Antihypertensive Mechanism of Orally Administered Acetylcholine in Spontaneously Hypertensive Rats

Acetylcholine (ACh) acts as a neurotransmitter and neuromodulator. A small dose of eggplant powder rich in ACh (equivalent to 22 g fresh eggplant/d) has been shown to reduce blood pressure (BP) in individuals with higher BP. Here, we investigated the mechanisms underlying the antihypertensive effects of low-dose orally administered ACh in spontaneously hypertensive rats (SHRs). The effects of ACh on BP and sympathetic nervous activity (SNA), including lumbar SNA (LSNA) and renal SNA (RSNA), were evaluated by subjecting conscious SHRs to a telemetry method. Single oral administration of ACh decreased LSNA and lowered BP. Repeated oral administration of ACh for 30 d decreased RSNA and suppressed the elevated BP. Noradrenaline levels in the urine also decreased. However, vagotomy and co-administration of M3 muscarinic ACh receptor antagonist reversed the BP-lowering effect; the dynamics of non-absorbable orally administered ACh was revealed using stable isotope-labeled ACh. In conclusion, ACh acts on the gastrointestinal M3 muscarinic ACh receptor to increase afferent vagal nerve activity, which decreases SNA by autonomic reflex, suppressing noradrenaline release and lowering BP. This study suggests the use of exogenous ACh as an antihypertensive food supplement for controlling the autonomic nervous system, without absorption into the blood.     

口服左氧氟沙星治疗化脓性扁桃体炎疗效分析

目的评价左氧氟沙星治疗急性化脓性扁桃体炎的有效性。方法120例急性化脓性扁桃体炎的患者随机分成两组,试验组给予口服左氧氟沙星片剂500 mg,1次/d;对照组静脉滴注青霉素钠,480万单位/次,2次/d,疗程7~14 d。结果共109例完成试验,试验组57例,临床有效率为92.98%,细菌清除率为87.81%;对照组52例,临床有效率为90.38%,细菌清除率为82.86%,试验组与对照组临床有效率及细菌清除率相比较差异均无统计学意义(P>0.05)。结论口服左氧氟沙星500 mg能有效地治疗急性化脓性扁桃体炎。     

Intratumoral Concentrations and Effects of Orally Administered Micellar Curcuminoids in Glioblastoma Patients

Background: The oral bioavailability of curcuminoids is low, but can be enhanced by incorporation into micelles. The major curcuminoid curcumin has antitumor effects on glioblastoma cells in vitro and in vivo. We therefore aimed to determine intratumoral concentrations and the clinical tolerance of highly bioavailable micellar curcuminoids in glioblastoma patients. Methods: Thirteen glioblastoma patients ingested 70 mg micellar curcuminoids [57.4 mg curcumin, 11.2 mg demethoxycurcumin (DMC), and 1.4 mg bis-demethoxycurcumin (BDMC)] three times per day for 4 days (total amount of 689 mg curcumin, 134 mg DMC, and 17 mg BDMC) prior to planned resection of their respective brain tumors. Tumor and blood samples were taken during the surgery and analyzed for total curcuminoid concentrations. ³¹P magnetic resonance spectroscopic imaging was performed before and after curcuminoid consumption. Results: Ten patients completed the study. The mean intratumoral concentration of curcumin was 56 pg/mg of tissue (range 9–151), and the mean serum concentration was 253 ng/ml (range 129–364). Inorganic phosphate was significantly increased within the tumor (P = 0.034). The mean ratio of phosphocreatine to inorganic phosphate decreased, and the mean intratumoral pH increased (P = 0.08) after curcuminoid intervention. Conclusion: Oral treatment with micellar curcuminoids led to quantifiable concentrations of total curcuminoids in glioblastomas and may alter intratumoral energy metabolism.     

