Health Effects of Soy Isoflavones and Green Tea Catechins on Cancer and Cardiovascular Diseases Based on Urinary Biomarker Levels.

Plant polyphenols have various health effects. Genistein, which is abundant in soybeans, and epigallocatechin-3-gallate, which is abundant in green tea, are major flavonoids, a subclass group of polyphenols. Several epidemiological studies have shown that these flavonoids have beneficial effects against cancer and cardiovascular diseases. However, other studies did not show such effects. Several confounding factors, including recall bias, are related to these inconsistent findings, and the determination of metabolites in the urine may be useful in reducing the number of confounding factors. Equipment, which can be used by research participants to collect samples from a portion of voided urine within 24 h without the help of medical workers, has been developed for epidemiological investigations. Previous studies, in which flavonoid metabolites in these urine samples were measured, revealed that soy intake was correlated with a reduced risk of certain types of cancer and cardiovascular diseases worldwide. Although soybeans and green tea consumption may have protective effects against cancer and cardiovascular diseases, further clinical studies that consider different confounding factors are required to provide evidence for the actual impact of dietary flavonoids on human diseases, including cancer and cardiovascular diseases. One possible mechanism involved is discussed in relation to the downregulation of reactive oxygen species and the upregulation of 5'-adenosine monophosphate-activated protein kinase elicited by these flavonoids.

Stroke-Prone SHR as Experimental Models for Cardiovascular Disease Risk Reduction in Humans.

Since stroke-prone spontaneously hypertensive rats (SHRSP) develop hypertension and stroke without exception, the prevention or reduction of risk by various nutrients was tested on blood pressure and the mortality caused by stroke and cardiovascular diseases (CVD). In addition to sodium (Na) accelerating hypertension and stroke and potassium (K) counteracting the adverse effect of Na, taurine (Tau), rich in seafood, and magnesium (Mg) contained in soy, nuts, grains, etc., were proven to reduce stroke and CVD and improve survival. Therefore, the Cardiovascular Diseases and Alimentary Comparison Study was started in 1985 to explore the association of biomarkers of diet in 24 h urine (24U) with CVD risks, and about 100 males and 100 females aged 48-56 in each of 50 populations were studied until 1995. Linear regression analysis indicated that the 24U Tau/creatinine and Mg/creatinine ratios were inversely associated with body mass index, systolic and diastolic blood pressure, and total cholesterol. In comparison with six Euro-Western regions, 24U Tau and Mg collected from six regions, respectively, in Japan and the Mediterranean countries were significantly higher and were significantly associated with lower CVD risks. Diets rich in Tau and Mg were concluded to be contributory to the prevention of CVD in SHRSP and humans.

Grading of Japanese Diet Intakes by 24-Hour Urine Analysis of Taurine and Soy Isoflavones in Relation to Cardiovascular Risks.

To investigate the association of the Japanese diet with risks for lifestyle-related diseases, the biomarkers of seafood and soybean consumption, taurine (T) and soy isoflavones (I), and others were analyzed in 24-hour urine (24U) samples collected from participants of the Cardiovascular Diseases and Alimentary Comparison (CARDIAC) Study coordinated by the World Health Organization (WHO). The data of T and I normalized for creatinine content in 24U were divided into five quintiles, T1 to T5, and I1 to I5. The total data of the collected samples were divided into 25 groups, which were obtained by 5 (T1-T5) × 5 (I1-I5) according to 24U excretions of T and I corresponding to the intake of seafood and soybeans from the least to the highest, respectively. Since these two nutrients were often consumed together in the Japanese diet, this characteristic was expressed as J1 to J5 based on the amounts of 24U T and I excretions. The risks for lifestyle-related diseases, obesity (body mass index, BMI), and cholesterolemia became lower during the transition from J1 to J5, while HDL cholesterol levels became higher from J1 to J5. On the contrary, urinary salt excretion and the sodium (Na)/potassium (K) ratio became higher from J1 to J5. Systolic blood measure was significantly lower in J3 than in J5. Diastolic blood pressure was also significantly lower in J3 than in J1. In conclusion, the higher the J score, which corresponds to Japanese dietary habits, the lower the BMI and cholesterol levels, as well as mortality rate from coronary heart disease, but the higher the average life expectancy among the Japanese. However, these higher J scorings were associated with high-salt intake and high Na/K ratios; therefore, they contributed to high blood pressure and high mortality rate caused by stroke in Japan. These results indicate that low-salt intake should be recommended to the Japanese who are consuming seafood and soy regularly in order to maintain lower blood pressure and to extend healthy life expectancy with a lower risk of stroke. Moreover, high scorings of the Japanese diet correspond to the high intake of magnesium (Mg) which is rich in seafood including seaweeds and soy. Therefore, low-salt seafood and soy intake is expected to reduce the incidence of the metabolic syndrome, the risk of which is inversely related to T and Mg intake.

