The nuclear receptor peroxisome proliferator-activated receptor ␦ [PPAR␦/ (NR1C2)] has been implicated in colorectal carcinogenesis by various molecular genetic observations. These observations have recently been supported by studies of activation of PPAR␦ by pharmacological agents. Here we present the first report of the stimulation of breast and prostate cancer cell growth using PPAR␦ selective agonists. Activation of PPAR␦ with compound F stimulated proliferation in breast (T47D, MCF7) and prostate (LNCaP, PNT1A) cell lines, which are responsive to sex hormones. Conversely, we have found that several steroid-independent cell lines, including colon lines, were unresponsive to compound F. These findings were confirmed with an additional high-affinity PPAR␦ agonist, GW501516. Conditional expression of PPAR␦ in MCF7 Tet-On cells resulted in a doxycycline-enhanced response to GW501516, thus providing direct genetic evidence for the role of PPAR␦ in the proliferative response to this drug. Activation of PPAR␦ in T47D cells resulted in increased expression of the proliferation marker Cdk2 and also vascular endothelial growth factor ␣ (VEGF␣) and its receptor, FLT-1, thus, suggesting that PPAR␦ may initiate an autocrine loop for cellular proliferation and possibly angiogenesis. Consistent with this hypothesis, we demonstrated a pro-proliferative effect of GW501516 on human umbilical vein endothelial cell cultures and found that GW501516 also regulated the expression of VEGF␣ and FLT-1 in these cells. Our observations provide the first evidence that activation of PPAR␦ can result in increased growth in breast and prostate cancer cell lines and primary endothelial cells and supports the possibility that PPAR␦ antagonists may be of therapeutic value in the treatment of breast and prostate cancer.
The current literature includes several studies investigating the association between physical activity and risk of Alzheimer's disease (AD). The aim of this review was to systematically evaluate available evidence on this association. Medline via PubMed and CINAHL databases were searched for original English language research articles assessing the relationship between physical activity and incident AD. The review was limited to prospective observational and intervention studies. Criteria for exclusion were studies focusing on individuals with dementia, cross-sectional study design, and case reports. The quality of included studies was assessed in 5 domains of bias. Twenty-four studies met the inclusion criteria. The number of participants ranged from 176 to 5,698. Follow-up time varied from 1 to 34 years. Physical activity was inversely associated with risk of AD in most studies (n = 18). Leisure-time physical activity was particularly protective against AD, but not work-related physical activity. The risk of bias assessment showed that overall quality of evidence was moderate for 16 and low for 8 studies. Beyond all the available general recommendations for health promotion, current evidence does not allow to draw specific practical recommendations concerning the types, frequency, intensity, or duration of physical activity that may be protective against AD.
Potential antiproliferative effects of tocotrienols, the major vitamin E component in palm oil, were investigated on the growth of both estrogen-responsive (ER+) MCF7 human breast cancer cells and estrogen-unresponsive (ER-) MDA-MB-231 human breast cancer cells, and effects were compared with those of alpha-tocopherol (alphaT). The tocotrienol-rich fraction (TRF) of palm oil inhibited growth of MCF7 cells in both the presence and absence of estradiol with a nonlinear dose-response but such that complete suppression of growth was achieved at 8 microg/mL. MDA-MB-231 cells were also inhibited by TRF but with a linear dose-response such that 20 microg/mL TRF was needed for complete growth suppression. Separation of the TRF into individual tocotrienols revealed that all fractions could inhibit growth of both ER+ and ER- cells and of ER+ cells in both the presence and absence of estradiol. However, the gamma- and delta-fractions were the most inhibitory. Complete inhibition of MCF7 cell growth was achieved at 6 microg/mL of gamma-tocotrienol/delta-tocotrienol (gammaT3/deltaT3) in the absence of estradiol and 10 microg/mL of deltaT3 in the presence of estradiol, whereas complete suppression of MDA-MB-231 cell growth was not achieved even at concentrations of 10 microg/mL of deltaT3. By contrast to these inhibitory effects of tocotrienols, alphaT had no inhibitory effect on MCF7 cell growth in either the presence or the absence of estradiol, nor on MDA-MB-231 cell growth. These results confirm studies using other sublines of human breast cancer cells and demonstrate that tocotrienols can exert direct inhibitory effects on the growth of breast cancer cells. In searching for the mechanism of inhibition, studies of the effects of TRF on estrogen-regulated pS2 gene expression in MCF7 cells showed that tocotrienols do not act via an estrogen receptor-mediated pathway and must therefore act differently from estrogen antagonists. Furthermore, tocotrienols did not increase levels of growth-inhibitory insulin-like growth factor binding proteins (IGFBP) in MCF7 cells, implying also a different mechanism from that proposed for retinoic acid inhibition of estrogen-responsive breast cancer cell growth. Inhibition of the growth of breast cancer cells by tocotrienols could have important clinical implications not only because tocotrienols are able to inhibit the growth of both ER+ and ER- phenotypes but also because ER+ cells could be growth-inhibited in the presence as well as in the absence of estradiol. Future clinical applications of TRF could come from potential growth suppression of ER+ breast cancer cells otherwise resistant to growth inhibition by antiestrogens and retinoic acid.
Background The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) was a multicenter randomized controlled trial that reported beneficial effects on cognition for a 2-year multimodal intervention (diet, exercise, cognitive training, vascular risk monitoring) versus control (general health advice). This study reports exploratory analyses of brain MRI measures. Methods FINGER targeted 1260 older individuals from the general Finnish population. Participants were 60–77 years old, at increased risk for dementia but without dementia/substantial cognitive impairment. Brain MRI scans were available for 132 participants (68 intervention, 64 control) at baseline and 112 participants (59 intervention, 53 control) at 2 years. MRI measures included regional brain volumes, cortical thickness, and white matter lesion (WML) volume. Cognition was assessed at baseline and 1- and 2-year visits using a comprehensive neuropsychological test battery. We investigated the (1) differences between the intervention and control groups in change in MRI outcomes (FreeSurfer 5.3) and (2) post hoc sub-group analyses of intervention effects on cognition in participants with more versus less pronounced structural brain changes at baseline (mixed-effects regression models, Stata 12). Results No significant differences between the intervention and control groups were found on the changes in MRI measures. Beneficial intervention effects on processing speed were more pronounced in individuals with higher baseline cortical thickness in Alzheimer’s disease signature areas (composite measure of entorhinal, inferior and middle temporal, and fusiform regions). The randomization group × time × cortical thickness interaction coefficient was 0.198 ( p = 0.021). A similar trend was observed for higher hippocampal volume (group × time × hippocampus volume interaction coefficient 0.1149, p = 0.085). Conclusions The FINGER MRI exploratory sub-study did not show significant differences between the intervention and control groups on changes in regional brain volumes, regional cortical thicknesses, or WML volume after 2 years in at-risk elderly without substantial impairment. The cognitive benefits on processing speed of the FINGER intervention may be more pronounced in individuals with fewer structural brain changes on MRI at baseline. This suggests that preventive strategies may be more effective if started early, before the occurrence of more pronounced structural brain changes. Trial registration ClinicalTrials.gov, NCT01041989 . Registered January 5, 2010.
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