Impact of diet and exercise on lipid management in the modern era.

Unfortunately, many patients as well as the medical community, continue to rely on coronary revascularization procedures and cardioprotective medications as a first-line strategy to stabilize or favorably modify established risk factors and the course of coronary artery disease. However, these therapies do not address the root of the problem, that is, the most proximal risk factors for heart disease, including unhealthy dietary practices, physical inactivity, and cigarette smoking. We argue that more emphasis must be placed on novel approaches to embrace current primary and secondary prevention guidelines, which requires attacking conventional risk factors and their underlying environmental causes. The impact of lifestyle on the risk of cardiovascular disease has been well established in clinical trials, but these results are often overlooked and underemphasized. Considerable data also strongly support the role of lifestyle intervention to improve glucose and insulin homeostasis, as well as physical inactivity and/or low aerobic fitness. Accordingly, intensive diet and exercise interventions can be highly effective in facilitating coronary risk reduction, complementing and enhancing medications, and in some instances, even outperforming drug therapy.

Effects of an intensive short-term diet and exercise intervention: comparison between normal-weight and obese children.

Lifestyle intervention programs currently emphasize weight loss secondary to obesity as the primary determinant of phenotypic changes. We examined whether the effects of a short-term lifestyle intervention program differ in normal-weight versus overweight/obese children. Nineteen overweight/obese (O; BMI = 33.6 ± 1.9 kg/m(2)) and 14 normal-weight (N; BMI = 19.9 ± 1.5 kg/m(2)) children participated in a 2-wk program consisting of an ad libitum high-fiber, low-fat diet and daily exercise (2-2.5 h). Fasting serum samples were taken pre- and postintervention for determination of lipids, glucose homeostasis, inflammatory cytokines, and adipokines. Only the O group lost weight (3.9%) but remained overweight/obese (32.3 ± 1.9 kg/m(2)). Both groups exhibited significant intervention-induced decreases (P < 0.05) in serum insulin (N: 52.5% vs. O: 28.1%; between groups, P = 0.38), homeostatic model assessment for insulin resistance (N: 53.1% vs. O: 28.4%, P = 0.43), leptin (N: 69.3% vs. O: 44.1%, P = 0.10), amylin (N: 28.7% vs. O: 26.1%, P = 0.80), resistin (N: 40.0% vs. O: 35.1%, P = 0.99), plasminogen activator-inhibitor-1 (N: 30.8% vs. O: 25.6%, P = 0.59), IL-6 (N: 58.8% vs. O: 48.5%, P = 0.78), IL-8 (N: 46.0% vs. O: 42.2%, P = 0.49), and TNFα (N: 45.8% vs. O: 40.8%, P = 0.99). No associations between indices of weight change and phenotypic changes were noted. A short-term, intensive lifestyle modification program is effective in ameliorating metabolic risk factors in N and O children. These results suggest that obesity per se was not the primary driver of the phenotypes noted and that dietary intake and physical inactivity induce the phenotypic abnormalities. These data may have implications for the weight loss-independent management of cardiometabolic risk in pediatric populations.

Metabolic syndrome and insulin resistance: underlying causes and modification by exercise training.

Metabolic syndrome (MS) is a collection of cardiometabolic risk factors that includes obesity, insulin resistance, hypertension, and dyslipidemia. Although there has been significant debate regarding the criteria and concept of the syndrome, this clustering of risk factors is unequivocally linked to an increased risk of developing type 2 diabetes and cardiovascular disease. Regardless of the true definition, based on current population estimates, nearly 100 million have MS. It is often characterized by insulin resistance, which some have suggested is a major underpinning link between physical inactivity and MS. The purpose of this review is to: (i) provide an overview of the history, causes and clinical aspects of MS, (ii) review the molecular mechanisms of insulin action and the causes of insulin resistance, and (iii) discuss the epidemiological and intervention data on the effects of exercise on MS and insulin sensitivity.

A short-term diet and exercise intervention ameliorates inflammation and markers of metabolic health in overweight/obese children.

