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Chen F.,CAS Shanghai Institutes for Biological Sciences | Chen F.,Shanghai University | Chen F.,Key Laboratory of Food Safety Risk Assessment | Qian L.-H.,CAS Shanghai Institutes for Biological Sciences | And 5 more authors.
CNS Neuroscience and Therapeutics | Year: 2013

Introduction: Hyperglycemia-induced oxidative stress has been implicated in diabetic vascular complications in which NADPH oxidase is a major source of reactive oxygen species (ROS) generation. Resveratrol is a naturally occurring polyphenol, which has vasoprotective effects in diabetic animal models and inhibits high glucose (HG)-induced oxidative stress in endothelial cells. Aims: We aimed to examine whether HG-induced NADPH oxidase activation and ROS production contribute to glucotoxicity to endothelial cells and the effect of resveratrol on glucotoxicity. Results: Using a murine brain microvascular endothelial cell line bEnd3, we found that NADPH oxidase inhibitor (apocynin) and resveratrol both inhibited HG-induced endothelial cell apoptosis. HG-induced elevation of NADPH oxidase activity and production of ROS were inhibited by apocynin, suggesting that HG induces endothelial cell apoptosis through NADPH oxidase-mediated ROS production. Mechanistic studies revealed that HG upregulated NADPH oxidase subunit Nox1 but not Nox2, Nox4, and p22phox expression through NF-κB activation, which resulted in elevation of NADPH oxidase activity and consequent ROS production. Resveratrol prevented HG-induced endothelial cell apoptosis through inhibiting HG-induced NF-κB activation, NADPH oxidase activity elevation, and ROS production. Conclusions: HG induces endothelial cell apoptosis through NF-κB/NADPH oxidase/ROS pathway, which was inhibited by resveratrol. Our findings provide new potential therapeutic targets against brain vascular complications of diabetes. © 2013 John Wiley & Sons Ltd.


Li M.,CAS Shanghai Institutes for Biological Sciences | Chen P.,CAS Shanghai Institutes for Biological Sciences | Li J.,CAS Shanghai Institutes for Biological Sciences | Chu R.,CAS Shanghai Institutes for Biological Sciences | And 6 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Circulating levels of 25-hydroxyvitamin D [25(OH)D] may affect the prognosis of cancer patients; however, the epidemiological results are not consistent. Objective: To perform a meta-analysis of all published studies to assess the associations of circulating 25(OH)D levels measured at or near the time of diagnosis and outcomes for cancer patients. Data Sources: Searches of the PubMed and MEDLINE databases were performed and updated to December 2013. Study Selection: Studies reporting an association between circulating 25(OH)D levels at or near the time of diagnosis and outcomes for the patients were included. Data Extraction: Data extraction was performed independently by two authors, and conflicts were resolved by a third investigator. Data Synthesis: Included in the meta-analysis were 25 studies with 17 332 cases. Significant associations between circulating 25(OH)D levels at or near the time of diagnosis and the outcomes for cancer patients were found. The pooled hazard ratio for the highest vs the lowest quartile of circulating 25(OH)D levels was 0.55 (95% confidence interval [CI] = 0.33-0.91) for overall survival of colorectal cancer patients, 0.63 (95% CI = 0.51-0.77) for breast cancer patients, and 0.48 (95% CI = 0.36-0.64) for lymphoma patients. Higher 25(OH)D levels were significantly associated with reduced cancer-specific mortality for patients with colorectal cancer (P = .005) and lymphoma (P < .001) and improved disease-free survival for patients with breast cancer (P < .001) or lymphoma (P < .05). A 10-nmol/L increment in circulating 25(OH)D levels conferred a hazard ratio of 0.96 (95% CI = 0.95-0.97) for overall survival of the cancer patients. Conclusions: The results indicate that cancer patients with higher circulating 25(OH)D levels at or near the time of diagnosis have better outcomes. Copyright © 2014 by the Endocrine Society.