Correction: Soy and fish as features of the Japanese diet and cardiovascular disease risks.

[This corrects the article DOI: 10.1371/journal.pone.0176039.].

Taurine Intake with Magnesium Reduces Cardiometabolic Risks.

WHO-CARDIAC (Cardiovascular Diseases and Alimentary Comparison) Study revealed the quintile analyses of 24-h urinary (24 U) taurine (T) and magnesium (Mg) excretions were inversely related with cardiometabolic risks (CMR) such as obesity, hypertension and hypercholesterolemia in 50 population samples in the world. To exclude the influence of ethnicity in the study, 24 U T and Mg excretions were analyzed for the association with CMR in one ethnicity, Japanese population.24 U T/creatinine (C) ratios were divided into 5 quintiles and the ratios of Japanese to the total of each quintile were analyzed from CARDIAC Study samples. The highest 24 U T quintile consisted of 60% Japanese, indicating high seafood consumption in Japanese.Over 600 Japanese aged 30-79 were invited to a health examination for blood pressure measurement and for fasting blood and 24 U samplings. Tertile analysis of 24 U T/C ratios in relation to CMR indicated the third tertile had significantly higher HDL cholesterol, 24 U potassium (K) and 24 U salt than the first (lowest) tertile. Tertile analysis of 24 U Mg/C ratios indicated the third tertile had significantly lower body mass index and significantly higher folic acid, 24 U isoflavones, K and salt than the first tertile after age and gender adjustment. The third tertile of both T/C and Mg/C had significantly lower body mass index, LDL/HDL and Na/K ratios, and significantly higher HDL cholesterol and folic acid than the first tertile, indicating seafood eaters taking Mg rich diets had lower risks of obesity, atherosclerosis, hypertension and higher folic acid, beneficial for healthy longevity.

Soy and fish as features of the Japanese diet and cardiovascular disease risks.

In the World Health Organization (WHO)-coordinated Cardiovascular Disease and Alimentary Comparison Study, isoflavones (I; biomarker for dietary soy) and taurine (T; biomarker for dietary fish) in 24-hour-urine (24U) were inversely related to coronary heart disease (CHD) mortality. High levels of these biomarkers are found in Japanese people, whose CHD mortality is lowest among developed countries. We analyzed the association of these biomarkers with cardiovascular disease risk in the Japanese to know their health effects within one ethnic population. First, to compare the Japanese intake of I and T with international intakes, the ratios of 24UI and 24UT to creatinine from the WHO Study were divided into quintiles for analysis. The ratio for the Japanese was the highest in the highest quintiles for both I and T, reaching 88.1%, far higher than the average ratio for the Japanese (26.3%) in the total study population. Second, 553 inhabitants of Hyogo Prefecture, Japan, aged 30 to 79 years underwent 24-U collection and blood analyses. The 24UT and 24UI were divided into tertiles and adjusted for age and sex. The highest T tertile, compared with the lowest tertile, showed significantly higher levels of high-density lipoprotein-cholesterol (HDL-C), total cholesterol, 24U sodium (Na) and potassium (K). The highest I tertile showed significantly higher folate, 24UNa and 24UK compared with the lowest tertile. The highest tertile of both T and I showed significantly higher HDL-C, folate, and 24UNa and 24UK compared with the lowest tertile. Thus, greater consumption of fish and soy were significantly associated with higher HDL-C and folate levels, possibly a contributor to Japan having the lowest CHD mortality and longest life expectancy among developed countries. As these intakes were also associated with a high intake of salt, a low-salt intake of fish and soy should be recommended for healthy life expectancy.