The present study was designed to examine the effects of short-term diet and exercise on markers of metabolic health, serum-stimulated production of inflammatory biomarkers from cultured monocytes and adipocytes, and serum lipomics. Twenty-one overweight/obese children (9 boys and 12 girls, age 13.0 ± 0.5 yr, BMI 33.0 ± 1.8 kg/m(2)) were placed on a 2-wk ad libitum, high-fiber, low-fat diet and daily exercise regimen. Fasting serum samples were taken pre- and postintervention for determination of cytokines, metabolic risk markers, and lipomics. Monocytes and adipocytes were incubated with pre- and postintervention serum to investigate changes in cytokine secretion. Correlative associations were calculated, followed by hierarchical clustering to determine relationships between fatty acid (FA) species and clinical biomarkers. Despite remaining overweight/obese, interleukin (IL)-6, IL-8, TNFα, PAI-1, resistin, amylin, leptin, insulin, and IL-1ra decreased and adiponectin increased. Culture studies indicated decreases in monocyte secretion of IL-6, TNFα, and IL-1ß and adipocyte secretion of IL-6. Lipomic analysis revealed a decrease in total lipids and decreases in saturated FAs and an increase in 18:1/18:0. In general, Pearson's correlations revealed that inflammatory markers are negatively associated with a cluster of polyunsaturated FAs and positively correlated with several saturated FAs. These results indicate significant modification of multiple indices of metabolic health with short-term rigorous lifestyle modification in overweight/obese children prior to obesity reversal.

Effect of a low-fat diet combined with IGF-1 receptor blockade on 22Rv1 prostate cancer xenografts.

In preclinical models, both dietary fat reduction and insulin-like growth factor I receptor (IGF-1R) blockade individually inhibit prostate cancer xenograft growth. We hypothesized that a low-fat diet combined with IGF-1R blockade would cause additive inhibition of prostate cancer growth and offset possible untoward metabolic effects of IGF-1R blockade antibody therapy. Fifty severe combined immunodeficient mice were injected with 22Rv1 cells subcutaneously. Ten days postinjection, the animals were randomized to four groups: (i) high-fat diet + saline (HF); (ii) high-fat diet + IGF-1R blocking antibody, ganitumab (HF/Ab); (iii) low-fat diet + saline (LF); and (iv) low-fat diet + ganitumab (LF/Ab). After 19 days of treatment, the animals were euthanized, serum was collected, and tumors were weighed. Tumor Ki67, Akt and extracellular signal-regulated kinase (ERK) activation, serum insulin, IGF-I and TNF-α were measured. In vitro, ganitumab treatment inhibited growth and induced apoptosis in several prostate cancer cell lines. In vivo, tumor weights and volumes were unaffected by the different treatments. The LF/Ab therapy significantly reduced proliferation (Ki67) and ERK activation in tumors. The HF/Ab group had significantly higher serum insulin levels than the HF group. However, LF/Ab combination significantly reduced serum insulin back to normal levels as well as normalizing serum TNF-α level. Whereas the combination of low-fat diet and IGF-1R blockade did not have additive inhibitory effects on tumor weight, it led to reduced tumor cell proliferation and a reduction in serum insulin and TNF-α levels.

Phase II prospective randomized trial of a low-fat diet with fish oil supplementation in men undergoing radical prostatectomy.

Preclinical studies suggest lowering dietary fat and decreasing the ratio of omega-6 to omega-3 polyunsaturated fatty acids decreases the risk of prostate cancer development and progression. We conducted a phase II randomized trial to test the effect of decreasing dietary fat combined with decreasing the dietary omega-6:omega-3 ratio on biomarkers related to prostate cancer development and progression. Patients undergoing radical prostatectomy were randomly assigned to receive a low-fat diet with 5 grams of fish oil daily (dietary omega-6:omega-3 ratio of 2:1) or a control Western diet (omega-6:omega-3 ratio of 15:1) for four to six weeks prior to surgery. The primary endpoint was change in serum insulin-like growth factor I (IGF-1) between arms. Secondary endpoints were serum IGFBP-1, prostate prostaglandin E2 levels, omega-6:omega-3 fatty acid ratios, COX-2, and markers of proliferation and apoptosis. Fifty-five patients were randomized and 48 completed the trial. There was no treatment difference in the primary outcome. Positive secondary outcomes in the low-fat fish oil versus Western group were reduced benign and malignant prostate tissue omega-6:omega-3 ratios, reduced proliferation (Ki-67 index), and reduced proliferation in an ex vivo bioassay when patient sera was applied to prostate cancer cells in vitro. In summary, four to six weeks of a low-fat diet and fish oil capsules to achieve an omega-6:omega-3 fatty acid ratio of 2:1 had no effect on serum IGF-1 levels, though in secondary analyses, the intervention resulted in decreased prostate cancer proliferation and decreased prostate tissue omega-6:omega-3 ratios. These results support further studies evaluating reduction of dietary fat with fish oil supplementation on modulating prostate cancer biology.