Zhou X.,CAS Shanghai Institutes for Biological Sciences | Wu W.,CAS Shanghai Institutes for Biological Sciences | Li H.,CAS Shanghai Institutes for Biological Sciences | Cheng Y.,CAS Shanghai Institutes for Biological Sciences | And 10 more authors.
Nucleic Acids Research | Year: 2014

Splicing factor SRSF10 is known to function as a sequence-specific splicing activator. Here, we used RNA-seq coupled with bioinformatics analysis to identify the extensive splicing network regulated by SRSF10 in chicken cells. We found that SRSF10 promoted both exon inclusion and exclusion. Motif analysis revealed that SRSF10 binding to cassette exons was associated with exon inclusion, whereas the binding of SRSF10 within downstream constitutive exons was associated with exon exclusion. This positional effect was further demonstrated by the mutagenesis of potential SRSF10 binding motifs in two minigene constructs. Functionally, many of SRSF10-verified alternative exons are linked to pathways of stress and apoptosis. Consistent with this observation, cells depleted of SRSF10 expression were far more susceptible to endoplasmic reticulum stress-induced apoptosis than control cells. Importantly, reconstituted SRSF10 in knockout cells recovered wild-type splicing patterns and considerably rescued the stress-related defects. Together, our results provide mechanistic insight into SRSF10-regulated alternative splicing events in vivo and demonstrate that SRSF10 plays a crucial role in cell survival under stress conditions.© The Author(s) 2014. Published by Oxford University Press.


Zhang Y.,Shanghai University | Guan D.-X.,CAS Shanghai Institutes for Biological Sciences | Shi J.,Shanghai University | Gao H.,CAS Shanghai Institutes for Biological Sciences | And 13 more authors.
Journal of Hepatology | Year: 2013

Background & Aims Systemic chemotherapy serves as an adjuvant treatment for post-operation patients with hepatocellular carcinoma (HCC), and provides curative option for the patients with unresectable HCC. However, its efficiency is largely limited because of the high incidence of chemo-resistance. Increasing evidence has shown that tumor initiating cells (TICs) not only have the ability to self-renew and drive the initiation and progression of cancer, but also exhibit greater resistance to conventional chemo- and radio-therapies than non-TICs. It was the aim of this study to investigate the effects of ATRA with and without cisplatin on TIC differentiation and apoptosis in human HCC. Methods In the present study, we evaluated the TICs of HCC cell differentiation induced by all-trans retinoic acid (ATRA), and developed a novel chemotherapeutic approach to HCC, by characterizing the function of combinatorial treatment with cis-diammineplatinum(II) (cisplatin) and ATRA in vitro and in vivo. Results ATRA effectively induced differentiation of TICs, which potentiated the cytotoxic effects of cisplatin. The combinatorial treatment of ATRA acid and cisplatin reduced protein kinase B (AKT) (Thr308) phosphorylation, and promoted apoptosis of HCC cells more significantly than treatment with cisplatin alone. In addition, the combined treatment with the two drugs exerted stronger inhibition on either HCC cell migration in vitro or metastasis in vivo, when compared to the treatment with either drug alone. Conclusions These results indicated that ATRA could significantly improve the effect of cisplatin, which is at least partially attributed to ATRA-induced differentiation of HCC TICs, and the subsequent decrease in this chemo-resistant subpopulation. © 2013 European Association for the Study of the Liver. Published.


Qin J.-J.,Texas Tech University Health Sciences Center | Nag S.,Texas Tech University Health Sciences Center | Wang W.,Texas Tech University Health Sciences Center | Zhou J.,Nanjing Medical University | And 4 more authors.
Biochimica et Biophysica Acta - Reviews on Cancer | Year: 2014

The NFAT signaling pathway regulates various aspects of cellular functions; NFAT acts as a calcium sensor, integrating calcium signaling with other pathways involved in development and growth, immune response, and inflammatory response. The NFAT family of transcription factors regulates diverse cellular functions such as cell survival, proliferation, migration, invasion, and angiogenesis. The NFAT isoforms are constitutively activated and overexpressed in several cancer types wherein they transactivate downstream targets that play important roles in cancer development and progression. Though the NFAT family has been conclusively proved to be pivotal in cancer progression, the different isoforms play distinct roles in different cellular contexts. In this review, our discussion is focused on the mechanisms that drive the activation of various NFAT isoforms in cancer. Additionally, we analyze the potential of NFAT as a valid target for cancer prevention and therapy. © 2014 Elsevier B.V.


