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Zhang J.,Shandong University | Zhang J.,Shandong Provincial Key laboratory of Cardiovascular Proteomics | Wang Q.-Z.,Shandong University | Wang Q.-Z.,Shandong Provincial Key laboratory of Cardiovascular Proteomics | And 13 more authors.
Biochimica et Biophysica Acta - General Subjects | Year: 2017

Background: Myocardial fibrosis contributes to cardiac dysfunction. Astaxanthin (AST), a member of the carotenoid family, is a well-known antioxidant, but its effect on and underlying mechanisms in myocardial fibrosis are poorly understood. Methods: In vivo, myocardial fibrosis and cardiac dysfunction were induced using transverse aortic constriction (TAC). AST was administered to mice for 12. weeks post-surgery. In vitro, transforming growth factor β1 (TGF-β1) was used to stimulate human cardiac fibroblasts (HCFs). EX-527 (6-chloro-2, 3, 4, 9-tetrahydro-1H-carbazole-1-carboxamide) and SIRT1 siRNA were used to inhibit SIRT1 in vivo and in vitro, respectively. The effects of AST on cardiac function and fibrosis were determined. SIRT1 expression and activity were measured to explore the mechanisms underlying its effects. Results: AST improved cardiac function and attenuated fibrosis. Receptor activated-SMADs (R-SMADs), including SMAD2 and SMAD3, played important roles in these processes. The TAC surgery-induced increases in the expression of phosphorylated and acetylated R-SMADs were attenuated by treatment with AST, the translocation and transcriptional activity of R-SMADs were also restrained. These effects were accompanied by an increase in the expression and activity of SIRT1. Inhibiting SIRT1 attenuated the acetylation and transcriptional activity of R-SMADs, but not their phosphorylation and translocation. Conclusions: Our data demonstrate that AST improves cardiac function and attenuates fibrosis by decreasing phosphorylation and deacetylation of R-SMADs. SIRT1 contributes to AST's protective function by reducing acetylation of R-SMADs. General significance: These data suggest that AST may be useful as a preventive/therapeutic agent for cardiac dysfunction and myocardial fibrosis. © 2017 Elsevier B.V.


Wang J.,General Hospital | Guo Y.,Military Command of Shandong Province | Wang B.,General Hospital | Bi J.,General Hospital | And 4 more authors.
Molecular Biology Reports | Year: 2012

The use of lymphatic microvessel density (LVD) and pro-lymphangiogenic mediators as prognostic factors for survival in breast cancer remains controversial. We searched the electronic databases PubMed and EMBASE without language restrictions for relevant literature to aggregate the survival results. To be eligible, every study had to include the assessment of the LVD or the expression of vascular endothelial growth factor (VEGF)-C or -D in patients with breast cancer and provide a survival comparison, including disease-free survival (DFS) or overall survival (OS), according to the LVD, VEGF-C or VEGF-D status. Across all studies, 56.64 % of patients were considered to have a VEGF-C-positive tumor, and 65.54 % of patients had VEGF-D-positive tumors. High LVD had an unfavorable impact on DFS, with a pooled hazard ratio (HR) of 2.222 (95 % CI 1.579-3.126) and an OS with a HR of 2.493 (95 % CI 1.183-5.25). According to the different lymphatic makers, the subgroup HR in the D2-40 studies was 2.431 (95 % CI 1.622-3.644) for DFS and 4.085 (95 % CI 1.896-8.799) for OS. VEGF-C overexpression, as assessed by immunochemistry, was a prognostic factor for decreased DFS (HR 2.164; 95 % CI 1.256-3.729) and for decreased OS (HR 2.613; 95 % CI 1.637-4.170). VEGF-D overexpression was a significant although weak prognostic factor for DFS only when assessed by immunochemistry, with a HR of 2.108 (95 % CI 1.014-4.384). Our meta-analysis demonstrated that LVD, VEGF-C and VEGF-D could predict poor prognosis in patients with breast cancer. However, standardization of the assessment of LVD and for the expression of lymphangiogenesis factors is needed. © 2012 Springer Science+Business Media Dordrecht.


Chu H.,General Hospital | Wang J.,General Hospital | Zhu Z.,General Hospital | Guo Y.,Military Command of Shandong Province | And 4 more authors.
Chinese Journal of Cancer Biotherapy | Year: 2013

Objective: To investigate the effect of interference of human antigen R (HuR) expression on sensitivity of human multidrug-resistant human breast cancer MCF-7/Adr cell line to Doxorubicn. Methods: The shRNA expression vector targeting HuR gene (pGenesil-siHuR) has been constructed and stably transfected into human breast cancer MCF-7/Adr cell line. The expression level of MDR1 mRNA in MCF-7/Adr cells was assayed by real-time PCR. The P-gp protein (encoded by the MDR1 gene) expression were determined by Western blotting. The survival rate and IC50 of MCF-7/Adr cells to doxorubicin after pGenesil-siHuR transfection were evaluated by MTT method. The apoptosis rate of MCF-7/Adr cells was detected by flow cytometry. Results: Compared with untransfected MCF-7/Adr cells, the MDR1 mRNA([0.184±0.029] vs [1.203±0.026],P<0.01)and P-gp protein expressions([0.314±0.011] vs [0.796±0.007 J, P <0.01 Jwere significantly reduced in pGenesil-siHuR transfected MCF-7/Adr cells (P<0.01). The IC50 of MCF-7/Adr cells to doxorubicin decreased from (148.2 ± 2.3) nmol/L to (42.9 ± 0.4) nmol/L after pGenesil-siHuR transfection. Compared with untransfected MCF-7/Adr cells, the ratio of cell apoptosis was significantly increased in pGenesil-siHuR transfected MCF-7/Adr cells ([34.6 ± 1.1]% vs [1.1 ± 0.2]%, P < 0.01) after the treatment with doxorubicin. Conclusion: RNA interference of HuR can inhibit the expression of MDR1 gene and increase the sensitivity of multidrug-resistant breast cancer cells to doxorubicin.


