Developmental expression and regulation of divalent metal transporter 1 in rat heart

2002-2003 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

L-DOPA Neurotoxicity Is Mediated by Up-Regulation of DMT1−IRE Expression

2008-2009 > Academic research: refereed > Publication in refereed journalpublished_fina

Signal pathways underlying homocysteine-induced production of MCP-1 and IL-8 in cultured human whole blood

Aim : To elucidate the mechanisms underlying homocysteine (Hcy)-induced chemokine production. Methods : Human whole blood was pretreated with inhibitors of calmodulin (CaM), protein kinase C (PKC), protein tyrosine kinase (PTK), mitogen-activated protein kinase (MAPK), and NF-ΚB and activators of PPARΓ for 60 min followed by incubation with Hcy 100 Μmol/L for 32 h. The levels of mitogen chemokine protein (MCP)-1 and interleukin-8 (IL-8) were determined by enzyme-linked immunosorbant assay (ELISA). Results : Inhibitors of PKC (calphostin C, 50-500 nmol/L and RO-31-8220, 10–100 nmol/L), CaM (W7, 28–280 Μmol/L), ERK1/2 MAPK (PD 98059, 2–20 Μmol/L), p38 MAPK (SB 203580, 0.6–6 Μmol/L), JNK MAPK (curcumin, 2–10 Μmol/L), and NF-ΚB (PDTC, 10-100 nmol/L) markedly reduced Hcy 100 Μmol/L-induced production of MCP-1 and IL-8 in human cultured whole blood, but the inhibitors of PTK (genistein, 2.6–26 Μmol/L and tyrphostin, 0.5-5 Μmol/L) had no obvious effect on MCP-1 and IL-8 production. PPARΓ activators (ciglitazone 30 Μmol/L and troglitazone 10 Μmol/L) depressed the Hcy-induced MCP-1 production but not IL-8 production in the cultured whole blood. Conclusion : Hcy-induced MCP-1 and IL-8 production is mediated by activated signaling pathways such as PKC, CaM, MAPK, and NF-ΚB. Our results not only provide clues for the signal transduction pathways mediating Hcy-induced chemokine production, but also offer a plausible explanation for a pathogenic role of hyperhomocysteinemia in these diseases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75644/1/j.1745-7254.2005.00005.x.pd

Effects of Combined Aspirin and Clopidogrel Therapy on Cardiovascular Outcomes: A Systematic Review and Meta-Analysis

BACKGROUND: Aspirin and clopidogrel monotherapies are effective treatments for preventing vascular disease. However, new evidence has emerged regarding the use of combined aspirin and clopidogrel therapy to prevent cardiovascular events. We therefore performed a comprehensive systematic review and meta-analysis to evaluate the benefits and harms of combined aspirin and clopidogrel therapy on major cardiovascular outcomes. METHODOLOGY/PRINCIPAL FINDINGS: We systematically searched Medline, Embase, the Cochrane Central Register of Controlled Trials, reference lists of articles, and proceedings of major meetings to identify studies to fit our analysis. Eligible studies were randomized controlled trials assessing the effect of combined aspirin and clopidogrel therapy compared with aspirin or clopidogrel monotherapy. We identified 7 trials providing data with a total of 48248 patients. These studies reported 5134 major cardiovascular events, 1626 myocardial infarctions, 1927 strokes, and 1147 major bleeding events. Overall, the addition of aspirin to clopidogrel therapy as compared to single drug therapy resulted in a 9% RR reduction (95%CI, 2 to 17) in major cardiovascular events, 14% RR reduction (95%CI, 3 to 24) in myocardial infarction, 16% RR reduction (95%CI, 1 to 28) in stroke, and 62% RR increase (95%CI, 26 to 108) in major bleeding events. We also present the data as ARR to explore net value as the reduction in cardiovascular events. Overall, we observed that combined therapy yielded 1.06% decrease (95%CI, 0.23% to 1.99%) in major cardiovascular events and 1.23% increase (95%CI, 0.52% to 2.14%) in major bleeding events. CONCLUSION/SIGNIFICANCE: Although the addition of aspirin to clopidogrel resulted in small relative reductions in major cardiovascular events, myocardial infarction, and stroke, it also resulted in a relative increase in major bleeding events. In absolute terms the benefits of combined therapy, a 1.06% reduction in major cardiovascular events, does not outweigh the harms, a 1.23% increase in major bleeding events

MAGE I Transcription Factors Regulate KAP1 and KRAB Domain Zinc Finger Transcription Factor Mediated Gene Repression

