Publications by authors named "Yunxia Zhu"

79 Publications

Therapeutic Dose of Hydroxyurea-Induced Synaptic Abnormalities on the Mouse Spermatocyte.

Front Physiol 2021 9;12:666339. Epub 2021 Jul 9.

Laboratory of Molecular Cytogenetics, School of Bioengineering, Xuzhou University of Technology, Xuzhou, China.

Hydroxyurea (HU) is a widely used pharmacological therapy for sickle cell disease (SCD). However, replication stress caused by HU has been shown to inhibit premeiotic S-phase DNA, leading to reproductive toxicity in germ cells. In this study, we administered the therapeutic doses of HU (i.e., 25 and 50 mg/kg) to male mice to explore whether replication stress by HU affects pachytene spermatocytes and causes the abnormalities of homologous chromosomes pairing and recombination during prophase I of meiosis. In comparison with the control group, the proportions of spermatocyte gaps were significantly different in the experimental groups injected with 25 mg/kg ( < 0.05) and 50 mg/kg of HU ( < 0.05). Moreover, the proportions of unrepaired double-stranded breaks (DSBs) observed by γH2AX staining also corresponded to a higher HU dose with a greater number of breaks. Additionally, a reduction in the counts of recombination foci on the autosomal SCs was observed in the pachytene spermatocytes. Our results reveal that HU has some effects on synaptonemal complex (SC) formation and DSB repair which suggest possible problems in fertility. Therefore, this study provides new evidence of the mechanisms underlying HU reproductive toxicity.
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http://dx.doi.org/10.3389/fphys.2021.666339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299468PMC
July 2021

The effects of increased dose of hepatitis B vaccine on mother-to-child transmission and immune response for infants born to mothers with chronic hepatitis B infection: a prospective, multicenter, large-sample cohort study.

BMC Med 2021 Jul 13;19(1):148. Epub 2021 Jul 13.

Artificial Liver Treatment Center, Beijing Youan Hospital, Capital Medical University, Beijing, China.

Background: Appropriate passive-active immunoprophylaxis effectively reduces mother-to-child transmission (MTCT) of hepatitis B virus (HBV), but the immunoprophylaxis failure was still more than 5% under the current strategy. The study objective was to investigate the effects of high dose of HB vaccine on MTCT and immune response for infants born to hepatitis B surface antigen (HBsAg)-positive mothers.

Methods: This was a prospective, multicenter, large-sample cohort study in four sites of China, and 955 pairs of HBsAg-positive mothers and their infants were enrolled in our investigation. The infants were given 10 μg or 20 μg HB vaccine (at age 0, 1, and 6 months) plus HB immunoglobulin (at age 0 and 1 month). Serum HBsAg, antibody to HBsAg (anti-HBs), and/or HBV DNA levels in the infants were determined at age 12 months. The safety of 20 μg HB vaccine was evaluated by adverse events and observing the growth indexes of infants.

Results: Thirteen of 955 infants were HBsAg-positive at 12 months. Stratification analysis showed that immunoprophylaxis failure rates in the 20 μg group were not significantly different from the 10 μg group, whatever maternal HBV load was high or not. But the high dose of HB vaccine significantly reduced low-response rate (anti-HBs 10-100 IU/L) (P = 0.002) and middle-response rate (anti-HBs 100-1000 IU/L) (P = 0.022) and improved high-response rate (anti-HBs ≥ 1000 IU/L) (P < 0.0001) in infants born to mothers with HBV DNA < 5 log IU/mL. For infants born to mothers with HBV DNA ≥ 5 log IU/mL, 20 μg HB vaccine did not present these above response advantages. The 20 μg HB vaccine showed good safety for infants.

Conclusions: The 20 μg HB vaccine did not further reduce immunoprophylaxis failure of infants from HBsAg-positive mothers, but increased the high-response and decreased low-response rates for infants born to mothers with HBV DNA < 5 log IU/mL.

Trial Registration: Chinese Clinical Trial Registry, ChiCTR-PRC-09000459.
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http://dx.doi.org/10.1186/s12916-021-02025-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276424PMC
July 2021

M1 macrophage-derived exosomes impair beta cell insulin secretion via miR-212-5p by targeting SIRT2 and inhibiting Akt/GSK-3β/β-catenin pathway in mice.

Diabetologia 2021 Jun 11. Epub 2021 Jun 11.

Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China.

Aims/hypothesis: Macrophage levels are elevated in pancreatic islets, and the resulting inflammatory response is a major contributor to beta cell failure during obesity and type 2 diabetes mellitus. Previous studies by us and others have reported that exosomes released by macrophages play important roles in mediating cell-to-cell communication, and represent a class of inflammatory factors involved in the inflammatory process associated with type 2 diabetes mellitus. However, to date, no reports have demonstrated the effect of macrophage-derived exosomes on beta cells, and little is known regarding their underlying mechanisms in beta cell injury. Thus, we aimed to study the impact of macrophage-derived exosomes on islet beta cell injury in vitro and in vivo.

Methods: The phenotypic profiles of islet-resident macrophages were analysed in C57BL/6J mice fed a high-fat diet (HFD). Exosomes were collected from the medium of cultured bone marrow-derived macrophages (BMDMs) and from isolated islet-resident macrophages of HFD-fed mice (HFD-Exos). The role of exosomes secreted by inflammatory M1 phenotype BMDMs (M1-Exos) and HFD-Exos on beta cell function was assessed. An miRNA microarray and quantitative real-time PCR (qPCR) were conducted to test the level of M1-Exos-derived miR-212-5p in beta cells. Then, miR-212-5p was overexpressed or inhibited in M1-Exos or beta cells to determine its molecular and functional impact.

Results: M1-polarised macrophages were enriched in the islets of obese mice. M1 macrophages and islet-resident macrophages of HFD-fed mice impaired beta cell insulin secretion in an exosome-dependent manner. miR-212-5p was notably upregulated in M1-Exos and HFD-Exos. Enhancing the expression of miR-212-5p impaired beta cell insulin secretion. Blocking miR-212-5p elicited a significant improvement in M1-Exos-mediated beta cell insulin secretion during injury. Mechanistically, M1-Exos mediated an intercellular transfer of the miR-212-5p, targeting the sirtuin 2 gene and regulating the Akt/GSK-3β/β-catenin pathway in recipient beta cells to restrict insulin secretion.

Conclusions/interpretation: A novel exosome-modulated mechanism was delineated for macrophage-beta cell crosstalk that drove beta cell dysfunction and should be explored for its therapeutic utility.
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http://dx.doi.org/10.1007/s00125-021-05489-1DOI Listing
June 2021

Vitamin D Status and Its Influence on the Health of Preschool Children in Hangzhou.

