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July 2010

Soy proteins and cardiovascular disease.

The soybean diet is the most potent dietary tool for hypercholesterolemia. The United States Food and Drug Administration recently approved the health claim for its role in reducing the risk of coronary disease. The hypocholesterolemic effect is directly correlated to the patient’s cholesterolemia, with minimal or no reductions occurring at cholesterol of 6 mmol/L or less, and the most benefit occurring in patients with cholesterol of greater than 7 mmol/L. Hypotheses on the mechanism of action include soy fiber, isoflavones (phytoestrogens), and the protein itself. Although there is no evidence for the effect of fiber, studies with ethanol-extracted soy (devoid of isoflavones) indicated a loss of effect, but the extract itself (isoflavone rich) has no hypocholesterolemic activity. In humans, soy protein activates the low-density lipoprotein (LDL) receptor pathway. Recent data suggest that soy protein subunits, particularly 7S, directly activiate LDL receptors in the human liver, thus providing a novel mechanism of plasma cholesterol reduction different from currently available diets and hypolipidemic drugs.

Curr Atheroscler Rep. 2001 Jan;3(1):47-53

The key importance of soy isoflavone bioavailability to understanding health benefits.

Research over the past two decades has provided significant epidemiological and other evidence for the health benefits of the consumption of soy-based foods. A large number of dietary intervention studies have examined the effects of soy isoflavones on risk factors for cardiovascular disease and hormone-dependent cancers. However, these report large variability in outcome measures, very limited reproducibility between studies, and in some cases, controversy between the results of clinical trials using dietary soy or soy protein and isoflavone supplementation. This highlights a major gap in our understanding of soy isoflavone uptake, metabolism, distribution, and overall bioavailability. There are many potential factors that may influence bioavailability and a better knowledge is necessary to rationalize the inconsistencies in the intervention and clinical studies. This review focuses attention on our current state of knowledge in this area and highlights the importance of metabolism of the parent soy isoflavones and the critical role of gut microbiota on the bioavailability of these compounds and their metabolites.

Crit Rev Food Sci Nutr. 2008 Jun;48(6):538-52

Soybean, a promising health source.

Health properties and uses of soybean, as well as the different chemical and botanical characteristics of this legume are shown in this review. Soybean represents an excellent source of high quality protein, it has a low content in saturated fat, it contains a great amount of dietary fibre and its isoflavone content makes it singular among other legumes. Many researches have been carried out into the benefits of legumes: chickpeas, beans, lentils and soy, among others, but characterization and positive health effects of soybeans have been recently studied. The interest in this legume has increased because of its functional components. Most of the studies have been focused on soybean protein as a possible source of prevention against cardiovascular disease. This positive effect may be due to a decrease in serum cholesterol concentrations. In addition, there are many studies on isoflavones, non-nutritive substances, associated with prevention and treatment of different chronic diseases. Moreover, some studies have shown the health properties of soy dietary fibre. Therefore, it would be interesting to consider the replacement of animal based foods for soybean foods in order to obtain some nutritional benefits.

Nutr Hosp. 2008 Jul-Aug;23(4):305-12

Health effects of soy protein and isoflavones in humans.

Epidemiological investigations suggest that soy consumption may be associated with a lower incidence of certain chronic diseases. Clinical studies also show that ingestion of soy proteins reduces the risk factors for cardiovascular disease. This led to the approval of the food-labeling health claim for soy proteins in the prevention of coronary heart disease by the U.S. FDA in 1999. Similar health petitions for soy proteins have also been approved thereafter in the United Kingdom, Brazil, South Africa, the Philippines, Indonesia, Korea, and Malaysia. However, the purported health benefits are quite variable in different studies. The Nutrition Committee of the American Heart Association has assessed 22 randomized trials conducted since 1999 and found that isolated soy protein with isoflavones (ISF) slightly decreased LDL cholesterol but had no effect on HDL cholesterol, triglycerides, lipoprotein(a), or blood pressure. The other effects of soy consumption were not evident. Although the contributing factors to these discrepancies are not fully understood, the source of soybeans and processing procedures of the protein or ISF are believed to be important because of their effects on the content and intactness of certain bioactive protein subunits. Some studies have documented potential safety concerns on increased consumption of soy products. Impacts of soy products on thyroid and reproductive functions as well as on certain types of carcinogenesis require further study in this context. Overall, existing data are inconsistent or inadequate in supporting most of the suggested health benefits of consuming soy protein or ISF.