An inverse association between magnesium in 24-h urine and cardiovascular risk factors in middle-aged subjects in 50 CARDIAC Study populations.

Serum, plasma and dietary magnesium (Mg) have been reported to be inversely associated with cardiovascular disease risk factors. We examined the associations between the 24-h urinary Mg/creatinine (Cre) ratio and cardiovascular disease risk factors, such as body mass index (BMI), blood pressure (BP), serum total cholesterol (TC) and prevalence of obesity, hypertension and hypercholesterolemia. A cross-sectional analysis was conducted among 4211 participants (49.7% women) aged 48-56 years in 50 population samples from 22 countries in the World Health Organization-coordinated Cardiovascular Diseases and Alimentary Comparison (CARDIAC) Study (1985-1994). In linear regression analyses, Mg/Cre ratio was inversely associated with BMI, systolic BP (SBP), diastolic BP (DBP) and TC (P for linear trend <0.001 for each). These associations were not markedly altered by adjustment for traditional risk factors, urinary markers or cohort effects. Multivariate-adjusted mean values for the subjects in the highest Mg/Cre ratio quintile were 6.3, 3.4, 5.3 and 4.6% lower than those for the subjects in the lowest quintile for BMI, SBP, DBP and TC (P < 0.001, respectively). The prevalence of obesity, hypertension and hypercholesterolemia was 2.10 (95% confidence interval: 1.50, 2.95), 1.55 (1.25, 1.92) and 2.06 (1.63, 2.62) times higher (P < 0.001, respectively) among the subjects in the lowest Mg/Cre ratio quintile than in the subjects in the highest quintile. These associations were not appreciably altered by adjustment for potential confounding variables. In conclusion, higher 24-h urinary Mg/Cre ratio was associated with lower cardiovascular disease risk factors, including BMI, BP, TC, obesity, hypertension and hypercholesterolemia.

Effects of docosahexaenoic Acid supplementation on blood pressure, heart rate, and serum lipids in Scottish men with hypertension and hypercholesterolemia.

To investigate the effects of daily supplementation with docosahexaenoic acid (DHA) on coronary heart disease risks in 38 middle-aged men with hypertension and/or hypercholesterolemia in Scotland, a five-week double-blind placebo-controlled dietary supplementation with either 2 g of DHA or active placebo (1 g of olive oil) was conducted. Percent composition of DHA in plasma phospholipids increased significantly in DHA group. Systolic and diastolic blood pressure and heart rate decreased significantly in DHA group, but not in placebo group. High-density lipoprotein cholesterol (HDL-C) increased significantly, and total cholesterol (TC)/HDL-C and non-HDL-C/HDL-C ratios decreased significantly in both groups. There was no change in TC and non-HDL-C. We conclude that 2 g/day of DHA supplementation reduced coronary heart disease risk factor level improving blood pressure, heart rate, and lipid profiles in hypertensive, hypercholesterolemic Scottish men who do not eat fish on a regular basis.

Taurine as the nutritional factor for the longevity of the Japanese revealed by a world-wide epidemiological survey.

The initial observation that taurine (T) prevented stroke in stroke-prone spontaneously hypertensive rats (SHRSP) led us to study the effects of T on cardiovascular diseases (CVD), as well as the epidemiological association of T and mortality rates, by using the data from WHO-coordinated Cardiovascular Disease and Alimentary Comparison Study, which covered 61 populations in 25 countries. In this study, 24 hour urine (24-U) samples were examined along with biomarkers of CVD risk. The mortality rate from ischemic heart disease (IHD), which was lowest among the Japanese compared to the populations of other developed countries, was positively related to total serum cholesterol (TC) and inversely related to 24-U taurine excretion (24-UT), as well as the n-3 fatty acid to total phospholipids ratio of the plasma membrane, both biomarkers of seafood intake. Analysis of 5 diet-related factors revealed that TC and BMI were positively associated with IHD mortality in both genders while Mg and T were negatively associated with IHD mortality. TC and sodium (Na) were negatively and positively associated with stroke mortality, respectively. 24-UT was negatively associated with stroke mortality. These five diet-related factors explained 61 and 49% of IHD and stroke variances in male, 63 and 36% of IHD and stroke variances in female, respectively.

