Tianjin Key Laboratory for Biomarkers of Occupational and Environmental Hazard

Tianjin, China

Tianjin Key Laboratory for Biomarkers of Occupational and Environmental Hazard

Tianjin, China
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Xu Z.-W.,Tianjin Key Laboratory for Biomarkers of Occupational and Environmental Hazard | Wang F.-M.,Tianjin 3rd Central Hospital | Hu W.-L.,Tianjin Key Laboratory for Biomarkers of Occupational and Environmental Hazard | Xu R.-C.,Tianjin Key Laboratory for Biomarkers of Occupational and Environmental Hazard
Biological and Pharmaceutical Bulletin | Year: 2010

Recent research has shown that the Na+/K+-ATPase α1 subunit is a novel anti-cancer target, which plays pivotal roles in malignant cell ion transport, metabolism, migration and signal transduction. The purpose of the present study was to investigate the anti-cancer effects of ouabain and Na+/K+-ATPase α1 small interfering ribo-nucleic acid (siRNA) on HepG2 cell proliferation, apoptosis and cell cycle, and to explore the molecular mecha-nisms. The expression of Na+/K+-ATPase α1 subunit in human hepatocellular carcinoma (HCC), normal liver tissues and human HCC line (HepG2, SMMC-7721 and Bel-7402) has been investigated. Using the ouabain and Na+/K+-ATPase α1 subunit siRNA, which target the Na+/K+-ATPase, we have evaluated the effects of inhibiting Na+/K+-ATPase α1 in human HepG2 cells with respect to cell proliferation, morphology, cell cycle, impact on intracellular Ca2+, reactive oxygen species (ROS) concentration, and correlated gene expression level on messenger ribonucleic acid (mRNA) and protein. Our data showed that the expression Na+/K+-ATPase α1 subunit in HCC tissues is higher than that in normal liver tissues. Ouabain and Na+/K+-ATPase α1 siRNA could inhibit HepG2 cell proliferation. Ouabain could induce HepG2 cell apoptosis and generate S phase arrest, and siRNA could enhance the anti-cancer effect of ouabain that induced HepG2 cells apoptosis via an intracellular C2+ and ROS increase-mediated, and generated cell cycle S phase arresting by decreasing the CyclinA1/cyclin-dependent kinase 2 (CDK2)/proliferating cell nuclear antigen (PCNA) complex product and increasing the expression of cyclin-dependent kinase inhibitor 1A (P21C1P1). We believe that targeting of the Na+/K+-ATPase α1 subunit in human HCC cells could provide new sight into the treatment of HCC. © 2010 Pharmaceutical Society of Japan.


Sun Y.-J.,Shenyang Pharmaceutical University | Li Z.-L.,Shenyang Pharmaceutical University | Chen H.,Tianjin Key Laboratory for Biomarkers of Occupational and Environmental Hazard | Liu X.-Q.,Shenyang Pharmaceutical University | And 2 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

Three new aryltetralin lignans, 4-acetyl-4-demethyl-podophyllotoxin (1) and sinolignans A, B (2-3), and two new natural products (4-5), were isolated from the roots and rhizomes of Sinopodophyllum emodi together with twelve known lignans (6-17). Their structures and stereochemistry were elucidated on the basis of spectroscopic evidence, and circular dichroism (CD) method. The cytotoxic activities of all isolated compounds were evaluated against HeLa and KB cell lines. Compared with etoposide, compounds 1, 6-9, and 13 showed more potent cytotoxicities against two tumor cell lines. On the basis of IC 50 values, deoxypodophyllotoxin (7) was about 579 and 1123 times more toxic than etoposide in HeLa and KB cell lines, respectively. The preliminary SAR study indicated that an oxygenated group at C-7′ might decrease cytotoxicity against two cell lines, which was different from most previous studies. However, this needs to be systematically verified by extensive pharmacological experiments. © 2011 Elsevier Ltd. All rights reserved.


Wang Y.,College of Logistics | Wang Y.,TianJin Key Laboratory for Biomarkers of Occupational and Environmental Hazard | Li L.,TianJin Key Laboratory for Biomarkers of Occupational and Environmental Hazard | Li L.,College of Logistics | And 5 more authors.
Cytokine | Year: 2012