Safety of Purified Isoflavones in Men With Clinically Localized Prostate Cancer

Our purpose was to evaluate the safety of 80 mg of purified isoflavones administered to men with early stage prostate cancer. A total of 53 men with clinically localized prostate cancer, Gleason score of 6 or below, were supplemented with 80 mg purified isoflavones or placebo for 12 wk administered in 2 divided doses of 40 mg to provide a continuous dose of isoflavones. Compliance, changes in plasma isoflavones, and clinical toxicity were analyzed at baseline, 4, and 12 wk. A total of 50 subjects completed the 12-wk intervention. A continuous, divided-dose administration of 80 mg/day of purified isoflavones at amounts that exceeded normal American dietary intakes significantly increased (P < 0.001) plasma isoflavones in the isoflavone-treated group compared to placebo and produced no clinical toxicity. With the current evidence on the cancer preventive properties of isoflavones, these results are significant and offer promise for these phytochemicals to be developed as potent agents to prevent cancer progression.     

Soy Isoflavones in Conjunction With Radiation Therapy in Patients With Prostate Cancer

Soy isoflavones sensitize prostate cancer cells to radiation therapy by inhibiting cell survival pathways activated by radiation. At the same time, soy isoflavones have significant antioxidant and anti-inflammatory activity, which may help prevent the side effects of radiation. Therefore, we hypothesized that soy isoflavones could be useful when given in conjunction with curative radiation therapy in patients with localized prostate cancer. In addition to enhancing the efficacy of radiation therapy, soy isoflavones could prevent the adverse effects of radiation. We conducted a pilot study to investigate the effects of soy isoflavone supplementation on acute and subacute toxicity (≤6 mo) of external beam radiation therapy in patients with localized prostate cancer. Forty-two patients with prostate cancer were randomly assigned to receive 200 mg soy isoflavone (Group 1) or placebo (Group 2) daily for 6 mo beginning with the first day of radiation therapy, which was administered in 1.8 to 2.5 Gy fractions for a total of 73.8 to 77.5 Gy. Adverse effects of radiation therapy on bladder, bowel, and sexual function were assessed by a self-administered quality of life questionnaire at 3 and 6 mo. Only 26 and 27 patients returned completed questionnaires at 3 and 6 mo, respectively. At each time point, urinary, bowel, and sexual adverse symptoms induced by radiation therapy were decreased in the soy isoflavone group compared to placebo group. At 3 mo, soy-treated patients had less urinary incontinence, less urgency, and better erectile function as compared to the placebo group. At 6 mo, the symptoms in soy-treated patients were further improved as compared to the placebo group. These patients had less dripping/leakage of urine (7.7% in Group 1 vs. 28.4% in Group 2), less rectal cramping/diarrhea (7.7% vs. 21.4%), and less pain with bowel movements (0% vs. 14.8%) than placebo-treated patients. There was also a higher overall ability to have erections (77% vs. 57.1%). The results suggest that soy isoflavones taken in conjunction with radiation therapy could reduce the urinary, intestinal, and sexual adverse effects in patients with prostate cancer.     

异黄酮对前列腺癌细胞的激素受体基因表达的影响

[目的] 通过大豆异黄酮的活性物质染料木黄酮和大豆苷元抑制前列腺癌PG-3和LNCaP细胞增殖和对激素基因表达的影响，探讨大豆异黄酮治疗和预防前列腺癌的可能机制。[方法] 0、10、20、40、60、80和160μmol／L剂量组的染料木黄酮和大豆苷元处理前列腺癌细胞，细胞存活率用MTT方法检测，α雌激素受体(ERα)、β雌激素受体(ERβ)、雄激素受体(AR)和血管上皮生长因子(VEGF)等基因的mRNA表达用RT-PCR进行检测。[结果] 染料木黄酮和大豆苷元对PC-3、LNCaP细胞具有明显的抑制生长作用，在160μmol／L的浓度时，染料木黄酮、大豆苷元作用72h后，PC-3细胞的存活率分别为12．28％和44．88％，LNCaP细胞的存活率分别为25．48％和43．14％，其抑制效应具有时间和剂量依赖性，同时发现对．PC-3细胞的VEGF、ERα和ERβ基因表达下调，AR基因处理前后没有检测到；对LNCaP细胞的VEGF和AR基因表达下调，ERα和ERβ的表达并无影响。[结论] 大豆异黄酮能抑制前列腺癌细胞的增殖效应，存在时间和剂量效应关系，雌激素受体基因可能直接在大豆苷元抑制PC-3细胞的增殖中参与作用，而染料木黄酮抑制PC-3细胞和染料木黄酮及大豆苷元抑制LNCaP细胞可能主要是通过Akt通路影响VEGF和AR等基因而实现。     

