Soy food and isoflavone intake and endometrial cancer risk: the Japan Public Health Center-based prospective study.

OBJECTIVE: Compared with western populations, the consumption of soy foods among Japanese is very high and the incidence of endometrial cancer very low. We evaluated the association of soy food and isoflavone intake with endometrial cancer risk in Japanese women. DESIGN: Prospective cohort study. SETTING: Ten public health centre areas in Japan. POPULATION: Forty nine thousand one hundred and twenty-one women of age 45-74 years who responded to a 5-year follow-up survey questionnaire. METHODS: Intakes of soy foods as well as other covariates were assessed in 1995-1998 by a self-administered food frequency questionnaire. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). MAIN OUTCOME MEASURE: Incidence of endometrial cancer. RESULTS: During an average of 12.1 years of follow up, 112 newly diagnosed endometrial cancer cases were identified. Energy-adjusted intakes of soy food and isoflavone were not associated with the risk of endometrial cancer. The multivariate-adjusted HR per 25 g/day increase in the intake of soy food was 1.02 (95% CI 0.94-1.10), and the corresponding value for isoflavone intake per 15 mg/day was 1.01 (95% CI 0.84-1.22). CONCLUSION: In this population-based prospective cohort study of Japanese women, we observed no evidence of a protective association between soy food or isoflavone intake and endometrial cancer risk.

Green tea consumption and gastric cancer in Japanese: a pooled analysis of six cohort studies.

BACKGROUND: Previous experimental studies have suggested many possible anti-cancer mechanisms for green tea, but epidemiological evidence for the effect of green tea consumption on gastric cancer risk is conflicting. OBJECTIVE: To examine the association between green tea consumption and gastric cancer. METHODS: We analysed original data from six cohort studies that measured green tea consumption using validated questionnaires at baseline. Hazard ratios (HRs) in the individual studies were calculated, with adjustment for a common set of variables, and combined using a random-effects model. RESULTS: During 2 285 968 person-years of follow-up for a total of 219 080 subjects, 3577 cases of gastric cancer were identified. Compared with those drinking <1 cup/day, no significant risk reduction for gastric cancer was observed with increased green tea consumption in men, even in stratified analyses by smoking status and subsite. In women, however, a significantly decreased risk was observed for those with consumption of > or =5 cups/day (multivariate-adjusted pooled HR = 0.79, 95% confidence interval (CI) = 0.65 to 0.96). This decrease was also significant for the distal subsite (HR = 0.70, 95% CI = 0.50 to 0.96). In contrast, a lack of association for proximal gastric cancer was consistently seen in both men and women. CONCLUSIONS: Green tea may decrease the risk of distal gastric cancer in women.

No association between green tea and prostate cancer risk in Japanese men: the Ohsaki Cohort Study.

In a prospective study of 19,561 Japanese men, green-tea intake was not associated with a lower risk of prostate cancer (110 cases), the multivariate hazard ratio for men drinking > or =5 cups compared with <1 cup per day being 0.85 (95% confidence interval 0.50-1.43, trend P = 0.81).

Inhibition of root elongation in microgravity by an applied electric field.

Roots grown in an applied electric field demonstrate a bidirectional curvature. To further understand the nature of this response and its implications for the regulation of differential growth, we applied an electric field to roots growing in microgravity. We found that growth rates of roots in microgravity were higher than growth rates of ground controls. Immediately upon application of the electric field, root elongation was inhibited. We interpret this result as an indication that, in the absence of a gravity stimulus, the sensitivity of the root to an applied electric stimulus is increased. Further space experiments are required to determine the extent to which this sensitivity is shifted. The implications of this result are discussed in relation to gravitropic signaling and the regulation of differential cell elongation in the root.

Role of the sympathetic nervous system and insulin in enhancing glucose uptake in peripheral tissues after intrahypothalamic injection of leptin in rats.