Zhong H.,CAS Shanghai Institutes for Biological Sciences | Zhong H.,University of Chinese Academy of Sciences | Zhong H.,Key Laboratory of Food Safety Risk Assessment | Yin H.,CAS Shanghai Institutes for Biological Sciences | And 3 more authors.
Redox Biology | Year: 2015

Oxidative stress-induced lipid peroxidation has been associated with human physiology and diseases including cancer. Overwhelming data suggest that reactive lipid mediators generated from this process, such as 4-hydroxynonenal (4-HNE), are biomarkers for oxidative stress and important players for mediating a number of signaling pathways. The biological effects of 4-HNE are primarily due to covalent modification of important biomolecules including proteins, DNA, and phospholipids containing amino group. In this review, we summarize recent progress on the role of 4-HNE in pathogenesis of cancer and focus on the involvement of mitochondria: generation of 4-HNE from oxidation of mitochondria-specific phospholipid cardiolipin; covalent modification of mitochondrial proteins, lipids, and DNA; potential therapeutic strategies for targeting mitochondrial ROS generation, lipid peroxidation, and 4-HNE. © 2014 The Authors.


Guo J.,CAS Shanghai Institutes for Biological Sciences | Xu Y.,CAS Shanghai Institutes for Biological Sciences | Ji W.,CAS Shanghai Institutes for Biological Sciences | Song L.,CAS Shanghai Institutes for Biological Sciences | And 3 more authors.
Toxicology Letters | Year: 2015

Metastasis is the leading cause of deaths in patients with breast cancer. Benzo[a]pyrene is a cumulative carcinogen and ubiquitous environmental pollutant with potent carcinogenic properties. As we report here, we established an accumulative mouse model mimicking the cumulative effects of benzo[a]pyrene exposure in human breast carcinogenesis. Our focus was on elucidating the mechanisms by which benzo[a]pyrene contributes to the process of breast cancer metastasis. Our study indicated that benzo[a]pyrene increased the migration of breast cancer cells both in vitro and in vivo. Specifically, we demonstrated that benzo[a]pyrene enhances breast cancer cell migration and invasion by up-regulating ROS-induced ERK signaling, leading to the activation of matrix metalloproteinases 9. Our results suggest that benzo[a]pyrene-induced mammary gland cancer metastasis is an important and intricate process facilitated by cumulative benzo[a]pyrene exposure leading to activation of the ROS-ERK-MMP9 signaling pathway. © 2015 Elsevier Ireland Ltd.


Sun H.,Chinese Academy of Sciences | Li X.,Chinese Academy of Sciences | Fan L.,Chinese Academy of Sciences | Wu G.,Fudan University | And 3 more authors.
International Journal of Biochemistry and Cell Biology | Year: 2014

TNF receptor associated factor 6 (TRAF6) plays a critical role in the regulation of innate immune responses and adaptive immune responses. Though recent studies indicate that TRAF6 is involved in cancer, its precise role in cancer including colon cancer has not been extensively investigated and remains largely unknown. The purpose of this work is to determine the expression of TRAF6 in colon cancer as well as the possible role of it in proliferation and apoptosis of colon cancer cells. Fifty colon cancer tissues paired with their adjacent non-cancerous tissues were analyzed. TRAF6 expression is upregulated in cancers (P = 0.000), which is correlated with tumor grades (P = 0.012). The tumor tissue-array analysis also indicates that expression of TRAF6 is upregulated in colon cancer (P = 0.000), but the TRAF6 upregulation has no association with patients' survival rate (P = 0.055). We found that knockdown of TRAF6 blocks proliferation of colon cancer cells through cyclin D1. Different from other reports, in our experiments knockdown of TRAF6 alone has little effect on survival of colon cancer cells examined. Knockdown of TRAF6 sensitizes the cells to treatment of the conventional anti-cancer drugs 5-fluorouracil and etoposide. Thus, inhibition of TRAF6 may improve the therapeutic treatment of these drugs. Together, our data suggest that TRAF6 promotes proliferation of colon cancer cells and it may serve as a potential target for therapy of colon cancer. © 2014 Elsevier Ltd.


