Quercetin prevents progression of disease in elastase/LPS-exposed mice by negatively regulating MMP expression

Abstract Background Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis, emphysema and irreversible airflow limitation. These changes are thought to be due to oxidative stress and an imbalance of proteases and antiproteases. Quercetin, a plant flavonoid, is a potent antioxidant and anti-inflammatory agent. We hypothesized that quercetin reduces lung inflammation and improves lung function in elastase/lipopolysaccharide (LPS)-exposed mice which show typical features of COPD, including airways inflammation, goblet cell metaplasia, and emphysema. Methods Mice treated with elastase and LPS once a week for 4 weeks were subsequently administered 0.5 mg of quercetin dihydrate or 50% propylene glycol (vehicle) by gavage for 10 days. Lungs were examined for elastance, oxidative stress, inflammation, and matrix metalloproteinase (MMP) activity. Effects of quercetin on MMP transcription and activity were examined in LPS-exposed murine macrophages. Results Quercetin-treated, elastase/LPS-exposed mice showed improved elastic recoil and decreased alveolar chord length compared to vehicle-treated controls. Quercetin-treated mice showed decreased levels of thiobarbituric acid reactive substances, a measure of lipid peroxidation caused by oxidative stress. Quercetin also reduced lung inflammation, goblet cell metaplasia, and mRNA expression of pro-inflammatory cytokines and muc5AC. Quercetin treatment decreased the expression and activity of MMP9 and MMP12 in vivo and in vitro, while increasing expression of the histone deacetylase Sirt-1 and suppressing MMP promoter H4 acetylation. Finally, co-treatment with the Sirt-1 inhibitor sirtinol blocked the effects of quercetin on the lung phenotype. Conclusions Quercetin prevents progression of emphysema in elastase/LPS-treated mice by reducing oxidative stress, lung inflammation and expression of MMP9 and MMP12.http://deepblue.lib.umich.edu/bitstream/2027.42/78260/1/1465-9921-11-131.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78260/2/1465-9921-11-131.pdfPeer Reviewe

Faecal occult blood screening and reduction of colorectal cancer mortality: a case-control study

To estimate the efficacy of screening on colorectal cancer mortality, a population-based case–control study was conducted in well-defined areas of Burgundy (France). Screening by faecal occult blood test prior to diagnosis in cases born between 1914 and 1943 and who died of colorectal cancer diagnosed in 1988–94 was compared with screening in controls matched with the case for age, sex and place of residence. Cases were less likely to have been screened than controls, with an odds ratio (OR) of 0.67 [95% confidence interval (CI) 0.48–0.94]. The negative overall association did not differ by gender or by anatomical location. The odds ratio of death from colorectal cancer was 0.64 (95% CI 0.46–0.91) for those screened within 3 years of case diagnosis compared with those not screened. It was 1.14 (95% CI 0.50–2.63) for those screened more than 3 years before case diagnosis. There was a negative association between the risk of death from colorectal cancer and the number of participations in the screening campaigns. The inverse association between screening for faecal occult blood and fatal colorectal cancer suggests that screening can reduce colorectal cancer mortality. This report further supports recommendations for population-based mass screening with faecal occult blood test. © 1999 Cancer Research Campaig

Social Intelligence and Academic Achievement as Predictors of Adolescent Popularity

This study compared the effects of social intelligence and cognitive intelligence, as measured by academic achievement, on adolescent popularity in two school contexts. A distinction was made between sociometric popularity, a measure of acceptance, and perceived popularity, a measure of social dominance. Participants were 512, 14–15 year-old adolescents (56% girls, 44% boys) in vocational and college preparatory schools in Northwestern Europe. Perceived popularity was significantly related to social intelligence, but not to academic achievement, in both contexts. Sociometric popularity was predicted by an interaction between academic achievement and social intelligence, further qualified by school context. Whereas college bound students gained sociometric popularity by excelling both socially and academically, vocational students benefited from doing well either socially or academically, but not in combination. The implications of these findings were discussed

Inverse association of NSAID use and ovarian cancer in relation to oral contraceptive use and parity

We examined the association between non-steroidal anti-inflammatory drug (NSAID) use and ovarian cancer by potential effect modifiers, parity and oral contraceptive use, in a population-based case–control study conducted in Wisconsin and Massachusetts. Women reported prior use of NSAIDs and information on risk factors in a telephone interview. A total of 487 invasive ovarian cancer cases and 2653 control women aged 20–74 years were included in the analysis. After adjustment for age, state of residence and other covariates, ever use of NSAIDs was inversely associated with ovarian cancer in never users of oral contraceptives (odds ratio (OR)=0.58, 95% confidence interval (CI) 0.42–0.80) but not for ever users (OR=0.98, 95% CI 0.71–1.35) (P-interaction=0.03). A reduced risk with NSAID use was also noted in nulliparous women (OR=0.47, 95% CI 0.27–0.82) but not among parous women (OR=0.81, 95% CI 0.64–1.04) (P-interaction=0.05). These results suggest that use of NSAIDs were beneficial to women at greatest risk for ovarian cancer