It has been widely reported that Interleukin-6 (IL-6) is overexpressed in the serum and ascites of ovarian cancer (OVCA) patients, and elevated IL-6 level correlates with poor prognosis and survival. However, the exact role that IL-6 plays in this malignancy or whether IL-6 can regulate tumorigenic properties has not been established. Here we demonstrate that overexpression of IL-6 in non-IL-6-expressing A2780 cells (by transfecting with plasmid encoding for sense IL-6) increases anchorage-independent growth, proliferation, adhesion and invasion, while depletion of endogenous IL-6 expression in IL-6-overexpressing SKOV-3 cells (by transfecting with plasmid encoding for antisense IL-6) decreases. Further investigation indicates that IL-6 promotes OVCA cell proliferation by altering cell cycle distribution rather than inhibiting apoptosis and that IL-6-enhanced OVCA cell invasive may be associated with increased matrix metalloproteinase (MMP)-9 but not MMP-2 proteolytic activity. In addition, overexpressing or deleting of IL-6 in OVCA cells enhances or reduces its receptor (IL-6Rα and gp130) expression and basal phosphorylation levels of both ERK and Akt, and additional treatment with specific inhibitor of the ERK or Akt signaling pathway significantly inhibits the proliferation of IL-6-overexpressing A2780 cells. Our data suggest that the autocrine production of IL-6 by OVCA cells regulates tumorigenic properties of these cells by inducing IL-6 signaling pathways. Thus, regulation of IL-6 expression or its related signaling pathway may be a promising strategy for controlling the progression of OVCA. © 2012 Elsevier Ltd.


Wang Y.,TianJin Key Laboratory for Biomarkers of Occupational and Environmental Hazard | Wang Y.,College of Logistics | Xu R.C.,TianJin Key Laboratory for Biomarkers of Occupational and Environmental Hazard | Zhang X.L.,College of Logistics | And 4 more authors.
Cytokine | Year: 2012

It has been shown that IL-8 is elevated in ovarian cyst fluid, ascites, serum, and tumor tissue from ovarian cancer (OVCA) patients, and increased IL-8 expression correlates with poor prognosis and survival. However, the exact role that IL-8 plays in this malignancy or whether IL-8 can regulate malignant behavior has not been established. Here we demonstrate that overexpression of IL-8 in non-IL-8-expressing A2780 cells (by transfecting with plasmid encoding for sense IL-8) increases anchorage-independent growth, proliferation, angiogenic potential, adhesion and invasion while depletion of endogenous IL-8 expression in IL-8-overexpressing SKOV-3 cells (by transfecting with plasmid encoding for antisense IL-8) decreases the above effects. Further investigation indicates that IL-8-stimulated cell proliferation correlates with alteration of cell cycle distribution by increasing levels of cell cycle-regulated Cyclin D1 and Cyclin B1 proteins as well as activation of PI3K/Akt and Raf/MEK/ERK, whereas IL-8-enhanced OVCA cell invasive correlates with increased MMP-2 and MMP-9 activity and expression. Our data suggest that IL-8 secreted by OVCA cells promotes malignant behavior of these cells via inducing intracellular molecular signaling. Therefore, modulation of IL-8 expression or its related signaling pathway may be a promising strategy for controlling the progression and metastasis of OVCA. © 2012 Elsevier Ltd.


Wang Y.,Tianjin Key Laboratory for Biomarkers of Occupational and Environmental Hazard | Li L.Z.,Tianjin Key Laboratory for Biomarkers of Occupational and Environmental Hazard
Cancer Letters | Year: 2010

It has been shown that IL-6 is elevated in the serum and ascites of ovarian cancer patients, and increased IL-6 concentration correlates with poor prognosis and chemoresistance. However, the role of IL-6 expression in the acquisition of the chemoresistance phenotype and the underlining mechanisms of drug resistance in ovarian cancer cells remain unclear. Here we demonstrate that both exogenous (a relatively short period of treatment with recombination IL-6) and endogenous IL-6 (by transfecting with plasmid encoding for sense IL-6) induce cisplatin and paclitaxel resistance in non-IL-6-expressing A2780 cells, while deleting of endogenous IL-6 expression in IL-6-overexpressing SKOV3 cells (by transfecting with plasmid encoding for antisense IL-6) promotes the sensitivity of these cells to anticancer drugs. IL-6-mediated resistance of ovarian cancer cells exhibits decreased proteolytic activation of caspase-3. Meanwhile, the further study demonstrates that the chemoresistance caused by IL-6 is associated with increased expression of both multidrug resistance-related genes (MDR1 and GSTpi) and apoptosis inhibitory proteins (Bcl-2, Bcl-xL and XIAP), as well as activation of Ras/MEK/ERK and PI3K/Akt signaling. Therefore, modulation of IL-6 expression or its related signaling pathway may be a promising strategy of treatment for drug-resistant ovarian cancer. © 2010 Elsevier Ireland Ltd.