Front Public Health 2021 17;9:675403. Epub 2021 May 17.

Department of Child Health Care, Hangzhou Women's Hospital (Hangzhou Maternity and Child Care Hospital), Hangzhou, China.

Vitamin D deficiency and insufficiency in children are global public health problems. However, few studies have focused on vitamin D status in healthy preschool children, especially in Asia. This study aimed to investigate vitamin D status and host-related factors in healthy preschool children in Hangzhou to analyze the impact of low vitamin D levels (<30 ng/mL) on health outcomes (obesity, early childhood caries, and respiratory tract infections). A total of 1,510 healthy children aged 24-72 months from 15 kindergartens in Hangzhou were included. Data on the children's gender, age, body mass index (BMI), caries, and blood samples available for vitamin D analysis were collected from June to August 2018. A total of 325 children aged 36-48 months took part in a survey on the frequency of respiratory tract infections in the last year. The children's mean 25(OH)D level was 28.01 ± 7.29 ng/mL. A total of 11.4% of the children had vitamin D deficiency, and 52.6% had vitamin D insufficiency. Only 36.0% had vitamin D sufficiency. No significant difference was found by gender or BMI group. However, children in the obesity group had the highest prevalence of vitamin D deficiency and the lowest 25(OH)D levels. A significant negative correlation was found between the 25(OH)D level and child age ( = -0.144, < 0.001). Regression analysis showed that the children's 25(OH)D levels decreased by 0.17 ng/mL per month with age. In addition, children with low vitamin D levels might increase the risk of obesity and early childhood caries. Multiple linear regression indicated that the number of caries in children increased by 0.08 per 1-ng/mL decrease in the 25(OH)D level ( = -0.08, < 0.001). Vitamin D deficiency/insufficiency is a serious problem among healthy preschool children in Hangzhou. Public health policies or interventions should be implemented to ensure that preschool children have adequate vitamin D to reduce the risk of related diseases.
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http://dx.doi.org/10.3389/fpubh.2021.675403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165265PMC
June 2021

Correction to: Maternal and fetal outcomes of patients with liver cirrhosis: a case-control study.

BMC Pregnancy Childbirth 2021 Apr 24;21(1):325. Epub 2021 Apr 24.

Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Qihelou street No.17, Dongcheng District, Beijing, 100006, China.

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http://dx.doi.org/10.1186/s12884-021-03823-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070274PMC
April 2021

Maternal and fetal outcomes of patients with liver cirrhosis: a case-control study.

BMC Pregnancy Childbirth 2021 Apr 8;21(1):280. Epub 2021 Apr 8.

Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Qihelou street No.17, Dongcheng District, Beijing, 100006, China.

Background: We aimed to describe the characteristics and outcomes in pregnant women with liver cirrhosis, and identify the predictors of adverse events of mother and fetus.

Methods: Retrospectively collected mothers with liver cirrhosis in our center from 6/2010 to 6/2019. Women without liver cirrhosis were selected as a control in a 1:2 ratio. The primary assessment was the frequency of maternal and fetal adverse events. The secondary assessment was the adverse events in patients continuing pregnancy or not and the factors to predict the severe adverse events.

Results: Of 126 pregnancies enrolled, 29 pregnancies were terminated for worrying disease progression and 97 pregnancies continued. One hundred ninety-four pregnancies without liver cirrhosis were selected as control. At baseline, patients with liver cirrhosis have a lower level of platelet, hemoglobin, prothrombin activity, and a higher level of ALT, total Bilirubin, creatinine. Compared to control, patients with liver cirrhosis had a higher frequency of adverse events, including bleeding gums (7.2%vs. 1.0%), TBA elevation (18.6%vs.3.1%), infection (10.3%vs.0.5%), cesarean section (73.6%vs.49.5%), postpartum hemorrhage (13.8% vs 2.1%), blood transfusion (28.9% vs 2.1%), new ascites or aggravating ascites (6.2% vs.0%), MODS (7.2% vs.0.5%) and intensive care unit admissions (24.1% vs 1.1%). The incidence of severe maternal adverse events was also higher (32.0% vs 1.5%). Women who chose to terminated the pregnancy had less severe adverse events (3.4% vs.32.0%). A higher frequency of fetal/infants' complications was observed in liver cirrhosis population than control, including newborn asphyxia (10.2% vs1.1%), low birth weight infant (13.6% vs. 2.6%). In patients who progressed into the third trimester, multivariable regression analysis demonstrated that severe adverse events were associated with a higher CTP score (OR 2.128, 95% CI [1.002, 4.521], p = 0.049). Wilson's disease related liver cirrhosis has a better prognosis (OR = 0.009, 95% CI [0, 0.763], p = 0.038).

Conclusions: The incidence of the adverse events was significantly increased in pregnancies complicated by cirrhosis. The predictor of severe adverse events is higher CTP score. Wilson's disease induced liver cirrhosis have a better prognosis. Timely termination of pregnancy during the first trimester may avoid the incidence of severe adverse events.
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http://dx.doi.org/10.1186/s12884-021-03756-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033723PMC
April 2021

Expression of miRNA-29 in Pancreatic β Cells Promotes Inflammation and Diabetes via TRAF3.

Cell Rep 2021 01;34(1):108576

Key Laboratory of Human Functional Genomics of Jiangsu Province, Biochemistry and Molecular Biology, Nanjing medical University, Nanjing, Jiangsu 211166, China. Electronic address:

Type 2 diabetes mellitus (T2DM) is recognized as a chronic, low-grade inflammatory disease characterized by insulin resistance and pancreatic β cell dysfunction; however, the underlying molecular mechanism remains unclear. Here, we report a key β cell-macrophage crosstalk pathway mediated by the miRNA-29-TNF-receptor-associated factor 3 (TRAF3) axis. β cell-specific transgenic miR-29a/b/c mice are predisposed to develop glucose intolerance and insulin resistance when fed a high-fat diet (HFD). The metabolic effect of β cell miR-29 is largely mediated through macrophages because either depletion of macrophages or reconstitution with miR-29-signaling defective bone marrow improves metabolic parameters in the transgenic mice. Mechanistically, our data show that miR-29 promotes the recruitment and activation of circulating monocytes and macrophages and, hence, inflammation, via miR-29 exosomes in a TRAF3-dependent manner. Our results demonstrate the ability of β cells to modulate the systemic inflammatory tone and glucose homeostasis via miR-29 in response to nutrient overload.
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http://dx.doi.org/10.1016/j.celrep.2020.108576DOI Listing
January 2021

Risk factors related to postpartum hepatic inflammation in pregnant women with chronic hepatitis B.