A “Coiled-Coil” Motif Is Important for Oligomerization and DNA Binding Properties of Human Cytomegalovirus Protein UL77

Human cytomegalovirus (HCMV) UL77 gene encodes the essential protein UL77, its function is characterized in the present study. Immunoprecipitation identified monomeric and oligomeric pUL77 in HCMV infected cells. Immunostaining of purified virions and subviral fractions showed that pUL77 is a structural protein associated with capsids. In silico analysis revealed the presence of a coiled-coil motif (CCM) at the N-terminus of pUL77. Chemical cross-linking of either wild-type pUL77 or CCM deletion mutant (pUL77ΔCCM) implicated that CCM is critical for oligomerization of pUL77. Furthermore, co-immunoprecipitations of infected and transfected cells demonstrated that pUL77 interacts with the capsid-associated DNA packaging motor components, pUL56 and pUL104, as well as the major capsid protein. The ability of pUL77 to bind dsDNA was shown by an in vitro assay. Binding to certain DNA was further confirmed by an assay using biotinylated 36-, 250-, 500-, 1000-meric dsDNA and 966-meric HCMV-specific dsDNA designed for this study. The binding efficiency (BE) was determined by image processing program defining values above 1.0 as positive. While the BE of the pUL56 binding to the 36-mer bio-pac1 containing a packaging signal was 10.0±0.63, the one for pUL77 was only 0.2±0.03. In contrast to this observation the BE of pUL77 binding to bio-500 bp or bio-1000 bp was 2.2±0.41 and 4.9±0.71, respectively. By using pUL77ΔCCM it was demonstrated that this protein could not bind to dsDNA. These data indicated that pUL77 (i) could form homodimers, (ii) CCM of pUL77 is crucial for oligomerization and (iii) could bind to dsDNA in a sequence independent manner

Colorectal cancer prevention by non-steroidal anti-inflammatory drugs: effects of dosage and timing

Epidemiological studies show that non-steroidal anti-inflammatory drugs (NSAIDs) reduce colorectal cancer incidence. We measured the rate ratio for colorectal adenocarcinoma according to dosage and the timing of exposure by means of a case–control study, nested in a non-concurrent cohort linkage study, using the population of beneficiaries of the Saskatchewan Prescription Drug Plan from 1981 to 1995 with no history of cancer since 1970 as the source population. Four controls per case, matched on age and gender and alive when the case was diagnosed, were randomly selected. Dispensing rates, calculated over successive time periods, characterized NSAID exposure. We accrued 3844 cases of colon cancer and 1971 cases of rectal cancer. For colon cancer a significant trend towards a decreasing rate ratio was associated with increasing exposure during the 6 months preceding diagnosis (P-trend = 0.002). For both cancers, significant trends were associated with exposure 11–15 years before diagnosis (colon: P-trend = 0.01; rectum: P-trend = 0.0001). At the highest exposure levels the rate ratio for colon cancer was 0.57 (95% confidence interval (CI) 0.36–0.89); for rectal cancer it was 0.26 (95% CI 0.11–0.61). No protection was associated with exposure during other periods. The timing of NSAID use must be considered in planning intervention trials to prevent colorectal cancer. There may be a 10-year delay before any preventive effect will appear. © 1999 Cancer Research Campaig

Oestrogen receptor α gene haplotype and postmenopausal breast cancer risk: a case control study

