations, does not inhibit the long-term immunogenicity of hepatitis B vaccine. Thus, current hepatitis B vaccination schedule for infants will be still effective in the future when most infants are positive for maternal anti-HBs due to the massive vaccination against hepatitis B.
PMCID: PMC3178586  PMID: 21966434
23.  Cardiovascular Effects of Losartan and Its Relevant Clinical Application 
Current medicinal chemistry  2009;16(29):3841-3857.
The renin-angiotensin system (RAS) plays an important role in the homeostasis of the cardiovascular system and in the development of cardiovascular diseases. An abnormal expression or over activation of the local RAS in the heart and vasculature system is one of the most common mechanisms in pathophysiological processes in cardiovascular diseases. This also provides a basis for medical prevention and treatments using chemical approaches. Losartan is a selective nonpeptite antagonist against type 1 angiotensin II receptors (AT1R), and has been applied in medical treatments of a variety of cardiovascular diseases, including essential hypertension. This article reviews direct and indirect cardiovascular effects of losartan on the heart and blood vessels. It summarizes the chemical basis of AT1R for the action site of losartan, focuses on the mechanisms underlying the action of losartan involved in both the heart and vasculature, and reviews the information that may be helpful in the development of new chemical candidates or approaches in the war against cardiovascular diseases.
PMCID: PMC2888651  PMID: 19747137
Angiotensin II; heart; losartan; renin-angiotensin system; cardiac remodeling; hypertension
24.  Changes of Renal AT1/AT2 Receptors and Structures in Ovine Fetuses following Exposure to Long-Term Hypoxia 
American Journal of Nephrology  2009;31(2):141-150.
The present study tested the hypothesis that chronic hypoxia adversely affects renal development in the ovine fetus.
Kidneys were collected from near-term fetuses of pregnant ewes maintained at sea level or high altitude (3,801 m, PaO2: approx. 60 mm Hg) for 110 days (n = 6 for each group).
Long-term high altitude hypoxia reduced the fetal kidney/body weight ratio. Histological analysis showed a significant enlargement in the Bowman's space and swelling of tubule epithelial cells in the kidney of the hypoxic fetus. The histological alterations were limited to the cortical, but not medullary, zone. These alterations were associated with an increase in serum creatinine and a decrease in the BUN-to-creatinine ratio in hypoxic fetuses. Angiotensin II receptors (AT1R and AT2R) were detected in the glomerular and tubular regions of the kidney. Chronic hypoxia caused a significant increase in AT1R and a decrease in AT2R protein and mRNA abundance, resulting in a large increase in the AT1R/AT2R ratio in the fetal kidney.
The results demonstrate an adverse effect of chronic hypoxia on renal AT1R and AT2R expression and functions in the fetus, suggesting a possible role of fetal hypoxia in the programming of renal diseases in fetal origins.
PMCID: PMC2853592  PMID: 19923800
Hypoxia; Angiotensin II receptors; Ovine fetus
25.  Low titers of measles antibody in mothers whose infants suffered from measles before eligible age for measles vaccination 
Virology Journal  2010;7:87.
Resurgence or outbreak of measles recently occurred in both developed and developing countries despite long-standing widespread use of measles vaccine. Measles incidence in China has increased since 2002, particularly in infants and in persons ≥ 15 years of age. It is speculated that infants may acquire fewer measles IgG from their mothers, resulting in the reduced duration of protection during their early months of life. This study aimed to clarify the reason of increased susceptibility to measles in young infants in China. Measles IgG in 24 measles infants ≤ 9 months of age and their vaccinated mothers was quantitatively measured. The mean measles neutralizing titer in the vaccinated mothers and in 13 age-match women with the histories of clinical measles were compared.
All the mothers were confirmed to be vaccinated successfully by the presence of measles IgG. Six vaccinated mothers were positive for measles IgM and had high concentrations of measles IgG and the neutralizing antibody, indicating underwent natural boosting. The mean measles neutralizing titer in 18 vaccinated mothers without natural boosting were significantly lower than that in 13 age-match women with the histories of clinical measles (1:37 vs 1:182, P < 0.05).
Our results suggest that infants born to mothers who acquired immunity to measles by vaccination may get a relatively small amount of measles antibody, resulting in loss of the immunity to measles before the vaccination age. Measures to improve the immunity in young infants not eligible for measles vaccination would be critical to interrupt the measles transmission in China.
PMCID: PMC2874774  PMID: 20444295

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