J Int Med Res 2020 Nov;48(11):300060520966439

Hepatology Center Department, Beijing YouAn Hospital, Capital Medical University, Beijing, China.

Objectives: To investigate liver function after pregnancy in women with chronic hepatitis B virus (HBV) and factors related to postpartum abnormalities.

Methods: A total of 317 pregnant women were included in this study and 138 had an HBV DNA level. In this trial, the highest number and proportion of hepatitis B surface antigen-positive mothers with postpartum hepatic inflammation were at 1 month after delivery.

Results: Baseline liver function of postpartum women with hepatic inflammation was significantly higher than that in those before delivery. The rates of hepatitis B e-antigen (HBeAg)-positive status, baseline HBV DNA levels, gestational diabetes mellitus, and antiviral therapy during pregnancy were significantly higher in the hepatic inflammation group than in the control group. Among the 138 women who received antiviral therapy, 83 withdrew from antiviral therapy immediately after delivery and 55 continued antiviral therapy for at least 1 month after delivery. Multivariate logistic regression analysis showed that HBeAg-positivity and gestational diabetes mellitus were associated with hepatic inflammation after delivery. Postpartum hepatic inflammation occurred mostly at 1 month after delivery in pregnant women with HBV infection.

Conclusions: Close monitoring of women with HBV during pregnancy is required, especially for those who are HBeAg-positive and have gestational diabetes mellitus.
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http://dx.doi.org/10.1177/0300060520966439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683929PMC
November 2020

Inhibition of miR-153, an IL-1β-responsive miRNA, prevents beta cell failure and inflammation-associated diabetes.

Metabolism 2020 10 12;111:154335. Epub 2020 Aug 12.

Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China. Electronic address:

Objective: Systemic levels of up-regulated IL-1β and IL-1 receptors promote the pathogenesis of inflammation-associated diabetes. IL-1 receptor antagonist (IL-Ra) has shown slightly elevated beta cell function in patients with type 2 diabetes without significant improvement of hyperglycaemia. We investigated whether miR-153, an IL-1β responsive miRNA, could mimic IL-1β effects and whether its interruption would improve blood glucose control then offer an assistant curative approach to inflammation-associated diabetes.

Materials/methods: Antago-miR-153 and Ago-miR-153 were injected into the abdominal aorta of leptin receptor-mutant db/db mice and C57BL/6 J mice, respectively. Blood glucose levels, glucose tolerance tests, insulin tolerance tests and insulin levels were regularly checked. Proteomic profiling combined with unbiased bioinformatics analysis, as well as experimental techniques, were utilized to identify target genes of miR-153. Anti-miR-153 and plasmid-based recovery assays were also performed using primary mouse islets and beta cell lines.

Results: The miR-153 expression level was increased in IL-1β-treated beta cells and primary islets from the diabetic rodents. Pancreas overexpression of miR-153 caused glucose intolerance in C57BL/6 J mice but no alterations in body weight or insulin sensitivity. The inhibition of miR-153 temporarily reduced hyperglycaemia of db/db mice due to enhanced insulin secretion. Antago-miR-153 treatment ameliorated glucose intolerance in db/db mice during our observation period but did not improve insulin sensitivity. Mechanistically, miR-153 targeted three members of SNAREs to disturb insulin granule docking, thereby decreasing basal insulin secretion. Overexpression of anti-miR-153 or SNARE rescued the IL-1β-induced basal insulin secretion defect. Furthermore, miR-153 targeted beta cell-specific transcriptional factors and survival molecules to inhibit insulin biosynthesis and cell viability.

Conclusions: The IL-1β-responsive miR-153 targets SNAREs, beta cell specific TFs and other key factors to eventually causes beta cell failure. Inhibiting miR-153 with Antago-miR-153 prevents hyperglycaemia in db/db mice, indicating that miR-153 may be a promising therapeutic target for the treatment of inflammation-associated diabetes.
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http://dx.doi.org/10.1016/j.metabol.2020.154335DOI Listing
October 2020

Pregnancy outcomes of patients with acute fatty liver of pregnancy: a case control study.

BMC Pregnancy Childbirth 2020 May 11;20(1):282. Epub 2020 May 11.

Department of Obstetrics and Gynecology, Beijing Youan Hospital, Capital Medical University, YouAn outer street No.8, Fengtai District, Beijing, 100006, China.

Background: Limited data exists regarding the pregnancy and infant outcomes of Acute Fatty Liver of Pregnancy (AFLP).

Methods: Retrospectively collected mothers with AFLP and mothers without AFLP in our center from 1/2008 to 6/2018. The primary assessment was to analyze and compare the frequency of negative maternal and fetal outcomes. The secondary assessment was to investigate the role of intrauterine balloon tamponade in reducing negative maternal outcomes.

Results: Compared to 220 matched mothers, 55 AFLP mothers were younger (P < 0.001), with fewer pregnancies (P = 0.033), complicated with more pregnancy induced hypertension (P < 0.001), twins(P = 0.002), fetal growth restriction (P = 0.044) and male fetus (P < 0.001). 3 (5.5%) of AFLP patients were diagnosed in the postpartum period. Mean gestational week of AFLP diagnosis was 35.25 ± 5.80 weeks. Jaundice (89.1%), nausea or vomiting (58.2%), anorexia (49.1%), fatigue (45.5%) and polydipsia (30.9%) were the main prodromal symptoms. The median duration from diagnosis to delivery was 1.55 ± 4.62 days and 75% (39/52) pregnancy were terminated the pregnancy at the day of diagnosis. 78.8% (41/52) patients received cesarean section, 53.6% (22/41) of which received preventive plasma transfusion before surgery and no one received artificial liver support during the treatment. In comparison, higher frequency of 16 maternal complications, severe negative outcomes (27.3% vs. 0.9%) and newborn asphyxia (24.6% vs.0.9%) were observed in AFLP population. 3 mothers (mortality rates: 5.5%) died of multiple organ system failure and 6 fetus/infants (death rates: 9.8%) died of distress. When compared to those without negative outcomes, patients with negative fetal outcomes were younger (P = 0.042), had more singleton rates (p = 0.041), increased mean value of ALT(P = 0.011) and T-Bilirubin (P = 0.014), decreased prothrombin activity (P = 0.011). Although no statistical significance for the small sample size, there were less refractory postpartum hemorrhage (0% vs.31.3%), hysterectomy (0% vs.12.5%), negative maternal outcomes (16.7% vs.56.3%) in patients underwent intrauterine balloon tamponade when postpartum hemorrhage exceeded 500 ml.