Class I MAGE proteins (MAGE I) are normally expressed only in developing germ cells but are aberrantly expressed in many cancers. They have been shown to promote tumor survival, aggressive growth, and chemoresistance but the underlying mechanisms and MAGE I functions have not been fully elucidated. KRAB domain zinc finger transcription factors (KZNFs) are the largest group of vertebrate transcription factors and regulate neoplastic transformation, tumor suppression, cellular proliferation, and apoptosis. KZNFs bind the KAP1 protein and direct KAP1 to specific DNA sequences where it suppresses gene expression by inducing localized heterochromatin characterized by histone 3 lysine 9 trimethylation (H3me3K9). Discovery that MAGE I proteins also bind to KAP1 prompted us to investigate whether MAGE I can affect KZNF and KAP1 mediated gene regulation. We found that expression of MAGE I proteins, MAGE-A3 or MAGE-C2, relieved repression of a reporter gene by ZNF382, a KZNF with tumor suppressor activity. ChIP of MAGE I (-) HEK293T cells showed KAP1 and H3me3K9 are normally bound to the ID1 gene, a target of ZNF382, but that binding is greatly reduced in the presence of MAGE I proteins. MAGE I expression relieved KAP1 mediated ID1 repression, causing increased expression of ID1 mRNA and ID1 chromatin relaxation characterized by loss of H3me3K9. MAGE I binding to KAP1 also induced ZNF382 poly-ubiquitination and degradation, consistent with loss of ZNF382 leading to decreased KAP1 binding to ID1. In contrast, MAGE I expression caused increased KAP1 binding to Ki67, another KAP1 target gene, with increased H3me3K9 and decreased Ki67 mRNA expression. Since KZNFs are required to direct KAP1 to specific genes, these results show that MAGE I proteins can differentially regulate members of the KZNF family and KAP1 mediated gene repression

IGFBP3 mRNA expression in benign and malignant breast tumors

INTRODUCTION: Most previous studies have focused on evaluating the association between circulating insulin-like growth factor binding protein 3 (IGFBP-3) levels and breast cancer risk. Emerging evidence over the past few years suggests that IGFBP-3 may act directly on mammary epithelial cells. METHODS: To understand the role of IGFBP-3 in breast tumorigenesis, we investigated IGFBP3 mRNA expression levels in benign and malignant breast tumors and their adjacent normal tissues using real-time quantitative PCR. RESULTS: Cancer tissues had significantly lower IGFBP3 expression than benign tumor tissues (p < 0.001). IGFBP3 expressions in both tumor and adjacent tissues were higher in patients who had proliferative benign tumors than in those who had non-proliferative benign tumors. Among patients with benign breast disease, IGFBP3 expression in the tumor was significantly higher than that in their adjacent normal tissue. There were no apparent associations of IGFBP3 expression in cancer tissues with either overall survival or disease-free survival in a cohort of 521 patients with breast cancer. CONCLUSION: Our findings suggest that the expression level of IGFBP3 in breast tissues may be involved in breast tumorigenesis

All-cause mortality and risk factors in a cohort of retired military male veterans, Xi'an, China: an 18-year follow up study

<p>Abstract</p> <p>Background</p> <p>Risk factors of all-cause mortality have not been reported in Chinese retired military veterans. The objective of the study was to examine the risk factors and proportional mortality in a Chinese retired military male cohort.</p> <p>Methods</p> <p>A total of 1268 retired military men aged 55 or older were examined physically and interviewed using a standard questionnaire in 1987. The cohort was followed up every two years and the study censored date was June30, 2005 with a follow-up of up to 18 years. Death certificates were obtained from hospitals and verified by two senior doctors. Data were entered (double entry) by Foxbase, and analysis was carried out by SAS for Windows 8.2. Multivariate Cox proportional hazard regression model was used to compute hazard ratio (HR) and 95% confidence interval (CI).</p> <p>Results</p> <p>The total person-years of follow-up was 18766.28. Of the initial cohort of 1268 men, 491 had died, 748 were alive and 29 were lost to follow up. Adjusted mortality (adjusted for age, blood pressure, body mass index, cholesterol, triglycerides, alcohol, exercise, and existing disease) was 2,616 per 100,000 person years. The proportional mortality of cancer, vascular disease and Chronic Obstructive Pulmonary Disease (COPD) were 39.71%, 28.10% and 16.90% respectively. Multivariate analysis showed that age, cigarettes per day, systolic blood pressure, triglyceride, family history of diseases (hypertension, stroke and cancer), existing diseases (stroke, diabetes and cancer), body mass index, and age of starting smoking were associated with all-cause mortality, HR (95%CI) was1.083(1.062–1.104), 1.026(1.013–1.039), 1.009(1.003–1.015), 1.002(1.001–1.003), 1.330(1.005–1.759), 1.330(1.005–1.759), 1.444(1.103–1.890), 2.237(1.244–4.022), 1.462(1.042–2.051), 2.079(1.051–4.115), 0.963(0.931–0.996)and 0.988(0.978–0.999)respectively. Compared with never-smokers, current smokers had increased risks of total mortality [HR 1.369(1.083–1.731)], CHD [HR 1.805 (1.022–3.188)], and lung cancer [HR 2.939 (1.311–6.585)].</p> <p>Conclusion</p> <p>The three leading causes of diseases were cancer, CHD and stroke, and COPD. Aging, cigarette smoking, high systolic blood pressure, high triglyceride, family history of cancer, hypertension and stroke, existing cases recovering from stroke, diabetes and cancer, underweight, younger age of smoking were risk factors for all-cause mortality. Quitting cigarette smoking, maintaining normal blood pressure, triglyceride and weight are effect control strategies to prevent premature mortality in this military cohort.</p