Our previous study demonstrated that microinjection of leptin into the ventromedial hypothalamus (VMH) dramatically increased glucose uptake in the heart, brown adipose tissue (BAT), and skeletal muscles, but not in white adipose tissue (WAT) in conscious unrestrained rats, as assessed in vivo by the 2-[3H]deoxyglucose method. Here we examined the role of the sympathetic nervous system and insulin in enhanced glucose uptake by tissues after hypothalamic leptin injection. Pretreatment with guanethidine significantly suppressed the increased glucose uptake by the tissues in response to leptin injected into the VMH, whereas bilateral adrenal demedullation had no significant effect. Treatment with propranolol but not phenoxybenzamine also decreased significantly enhanced glucose uptake by the tissues. We further examined the interaction of the effects of hypothalamic leptin and insulin administered peripherally by clamping the glucose concentrations at a constant level. When leptin was injected into the VMH and a maximal dose of insulin was administered intravenously, the rates of glucose uptake by the heart, BAT, and skeletal muscles, but not by WAT, markedly increased beyond the values reached by insulin stimulation alone. Surgical sympathetic denervation of BAT abolished the enhancement of glucose uptake in this tissue, decreasing to the level stimulated by insulin alone. These results appear to indicate that leptin in the hypothalamus enhances glucose uptake in certain peripheral tissues through mediation of a beta-adrenergic mechanism for the sympathetic nerves innervating the tissues and that central leptin and peripheral insulin have a synergistic role in augmenting tissue glucose uptake.

Does growth hormone augment brain edema caused by brain injury? A study with a freeze brain injury model in the rat.

OBJECTIVE: Because of the known sodium and water retention associated with growth hormone (GH) therapy, it is crucial to evaluate the safety of GH after brain injury. To clarify this issue, we investigated whether GH affects brain edema in a rat brain freeze-injury model. METHODS: Male Wistar rats (n = 29) were divided into four groups according to the substance injected (GH vs. normal saline) and whether the brain was injured or not. The subcutaneous injections of GH (0.8 IU/kg) or saline were given 24 hours apart. In the injury groups, after the second injection, an aluminum rod (4-mm diameter) cooled to -50 degrees C was placed on the exposed dura mater in the right parietal region for 4 minutes, under anesthesia. At 4 hours after the insult, brain and skeletal muscle were excised and their water content was measured by drying. RESULTS: Freeze injury of the brain caused an increase in water and sodium content in skeletal muscle. GH injection augmented this edema in skeletal muscle. Freeze injury of the brain also caused an increase in water and sodium content in the injured hemisphere of the brain. GH injection did not exacerbate this edema in injured brain tissue. Neither freeze injury nor GH injection caused brain edema in the noninjured hemisphere or in the cerebellum. CONCLUSION: GH administration did not augment brain edema caused by brain injury in our model.

Inhibition of root elongation in microgravity by an applied electric field.

Roots grown in an applied electric field demonstrate a bidirectional curvature. To further understand the nature of this response and its implications for the regulation of differential growth, we applied an electric field to roots growing in microgravity. We found that growth rates of roots in microgravity were higher than growth rates of ground controls. Immediately upon application of the electric field, root elongation was inhibited. We interpret this result as an indication that, in the absence of a gravity stimulus, the sensitivity of the root to an applied electric stimulus is increased. Further space experiments are required to determine the extent to which this sensitivity is shifted. The implications of this result are discussed in relation to gravitropic signaling and the regulation of differential cell elongation in the root.

Role of the hypothalamus in insulin-independent glucose uptake in peripheral tissues.