Global Igfbp1 deletion does not affect prostate cancer development in a c-Myc transgenic mouse model.

Circulating insulin-like growth factor binding protein 1 (IGFBP1) levels vary in response to nutritional status, and pre-clinical studies suggest that elevated IGFBP1 may be protective against the development and progression of prostate cancer. We hypothesized that global deletion of Igfbp1 would accelerate the development of prostate cancer in a c-Myc transgenic mouse model. To test our hypothesis, c-Myc transgenic mice (Myc/BP-1 wild-type (WT)) were crossed and interbred with the Igfbp1 knockout mice (Myc/BP-1 KO). The animals were placed on a high-protein diet at weaning, weighed every 2 weeks, and euthanized at 16 weeks of age. Prostate histopathology was assessed and proliferation status was determined by Ki-67 and proliferating cell nuclear antigen analyses. IGF-related serum biomarkers and body composition were measured. No significant difference in the incidence of prostate cancer was observed between the Myc/BP-1 KO and the Myc/BP-1 WT mice (65 and 80% respectively, P=0.48). Proliferation was significantly decreased by 71% in prostate tissue of Myc/BP-1 KO mice compared with Myc/BP-1 WT mice. Myc/BP-1 KO mice exhibited a significant 6.7% increase in body weight relative to the Myc/BP-1 WT mice that was attributed to an increase in fat mass. Fasting insulin levels were higher in the Myc/BP-1 KO mice without any difference between the groups in fasting glucose concentrations. Thus, contrary to our hypothesis, global deletion of Igfbp1 in a c-Myc transgenic mouse model did not accelerate the development of prostate cancer. Global Igfbp1 deletion did result in a significant increase in body weight and body fat mass. Further studies are required to understand the underlying mechanisms for these metabolic effects.

Analyzing serum-stimulated prostate cancer cell lines after low-fat, high-fiber diet and exercise intervention.

Serum from men undergoing a low-fat, high-fiber diet and exercise intervention has previously been shown to decrease growth and increase apoptosis in serum-stimulated, androgen-dependent LNCaP cells associated with a reduction in serum IGF-I. Here we sought to determine the underlying mechanisms for these anticancer effects. Again, the intervention slowed growth and increased apoptosis in LNCaP cells; responses that were eliminated when IGF-I was added back to the post-intervention samples. The p53 protein content was increased and NFκB activation reduced in the post serum-stimulated LNCaP cells. Similar results were observed when the IGF-I receptor was blocked in the pre-intervention serum. In androgen-independent PC-3 cells, growth was reduced while none of the other factors were changed by the intervention. We conclude that diet and exercise intervention might help prevent clinical PCa as well as aid in the treatment of PCa during the early stages of development.

Growth inhibitory effect of low fat diet on prostate cancer cells: results of a prospective, randomized dietary intervention trial in men with prostate cancer.

