Yoshiko Ishimi

Possible role of equol status in the effects of isoflavone on bone and fat mass in postmenopausal Japanese women: a double-blind, randomized, controlled trial.

Objective:Equol is more biologically active than its precursor daidzein, which is the principal isoflavone found in soybean. There are interindividual differences in the ability to produce equol; these may lead to differences in the effects of isoflavone intervention on human health. This study aimed to investigate whether the effects of soy isoflavones on bone and fat mass are related to an individuals equol status. Design:We performed a 1-year double-blind, randomized trial to compare the effects of isoflavone (75 mg of isoflavone conjugates/day) with those of placebo on bone mineral density, fat mass, and serum isoflavone concentrations in early postmenopausal Japanese women who were classified based on their equol-producer phenotype. Results:After 1 year, the isoflavone intervention significantly increased the serum equol concentration in the equol producers but not in the nonproducers. In the isoflavone group, the annualized changes in the bone mineral density of the total hip and intertrochanteric regions were −0.46% and −0.04%, respectively, in the equol producers and −2.28% and −2.61%, respectively, in the nonproducers; these values were significantly different (P < 0.05 for both the regions). Significant differences were observed between the equol producers and nonproducers in the isoflavone group with regard to the annualized changes in the fat mass. No significant difference in the annualized changes in bone mineral density and fat mass was observed between the equol producers and nonproducers in the placebo group. Conclusions:Our data suggest that the preventive effects of isoflavones on bone loss and fat accumulation in early postmenopausal women depend on an individuals equol-producing capacity.

Effects of Isoflavone and Exercise on BMD and Fat Mass in Postmenopausal Japanese Women: A 1-Year Randomized Placebo-Controlled Trial†

The combined intervention of isoflavone intake and walking exercise over 1 year in postmenopausal Japanese women exhibited a trend for a greater effect on prevention of bone loss at the total hip and Wards triangle regions.

Assessment of effectiveness of oral administration of collagen peptide on bone metabolism in growing and mature rats

The purpose of this study was to examine the effectiveness of collagen peptide intake on bone metabolism in growing (G) and calcium-deficient mature (M) rats. As for the dosages used, they were amounts equal to the recommended supplements for humans (0.166 g/kg body weight (BW) per day: Coll-1G and Coll-1M groups), 10-fold higher (1.66 g/kg BW per day: Coll-10G and Coll-10M groups), and 100-fold higher (16.6 g/kg BW per day: Coll-100G group). In growing male rats, bone mineral density (BMD) of the femur in the Coll-100G group was significantly higher than that in the other groups after the 4-week experimental period. On the other hand, kidneys in the rats from the Coll-100G group exhibited hypertrophy. To examine the effects of collagen peptide on bone metabolism in a calcium-deficient status, mature female rats were fed a 0.01% Ca diet for 9 weeks and then fed a diet with 0.2% calcium with or without collagen peptide (control, Coll-1M, and Coll-10M groups) or a 0.5% calcium diet (normal Ca) for 8 weeks. BMD of the whole femur in the Coll-10M group was significantly higher than that in the control and Coll-1M groups, and the level was similar to that in the normal Ca group. BMD of the lumbar spine in the Coll-10M group was significantly higher than their baseline value, as well as being significantly higher than that in the control and Coll-1M groups. These results suggest that orally administered collagen peptide may provide beneficial effects on bone metabolism, especially in the calcium-deficient condition, without obvious undesirable effects.

Cooperative effects of exercise training and genistein administration on bone mass in ovariectomized mice.

We reported that genistein, a soybean isoflavone, prevents bone loss caused by estrogen deficiency, without undesirable effects on the uterus. In this study, we examined cooperative effects of genistein administration and running exercise on bone mass in ovariectomized (OVX) mice. Female mice aged 7 weeks were either sham‐operated or OVX and divided into six groups: (1) sham; (2) OVX; (3) OVX, treated with genistein at a submaximal dose (0.4 mg/day) subcutaneously (G); (4) OVX, exercised on a treadmill daily for 30 minutes/day at 12 m/minute on a 10° uphill slope (Ex); (5) OVX, given genistein and exercised (ExG); and (6) OVX, treated with 17β‐estradiol (0.03 μg/day) in the same manner as genistein (E2). Four weeks after intervention, bone mass was estimated by dual‐energy X‐ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT). Bone mineral density (BMD) of the whole femur measured by DXA was higher in both the G and the Ex groups than in the OVX group. Furthermore, BMD in the ExG group was significantly higher than that in the groups receiving either intervention alone. Bone area in distal region of the femur was significantly higher in Ex and ExG groups as compared with those in the OVX and G groups. pQCT analysis showed that the cross‐sectional areas (CSAs) and periosteum perimeter at midshaft of the femur did not differ in the sham and OVX groups but were significantly higher in Ex and ExG groups. Histomorphometric analysis showed that bone formation rate/bone surface (BFR/BS) was significantly higher in both Ex and ExG groups as compared with that in non‐exercised groups. The bone volume (BV/TV) in the distal femoral cancellous bone was lower in the OVX than that in the sham group, and it was restored completely in the ExG group, as in the E2 group. Thickness of the trabecular bone (Tb.Th) was higher in Ex and ExG groups than that in the OVX and G groups. These results indicate that the combined intervention of moderate exercise and the submaximal dose of genistein administration show a cooperative effect in preventing bone loss in OVX mice.