To clarify the role of the ventromedial hypothalamus (VMH)-sympathetic nervous system in insulin-independent glucose uptake in peripheral tissues, tissue glucose uptake was assessed in vivo by the 2-[3H]deoxyglucose method during electrical stimulation of the VMH in anesthetized rats. VMH stimulation significantly increased the rate constant of glucose uptake in brown adipose tissue (BAT), heart and skeletal muscles, but not in white adipose tissue and brain. The effect of VMH stimulation on glucose uptake in BAT was abolished by local sympathetic denervation, indicating that the increase in glucose uptake is mediated by the sympathetic nerves. Electrical stimulation of the lateral hypothalamus, on the other hand, had no appreciable effects on 2-[3H]deoxyglucose uptake in any tissues. Changes in glucose transporters after VMH stimulation were also examined by the [3H]cytochalasin B binding method using sarcolemmal membranes isolated from heart muscle. Scatchard analysis of cytochalasin B binding indicated that VMH stimulation did not alter both the number and affinity (dissociation constant) of glucose transporters in the heart sarcolemmal membranes, whereas insulin administration increased the number of transporters in the membranes. These results suggest that the mechanism by which VMH stimulation increases glucose uptake in muscle is different from that of insulin.

Effects of ventromedial and lateral hypothalamic stimulation on chemically-induced liver injury in rats.

The effects of hypothalamic stimulation on experimental liver injury induced by carbon tetrachloride (CCl4) or dimethylnitrosamine (DMN) were studied in rats, by measuring plasma alanine aminotransferase (ALT) activity as an index of acute liver injury. Electrical stimulation of the ventromedial hypothalamus (VMH) in CCl4-treated rats caused a marked increase in plasma ALT activity, accompanied by a significant decrease in ALT activity in the liver, although CCl4 treatment alone had no significant effect on plasma ALT activity. A similar effect of VMH stimulation on plasma ALT activity was observed in rats treated with DMN, another hepatotoxic chemical. No such exaggerated effect of VMH stimulation on plasma ALT activity was observed after stimulation of the lateral hypothalamic area (LH). Surgical sympathetic denervation of the liver greatly suppressed the increase in plasma ALT activity after CCl4 injection and VMH stimulation. Measurement of regional blood flow indicated that VMH stimulation did not produce a significant change in blood flow to the liver. These results suggest that the VMH is involved in the progress of chemically-induced liver injury through activation of the sympathetic nerve (hepatic nerves), possibly by affecting liver metabolism more than the blood flow change to the liver.

Hypothalamic regulation of lipid metabolism in the rat: effect of hypothalamic stimulation on lipogenesis.

The rates of fatty acid synthesis and syntheses of other lipids were measured in vivo by determining 3H-incorporation from tritiated water or 14C-incorporation from [U-14C]glucose into white adipose tissues (WAT), brown adipose tissue (BAT) and liver, during electrical stimulation of the ventromedial hypothalamic nucleus (VMH) and the lateral hypothalamic nucleus (LH) of female rats. Electrical stimulation of the VMH markedly increased the rate of fatty acid synthesis and the conversion of glucose to total lipids, glyceride glycerol and phospholipids in interscapular BAT, but not in parametrial or retroperitoneal WAT. Conversely, on VMH stimulation, the syntheses of total lipids, glyceride glycerol and phospholipids from glucose in the liver decreased slightly, though not significantly. Electrical stimulation of the LH had no such effect. Administration of insulin increased the rate of fatty acid synthesis in both brown and white adipose tissues and in the liver. The rate of disappearance of [14C]glucose and the concentration of insulin in the blood were not changed significantly by stimulation of the VMH. These data indicate that electrical stimulation of the VMH, but not the LH, enhances lipogenesis in BAT preferentially through a mechanism not involving insulin, but probably through activation of sympathetic innervation of BAT. The physiological significance of the findings is discussed in relation to hypothalamic function in controlling non-shivering thermogenesis and obesity.

Effects of acetylcholine injection into the hypothalamus on the insulin and glucagon release.