PURPOSE: A high fat Western diet and sedentary lifestyle may predispose men to prostate cancer through changes in serum hormones and growth factors. We evaluated the effect of a low fat diet on serum factors affecting prostate cancer cell growth by performing a prospective, randomized dietary intervention trial in men with prostate cancer. MATERIALS AND METHODS: We randomized 18 men with prostate cancer who did not receive prior therapy to a low fat (15% kcal), high fiber, soy protein supplemented diet or a Western (40% kcal fat) diet for 4 weeks. Fasting serum was collected at baseline and after the intervention to measure prostate specific antigen, sex hormones, insulin, insulin-like growth factor I and II, insulin-like growth factor binding proteins, lipids and fatty acids. LNCaP cells (ATCC(R)) were cultured in medium containing pre-intervention and post-intervention human serum to assess the in vitro effect of the diet on prostate cancer cell proliferation. RESULTS: Subjects in each group were highly compliant with the dietary intervention. Serum from men in the low fat group significantly decreased the growth of LNCaP cells relative to Western diet serum (p = 0.03). There were no significant between group changes in serum prostate specific antigen, sex hormones, insulin, insulin-like growth factor I and II, and insulin-like growth factor binding proteins. Serum triglyceride and linoleic acid (omega-6) levels were decreased in the low fat group (p = 0.034 and 0.005, respectively). Correlation analysis revealed that decreased omega-6 and increased omega-3 fatty acid correlated with decreased serum stimulated LNCaP cell growth (r = 0.64, p = 0.004 and r = -0.49, p = 0.04, respectively). CONCLUSIONS: In this prospective, randomized dietary intervention trial a low fat diet resulted in changes in serum fatty acid levels that were associated with decreased human LNCaP cancer cell growth. Further prospective trials are indicated to evaluate the potential of low fat diets for prostate cancer prevention and treatment.

Benign prostatic hyperplasia: does lifestyle play a role?

Benign prostatic hyperplasia (BPH) is a very common condition in older men, affecting up to 80% of men aged >or= 80 years in the United States. It typically leads to lower urinary tract symptoms, which often require medical management. The exact cause of BPH is unknown, and the only 2 established factors associated with BPH are age and the presence of androgens. Although the presence of testosterone is required for the development of BPH, testosterone is not thought to be the underlying factor causing BPH because testosterone levels decrease in older men. Recent studies have reported that BPH is associated with elevations in plasma estradiol/testosterone ratio, insulin, and insulin-like growth factor-I. Daily aerobic exercise can reduce all of these plasma factors, particularly when combined with a low-fat, high-fiber diet consisting of whole grains, fruits, and vegetables. In cell culture studies, this type of lifestyle regimen has recently been shown to reduce the growth of serum-stimulated prostate epithelial cells and the growth of androgen-dependent prostate cancer cell lines.

Effect of low-fat diet on development of prostate cancer and Akt phosphorylation in the Hi-Myc transgenic mouse model.

This study evaluated the effect of dietary fat on prostate cancer development by using the Hi-Myc mouse transgenic prostate cancer model. Hi-Myc mice develop murine prostatic intraepithelial neoplasia (mPIN) as early as 2 to 4 weeks and invasive adenocarcinoma between 6 and 9 months due to the overexpression of human c-Myc in the mouse prostate. Three-week-old male Hi-Myc mice were placed on high-fat (HF; 42% Kcal) or low-fat (LF; 12% Kcal) diets, and equal caloric intake was maintained until euthanasia at 7 months. The number of mice that developed invasive adenocarcinoma at 7 months was 27% less in the LF diet group (12/28) compared with the HF diet group (23/33, P < 0.05). Epithelial cells in mPIN lesions in the LF group had a significantly lower proliferative index compared with epithelial cells in the HF group (21.7% versus 28.9%, P < 0.05). During the mPIN phase of carcinogenesis (4 months), the LF group had higher serum insulin-like growth factor (IGF) binding protein-1 levels (21.0 +/- 8.9 ng/mL versus 3.2 +/- 0.8 ng/mL, P < 0.05) relative to the HF group. Akt (Ser(473)) phosphorylation, Akt kinase activity, and phosphorylation of downstream targets of Akt in prostates were significantly reduced in the LF diet group compared with the HF group. We conclude that dietary fat reduction delays transition from mPIN to invasive cancer in this Myc-driven transgenic mouse model, possibly through suppression of the IGF-Akt pathway and decreased proliferation of mPIN epithelial cells.

A mechanism to explain how regular exercise might reduce the risk for clinical prostate cancer.