Wang Y.,TianJin Key Laboratory for Biomarkers of Occupational and Environmental Hazard | Li L.Z.,TianJin Key Laboratory for Biomarkers of Occupational and Environmental Hazard
Cytokine | Year: 2011

It has been widely reported that interleukin-8 (IL-8) is overexpressed in ovarian cyst fluid, ascites, serum, and tumor tissue from ovarian cancer (OVCA) patients, and elevated IL-8 expression correlates with a poor final outcome and chemosensitivity. However, the role of IL-8 expression in the acquisition of the chemoresistance phenotype and the underlining mechanisms of drug resistance in OVCA cells are not yet fully understood. Here we show that both exogenous (a relatively short period of treatment with recombination IL-8) and endogenous IL-8 (by transfecting with plasmid encoding for sense IL-8) induce cisplatin and paclitaxel resistance in non-IL-8-expressing A2780 cells, while deleting of endogenous IL-8 expression in IL-8-overexpressing SKOV-3 cells (by transfecting with plasmid encoding for antisense IL-8) promotes the sensitivity of these cells to anticancer drugs. IL-8-mediated resistance of OVCA cells exhibits decreased proteolytic activation of caspase-3. Meanwhile, the further study demonstrates that the chemoresistance caused by IL-8 is associated with increased expression of both multidrug resistance-related genes (MDR1) and apoptosis inhibitory proteins (Bcl-2, Bcl-xL, and XIAP), as well as activation of PI3. K/Akt and Ras/MEK/ERK signaling. Therefore, modulation of IL-8 expression or its related signaling pathway may be a promising strategy of treatment for drug-resistant OVCA. © 2011.


Wang Y.,TianJin Key Laboratory for Biomarkers of Occupational and Environmental Hazard | Li L.Z.,TianJin Key Laboratory for Biomarkers of Occupational and Environmental Hazard | Zhang Y.L.,TianJin Key Laboratory for Biomarkers of Occupational and Environmental Hazard
Molecular and Cellular Endocrinology | Year: 2011

Estrogen analogues are promising drugs for postmenopausal osteoporosis, but because of their possible side effects such as increased risk of cancer, estrogens which exert their estrogenic effects selectively on bone are desired. It has been shown that rhein inhibits osteoclast formation and bone resorption activity and has an antitumor role in several types of cancers. Having found that rhein had high affinity for the bone mineral, we synthesized estrone-rhein hybrid compounds and confirmed that one of these hybrid compounds, LC, exhibited a selective profile in the bone and prevented bone loss but had no effect on endometrium growth in ovariectomized rats. However, the mechanisms underlying its actions on human bone cells have not been well defined. Here we show that LC concurrently stimulates osteoprotegerin (OPG) and inhibits receptor activator of nuclear factor-κB ligand (RANKL) and Interleukin-6 (IL-6) production by human osteoblastic MG-63 cells containing two estrogen receptor (ER) isotypes. Treatment with the ER antagonist ICI 182,780 abrogates the above actions of LC on osteoblast-derived cells. Using small interfering double-stranded RNAs (siRNA) technology, we further demonstrate that the effects of LC on IL-6 production are mediated by both ERα and ERβ but those on OPG and RANKL expression primarily by ERα. Furthermore, we also demonstrate that LC functions at least partially through activation of the classic estrogen response element (ERE) pathway as well as Ras/MEK/ERK and PI3K/Akt signaling. The effect of LC on bone is due to not only its estrogenic activity but also action of its rhein moiety. Also, this compound shows much weaker effect on breast epithelial cell growth than that of estrone. Therefore, using rhein for conjugating compounds is a promising method of effectively targeting estrogens to the bone. © 2011 Elsevier Ireland Ltd.


Sun Y.-J.,Shenyang Pharmaceutical University | Li Z.-L.,Shenyang Pharmaceutical University | Chen H.,Tianjin Key Laboratory for Biomarkers of Occupational and Environmental Hazard | Liu X.-Q.,Shenyang Pharmaceutical University | And 2 more authors.
Planta Medica | Year: 2012

Four new tetrahydrofuranoid lignans, (-)-tanegool-7′-methyl ether (1), (+)-7′-methoxylariciresinol (2), sinolignan C (3), and epipinoresinol-4,4-di-Oβ- D-glucopyranoside (4), were isolated from the roots and rhizomes of Sinopodophyllum emodi together with one known lignan (5). Their structures and stereochemistry were elucidated on the basis of spectroscopic and mass spectrometric evidence. The isolation of compounds 1-5 represents the first report of tetrahydrofuran lignans from the genus Sinopodophyllum. The cytotoxic activities of all isolated compounds were evaluated against HeLa and KB cell lines, and compound 1 showed the most potent cytotoxicity with ICvalues of 9.7 μM and 4.7 μM, respectively.