To evaluate the role of cholinergic neurones within the hypothalamus in modulating pancreatic-endocrine function, plasma levels of glucagon, insulin and glucose were measured after microinjection of acetylcholine into the ventromedial hypothalamic nucleus (VMH) of rabbits. Injection of acetylcholine (5 X 10(-8) mol in 2 microliter of saline) into the VMH of unanesthetized, unrestrained animals resulted in a prompt elevation of immunoreactive glucagon and glucose levels without any significant change in immunoreactive insulin level. The suppression of insulin secretion following cholinergic stimulation of the VMH was not counteracted by intravenous infusion of glucose (0.25 g/kg). Bilateral adrenalectomy prevented both hyperglucagonemia and hyperglycemia induced by the acetylcholine injection into the VMH. In adrenalectomized rabbits, exogenous glucose load was followed by a significant rise in the plasma insulin level despite the hypothalamic injection of acetylcholine. However, the response of insulin release to glucose load in these animals was much less than in adrenalectomized, saline-treated, control animals. These data support the conclusion that the action of acetylcholine within the hypothalamus on the pancreatic hormone secretions is mediated to a large part through sympatho-adrenomedullary activity. However, a part of the decreased insulin response to glucose may be mediated by direct innervation of the pancreas.

Hypothalamic regulation of lipid metabolism in the rat: effect of hypothalamic stimulation on lipolysis.

In unanesthetized rats, electrical stimulation of the ventromedial hypothalamic nucleus (VMH) induced a marked increase in plasma concentration of glycerol, but did not increase the plasma free fatty acid (FFA) concentration, probably owing to a great elevation of plasma lactate which might inhibit the release of FFA from adipose tissue. In anesthetized rats, on stimulation of the VMH there was no remarkable increase in the plasma lactate, and the plasma glycerol and FFA concentrations were both elevated markedly. Electrical stimulation of the lateral hypothalamic nucleus (LH), on the other hand, had no significant effects on plasma glycerol and FFA levels. Bilateral adrenodemedullation did not prevent the lipolytic response to VMH stimulation, although it reduced slightly the increment of plasma glycerol and FFA. However, the lipolytic response was completely blocked by previous treatment of the animals with hexamethonium or propranolol, but not with phentolamine. These results suggest that sympathetic innervation of the adipose tissue is the dominant factor involved in VMH-induced lipolysis in the rat, while the role of the adrenal medulla is subdominant; the effect of VMH stimulation is mainly transmitted through the sympathetic nervous system to beta-adrenergic receptor of the adipose tissue.

Central nervous system regulation of liver and adipose tissue metabolism.

Hypothalamic and autonomic nervous regulation of carbohydrate and amino acid metabolism in the liver and of lipid metabolism in adipose tissues is described. The direct neural mechanism underlying this regulation has been evaluated. Electrical stimulation of the ventromedial hypothalamic nucleus (VMH)-splanchnic nerve system causes glycogenolysis in the liver by rapid activation of glycogen phosphorylase, whereas electrical stimulation of the lateral hypothalamic nucleus (LH)-vagus nerve system promotes glycogenesis in the liver by activation of glycogen synthetase, through direct neural and neural-hormonal mechanisms. Studies on chemical coding of the hypothalamic neurones have revealed that norepinephrine-sensitive neurones in the VMH and acetylcholine-sensitive neurones in the LH are specifically involved in the regulation of liver phosphorylase and glycogen synthetase, respectively. Acetylcholine-sensitive neurones of the LH were also found to be concerned in regulation of hepatic tyrosine and aminotransferase activity, through intermediation of the cholinergic system in the LH-vagal pathway. Finally, it has been shown that the VMH acts as a regulatory centre for lipolysis in adipose tissues by modulating activation of the sympathetic nervous system. In addition, stimulation of the VMH enhanced lipogenesis in brown adipose tissue preferentially, probably through a mechanism mediated by sympathetic innervation of this tissue. The latter finding suggests that both the breakdown and resynthesis of triglycerides in brown adipose tissue, but not in white adipose tissue, are accelerated by stimulation of the VMH.