Glucuronides are the main isoflavone metabolites in women

Three experiments were conducted to characterize the metabolism of isoflavones from soy milk in women: two meals in 2 wk separated by a 1-wk washout period (Experiment 1), one meal feeding (Experiment 2) and six consecutive days of feeding (Experiment 3). Urine and plasma samples were extracted directly or predigested before extraction with H-2 beta-glucuronidase/sulfatase or B-3 beta-glucuronidase so that isoflavone glucuronide and sulfate conjugates could be determined by difference. Among the three experiments, no significant differences were found in the proportion of glucuronide, sulfate and aglycone isoflavones recovered from plasma samples taken 3 h after isoflavone dosing or in 24-h urine samples taken after isoflavone dosing. In the 6-d feeding study, samples taken on d 5 and 6 did not differ significantly in isoflavone content or proportion of the metabolites studied. The percentages of daidzein and genistein glucuronides were 73 +/- 4 and 71 +/- 5% of total daidzein and genistein excreted in urine, and 62 +/- 4 and 53 +/- 6% of total daidzein and genistein present in plasma, respectively. Percentages of aglycone daidzein and genistein were 4 +/- 1 and 5 +/- 1% of total daidzein and genistein in urine, and 18 +/- 2 and 26 +/- 7% of total daidzein and genistein present in plasma, respectively. These studies showed that about one fifth of circulating isoflavones are aglycones. Concentrations of isoflavones chosen for in vitro studies should take this into account. Because the glucuronide isoflavones predominate in vivo, these metabolites should not be overlooked as possible contributors to observed effects of isoflavones.     

A 6-Month Study on the Toxicity of High Doses of Policosanol Orally Administered to Sprague-Dawley Rats

Policosanol is a cholesterol-lowering drug purified from sugar cane. Previous toxicological studies have not demonstrated any policosanol-related toxicity, even with long-term oral administration at 500 mg/kg, a dose 1,724 times larger than the maximal therapeutic dose (20 mg/day) recommended to date. The present study was undertaken to investigate the oral toxicity of policosanol administered for 6 months in doses up to 5,000 mg/kg to Sprague-Dawley rats. Animals were randomly distributed in five groups (15 animals per dose per sex): a control and four groups given oral policosanol (50, 500, 2,500, or 5,000 mg/kg). Eight treated rats (6 males, 2 females) died during the study, five of them (4 males, 1 female) from among those receiving the highest dose (5,000 mg/kg). According to necropsy, all deaths were related to gavage manipulation of higher doses. Although the differences were not significant, body weight gain and food consumption in the groups receiving 2,500 or 5,000 mg/kg tended to be lower than in the control group. Nevertheless, no drug-related toxicity symptoms were detected. Analysis of blood biochemistry, hematology, organ weight ratios, and histopathological findings did not show significant differences compared with controls, nor any tendency with the dose. Therefore, the present study did not show any new evidence of oral toxicity of policosanol, and the findings observed were a consequence of long-term administration by gastric gavage of the highly concentrated suspensions needed to reach the higher doses. It is concluded that policosanol chronically administered by the oral route is safe and that no drug-related toxicity was demonstrated.     