Meng B.,Institute of Health and Environmental Medicine | Meng B.,Tianjin Key Laboratory for Biomarkers of Occupational and Environmental Hazard | Gao W.,Institute of Health and Environmental Medicine | Wei J.,Institute of Health and Environmental Medicine | And 4 more authors.
Nutrition | Year: 2013

Objective: The aim of this study was to determine the effects of quercetin on homocysteine (Hcy) metabolism and hepatic antioxidant status in high methionine (Met)-fed rats. Methods: Rats were fed for 6 wk the following diets: control, 1.0% Met, 1.0% Met and 0.1% quercetin, 1.0% Met and 0.5% quercetin, 1.0% Met and 2.5% quercetin-supplemented diets. Serum Hcy, Met, cysteine, serine, taurine, glutathione (GSH), quercetin and its metabolites, and activities of alanine transaminase (ALT) and aspartate transaminase (AST) were assayed. Hepatic malondialdehyde, GSH and carbonyls, and activity of superoxide dismutase and ferric-reducing antioxidant power also were measured. Results: Serum Hcy was increased significantly after Met treatment and decreased after quercetin supplementation. Meanwhile, serum taurine was increased and serine decreased. However, the content of GSH in serum and liver was decreased in the quercetin-supplemented groups and activities of serum ALT and AST were enhanced in the 1.0% Met and 2.5% quercetin-supplemented groups. Conclusions: Quercetin is effective in decreasing serum Hcy level in high Met-fed rats and one of possible mechanisms is associated with increased transsulfuration of Hcy. Quercetin can acts as a prooxidant at high intake levels. © 2013 Elsevier Inc.


Wang Y.,Tianjin Key Laboratory for Biomarkers of Occupational and Environmental Hazard
Zhonghua fu chan ke za zhi | Year: 2010

To study the mechanism of chemotherapy resistance caused by interleukin-6 (IL-6) in ovarian cancer cells and its related signal pathways. Ovarian cancer cell lines A2780 (IL-6 receptor positive, while non-IL-6-expressing and cisplatin/paclitaxel-responsive) and SKOV3 cell lines (overexpressing of IL-6 receptor and IL-6 and cisplatin/paclitaxel-resistant) were suitable models for this study. The effect of exogenous (a short period of treatment with recombination IL-6) and endogenous IL-6 (by transfecting with plasmid encoding for sense IL-6) in A2780 cells or deleting of endogenous IL-6 expression in SKOV3 cells (by transfecting with plasmid encoding for antisense IL-6) on the sensitivity to cisplatin and paclitaxel was investigated. Meanwhile, the mechanism of chemotherapy resistance caused by IL-6 in ovarian cancer cells and its related signal pathways were also analyzed. We found that both exogenous and endogenous IL-6 induce cisplatin and paclitaxel resistance in non-IL-6-expressing A2780 cells (the resistance multiple to cisplatin and paclitaxel was: exogenous, 6.25 and 7.31; endogenous, 7.13-8.34 and 7.61-10.70), while deleting of endogenous IL-6 expression in IL-6-overexpressing SKOV3 cells promotes its sensitivity to anticancer drugs (the resistance multiple to cisplatin and paclitaxel was 0.15 and 0.10, 0.10 and 0.08). IL-6 significantly up-regulated the expression levels of mRNA and protein of drug resistance-associated genes, MDR1 and GST-π, and apoptosis-inhibiting genes, bcl-2, bcl-xL and XIAP in a dose-dependent manner in A2780 cells. In accordance with this finding, the mRNA and protein levels of MDR1 and GST-π enhanced in sense IL-6-transfected A2780 cells, and reduced in antisense IL-6-transfected SKOV3 cells compared with the corresponding parental and control vector-transfected cells, which had no difference. It was found that PD98059 [mitogen-activated protein kinase-extracellular signal-regulated kinase (MEK) inhibitor] and wortmannin [phosphatidylinositol 3-kinase (PI3K) inhibitor] significantly antagonized IL-6-induced phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt), respectively, and both of them blocked IL-6-induced cisplatin and paclitaxel resistance and the inhibitory effects of PD98059 and wortmannin were dependent on its concentration. These data suggest that IL-6-induced chemoresistance may be associated with increase of both drug resistance-associated genes (MDR1 and GST-π) and apoptosis-inhibiting genes (bcl-2, bcl-xL and XIAP), and activation of MEK/ERK and PI3K/Akt. Therefore, modulation of IL-6 expression or its related signaling pathway may be a promising strategy of treatment for drug-resistant ovarian cancer.

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