Effects of dietary intake of soy protein and isoflavones on cardiovascular disease risk factors in high risk, middle-aged men in Scotland.

OBJECTIVE: To investigate the effects of soy protein and isoflavones on blood pressure (BP) and cholesterol levels among high risk middle-aged Scottish men. DESIGN: A randomized, double-blind, placebo-controlled, parallel-group dietary intervention study SETTING: Inhabitants on Isles of Lewis and Harris in Scotland SUBJECTS: Sixty-one men with relatively higher BP and/or total cholesterol (TC) levels aged 45 to 59 went through the dietary intervention. INTERVENTION: Diets containing at least 20 g of soy protein and 80 mg of isoflavones were compared to the placebo diets. Intervention period was 5 weeks duration. RESULTS: Significant difference was found in 24-hour urinary isoflavone excretion between the two groups after intervention. Significant reductions from the baselines were observed in systolic BP (SBP) and diastolic BP (DBP), TC and non-high density lipoprotein cholesterol (non-HDL-C) in the soy-containing diet group, but not in the olive oil containing active placebo group. Significant increases in high density lipoprotein cholesterol (HDL-C) were observed in both groups. CONCLUSION: Dietary intakes of soy protein (at least 20 g) and isoflavones (at least 80 mg) for 5 weeks would be effective in reducing CHD risk among high-risk, middle-aged men.

Soy isoflavones improve bone metabolism in postmenopausal Japanese women.

1. This study examines whether the supplementation of isoflavones (ISO) exerts beneficial effects on serum and urinary biomarkers of bone metabolism. 2. A total of 102 women were randomly assigned to three groups taking either ISO (40 mg) tablets, tablets containing vitamins C (25 mg) and E (5 mg) (V) or placebo tablets (vehicle only) (P) daily for 4 weeks, in a double-blind parallel placebo controlled design. 3. Among the 67 women who completed the study (24 on ISO, 24 on V, 19 on P), only ISO tablets were proven to decrease significantly urinary deoxypyridinoline (Dpd) excretion (P < 0.05 vs before), a specific biomarker of bone resorption, but there was no significant difference in serum bone gamma-carboxyglutamic acid-containing protein (BGP), a specific serum biomarker of bone formation. 4. Among the 67, 25 women were postmenopausal (8 on ISO, 12 on V, 8 on P) and only ISO tablets decreased significantly urinary Dpd excretion (P < 0.05 vs before) in them. The reduction rate of Dpd in ISO group was also significantly greater than that in P group (P < 0.01). 5. Dietary supplementation of vitamins C 25 mg and E 5 mg did not affect urinary Dpd.

Proposition of a feasible protocol to evaluate salt sensitivity in a population-based setting.

Although a variety of techniques have been devised to assess salt sensitivity, most have proven cumbersome from a methodological perspective. We therefore attempted to develop a 2-week method by which participants could be tested in an outpatient setting without requirement of a strict dietary regimen. In this method, subjects take 140 mEq of an NaCl supplement per day for 1 week and 25 mg of hydrochlorothiazide daily for another week while maintaining their customary diet. In our first trial, 8 healthy volunteers submitted to this method, as well as to a widely-used rapid volume expansion and contraction protocol. Blood pressure measurements, blood sampling and 24-h urine collection were performed before, in the middle of, and after each intervention. There was a fair correlation (r = 0.69) between the two protocols with respect to the changes in mean blood pressure (deltaMBP), a measure of salt sensitivity. In our second trial, we tested the method on 82 Japanese subjects who had never been treated with antihypertensive drugs. DeltaMBP was significantly correlated with plasma renin activity (PRA) during salt loading (r = 0.52, p < 0.0001) and with the changes in atrial natriuretic peptide (deltaANP) (r = -0.34, p = 0.0018). When total subjects were divided into two subgroups by age, a similar tendency of correlation was observed. Age, PRA during salt loading, deltaANP, and delta norepinephrine were proven to be significant predictors of salt sensitivity and accounted for 46% of the deltaMBP variances. Based on these results, the dietary method presented here seems to be applicable for a population-based survey. Our preliminary data also suggest that PRA and ANP would be of predictive value in the salt sensitivity test.