J Nutr. 2008 Jun;138(6):1244S-9S

Soy, phytoestrogens and metabolism: A review.

Of any plant, soy contains the largest concentration of isoflavones, a class of phytoestrogens. Phytoestrogens are structurally similar to estradiol and mimic its effects. Soy and phytoestrogens receive increasing attention due to the health benefits associated with their consumption. Here we review the data collected on the effects of soy and phytoestrogens on glucose and lipid metabolism and their possible mechanisms of action. Overall, there is a suggestive body of evidence that soy and dietary phytoestrogens favorably alter glycemic control, improve weight and fat loss, lower triglycerides, low density lipoprotein (LDL) cholesterol and total cholesterol.

However, these results must be interpreted with care, and additional evidence is needed before a firm conclusion can be drawn. In particular, since not all activities related to soy can be assigned to the estrogenic-like activity, further studies are needed to identify firstly which soy constituent(s) improve metabolic parameters when ingested and secondly, which are the mechanisms whereby dietary soy improves metabolic-related conditions like obesity and diabetes. Finally, the potential detrimental effects of soy and phytoestrogens are briefly discussed.

Mol Cell Endocrinol. 2009 May 25;304(1-2):30-42

Soybean isoflavones in bone health.

Soybean isoflavones are structurally similar to estrogen, bind to estrogen receptors, and exhibit weak estrogenic activity. It has been reported that isoflavones play an important role in the prevention of hormone-dependent diseases, including osteoporosis, cardiovascular diseases, cancer, and postmenopausal syndrome. There are many researches indicating isoflavones prevent bone loss caused by estrogen deficiency in animal models. Furthermore, it has been demonstrated that a combination of isoflavone treatment and exercise cooperatively prevented bone loss in the estrogen-deficient status. Epidemiological studies demonstrated the relationship between the lower incidence of osteoporosis in Asian women and a diet rich in soy foods. Although a number of observational studies confirm the findings from the animal studies, the results from intervention studies are still controversial. One of the potential reasons for these inconsistencies could be individual differences in the isoflavone metabolism. Recently, it has been suggested that the clinical effectiveness of isoflavones might partly depend on the ability to produce equol, a gut bacterial metabolite of daidzein showing stronger estrogenic activity than the predominant isoflavones. Several candidate bacteria responsible for equol production have been suggested, for example Lactococcus 20-92 strain. From these findings, food factors enhancing equol production have received great deal of attention recently. On the other hand, safety assessment of isoflavones has been conducted by the Japanese Food Safety Commission. Further studies are required to address the numerous questions on the potential benefits, mechanisms of action, and safety of isoflavones.

Forum Nutr. 2009;61:104-16. Epub 2009 Apr 7

Isoflavones, equol and cardiovascular disease: pharmacological and therapeutic insights.

Isoflavones are an important class of phytoestrogens that are found at extrememly high levels in soy. Up until recently, daidzein and genistein were considered to be the most important and hence most studied isoflavones, however more recently attention has shifted to isoflavone metabolies. Equol represents the main active product of daidzein metabolism, produced via specific microflora in the gut. It has a longer half life and greater biological activity, including superior antioxidant activity. Yet, whilst the majority of animals produce equol following soy consumption, as much as 30-50% of the adult human population cannot. This inability to produce equol in as much as half the population is thought to provide some explanation for the failure of soy to reveal any substantial health benefits in clinical studies. This article will comprehensively review literature investigating the potential cardiovascular benefits of daidzein and its metabolites, paying particular attention to equol. It will focus on the relative vasorelaxant activity, effects on nitric oxide synthase (NOS), antioxidant activity and potential for the treatment and prevention of hypertension and stroke. Findings obtained in both animal and human studies will be reviewed with the hope of gaining an insight into the experimental and clinical importance of equol to the cardiovascular benefits of soy.