Puerariae radix prevents bone loss in ovariectomized mice

Puerariae radix (PR), the root of Pueraria labata (Willd.) Ohwi, a wild creeper leguminous plant, is one of the earliest and most important crude herbs used in Chinese medicine for various medicinal purposes. PR contains a high amount of isoflavonoids such as daidzein and genistein, which are known to prevent bone loss induced by estrogen deficiency. We have demonstrated that soybean isoflavones prevent bone loss in an osteoporotic animal model. To examine the possible role of PR in bone metabolism, female mice were ovariectomized (OVX), and some OVX mice were fed a diet containing low, middle, and high doses (5%, 10%, and 20% of diet, respectively) of PR for 4 weeks. In OVX mice, the uterine weight declined, and intake of PR at any dose did not affect uterine weight. The total femoral bone mineral density (BMD) was significantly reduced by OVX, and the decrease in BMD caused by OVX was significantly inhibited by intake of the diet with the low dose of PR and completely prevented by the middle dose of PR. Histological analysis of the femoral metaphysis showed that intake of the diet with the middle dose of PR completely prevented decrease in trabecular bone volume (BV/TV) and trabecular thickness (Tb.Th) and restored the increase in trabecular separation (Tb.Sp) in OVX mice. In contrast, intake of the diet with the high dose of PR further increased BV/TV and Tb.Th and decreased Tb.Sp in OVX mice compared with that in the sham-operated mice. These results suggest that PR may represent a potential alternative medicine for hormone replacement therapy (HRT) in the prevention of osteoporosis in postmenopausal women.

Natural S-equol decreases bone resorption in postmenopausal, non-equol-producing Japanese women: a pilot randomized, placebo-controlled trial.

Objective: Equol is a metabolite of the isoflavone daidzein and may play a critical role in preventing bone loss by soy isoflavones in postmenopausal women. However, results from clinical trials have not been published. The aim of this study was to investigate the effects of equol on bone metabolism and serum sex and thyroid hormone levels in postmenopausal Japanese women. Methods: We performed a 1-year double-blind, randomized, placebo-controlled trial with natural S-equol supplements for 93 non-equol-producing menopausal Japanese women. Participants were randomly assigned to four groups receiving the following: placebo, 2 mg of equol supplement per day, 6 mg of equol supplement per day, and 10 mg of equol supplement per day. Results: Equol intervention increased equol concentrations in serum and urine in a dose-dependent manner. Urinary deoxypyridinoline was significantly decreased, with a −23.94% change in the group that received 10 mg of equol supplement per day as compared with a −2.87% change in the group that received placebo after 12 months of intervention (P = 0.020). Thus, 10 mg/day of equol supplement markedly inhibited bone resorption. Treatment with 10 mg/day of equol prevented a decrease in bone mineral density in the entire body in postmenopausal women after 12 months. Sex and thyroid hormone concentrations in serum did not differ among the four groups after intervention. Conclusions: These findings suggest that 10 mg/day of natural S-equol supplementation contributes to bone health in non-equol-producing postmenopausal women without adverse effects.

Dietary Hesperidin Exerts Hypoglycemic and Hypolipidemic Effects in Streptozotocin-Induced Marginal Type 1 Diabetic Rats

Citrus bioflavonoids may offer some protection against the early stage of diabetes mellitus and the development of complications. We investigated the effect of hesperidin on blood glucose levels, hepatic glucose-regulating enzyme activities, serum insulin and adiponectin levels, serum and hepatic lipid levels, and parameters of bone loss in streptozotocin (STZ)-induced marginal type 1 diabetic rats. Weanling male rats were randomly assigned to experimental 3 groups: a control (C) group, a STZ induced marginal type 1 diabetes (S) group, and a diabetes and hesperidin group, and fed their respective diets for 4 weeks. STZ injection increased blood glucose in rats, but the increase was marginal. Serum and hepatic lipids, serum adiponectin and insulin levels were significantly changed by STZ injection. Dietary hesperidin (10 g/kg diet) decreased blood glucose by altering the activity of glucose-regulating enzymes, and normalized the lipids and adiponectin levels, but did not change bone parameters in the marginal type 1 diabetic rats. Hesperidin showed both hypoglycemic and hypolipidemic effects but did not affect bone tissue and bone metabolic makers in STZ-injected marginal diabetic weanling rats without any body weight loss due to STZ injection.