Zhu Z.,General Hospital | Wang B.,General Hospital | Bi J.,General Hospital | Zhang C.,General Hospital | And 5 more authors.
Tumor Biology | Year: 2013

HuR is an ubiquitously expressed RNA-binding protein that stabilizes messenger RNA and regulates translation. This protein has been shown to play an important role in carcinogenesis and cancer progression. P-glycoprotein (P-gp) is the product of the multidrug resistance 1 gene, and the overexpression of P-gp induces multidrug resistance and represents a major obstacle in cancer chemotherapy. The purpose of this study was to determine the expression of HuR and P-gp in human breast cancer tissues and analyze the relationship between HuR or P-gp expression and the clinical-pathological variables and patient outcomes. Immunohistochemistry was used to determine HuR and P-gp expression in 82 human breast cancer tissues and 20 matched adjacent noncancerous tissues. Additionally, 16 benign breast tumor samples were used as controls. The overexpression of cytoplasmic HuR was found in breast cancer but not in the matched adjacent noncancerous tissues or benign breast tumors. The expression levels of cytoplasmic HuR were significantly associated with increased age, high nuclear grade, and the positive expression of the ER, PR, and HER-2/neu. HuR was also associated with the expression of P-gp protein. Furthermore, univariate analysis indicates that patients with high expression levels of cytoplasmic HuR or P-gp had significantly reduced survival compared to patients with low expression levels. A multivariate analysis showed that age at diagnosis, nuclear grade, and cytoplasmic HuR positivity were independent indicators for disease-free survival and overall survival in patients with breast cancer. In conclusion, cytoplasmic HuR expression detected by immunohistochemical staining is a negative prognostic indicator for survival in patients with breast cancer. © 2013 International Society of Oncology and BioMarkers (ISOBM).


Wang J.,General Hospital | Guo Y.,Military Command of Shandong Province | Chu H.,General Hospital | Guan Y.,General Hospital | And 2 more authors.
International Journal of Molecular Sciences | Year: 2013

The human embryonic lethal abnormal vision-like protein, HuR, is a member of the Hu family of RNA-binding proteins. Over the past decade, this ubiquitously expressed protein has been extensively investigated in cancer research because it is involved in the regulation of mRNA stability and translation in many cell types. HuR activity and function is associated with its subcellular distribution, transcriptional regulation, translational and post-translational modifications. HuR regulation of target mRNAs is based on the interaction between the three specific domains of HuR protein and one or several U- or AU-rich elements (AREs) in the untranslated region of target mRNAs. A number of cancer-related transcripts containing AREs, including mRNAs for proto-oncogenes, cytokines, growth factors, and invasion factors, have been characterized as HuR targets. It has been proposed that HuR has a central tumorigenic activity by enabling multiple cancer phenotypes. In this review, we comprehensively survey the existing evidence with regard to the diverse functions of HuR in caner development and progression. The current data also suggest that HuR might be a novel and promising therapeutic target and a marker for treatment response and prognostic evaluation. © 2013 by the authors; licensee MDPI, Basel, Switzerland.


Wang J.,General Hospital | Wang B.,General Hospital | Zhao W.,Tianjin Medical University | Guo Y.,Military Command of Shandong Province | And 4 more authors.
PLoS ONE | Year: 2012

Background: Lymphatic vessel invasion (LVI) exerts an important process in the progression and local spread of cancer cells. However, LVI as a prognostic factor for survival in non-small cell lung cancer (NSCLC) remains controversial. Methodology/Principal Findings: A meta-analysis of published studies from PubMed and EMBASE electronic databases was performed to quantity the effects of LVI on both relapse-free survival and overall survival for patients with NSCLC. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were used to assess the strength of these effects. This meta-analysis included 18,442 NSCLC patients from 53 eligible studies. LVI appeared in 32.1% (median; range, 2.8% to 70.9%) of tumor samples. In all, patients with LVI were 2.48 times more likely to relapse by univariate analysis (95% CI: 1.92-3.22) and 1.73 times by multivariate analysis (95% CI: 1.24-2.41) compared with those without LVI. For the analyses of LVI and overall survival, the pooled HR estimate was 1.97 (95% CI: 1.75-2.21) by univariate analysis and 1.59 (95% CI: 1.41-1.79) by multivariate analysis. Multivariate analysis showed a risk was 91% higher for recurrence (HR = 1.91, 95% CI: 1.14-2.91) and 70% higher for mortality (HR = 1.70, 95% CI: 1.38-2.10) in LVI-positive I stage patients compared with LVI-negative I stage patients. Subgroup analyses showed similar significant adjusted risks for recurrence and death in adenocarcinomas, and a significant adjusted risk for death in studies that utilized elastic staining with or without immunohistochemistry in defining LVI. Conclusions/Significance: The present study indicates that LVI appears to be an independent poor prognosticator in surgically managed NSCLC. NSCLC patients with LVI would require a more aggressive treatment strategy after surgery. However, large, well-designed prospective studies with clinically relevant modeling and standard methodology to assess LVI are required to address some of these important issues. © 2012 Wang et al.

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