Chen P.,University of Chinese Academy of Sciences | Li C.,University of Chinese Academy of Sciences | Li X.,University of Chinese Academy of Sciences | Li J.,University of Chinese Academy of Sciences | And 4 more authors.
British Journal of Cancer | Year: 2014

Background: Many epidemiological studies have investigated the association between folate intake, circulating folate level and risk of breast cancer; however, the findings were inconsistent between the studies. Methods: We searched the PubMed and MEDLINE databases updated to January, 2014 and performed the systematic review and meta-analysis of the published epidemiological studies to assess the associations between folate intake level, circulating folate level and the overall risk of breast cancer. Results: In all, 16 eligible prospective studies with a total of 744 068 participants and 26 205 breast cancer patients and 26 case-control studies with a total of 16 826 cases and 21 820 controls that have evaluated the association between folate intake and breast cancer risk were identified. Pooled analysis of the prospective studies and case-control studies suggested a potential nonlinearity relationship for dietary folate intake and breast cancer risk. Prospective studies indicated a U-shaped relationship for the dietary folate intake and breast cancer risk. Women with daily dietary folate intake between 153 and 400 μg showed a significant reduced breast cancer risk compared with those <153 μg, but not for those >400 μg. The case-control studies also suggested a significantly negative correlation between the dietary folate intake level and the breast cancer risk. Increased dietary folate intake reduced breast cancer risk for women with higher alcohol intake level, but not for those with lower alcohol intake. No significant association between circulating folate level and breast cancer risk was found when the results of 8 identified studies with 5924 participants were pooled. Conclusions: Our studies suggested that folate may have preventive effects against breast cancer risk, especially for those with higher alcohol consumption level; however, the dose and timing are critical and more studies are warranted to further elucidate the questions.© 2014 Cancer Research UK. All rights reserved.


Liu Q.,Key Laboratory of Food Safety Risk Assessment | Han F.,Key Laboratory of Food Safety Risk Assessment | Xie K.,Key Laboratory of Food Safety Risk Assessment | Miao H.,Key Laboratory of Food Safety Risk Assessment | Wu Y.,Key Laboratory of Food Safety Risk Assessment
Journal of Chromatography A | Year: 2013

This study aimed to establish a novel robust method for the simultaneous determination of total fatty acid esters of 4 chloropropanols including fatty acid esters of 3-monochloropropane-1,2-diol (3-MCPD esters), 2-monochloropropane-1,3-diol (2-MCPD esters), 1,3-dichloropropan-2-ol (1,3-DCP esters) and 2,3-dichloropropan-1-ol (2,3-DCP esters) in edible oils. In this method, sodium methylate in methanol was used as the reagent for the ester cleavage reaction of chloropropanols esters. The reaction products were extracted by a sodium sulfate solution, and then purified by solid-supported liquid-liquid extraction (SLE) using diatomaceous earth (Hydromatrix™) as the sorbent. Finally, the extracts were derivatized with heptafluorobutyrylim idazole (HFBI) and analyzed by gas chromatography-mass spectrometry (GC-MS). Quantification was achieved using deuterated chloropropanols as their respective internal standards, including 3-MCPD-d5, 2-MCPD-d5, 1,3-DCP-d5 and 2,3-DCP-d5. A good linear relationship between peak area and concentrations was obtained within the range of 0.025-2.000mgL-1 with a correlation coefficients not less than 0.999 for all the chloropropanols esters. The limits of detection (LODs) of esters of 3-MCPD, 2-MCPD, 1,3-DCP and 2,3-DCP (calculated as corresponding chloropropanols) were 30, 30, 100 and 30μgkg-1, respectively. The average recoveries of the 3-MCPD esters and the 4 chloropropanols spiked at 0.1, 0.5 and 2mgkg-1 into blank oil matrix were typically in a range from 70.7% to 113.3%. The robust method validation data including calibration, LOD/LOQ, accuracy and repeatability and proficiency test results (Z-score: -0.5) of the official Food Analysis Performance Assessment Scheme (FAPAS) indicated that the present quantitative method could be successfully applied to the determination of total chloropropanols esters in various edible oils. © 2013 .

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