Conclusions: Several symptoms were found to be the main prodromal symptoms of AFLP. Higher frequency of adverse maternal and fetal outcomes was observed in mothers with AFLP than mothers without AFLP. We found five potential risk factors of negative fetal outcomes.
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http://dx.doi.org/10.1186/s12884-020-02980-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216501PMC
May 2020

Perilipin 5 Reduces Oxidative Damage Associated With Lipotoxicity by Activating the PI3K/ERK-Mediated Nrf2-ARE Signaling Pathway in INS-1 Pancreatic β-Cells.

Front Endocrinol (Lausanne) 2020 31;11:166. Epub 2020 Mar 31.

Department of Geriatrics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

Oxidative stress induced by free fatty acid overload in pancreatic β-cells is a potential contributory factor to dysfunction of insulin secretion and apoptotic cell death. Perilipin 5 (Plin5) has been reported to ameliorate oxidative stress-mediated damage in non-insulin-secreting tissues. We tested the hypothesis that Plin5 plays a similar role in pancreatic β-cells, which are extremely sensitive to oxidative stress. Here, our data showed that Plin5-mediated alleviation of palmitate-triggered apoptosis involves the mitochondrial pathway. And the protective role of Plin5 on β-cells was partially dependent on its modulation in oxidative stress. Upregulation of in INS-1 cells decreased reactive oxygen species production, enhanced cellular glutathione levels, and induced expression of antioxidant enzymes glutamate-cysteine ligase catalytic subunit and heme oxygenase-1. However, knocking out of abolished all of these beneficial effects. Furthermore, by using the O scavenger MnTMPyP, we verified that altering expression impacted lipotoxic cell death partially via modulating oxidative stress. Mechanistic experiments revealed that Plin5 induced Nrf2-ARE system, a master regulator in the cellular adaptive response to oxidative stress, by activating PI3K/Akt and ERK signal pathways, contributing to the increase of antioxidant defense and consequently improving β-cell function and survival in the presence of lipotoxic oxidative stress. Overall, our findings indicate that Plin5 abrogates oxidative damage in INS-1 β-cells during lipotoxic stress partially through the enhancement of antioxidant defense involving the PI3K/Akt and ERK mediated Nrf2-ARE system.
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http://dx.doi.org/10.3389/fendo.2020.00166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136399PMC
March 2021

Predictive Value of Nutritional Risk Screening 2002 and Mini Nutritional Assessment Short Form in Mortality in Chinese Hospitalized Geriatric Patients.

Clin Interv Aging 2020 20;15:441-449. Epub 2020 Mar 20.

Department of Geriatrics, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, People's Republic of China.

Background And Aim: The presence of malnutrition in hospitalized geriatric patients is associated with an increased risk of mortality. This study aimed to examine the performance of Nutritional Risk Screening 2002 (NRS2002) and Mini Nutritional Assessment Short Form (MNA-SF) in predicting mortality for hospitalized geriatric patients in China.

Methods: A prospective analysis was performed in 536 hospitalized geriatric patients aged ≥65 years. Nutrition status was assessed using the MNA-SF and NRS2002 scales within 24 hrs of admission. Anthropometric measures and biochemical parameters were carried out for each patient. Patients were follow-up for up to 2.5 years.

Results: At baseline, 161 (30.04%) patients had malnutrition/nutritional risk according to NRS2002 assessment. According to MNA-SF, 284 (52.99%) patients had malnutrition/nutritional risk. Malnutrition/nutritional risk patients had lower anthropometric and biochemical parameters (<0.05). NRS2002 and MNA-SF had a strong correlation with classical nutritional markers (<0.05). NRS2002 versus MNA-SF showed moderate agreement (kappa=0.493, <0.001). During a median follow-up time of 795 days (range 10-947 days), 118 (22%) participants died. The Kaplan-Meier curve demonstrated that malnutrition/nutritional risk patients according to NRS2002 or MNA-SF assessment had a higher risk of mortality than the normal nutrition patients ( =17.67, <0.001; =28.999, <0.001, respectively). From the components of the Cox regression multivariate models, only the NRS2002 score was an independent risk factor influencing the mortality.

Conclusion: Both NRS2002 and MNA-SF scores could predict mortality in Chinese hospitalized geriatric patients. But only NRS2002 score was the independent predictor for mortality.
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http://dx.doi.org/10.2147/CIA.S244910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093094PMC
September 2020

Abnormal IL-10 levels were related to alanine aminotransferase abnormalities during postpartum in HBeAg positive women with chronic hepatitis B.

Medicine (Baltimore) 2019 Nov;98(46):e17969

Department of Obstetrics and Gynecology, Beijing YouAn Hospital.

Alanine transaminase (ALT) abnormalities are common in chronic hepatitis B (CHB) carriers during postpartum period. Disturbances in cytokines are considered to be associated with hepatitis Flares. There are limited data on cytokines changes in HBeAg positive patients with ALT abnormalities.This is an observational study. Pregnant patients with hepatitis B e-antigen (HBeAg) positive were enrolled from January 2014 to September 2018. Patients were assigned into three groups based on ALT levels in postpartum 6 to 8 weeks: ALT in normal range, ALT in 1 to 2-fold upper limits of normal (ULN) and ALT >2-fold ULN. Serum cytokines, ratios of regulatory T cells, and the concentration of cortisol were collected and compared among the three groups.Of the 135 mothers enrolled, 80.7% (109/135) completed the postpartum 6-week study. 13.8% (15/109) patients had postpartum ALT higher than 2ULN, 27.5% (30/109) patients had ALT in 1 to 2ULN and 58.7% (64/109) patients had ALT in normal range. Compared to control group, patients with ALT >2ULN had a higher IL-10 level (P < .05). No differences of IL-10 levels were found in the comparison of other inter comparison among three groups. No differences were found in the levels of other collected serum cytokines, cortisol, and regulatory T cells among three groups. On multivariate analysis, abnormal IL-10 level was independent risk factor for postpartum ALT elevating >2ULN. At the same time, the incidence of postpartum ALT elevated >2ULN were higher in patients with abnormal elevation IL-10 level than in patients with normal IL-10 level (14/68 vs 1/41, P = .008).CHB patients with postpartum ALT abnormalities show higher IL-10 level and postpartum ALT abnormalities were mainly occurred in patients with abnormal IL-10 level. IL-10 may be an underlying predictor and treatment target of hepatitis B, and further studies are needed.
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http://dx.doi.org/10.1097/MD.0000000000017969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867749PMC
November 2019

Perilipin5 protects against lipotoxicity and alleviates endoplasmic reticulum stress in pancreatic β-cells.

Nutr Metab (Lond) 2019 30;16:50. Epub 2019 Jul 30.

1Department of Geriatrics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600, Yishan Road, Shanghai, 200233 China.