INTRODUCTION: Oestrogen receptor α, which mediates the effect of oestrogen in target tissues, is genetically polymorphic. Because breast cancer development is dependent on oestrogenic influence, we have investigated whether polymorphisms in the oestrogen receptor α gene (ESR1) are associated with breast cancer risk. METHODS: We genotyped breast cancer cases and age-matched population controls for one microsatellite marker and four single-nucleotide polymorphisms (SNPs) in ESR1. The numbers of genotyped cases and controls for each marker were as follows: TA(n), 1514 cases and 1514 controls; c.454-397C → T, 1557 cases and 1512 controls; c.454-351A → G, 1556 cases and 1512 controls; c.729C → T, 1562 cases and 1513 controls; c.975C → G, 1562 cases and 1513 controls. Using logistic regression models, we calculated odds ratios (ORs) and 95% confidence intervals (CIs). Haplotype effects were estimated in an exploratory analysis, using expectation-maximisation algorithms for case-control study data. RESULTS: There were no compelling associations between single polymorphic loci and breast cancer risk. In haplotype analyses, a common haplotype of the c.454-351A → G or c.454-397C → T and c.975C → G SNPs appeared to be associated with an increased risk for ductal breast cancer: one copy of the c.454-351A → G and c.975C → G haplotype entailed an OR of 1.19 (95% CI 1.06–1.33) and two copies with an OR of 1.42 (95% CI 1.15–1.77), compared with no copies, under a model of multiplicative penetrance. The association with the c.454-397C → T and c.975C → G haplotypes was similar. Our data indicated that these haplotypes were more influential in women with a high body mass index. Adjustment for multiple comparisons rendered the associations statistically non-significant. CONCLUSION: We found suggestions of an association between common haplotypes in ESR1 and the risk for ductal breast cancer that is stronger in heavy women

Cirrhotic livers reveal genetic changes in the MDM2-P14ARF system of cell cycle regulators

The genesis of hepatocellular carcinoma is promoted by changes in the regulatory MDM2-P14ARF system. The incidence of such changes has to date not been analysed in non-tumourous livers showing regenerative proliferation. In the present study, 24 cirrhotic livers of alcohol-, autoimmue disorder- or HCV-caused genesis were screened for MDM2-P14ARF alterations at the level of protein, DNA and mRNA. Using confocal laser scanning microscopy, the absence of MDM2 and P14ARF expression was detected in all samples except three HCV-infected livers (four livers) which contained hepatocytes overexpressing MDM2 (P14ARF) protein. In two of the samples lacking P14ARF expression, laser microdissection and PCR demonstrated deletion of the P14ARF gene. The P14ARF gene amplified from other specimens did not carry mutations. MDM2 splicing variants were present in tissues from alcohol- and autoimmune disorder-induced cirrhoses. Sequencing of full-size mRNA revealed a MDM2 mis-sense mutation in an alcohol-induced cirrhosis. One sample contained regenerative nodules with genetic instability occurring at MDM2 locus D12S83 according to the data of automatic PCR fragment analysis. In summary, this study gives first evidence for different types of MDM2 and P14ARF alterations in cirrhotic livers. We suggest that the changes impair the regulatory MDM2-P14ARF system, thus possibly favouring regenerative proliferation and transformation

Associated risk factors of STIs and multiple sexual relationships among youths in Malawi

Having unprotected sex with multiple sexual partners (MSP) is the greatest risk factor for human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs) among youths. Young people with MSPs are less likely to use a condom and the greater the risk for STIs. This study examines the associated risk factors of STIs and multiple sexual partnerships among youths aged 15–24 years. The Malawi Demographic Health Survey 2010 data was used. Out of a sample of 2,987 males and 9,559 females aged 15–24 years, 2,026 males and 6,470 females were considered in the study. Chi square test and logistic regression techniques were performed. Analysis was performed using Statistical Package for Social Sciences (SPSS) version 22.Article writing fellowships were received from the Research Development Office, University of the Western Cape, 7535 Bellville, Cape Town, South Africa.Web of Scienc

Attitudes to colorectal cancer screening among ethnic minority groups in the UK

Background: Colorectal screening by Flexible Sigmoidoscopy (FS) is under evaluation in the UK. Evidence from existing cancer screening programmes indicates lower participation among minority ethnic groups than the white-British population. To ensure equality of access, it is important to understand attitudes towards screening in all ethnic groups so that barriers to screening acceptance can be addressed.Methods: Open- and closed-ended questions on knowledge about colorectal cancer and attitudes to FS screening were added to Ethnibus (TM) - a monthly, nationwide survey of the main ethnic minority communities living in the UK (Indian, Pakistani, Bangladeshi, Caribbean, African, and Chinese). Interviews (n = 875) were conducted, face-to-face, by multilingual field-workers, including 125 interviews with white-British adults.Results: All respondents showed a notable lack of knowledge about causes of colorectal cancer, which was more pronounced in ethnic minority than white-British adults. Interest in FS screening was uniformly high (> 60%), with more than 90% of those interested saying it would provide 'peace of mind'. The most frequently cited barrier to screening 'in your community' was embarrassment, particularly among ethnic minority groups.Conclusion: Educational materials should recognise that non-white groups may be less knowledgeable about colorectal cancer. The findings of the current study suggest that embarrassment may be a greater deterrent to participation to FS screening among ethnic minority groups, but this result requires exploration in further research