3,3′Diindolylmethane Suppresses Vascular Smooth Muscle Cell Phenotypic Modulation and Inhibits Neointima Formation after Carotid Injury

3,3'Diindolylmethane (DIM), a natural phytochemical, has shown inhibitory effects on the growth and migration of a variety of cancer cells; however, whether DIM has similar effects on vascular smooth muscle cells (VSMCs) remains unknown. The purpose of this study was to assess the effects of DIM on the proliferation and migration of cultured VSMCs and neointima formation in a carotid injury model, as well as the related cell signaling mechanisms.DIM dose-dependently inhibited the platelet-derived growth factor (PDGF)-BB-induced proliferation of VSMCs without cell cytotoxicity. This inhibition was caused by a G0/G1 phase cell cycle arrest demonstrated by fluorescence-activated cell-sorting analysis. We also showed that DIM-induced growth inhibition was associated with the inhibition of the expression of cyclin D1 and cyclin-dependent kinase (CDK) 4/6 as well as an increase in p27(Kip1) levels in PDGF-stimulated VSMCs. Moreover, DIM was also found to modulate migration of VSMCs and smooth muscle-specific contractile marker expression. Mechanistically, DIM negatively modulated PDGF-BB-induced phosphorylation of PDGF-recptorβ (PDGF-Rβ) and the activities of downstream signaling molecules including Akt/glycogen synthase kinase(GSK)3β, extracellular signal-regulated kinase1/2 (ERK1/2), and signal transducers and activators of transcription 3 (STAT3). Our in vivo studies using a mouse carotid arterial injury model revealed that treatment with 150 mg/kg DIM resulted in significant reduction of the neointima/media ratio and proliferating cell nuclear antigen (PCNA)-positive cells, without affecting apoptosis of vascular cells and reendothelialization. Infiltration of inflammatory cells was also inhibited by DIM administration.These results demonstrate that DIM can suppress the phenotypic modulation of VSMCs and neointima hyperplasia after vascular injury. These beneficial effects on VSMCs were at least partly mediated by the inhibition of PDGF-Rβ and the activities of downstream signaling pathways. The results suggest that DIM has the potential to be a candidate for the prevention of restenosis

Leisure Time Physical Activity of Moderate to Vigorous Intensity and Mortality: A Large Pooled Cohort Analysis

Background: Leisure time physical activity reduces the risk of premature mortality, but the years of life expectancy gained at different levels remains unclear. Our objective was to determine the years of life gained after age 40 associated with various levels of physical activity, both overall and according to body mass index (BMI) groups, in a large pooled analysis. Methods and Findings: We examined the association of leisure time physical activity with mortality during follow-up in pooled data from six prospective cohort studies in the National Cancer Institute Cohort Consortium, comprising 654,827 individuals, 21–90 y of age. Physical activity was categorized by metabolic equivalent hours per week (MET-h/wk). Life expectancies and years of life gained/lost were calculated using direct adjusted survival curves (for participants 40+ years of age), with 95% confidence intervals (CIs) derived by bootstrap. The study includes a median 10 y of follow-up and 82,465 deaths. A physical activity level of 0.1–3.74 MET-h/wk, equivalent to brisk walking for up to 75 min/wk, was associated with a gain of 1.8 (95% CI: 1.6–2.0) y in life expectancy relative to no leisure time activity (0 MET-h/wk). Higher levels of physical activity were associated with greater gains in life expectancy, with a gain of 4.5 (95% CI: 4.3–4.7) y at the highest level (22.5+ MET-h/wk, equivalent to brisk walking for 450+ min/wk). Substantial gains were also observed in each BMI group. In joint analyses, being active (7.5+ MET-h/wk) and normal weight (BMI 18.5–24.9) was associated with a gain of 7.2 (95% CI: 6.5–7.9) y of life compared to being inactive (0 MET-h/wk) and obese (BMI 35.0+). A limitation was that physical activity and BMI were ascertained by self report. Conclusions: More leisure time physical activity was associated with longer life expectancy across a range of activity levels and BMI groups