Background: Chronic exposure of pancreatic β-cells to excess free fatty acids is thought to contribute to type 2 diabetes pathogenesis in obesity by impairing β-cell function and even leading to apoptosis. In β-cells, lipid droplet-associated protein perilipin 5 (PLIN5) has been shown to enhance insulin secretion by regulating intracellular lipid metabolism; the roles of PLIN5 in response to lipotoxicity remain poorly understood.

Methods: INS-1 β-cells were transfected with PLIN5-overexpression adenovirus (Ad-PLIN5) and treated with palmitate. C57BL/6 J male mice were fed with high fat diet and tail intravenous injected with adeno-associated virus overexpressing PLIN5 (AAV-PLIN5) in β-cells.

Results: Our data showed that palmitate and PPAR agonists including WY14643 (PPARα), GW501516 (PPARβ/δ), rosiglitazone (PPARγ) in vitro all induced PLIN5 expression in INS-1 cells. Under palmitate overload, although upregulating PLIN5 promoted lipid droplet storage, it alleviated lipotoxicity in INS-1 β-cells with improved cell viability, cell apoptosis and β-cell function. The protection role of PLIN5 in β-cell function observed in cell experiments were further verified in in vivo study indicated by mitigated glucose intolerance in high fat diet fed mice with β-cell-specific overexpression of PLIN5. Mechanistic experiments revealed that enhanced FAO induced by elevation of PLIN5, followed by decreased ER stress may be a major mechanism responsible for alleviation of lipotoxicity observed in the present study.

Conclusions: Our finding substantiated the important role of PLIN5 in protection against lipotoxicity in β-cells.
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http://dx.doi.org/10.1186/s12986-019-0375-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668071PMC
July 2019

Ets-1 deficiency alleviates nonalcoholic steatohepatitis via weakening TGF-β1 signaling-mediated hepatocyte apoptosis.

Cell Death Dis 2019 06 12;10(6):458. Epub 2019 Jun 12.

Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China.

Hepatocyte apoptosis is a hallmark of nonalcoholic steatohepatitis (NASH) and contributes to liver injury, fibrosis, and inflammation. However, the molecular mechanisms underlying excessive hepatocyte apoptosis in NASH remain largely unknown. This study aimed to explore whether and how the v-ets avian erythroblastosis virus E26 oncogene homolog 1 (Ets-1) is involved in diet-induced hepatocyte apoptosis in mice. The study found that the expression level of hepatic Ets-1 was elevated in a NASH mouse model as a result of the activation of transforming growth factor beta1 (TGF-β1) signaling. In the presence of TGF-β1, phosphorylated mothers against decapentaplegic homolog 2/3 (p-Smad2/3) translocated to the binding sites of the Ets-1 promoter to upregulate the expression of Ets-1 in primary hepatocytes. In addition, Ets-1 bound directly to phosphorylated Smad3 (p-Smad3), thereby preventing the ubiquitination and proteasomal degradation of p-Smad3 and enhancing the activity of TGF-β1/Smad3 signaling. Consequently, elevated Ets-1 stimulated TGF-β1-induced hepatocyte apoptosis. However, Ets-1 knockdown alleviated diet-induced hepatocyte apoptosis and NASH with reduced liver injury, inflammation, and fibrosis. Taken together, Ets-1 had an adverse impact on hepatocyte survival under TGF-β1 treatment and accelerated the development of NASH in mice.
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http://dx.doi.org/10.1038/s41419-019-1672-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561928PMC
June 2019

MicroRNA-24 promotes pancreatic beta cells toward dedifferentiation to avoid endoplasmic reticulum stress-induced apoptosis.

J Mol Cell Biol 2019 09;11(9):747-760

Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 210029, China.

Current research indicates that beta cell loss in type 2 diabetes may be attributed to beta cell dedifferentiation rather than apoptosis; however, the mechanisms by which this occurs remain poorly understood. Our previous study demonstrated that elevation of microRNA-24 (miR-24) in a diabetic setting caused beta cell dysfunction and replicative deficiency. In this study, we focused on the role of miR-24 in beta cell apoptosis and dedifferentiation under endoplasmic reticulum (ER) stress conditions. We found that miR-24 overabundance protected beta cells from thapsigargin-induced apoptosis at the cost of accelerating the impairment of glucose-stimulated insulin secretion (GSIS) and enhancing the presence of dedifferentiation markers. Ingenuity® Pathway Analysis (IPA) revealed that elevation of miR-24 had an inhibitory effect on XBP1 and ATF4, which are downstream effectors of two key branches of ER stress, by inhibiting its direct target, Ire1α. Notably, elevated miR-24 initiated another pathway that targeted Mafa and decreased GSIS function in surviving beta cells, thus guiding their dedifferentiation under ER stress conditions. Our results demonstrated that the elevated miR-24, to the utmost extent, preserves beta cell mass by inhibiting apoptosis and inducing dedifferentiation. This study not only provides a novel mechanism by which miR-24 dominates beta cell turnover under persistent metabolic stress but also offers a therapeutic consideration for treating diabetes by inducing dedifferentiated beta cells to re-differentiation.
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http://dx.doi.org/10.1093/jmcb/mjz004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821228PMC
September 2019

Associations between G6PD, OATP1B1 and BLVRA variants and susceptibility to neonatal hyperbilirubinaemia in a Chinese Han population.

J Paediatr Child Health 2019 Sep 12;55(9):1077-1083. Epub 2019 Jan 12.

Department of Child Health Care, Hangzhou Women's Hospital, Hangzhou Maternity and Child Health Care Hospital, Hangzhou, China.

Aim: Hyperbilirubinaemia is a common disorder in newborns. The aim of this study was to investigate the associations between G6PD 1388 G>A, SLCO1B1 rs4149056 and BLVRA rs699512 variants and the risk of neonatal hyperbilirubinaemia in a Chinese neonate population.

Methods: A total of 447 Chinese neonates with hyperbilirubinaemia were selected as the study group and 544 healthy subjects were recruited as the control group matched by baseline sex, age, feeding pattern and delivery mode. About 2 mL of peripheral venous blood was taken from all subjects. The single nucleotide polymorphisms (SNPs) of G6PD 1388 G>A, SLCO1B1 rs4149056 and BLVRA rs699512 loci were examined by the polymerase chain reaction and Sanger sequencing technique in the peripheral blood of all subjects.