Epidemiological studies report that regular physical activity can reduce the risk for prostate cancer. This study was conducted to investigate possible mechanisms to explain the epidemiological data. Serum from sedentary controls or men with regular (5 days/week) aerobic exercise was used to stimulate lymph node cancer of the prostate (LNCaP) tumor cells in vitro. Growth and apoptosis were assessed and cell lysate p53, p21 and Bcl-2 proteins measured. Tryphostin was used to block the insulin-like growth factor-I receptor. Exercise serum-stimulated growth was reduced at 2 and 4 days while apoptosis was increased. Tryphostin reduced growth in the control but not in the exercise serum-stimulated samples. Total cell lysate p53 protein was higher in the exercise serum-stimulated cells at both 2 and 4 days. The levels of p21 protein, a downstream effector of p53, were elevated at 2 days but were normal at 4 days. Bcl-2, an antiapoptotic protein, was significantly reduced at 2 days in the exercise serum-stimulated lysates. These results indicate that exercise training alters serum insulin-like growth factor axis factors in vivo that increase LNCaP cellular p53 protein content in vitro leading to reduced growth via p21 and induced apoptosis via the mitochondrial pathway.

Relationship of dietary protein and soy isoflavones to serum IGF-1 and IGF binding proteins in the Prostate Cancer Lifestyle Trial.

High levels of insulin-like growth factor 1 (IGF-1) are associated with increased risk of prostate cancer, whereas increased levels of some of its binding proteins (IGFBPs) seem to be protective. High intakes of dietary protein, especially animal and soy protein, appear to increase IGF-1. However, soy isoflavones have demonstrated anti-proliferative and apoptotic effects both in vitro and in vivo. We evaluated dietary intakes of total protein and soy isoflavones in relation to the IGF axis in prostate cancer patients making comprehensive lifestyle changes including a very low-fat vegan diet supplemented with soy protein (58 g/day). After one year, intervention group patients reported significantly higher intakes of dietary protein and soy isoflavones compared to usual-care controls (P < 0.001). IGF-1 increased significantly in both groups, whereas IGFBP-1 rose in the experimental group only (P < 0.01). Increases in vegetable protein over one year were associated with increases in IGFBP-1 among intervention group patients (P < 0.05). These results suggest that dietary protein and soy isoflavones, in the context of comprehensive lifestyle changes, may not significantly alter IGF-1. However, given the recent literature indicating that high intake of protein rich in essential amino acids (animal or soy protein) may increase IGF-1, it may be prudent for men with early stage prostate cancer not to exceed dietary protein recommendations.

Effect of a short-term diet and exercise intervention in youth on atherosclerotic risk factors.

Early stages of atherosclerosis are commonly noted in youth. The present study was designed to examine the effects of lifestyle modification in 19 overweight children (age 8-17) who were placed on a high-fiber, low-fat diet in a 2-week residential program where food was provided ad libitum and daily exercise (2-2.5h) was performed. In each subject, pre- and post-intervention fasting blood was drawn to measure serum lipids, oxidative stress marker 8-isoprostaglandin F2alpha (8-iso-PGF2alpha) and generating enzyme myeloperoxidase (MPO), soluble intracellular adhesion molecule (sICAM)-1 and sE-selectin as indicators of endothelial activation, the inflammatory protein C-reactive protein (CRP) and total matrix metalloproteinase-9 (MMP-9). Using subject sera and human aortic endothelial cell (HAEC) culture systems, monocyte chemotactic protein-1 (MCP-1) production, as well as nitric oxide (NO), superoxide and hydrogen peroxide production were measured in vitro by fluorometric detection. After 2 weeks, significant reductions (p<0.05) in all serum lipids (except HDL cholesterol), 8-iso-PGF2alpha, MPO, sICAM-1, sE-selectin, CRP, MMP-9, and cellular MCP-1 production were noted. Additionally, there was a significant decrease in cultured, serum-stimulated HAEC production of superoxide and hydrogen peroxide, and a concomitant increase in NO production (all p<0.01), These results indicate amelioration of several traditional as well as novel factors associated with atherosclerosis after lifestyle modification, even in youth without documented disease.

Prostate cancer prevention by nutritional means to alleviate metabolic syndrome.