Curr Med Chem. 2007;14(26):2824-30

Targeting the redox sensitive Nrf2-Keap1 defense pathway in cardiovascular disease: protection afforded by dietary isoflavones.

Cells have evolved highly regulated defense systems, including the redox sensitive Nrf2-Keap1 signaling pathway involved in the transcriptional activation of phase II defense and antioxidant genes in oxidative stress. Increased generation of reactive oxygen species (ROS) in cardiovascular disease (CVD) leads to impaired endothelial function and reduced nitric oxide (NO) bioavailability. Although epidemiological evidence suggests that diets containing plant-derived isoflavones (phytoestrogens) afford protection against CVDs, supplementation trials have largely reported only marginal health benefits. The molecular mechanisms by which soy isoflavones (genistein, daidzein, and equol) afford protection against oxidative stress in CVD remain to be investigated in large-scale clinical trials. Studies in animal models and cultured vascular cells have established that isoflavones increase eNOS activity and expression and activate the Nrf2-Keap1 signaling pathway, leading to an upregulation of detoxifying and antioxidant defense genes. We review recent advances in the understanding of the signal transduction pathways involved in the activation of endothelial NO production and Nrf2-Keap1-mediated antioxidant gene expression by dietary isoflavones.

Curr Opin Pharmacol. 2009 Apr;9(2):139-45

Dietary isoflavones in the prevention of cardiovascular disease—a molecular perspective.

The Food and Drugs Administration has approved a health claim for soy based on clinical trials and epidemiological data indicating that high soy consumption is associated with a lower risk of coronary artery disease. Soy products contain a group of compounds called isoflavones, with genistein and daidzein being the most abundant. A number of cardioprotective benefits have been attributed to dietary isoflavones including a reduction in LDL cholesterol, an inhibition of pro-inflammatory cytokines, cell adhesion proteins and inducible nitric oxide production, potential reduction in the susceptibility of the LDL particle to oxidation, inhibition of platelet aggregation and an improvement in vascular reactivity. There is increasing interest in the use of nutrigenomic methods to understand the mechanisms by which isoflavones induce these changes, and in the use of nutrigenetics to understand why the effects vary between individuals. Nutrigenomics is a rapidly growing field making use of molecular biology methodologies, such as microarray technology and proteomics, to study how specific nutrients or diets affect gene expression and cellular protein levels. The analysis of differential gene expression and protein levels in endothelial cells, macrophages and smooth muscle cells is critical to elucidating the sequence of events leading to the formation of atherosclerotic lesions, and to understanding the potential anti-atherogenic properties of soy isoflavones. An increasing number of studies demonstrate a significant impact of genetic variation on changes in cardiovascular risk factors in response to dietary intervention. Nutrigenetic effects of this type have recently been reported for dietary isoflavones, and may help to explain some of the disparities in the current literature concerning isoflavones and cardiovascular health.

Food Chem Toxicol. 2008 Apr;46(4):1308-19

Investigating the optimal soy protein and isoflavone intakes for women: a perspective.

Traditional soyfoods have been consumed for centuries throughout much of East Asia and, recently, these foods have also become popular in the West. Soyfoods and specific soybean components, such as the protein and isoflavones, have attracted attention for their possible health benefits. Isoflavones are classified as phytoestrogens and have been postulated to be natural alternatives to hormone therapy for menopausal women. To provide guidance on optimal soy intake, this article evaluates Asian soy consumption and both clinical and Asian epidemiologic studies that examined the relationship between soy intake and a variety of health outcomes. On the basis of these data and the standard principles of dietary practice the author suggests that optimal soy protein and isoflavone intakes are 15-20 g/day and 50-90 mg/day, respectively. In addition, an intake of 25 g/day soy protein can be specifically used as the recommendation for cholesterol reduction.