Results: For the G6PD 1388 G>A SNP, individuals carrying the A-allele were associated with a significantly increased risk of neonatal hyperbilirubinaemia (adjusted odds ratio (OR) = 1.49, P < 0.001, 95% confidence interval (CI): 1.31-1.67). This risk increased significantly in the CC genotype carriers at the rs4149056 locus of the SLCO1B1 gene (OR = 2.17, 95% CI: 1.87-2.33), whereas it decreased significantly in individuals carrying the G-allele at the rs699512 locus of the BLVRA gene (adjusted OR = 0.84, P = 0.01, 95% CI: 0.75-0.95). The G6PD 1388 G>A, SLCO1B1 rs4149056 and BLVRA rs699512 SNPs had a significant impact on serum total bilirubin levels. Moreover, individuals carrying the A-allele of G6PD 1388 G>A and BLVRA rs699512 had a significantly increased risk of developing neonatal hyperbilirubinaemia (OR = 5.01, P < 0.001, 95% CI: 3.42-7.85).

Conclusion: Genetic variants of bilirubin metabolism genes, including G6PD 1388 G>A, SLCO1B1 rs4149056 and BLVRA rs699512, are associated with the risk of neonatal hyperbilirubinaemia, and are potential markers for predicting the disorder.
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http://dx.doi.org/10.1111/jpc.14346DOI Listing
September 2019

SAD-A, a downstream mediator of GLP-1 signaling, promotes the phosphorylation of Bad S155 to regulate in vitro β-cell functions.

Biochem Biophys Res Commun 2019 01 17;509(1):76-81. Epub 2018 Dec 17.

Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, China; Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, 211166, China. Electronic address:

The incretin hormone GLP-1 reduces β-cell failure in patients with type 2 diabetes. Previous studies demonstrated that GLP-1 activates SAD-A, a member of the AMPK family, to regulate glucose-stimulated secretion (GSIS), but the underlying mechanisms of SAD-A regulation of β-cell functions remain poorly understood. Here, we propose that activation of SAD-A by GLP-1 promotes the phosphorylation of Bad S155, which in turn positively affects GSIS and β-cell survival. Bad therefore appears to be a downstream molecule of a SAD-A pathway that mediates the GLP-1-triggered reduction in β-cell failure. Knockdown of endogenous SAD-A expression significantly exacerbated in vitro β-cell dysfunction under lipotoxic conditions and promoted lipotoxicity-induced apoptosis, whereas overexpression of SAD-A inhibited β-cell apoptosis. SAD-A silencing increased ER stress and inhibited the autophagic flux, which contributed to β-cell apoptosis. Thus, SAD-A appears to function as a downstream molecule of GLP-1 signaling that results in Bad S155 phosphorylation. This phosphorylation might therefore be involved in the GLP-1-linked protection against β-cell dysfunction and apoptosis.
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http://dx.doi.org/10.1016/j.bbrc.2018.12.063DOI Listing
January 2019

Characterization of the bagremycin biosynthetic gene cluster in Streptomyces sp. Tü 4128.

Biosci Biotechnol Biochem 2019 Mar 10;83(3):482-489. Epub 2018 Dec 10.

a State Key Laboratory of Bioreactor Engineering , East China University of Science and Technology , Shanghai , China.

Bagremycin A and bagremycin B isolated from Streptomyces sp. Tü 4128 have activities against Gram-positive bacteria, fungi and also have a weak antitumor activity, which make them have great potential for development of novel antibiotics. Here, we report a draft genome 8,424,112 bp in length of S. sp. Tü 4128 by Illumina Hiseq2000, and identify the bagremycins biosynthetic gene cluster (BGC) by bioinformatics analysis. The putative bagremycins BGC includes 16 open reading frames (ORFs) with the functions of biosynthesis, resistance and regulation. Disruptions of relative genes and HPLC analysis of bagremycins production demonstrated that not all the genes within the BGC are responsible for the biosynthesis of bagremycins. In addition, the biosynthetic pathways of bagremycins are proposed for deeper inquiries into their intriguing biosynthetic mechanism.
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http://dx.doi.org/10.1080/09168451.2018.1553605DOI Listing
March 2019

Real-world study of tenofovir disoproxil fumarate to prevent hepatitis B transmission in mothers with high viral load.

Aliment Pharmacol Ther 2019 01 2;49(2):211-217. Epub 2018 Dec 2.

Division of Gastroenterology, Department of Medicine, NYU Langone Health, NYU School of Medicine, New York City, NY.

Background: Data on tenofovir disoproxil fumarate (TDF) therapy for preventing vertical transmission of hepatitis B virus (HBV) in the real-world setting are limited.

Aim: To investigate TDF for preventing vertical transmission of HBV in real-world practice.

Methods: Hepatitis B e-antigen (HBeAg)-positive mothers with HBV-DNA >6 log IU/mL to receive TDF between gestational weeks 24-33 and delivery were prospectively enrolled and followed until post-partum week 28. All infants received immunoprophylaxis. Primary endpoints were safety of TDF use and mother-to-child transmission rates. Secondary outcomes were maternal HBV-DNA level suppression (<200 000 IU/mL) at delivery and HBeAg and hepatitis B surface antigen (HBsAg) serologic changes during the study.

Results: Among 147 mothers enrolled, 143 started TDF and 143/144 infants completed the study. At delivery, 93.7% (134/143) of the mothers achieved HBV-DNA<200 000 IU/L. On-treatment, alanine aminotransferase (ALT) flares were observed in 8.4% (12/143) of mothers. After TDF cessation, ALT increased in 7.7% (11/143) of the mothers and 2.8% (4/143) achieved HBeAg negativity, but none had HBsAg loss. At birth, HBsAg was detected in 13.9% (20/144) of newborns and none at post-partum week 28. Vertical transmission rates among infants were 0.7% (1/144, intention-to-treat) and 0% (per-protocol). No infants had birth defects. No serious adverse effects were reported in either mothers or infants. Breastfeeding did not increase the HBV infection rate among infants although mothers had viral rebound after TDF cessation.

Conclusions: TDF for highly viraemic mothers was well tolerated and reduced vertical transmission of HBV in a real-world setting. There were no safety concerns during the postpartum 28-week follow-up. Registry number: Chinese Clinical Trial Registration No. ChiCTR-OIC-17010869.
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http://dx.doi.org/10.1111/apt.15064DOI Listing
January 2019

Glucolipotoxicity-Inhibited Regulates Pancreatic β-Cell Function and Survival.

Diabetes 2018 11 21;67(11):2280-2292. Epub 2018 Aug 21.

Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China

Inhibition of microRNAs (miRNAs) essential for pancreatic β-cell biology (e.g., ) results in β-cell failure and diabetes in rodent models. Whether the downregulation of miRNAs in pancreatic islets is involved in the development of human type 2 diabetes remains unclear. Here, with the use of an miRNA microarray, we identified a set of miRNAs that were differentially expressed in healthy human islets under glucolipotoxic conditions. A downregulated miRNA, , was preferentially studied because its inhibition causes dramatic β-cell dysfunction and apoptosis. Proteomic profiling and bioinformatics methods identified four target genes, including a Trp53 effector, , that were further confirmed by luciferase reporter assays. We narrowed down the effector of downregulation to PERP owing to its upregulation in islets from diabetic rodents. Indeed, inhibition prevented the β-cell impairment caused by either reduction or glucolipotoxicity. Additional investigations confirmed the modulatory effect of PERP on insulin secretion. Collectively, appears to be an essential regulator of β-cell biology, and its downregulation links PERP enhancement to β-cell dysfunction and apoptosis in glucolipotoxic settings. Our work demonstrates a novel mechanism of glucolipotoxicity-induced β-cell failure mediated through downregulation.
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http://dx.doi.org/10.2337/db18-0223DOI Listing
November 2018

MicroRNA-218 Negatively Regulates Osteoclastogenic Differentiation by Repressing the Nuclear Factor-κB Signaling Pathway and Targeting Tumor Necrosis Factor Receptor 1.

Cell Physiol Biochem 2018 17;48(1):339-347. Epub 2018 Jul 17.

Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Background/aims: Postmenopausal osteoporosis is a common disease associated with estrogen deficiency leading to bone loss and bone tissue changes. The resultant bone fragility and increased risk of fracture has serious adverse effects on health and quality of life of the elderly, making it an important health issue. MicroRNA-218 (miR-218) is closely related to the development of osteoporosis. In this study, we investigated the regulatory mechanisms of miR-218 in osteoclastogenesis.

Methods: We investigated miR-218 levels on differentiation of RAW 264.7 cells into osteoclasts compared with normal cells. Next, RAW 264.7 cells were transfected with miR-218 mimics or inhibitors to study the role of miR-218 in osteoclastogenic differentiation. Tartrate-resistant acid phosphatase (TRAP) staining was performed to determine osteoclastogenic differentiation. Bioinformatics analysis and luciferase reporter assay were used to identify and validate miR-218 target genes.

Results: miR-218 was downregulated following RAW 264.7 cell differentiation into osteoclasts. miR-218 overexpression attenuated osteoclast differentiation, whereas low miR-218 expression promoted it as demonstrated by increased expression of osteoclast-specific genes and TRAP staining. Bioinformatics analysis and the luciferase reporter assay showed that tumor necrosis factor receptor 1 (TNFR1), a cell membrane receptor of TNF (TNF is an activator of nuclear factor-κB [NF-κB]), is a direct target of miR-218.

Conclusions: Our findings indicate that miR-218 regulates osteoclastogenic differentiation negatively by repressing NF-κB signaling by targeting TNFR1, suggesting that targeting miR-218 may be a therapeutic approach in postmenopausal osteoporosis.
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http://dx.doi.org/10.1159/000491740DOI Listing
September 2018

Two Novel MicroRNA Biomarkers Related to β-Cell Damage and Their Potential Values for Early Diagnosis of Type 1 Diabetes.

J Clin Endocrinol Metab 2018 04;103(4):1320-1329

Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.

Context: New strategies and biomarkers are needed in the early detection of β-cell damage in the progress of type 1 diabetes mellitus (T1DM).

Objective: To explore whether serum microRNAs (miRNA) should be served as biomarkers for T1DM.

Design, Settings, And Patients: The miRNA profile was established with miRNA microarray in discovery phase (six T1DM, six controls). A miRNA-based model for T1DM diagnosis was developed using logistic regression analysis in the training dataset (40 T1DM, 56 controls) and then validated with leave-one-out cross validation and another independent validation dataset (33 T1DM, 29 controls).

Main Outcome Measures: Quantitative reverse transcription polymerase chain reaction was applied to confirm the differences of candidate miRNAs between T1DM and controls. Area under the receiver-operating characteristic (ROC) curve (AUC) was used to evaluate diagnostic accuracy. INS-1 cells, streptozotocin-treated mice (n = 4), and nonobese diabetic (NOD) mice (n = 12) were used to evaluate the association of miRNAs with β-cell damage.

Results: A miRNA -based model was established in the training dataset with high diagnostic accuracy for T1DM (AUC = 0.817) based on six candidate differential expressed miRNAs identified in discovery phase. The validation dataset showed the model's satisfactory diagnostic performance (AUC = 0.804). Secretions of miR-1225-5p and miR-320c were significantly increased in streptozotocin-treated mice and INS-1 cells. Noteworthy, the elevation of these two miRNAs was observed before glucose elevation in the progress of diabetes in NOD mice.

Conclusions: Two miRNA biomarkers (miR-1225-5p and miR-320c) related to β-cell damage were identified in patients with recent-onset T1DM. The miRNA-based model established in this study exhibited a good performance in diagnosis of T1DM.
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http://dx.doi.org/10.1210/jc.2017-01417DOI Listing
April 2018

Boronic Acid-Modified Magnetic [email protected] Microspheres for Highly Sensitive and Selective Enrichment of N-Glycopeptides in Amniotic Fluid.

Sci Rep 2017 07 4;7(1):4603. Epub 2017 Jul 4.

State Key Laboratory of Reproductive Medicine, Department of Biochemistry and Molecular Biology of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, 210029, China.

Although mesoporous materials and magnetic materials are used to enrich glycopeptides, materials sharing both mesoporous structures and magnetic properties have not been reported for glycopeptide analyses. Here we prepared boronic acid-modified magnetic [email protected] microspheres by covalent binding of boronic acid molecules onto the surfaces of silanized [email protected] microspheres. The final particles (denoted as [email protected]) showed a typical magnetic hysteresis curve, indicating superparamagnetic behavior; meanwhile, their mesoporous sizes did not change in spite of the reduction in surface area and pore volume. By using these particles together with conventional poly(methyl methacrylate) (PMMA) nanobeads, we then developed a synergistic approach for highly specific and efficient enrichment of N-glycopeptides/glycoproteins. Owing to the introduction of PMMA nanobeads that have strong adsorption towards nonglycopeptides, the number of N-glycopeptides detected and the signal-to-noise ratio in analyzing standard proteins mixture both increased appreciably. The recovery of N-glycopeptides by the synergistic method reached 92.1%, much improved than from [email protected] alone that was 75.3%. Finally, we tested this approach in the analysis of amniotic fluid, obtaining the maximum number and ratio of N-glycopeptides compared to the use of [email protected] alone and commercial SiMAG-boronic acid particles. This ensemble provides an interesting and efficient enrichment platform for glycoproteomics research.
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http://dx.doi.org/10.1038/s41598-017-04517-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496847PMC
July 2017

Bioluminescent Turn-On Probe for Sensing Hypochlorite in Vitro and in Tumors.

Anal Chem 2017 06 10;89(11):5693-5696. Epub 2017 May 10.