Hypoglycemic and Hypolipidemic Effects of Hesperidin and Cyclodextrin-Clathrated Hesperetin in Goto-Kakizaki Rats with Type 2 Diabetes

We investigated the hypoglycemic and hypolipidemic effects of two hesperertin glycosides, namely, hesperidin and cyclodextrin (CD)-clathrated hesperetin, in Goto-Kakizaki (GK) weanling rats with type 2 diabetes. We demonstrated that hesperidin and CD-hesperetin normalized glucose metabolism by altering the activities of glucose-regulating enzymes and reducing the levels of lipids in the serum and liver of the GK rats. These effects of hesperidin glycosides were partly produced by altering the expression of genes encoding the peroxisome proliferator-activated receptors, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, and the low-density lipoprotein receptor.

Effects of Geranylgeranoic Acid in Bone: Induction of Osteoblast Differentiation and Inhibition of Osteoclast Formation

Retinoids are known to be of special importance for normal bone growth and development. Recently, we reported that retinoids not only induced osteoblast differentiation, but also inhibited osteoclast formation in vitro. In this study, we examined the osteogenic effects of geranylgeranoic acid (GGA), a chemically synthesized acyclic retinoid, in bone in vitro and in vivo. GGA not only suppressed proliferation of osteoblastic MC3T3‐E1 cells, but also up‐regulated differentiation markers of osteoblasts such as alkaline phosphatase (ALP) activity and expression of osteopontin (OP) messenger RNA (mRNA). In contrast, GGA inhibited osteoclast formation induced by 1α,25‐dihydroxyvitamin D3 [1α,25(OH)2D3] in cocultures of mouse bone marrow cells and primary osteoblasts. Treatment of stromal ST2 cells with GGA restored the 1α,25(OH)2D3‐ or prostaglandin E2 (PGE2)‐induced suppression of osteoprotegerin (OPG) mRNA expression. GGA inhibited osteoclast formation induced by macrophage colony‐stimulating factor (M‐CSF) and soluble receptor activator of nuclear factor κB ligand (sRANKL) in the culture of bone marrow macrophages. Thus, it is likely that GGA inhibits osteoclast formation by affecting both osteoblasts and osteoclast progenitors in the coculture system. Furthermore, in vivo, GGA increased bone mineral density (BMD) of total as well as distal femur in a P6 strain of senescence‐accelerated mice (SAMP6). These results indicate that GGA increases bone mass by maintaining a positive balance of bone turnover by inducing osteoblast differentiation and suppressing osteoclast formation.

Effects of extracted soy isoflavones alone on blood total and LDL cholesterol: Meta-analysis of randomized controlled trials

When provided concurrently with soy protein for 1–3 months, soy isoflavones exert synergistic or additive cholesterol-lowering effects. This meta-analysis was performed to evaluate the effects of extracted soy isoflavones alone (not ingested concurrently with soy protein) on total and low density lipoprotein (LDL) cholesterol. MEDLINE (1966–2007), EMBASE (1966–2007), CENTRAL (1966–2007), ICHUSHI (1983–2008), and CNKI (1979–2007) were searched for randomized placebo-controlled trials published in English, Japanese, and Chinese, describing the changes in lipid profiles in adult humans resulting from ingestion of extracted soy isoflavones for 1–3 months. Reference lists of relevant systematic reviews and meta-analyses were hand-searched. Meta-analysis of 10 and 9 trials with usable information using REVMAN found that an average of 70 mg soy isoflavones/day (27–132 mg, as the aglycone form) alone had a nonsignificant effect on total (0.01 mmol/L [95% CI: –0.12, 0.14]; P = 0.86) and LDL (0.03 mmol/L [95% CI: –0.11, 0.16]; P = 0.71) cholesterol in menopausal women, respectively. It is concluded that ingestion of about 70 mg extracted soy isoflavones/day alone for 1–3 months does not improve total and LDL cholesterol levels in normocholesterolemic menopausal women; further studies are needed to verify the effects of extracted soy isoflavones.