Single nucleotide polymorphisms in obesity-related genes and all-cause and cause-specific mortality: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to examine the associations between 16 specific single nucleotide polymorphisms (SNPs) in 8 obesity-related genes and overall and cause-specific mortality. We also examined the associations between the SNPs and body mass index (BMI) and change in BMI over time.</p> <p>Methods</p> <p>Data were analyzed from 9,919 individuals who participated in two large community-based cohort studies conducted in Washington County, Maryland in 1974 (CLUE I) and 1989 (CLUE II). DNA from blood collected in 1989 was genotyped for 16 SNPs in 8 obesity-related genes: monoamine oxidase A (<it>MAOA</it>), lipoprotein lipase (<it>LPL</it>), paraoxonase 1 and 2 (<it>PON1 </it>and <it>PON2</it>), leptin receptor (<it>LEPR</it>), tumor necrosis factor-α (<it>TNFα</it>), and peroxisome proliferative activated receptor-γ and -δ (<it>PPARG </it>and <it>PPARD</it>). Data on height and weight in 1989 (CLUE II baseline) and at age 21 were collected from participants at the time of blood collection. All participants were followed from 1989 to the date of death or the end of follow-up in 2005. Cox proportional hazards regression was used to obtain the relative risk (RR) estimates and 95% confidence intervals (CI) for each SNP and mortality outcomes.</p> <p>Results</p> <p>The results showed no patterns of association for the selected SNPs and the all-cause and cause-specific mortality outcomes, although statistically significant associations (p < 0.05) were observed between <it>PPARG </it>rs4684847 and all-cause mortality (CC: reference; CT: RR 0.99, 95% CI 0.89, 1.11; TT: RR 0.60, 95% CI 0.39, 0.93) and cancer-related mortality (CC: reference; CT: RR 1.01, 95% CI 0.82, 1.25; TT: RR 0.22, 95% CI 0.06, 0.90) and <it>TNFα </it>rs1799964 and cancer-related mortality (TT: reference; CT: RR 1.23, 95% CI 1.03, 1.47; CC: RR 0.83, 95% CI 0.54, 1.28). Additional analyses showed significant associations between SNPs in <it>LEPR </it>with BMI (rs1137101) and change in BMI over time (rs1045895 and rs1137101).</p> <p>Conclusion</p> <p>Findings from this cohort study suggest that the selected SNPs are not associated with overall or cause-specific death, although several <it>LEPR </it>SNPs may be related to BMI and BMI change over time.</p

Combined Impact of Lifestyle-Related Factors on Total and Cause-Specific Mortality among Chinese Women: Prospective Cohort Study

Findings from the Shanghai Women's Health Study confirm those derived from other, principally Western, cohorts regarding the combined impact of lifestyle-related factors on mortality

Wine and other alcohol consumption and risk of ovarian cancer in the California Teachers Study cohort

OBJECTIVE: Whether alcohol consumption influences ovarian cancer risk is unclear. Therefore, we investigated the association between alcohol intake at various ages and risk of ovarian cancer. METHODS: Among 90,371 eligible members of the California Teachers Study cohort who completed a baseline alcohol assessment in 1995–1996, 253 women were diagnosed with epithelial ovarian cancer by the end of 2003. Multivariate Cox proportional hazards regression analysis was performed to estimate relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: Consumption of total alcohol, beer, or liquor in the year prior to baseline, at ages 30–35 years, or at ages 18–22 years was not associated with risk of ovarian cancer. Consumption of at least one glass per day of wine, compared to no wine, in the year before baseline was associated with increased risk of developing ovarian cancer: RR = 1.57 (95% CI 1.11–2.22), P(trend) = 0.01. The association with wine intake at baseline was particularly strong among peri-/post-menopausal women who used estrogen-only hormone therapy and women of high socioeconomic status. CONCLUSIONS: Alcohol intake does not appear to affect ovarian cancer risk. Constituents of wine other than alcohol or, more likely, unmeasured determinants of wine drinking were associated with increased risk of ovarian cancer

Milk and dairy products: good or bad for human health? An assessment of the totality of scientific evidence

Background: There is scepticism about health effects of dairy products in the public, which is reflected in an increasing intake of plant-based drinks, for example, from soy, rice, almond, or oat. Objective: This review aimed to assess the scientific evidence mainly from meta-analyses of observational studies and randomised controlled trials, on dairy intake and risk of obesity, type 2 diabetes, cardiovascular disease, osteoporosis, cancer, and all-cause mortality. Results: The most recent evidence suggested that intake of milk and dairy products was associated with reduced risk of childhood obesity. In adults, intake of dairy products was shown to improve body composition and facilitate weight loss during energy restriction. In addition, intake of milk and dairy products was associated with a neutral or reduced risk of type 2 diabetes and a reduced risk of cardiovascular disease, particularly stroke. Furthermore, the evidence suggested a beneficial effect of milk and dairy intake on bone mineral density but no association with risk of bone fracture. Among cancers, milk and dairy intake was inversely associated with colorectal cancer, bladder cancer, gastric cancer, and breast cancer, and not associated with risk of pancreatic cancer, ovarian cancer, or lung cancer,while the evidence for prostate cancer risk was inconsistent.Finally,consumption of milk and dairy products was not associated with all-cause mortality. Calcium-fortified plant-based drinks have been included as an alternative to dairy products in the nutrition recommendations in several countries. However, nutritionally, cow’s milk and plant-based drinks are completely different foods,and an evidence-based conclusion on the health value of the plant-based drinks requires more studies in humans. Conclusion: The totality of available scientific evidence supports that intake of milk and dairy products contribute to meet nutrient recommendations, and may protect against the most prevalent chronic diseases, whereas very few adverse effects have been reported

Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry.

BACKGROUND: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. METHODS: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. RESULTS: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10-6) and AC058822.1 (P = 1.47 × 10-4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. CONCLUSIONS: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10-5), demonstrating the importance of diversifying study cohorts