In 1987 when Reaven introduced syndrome X (metabolic syndrome, or MS), we were studying skeletal muscle insulin resistance and found that when rodents were fed a high-fat, refined-sugar (HFS) diet, insulin resistance developed along with aspects of MS, including hyperinsulinemia, hypertension, hypertriglyceridemia, and obesity. MS was controlled in rodents by switching them to a low-fat, starch diet and was controlled in humans with a low-fat starch diet and daily exercise (Pritikin Program). Others reported inverse relations between serum insulin and sex hormone-binding globulin (SHBG). When subjects were placed on the Pritikin Program, insulin fell and SHBG rose and it was suggested that prostate cancer might also be an aspect of MS. A bioassay was developed with tumor cell lines grown in culture and stimulated with serum before and after a diet and exercise intervention. Diet and exercise altered serum factors that slowed the growth rate and induced apoptosis in androgen-dependent prostate cancer cells. Changes in serum with diet and exercise that might be important include reductions in insulin, estradiol, insulin-like growth factor-I (IGF-I), and free testosterone with increases in SHBG and IGF binding protein-1. Hyperinsulinemia stimulates liver production of IGF-I, plays a role in the promotion of prostate cancer, and thus is the cornerstone for both MS and prostate cancer. Adopting a low-fat starch diet with daily exercise controls MS and should reduce the risk of prostate cancer.

Effects of a low-fat, high-fiber diet and exercise program on breast cancer risk factors in vivo and tumor cell growth and apoptosis in vitro.

The present study investigated the effects of a diet and exercise intervention on known breast cancer (BCa) risk factors, including estrogen, obesity, insulin, and insulin-like growth factor-I (IGF-I), in overweight/obese, postmenopausal women. In addition, using the subjects' pre- and postintervention serum in vitro, serum-stimulated growth and apoptosis of three estrogen receptor-positive BCa cell lines were studied. The women where placed on a low-fat (10-15% kcal), high-fiber (30-40 g per 1,000 kcal/day) diet and attended daily exercise classes for 2 wk. Serum estradiol was reduced in the women on hormone treatment (HT; n = 28) as well as those not on HT (n = 10). Serum insulin and IGF-I were significantly reduced in all women, whereas IGF binding protein-1 was increased significantly. In vitro growth of the BCa cell lines was reduced by 6.6% for the MCF-7 cells, 9.9% for the ZR-75-1 cells, and 18.5% for the T-47D cells. Apoptosis was increased by 20% in the ZR-75-1 cells, 23% in the MCF-7 cells, and 30% in the T-47D cells (n = 12). These results show that a very-low-fat, high-fiber diet combined with daily exercise results in major reductions in risk factors for BCa while subjects remained overweight/obese. These in vivo serum changes slowed the growth and induced apoptosis in serum-stimulated BCa cell lines in vitro.

Effect of altering dietary omega-6/omega-3 fatty acid ratios on prostate cancer membrane composition, cyclooxygenase-2, and prostaglandin E2.

PURPOSE: To determine whether altering the dietary content of omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids affects the growth of androgen-sensitive prostate cancer xenografts, tumor membrane fatty acid composition, and tumor cyclooxygenase-2 and prostaglandin E(2) (PGE(2)) levels. EXPERIMENTAL DESIGN: Individually caged male severe combined immunodeficiency mice were fed isocaloric 20% kcal fat diets with the fat derived either primarily from n-6 fatty acids (n-6 group) or with the fat consisting of n-6 and n-3 fatty acids in a ratio of 1:1 (n-3 group), and injected s.c. with Los Angeles Prostate Cancer 4 (LAPC-4) cells. Tumor volumes and mouse weights were measured weekly, caloric intake was measured 3 days per week, and tumors and serum were harvested at 8 weeks postinjection. RESULTS: Tumor growth rates, final tumor volumes, and serum prostate-specific antigen levels were reduced in the n-3 group relative to the n-6 group. The n-3 group tumors had decreased proliferation (Ki67 staining) and increased apoptosis (terminal nucleotidyl transferase-mediated nick end labeling staining). In vitro proliferation of LAPC-4 cells in medium containing n-3 group serum was reduced by 22% relative to LAPC-4 cells cultured in medium containing serum from the n-6 group. The n-6/n-3 fatty acid ratios in serum and tumor membranes were lower in the n-3 group relative to the n-6 group. In addition, n-3 group tumors had decreased cyclooxygenase-2 protein and mRNA levels, an 83% reduction in PGE(2) levels, and decreased vascular endothelial growth factor expression. CONCLUSION: These results provide a sound basis for clinical trials evaluating the effect of dietary n-3 fatty acids from fish oil on tumor PGE(2) and membrane fatty acid composition, and serum and tumor biomarkers of progression in men with prostate cancer.