Womens Health (Lond Engl). 2008 Jul;4(4):337-56

Long-term intake of soy protein improves blood lipid profiles and increases mononuclear cell low-density-lipoprotein receptor messenger RNA in hypercholesterolemic, postmenopausal women.

The long-term clinical effects of soy protein containing various amounts of isoflavones on lipoproteins, mononuclear cell LDL receptor messenger RNA concentrations, and other selected cardiovascular risk factors are not well known. Sixty-six hypercholesterolemic, free-living, postmenopausal women were investigated during a 6-mo parallel-group, double-blind trial with 3 interventions. After a control period of 14 d, all subjects were randomly assigned to 1 of 3 dietary groups (all with 40 g protein): a National Cholesterol Education Program (NCEP) Step 1 diet with protein from casein and nonfat dry milk (control), an NCEP Step 1 diet with protein from isolated soy protein containing moderate amounts of isoflavones (ISP56), or an NCEP Step 1 diet with protein from isolated soy protein containing high amounts of isoflavones (ISP90). Non-HDL cholesterol in both the ISP56 and ISP90 groups was reduced compared with the control group (P < 0.05), whereas total cholesterol was not changed. HDL cholesterol increased in both the ISP56 and ISP90 groups (P < 0.05), whereas the ratio of total to HDL cholesterol decreased significantly in both groups compared with the control (P < 0.05). Mononuclear cell LDL receptor messenger RNA concentrations increased in subjects consuming ISP56 or ISP90 compared with the control (P < 0.05). These results indicate that soy protein, with different amounts of isoflavones, may decrease the risk of cardiovascular disease via improved blood lipid profiles, and that the mechanism by which apolipoprotein B-containing lipoproteins were depressed may be via alterations in LDL receptor quantity or activity.

Am J Clin Nutr. 1998 Sep;68(3):545-51.

Effect of soy protein foods on low-density lipoprotein oxidation and ex vivo sex hormone receptor activity—a controlled crossover trial.

Plant-derived estrogen analogs (phytoestrogens) may confer significant health advantages including cholesterol reduction, antioxidant activity, and possibly a reduced cancer risk. However, the concern has also been raised that phytoestrogens may be endocrine disrupters and major health hazards. We therefore assessed the effects of soy foods as a rich source of isoflavonoid phytoestrogens on LDL oxidation and sex hormone receptor activity. Thirty-one hyperlipidemic subjects underwent two 1-month low-fat metabolic diets in a randomized crossover study. The major differences between the test and control diets were an increase in soy protein foods (33 g/d soy protein) providing 86 mg isoflavones/2,000 kcal/d and a doubling of the soluble fiber intake. Fasting blood samples were obtained at the start and at weeks 2 and 4, with 24-hour urine collections at the end of each phase. Soy foods increased urinary isoflavone excretion on the test diet versus the control (3.8+/-0.7 v 0.0+/-0.0 mg/d, P < .001). The test diet decreased both oxidized LDL measured as conjugated dienes in the LDL fraction (56+/-3 v 63+/-3 micromol/L, P < .001) and the ratio of conjugated dienes to LDL cholesterol (15.0+/-1.0 v 15.7+/-0.9, P = .032), even in subjects already using vitamin E supplements (400 to 800 mg/d). No significant difference was detected in ex vivo sex hormone activity between urine samples from the test and control periods. In conclusion, consumption of high-isoflavone foods was associated with reduced levels of circulating oxidized LDL even in subjects taking vitamin E, with no evidence of increased urinary estrogenic activity. Soy consumption may reduce cardiovascular disease risk without increasing the risk for hormone-dependent cancers.

Metabolism. 2000 Apr;49(4):537-43