CAS Key Laboratory of Soft Matter Chemistry, Department of Chemistry, University of Science and Technology of China , Hefei, Anhui 230026, China.

Hypochlorite (ClO) is one of the most important reactive oxygen species but using a BL probe for its selective detection (or imaging) still remains challenging. Herein, we report a latent BL probe benzoylhydrazine luciferin (1) for highly selective detection of ClO in vitro and imaging ClO in living cells and tumors. In vitro tests indicated that 1 could be applied for highly selective detection of ClO within the range of 0-62.5 μM with a limit of detection of 0.705 μM. Using these unique features of 1, we successfully applied it to image ClO in living cells and tumors. We envision that probe 1 might be applied to elucidate the biological roles of ClO in wider physiological and pathological processes in the near future.
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http://dx.doi.org/10.1021/acs.analchem.7b01103DOI Listing
June 2017

Mechanistic study of CBT-Cys click reaction and its application for identifying bioactive N-terminal cysteine peptides in amniotic fluid.

Chem Sci 2017 Jan 11;8(1):214-222. Epub 2016 Aug 11.

CAS Key Laboratory of Soft Matter Chemistry , Department of Chemistry , University of Science and Technology of China , Hefei , Anhui 230026 , China . Email: ; Email:

CBT-Cys click condensation reaction has a high second-order reaction rate constant and has found wide applicability in recent years. However, its reaction mechanism has not been experimentally validated and its application for identifying bioactive N-terminal Cys peptides in real clinical samples has not been reported. Herein, firstly, by employing induced nanoelectrospray ionization-mass spectrometry (InESI-MS) and a home-built micro-reactor, we successfully intercepted and structurally characterized the crucial intermediate in this click reaction for the first time. With the intermediate, the proposed mechanism of this reaction was corroborated. Moreover, we also applied this MS setup to monitor the reaction in real time and obtained the second-order reaction rate constants of this reaction at different pH values. After mechanistic study, we applied this click reaction for identifying bioactive N-terminal cysteine peptides in amniotic fluid (AF). Eight unique N-terminal Cys peptides in AF, three of which are located in the functional domain regions of their corresponding proteins, were identified with a false positive rate less than 1%. One of the three peptides was found able to inhibit the growth of uterine endometrial cancer HEC-1-B cells but not the endometrial normal cells a typical apoptotic pathway. With its mechanism satisfactorily elucidated, the kinetic parameters obtained, as well as its application for fishing bioactive N-terminal Cys peptides from vast complex clinical samples, we anticipate that this CBT-Cys click reaction could be applied more widely for the facile isolation, site-specific identification, and quantification of N-terminal Cys-containing peptides in complex biological samples.
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http://dx.doi.org/10.1039/c6sc01461eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5308401PMC
January 2017

TIMP-1 and CD82, a promising combined evaluation marker for PDAC.

Oncotarget 2017 Jan;8(4):6496-6512

Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China.

Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a widely secreted protein that regulates cell motility, proliferation, and apoptosis. Although it is recognized that TIMP-1-tetraspanin CD63 regulates epithelial cell apoptosis and proliferation, how TIMP-1 controls cell motility is not well understood. In this study, we identify tetraspanin CD82 (also called KAI1) as a component of the promiscuous TIMP-1 interacting protein complex on cell surface of human pancreatic adenocarcinoma cells. CD82 directly binds to TIMP-1 N-terminal region through its large extracellular loop and co-localizes with TIMP-1 in both cancer cell lines and clinical samples. Moreover, CD82 facilitates membrane-bound TIMP-1 endocytosis, which significantly contributes to the anti-migration effect of TIMP-1. CD82 silencing partially eliminates these functions. TIMP-1 and CD82 expression status in patients with pancreatic ductal adenocarcinoma (PDAC) might demonstrate future usefulness as a differentiation marker and give us new insight into tumorigenic metastatic potential.
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http://dx.doi.org/10.18632/oncotarget.14133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351648PMC
January 2017

Decrease in Circulating Fatty Acids Is Associated with Islet Dysfunction in Chronically Sleep-Restricted Rats.

Int J Mol Sci 2016 Dec 14;17(12). Epub 2016 Dec 14.

Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing 210029, China.

Previous studies have shown that sleep restriction-induced environmental stress is associated with abnormal metabolism, but the underlying mechanism is poorly understood. In the current study, we investigated the possible lipid and glucose metabolism patterns in chronically sleep-restricted rat. Without changes in food intake, body weight was decreased and energy expenditure was increased in sleep-restricted rats. The effects of chronic sleep disturbance on metabolites in serum were examined using ¹H NMR metabolomics and GC-FID/MS analysis. Six metabolites (lipoproteins, triglycerides, isoleucine, valine, choline, and phosphorylcholine) exhibited significant alteration, and all the fatty acid components were decreased, which suggested fatty acid metabolism was impaired after sleep loss. Moreover, increased blood glucose, reduced serum insulin, decreased glucose tolerance, and impaired glucose-stimulated insulin secretion of islets were also observed in sleep-restricted rats. The islet function of insulin secretion could be partially restored by increasing dietary fat to sleep-disturbed rats suggested that a reduction in circulating fatty acids was related to islet dysfunction under sleep deficiency-induced environmental stress. This study provides a new perspective on the relationship between insufficient sleep and lipid/glucose metabolism, which offers insights into the role of stressful challenges in a healthy lifestyle.
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http://dx.doi.org/10.3390/ijms17122102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5187902PMC
December 2016

Luteolin improves non-alcoholic fatty liver disease in db/db mice by inhibition of liver X receptor activation to down-regulate expression of sterol regulatory element binding protein 1c.

Biochem Biophys Res Commun 2017 Jan 22;482(4):720-726. Epub 2016 Nov 22.

Department of Neurosurgery, Jingling Hospital, School of Medicine, Nanjing University, China. Electronic address:

In this study, we report that daily administration of luteolin for 8 weeks improved hepatic steatosis by repressing hepatic TG accumulation and increasing glycogen storage. Luteolin inhibited hepatic de novo lipid synthesis by regulating the LXR-SREBP-1c signaling pathway, which is over-activated in the livers of db/db mice. Further in vitro studies revealed that luteolin can competitively bind to the ligand binding domain to suppress the LXR activation induced by an LXR agonist and high glucose, thereby decreasing TG accumulation in HepG2 cells and primary hepatocytes. Taken together, our results indicate that luteolin can abolish lipid accumulation induced by LXR-SREBP-1c activation both in vivo and in vitro, and may have potential as a therapeutic agent for treating NAFLD.
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http://dx.doi.org/10.1016/j.bbrc.2016.11.101DOI Listing
January 2017
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