Effect of a short-term diet and exercise intervention on inflammatory/anti-inflammatory properties of HDL in overweight/obese men with cardiovascular risk factors.

There is significant debate regarding high-density lipoprotein cholesterol (HDL-C) and high-fiber, low-fat diets. The present study was designed to examine the effects of lifestyle modification on the inflammatory/anti-inflammatory properties of HDL in obese men (n = 22) with metabolic syndrome factors. Subjects were placed on a high-fiber, low-fat diet in a 3-wk residential program where food was provided ad libitum and daily aerobic exercise was performed. Fasting blood was drawn pre- and postintervention for serum lipids, lipid hydroperoxides, and the ability of subject HDL to alter low-density lipoprotein (LDL)-induced monocyte chemotactic activity (MCA) in a human artery wall coculture. Induction of MCA by control LDL in the absence of HDL was normalized to 1.0. Values >1.0 after HDL addition indicated proinflammatory HDL; values <1.0 indicated anti-inflammatory HDL. In addition, proteins involved in regulating HDL function, apolipoprotein A-I (apoA-I), paraoxonase 1 and 3, and platelet-activating factor acetylhydrolase were measured. After 3 wk, decreases in total-cholesterol, LDL-cholesterol, HDL-C, triglycerides, total cholesterol-to-HDL cholesterol ratio, and lipid hydroperoxides (all P < 0.05) were noted. The HDL inflammatory index decreased (P < 0.05) from pro- (1.14 +/- 0.11) to anti-inflammatory (0.94 +/- 0.09). ApoA-I level and paraoxonase activity did not change; however, platelet-activating factor acetylhydrolase activity increased (P < 0.05). Despite a quantitative reduction in HDL-C, HDL converted from pro- to anti-inflammatory. These data indicate that intensive lifestyle modification improves the function of HDL even in the face of reduced levels, suggesting increased turnover of proinflammatory HDL.

Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer.

PURPOSE: Phytochemicals in plants may have cancer preventive benefits through antioxidation and via gene-nutrient interactions. We sought to determine the effects of pomegranate juice (a major source of antioxidants) consumption on prostate-specific antigen (PSA) progression in men with a rising PSA following primary therapy. EXPERIMENTAL DESIGN: A phase II, Simon two-stage clinical trial for men with rising PSA after surgery or radiotherapy was conducted. Eligible patients had a detectable PSA > 0.2 and < 5 ng/mL and Gleason score < or = 7. Patients were treated with 8 ounces of pomegranate juice daily (Wonderful variety, 570 mg total polyphenol gallic acid equivalents) until disease progression. Clinical end points included safety and effect on serum PSA, serum-induced proliferation and apoptosis of LNCaP cells, serum lipid peroxidation, and serum nitric oxide levels. RESULTS: The study was fully accrued after efficacy criteria were met. There were no serious adverse events reported and the treatment was well tolerated. Mean PSA doubling time significantly increased with treatment from a mean of 15 months at baseline to 54 months posttreatment (P < 0.001). In vitro assays comparing pretreatment and posttreatment patient serum on the growth of LNCaP showed a 12% decrease in cell proliferation and a 17% increase in apoptosis (P = 0.0048 and 0.0004, respectively), a 23% increase in serum nitric oxide (P = 0.0085), and significant (P < 0.02) reductions in oxidative state and sensitivity to oxidation of serum lipids after versus before pomegranate juice consumption. CONCLUSIONS: We report the first clinical trial of pomegranate juice in patients with prostate cancer. The statistically significant prolongation of PSA doubling time, coupled with corresponding laboratory effects on prostate cancer in vitro cell proliferation and apoptosis as well as oxidative stress, warrant further testing in a placebo-controlled study.