The Impact on Reproduction of an Orally Administered Mixture of Selected PCBs in Zebrafish (Danio rerio)

Zebrafish (Danio rerio) were orally exposed to a mixture of 20 PCBs in three different dose levels (0.008, 0.08, and 0.4 μg of each congener per gram of freeze-dried chironomids). Generally, the PCBs accumulated in a dose-related manner. After 13 weeks of exposure body, liver, and ovary weights, as well as the liver and ovary somatic index, were significantly lower in exposed groups. In addition, the PCB mixture was an effective inducer of hepatic EROD activity. The reproduction study performed with exposed females and unexposed males after 9 weeks revealed that median survival time for larvae was only 7.7 days in the high-dose group as compared with 14 days in controls. Furthermore, egg production was reduced in all three groups exposed. No differences in hatching frequency or median hatching time were recorded. Histologically, females in both the intermediate and high-dose groups contained a reduced number of mature oocytes. The present study demonstrates that the potency of the mixture of selected PCBs induces hepatic EROD activity and has a clearly negative effect on zebrafish reproduction. Received: 7 May 1997/Accepted: 29 November 1997     

Human Milk Oligosaccharides Are Present in Amniotic Fluid and Show Specific Patterns Dependent on Gestational Age

(1) Background: Human milk oligosaccharides (HMOs) are already found in maternal circulation in early pregnancy, changing with gestational age. HMOs are also present in cord blood and amniotic fluid (AF). We aimed to assess HMO profiles in AF over the course of gestation. (2) Methods: AF was collected during diagnostic amniocentesis, fetal surgery, or C-section from 77 women with a gestational age of ranging from 14.3 to 40.9 weeks. Samples were analysed using high performance liquid chromatography with fluorescence detection. (3) Results: We found lactose and up to 16 HMO structures in all AF samples investigated, starting at 14 weeks of gestation. Overall, 3′-sialyllactose (3′SL) and 2′-fucosyllactose (2′FL) were the most abundant HMOs. Individual and total HMO concentrations were significantly positively correlated with gestational age. HMO composition also changed between early, mid- and late pregnancy, with relative concentrations of 3′SL significantly decreasing (44%, 25%, 24%) and 2′FL increasing (7%, 13%, 21%), respectively. (4) Conclusion: Our study shows that HMOs are already present in AF early in pregnancy. This demonstrates extensive contact of the fetus with a broad variety of HMOs, suggesting roles for HMOs in fetal tissue development during the time course of pregnancy.     

Scientific Evidence Supporting the Beneficial Effects of Isoflavones on Human Health

Isoflavones are phenolic compounds with a chemical structure similar to that of estradiol. They are present in several vegetables, mainly in legumes such as soy, white and red clover, alfalfa and beans. The most significant food source of isoflavones in humans is soy-derived products. Isoflavones could be used as an alternative therapy for pathologies dependent on hormonal disorders such as breast and prostate cancer, cardiovascular diseases, as well as to minimize menopausal symptoms. According to the results gathered in the present review, it can be stated that there is scientific evidence showing the beneficial effect of isoflavones on bone health and thus in the prevention and treatment of osteoporosis on postmenopausal women, although the results do not seem entirely conclusive as there are discrepancies among the studies, probably related to their experimental designs. For this reason, the results should be interpreted with caution, and more randomized clinical trials are required. By contrast, it seems that soy isoflavones do not lead to a meaningful protective effect on cardiovascular risk. Regarding cancer, scientific evidence suggests that isoflavones could be useful in reducing the risk of suffering some types of cancer, such as breast and endometrial cancer, but further studies are needed to confirm these results. Finally, isoflavones could be useful in reducing hot flushes associated with menopause. However, a limitation in this field is that there is still a great heterogeneity among studies. Lastly, with regard to isoflavone consumption safety, it seems that they are safe and that the most common adverse effect is mild and occurs at the gastrointestinal level.     

Treatment of Lead Poisoning: A Comparison between the Effects of Sodium Calciumedetate and Penicillamine Administered Orally and Intravenously

In 16 workers with lead poisoning of varying degrees, a comparison was made between the therapeutic efficacy of sodium calciumedetate (Ca-EDTA) and penicillamine (PCA), administered intravenously and orally. The question of comparable dosages of ligands, forming metal complexes in different ways, is discussed. With the dosages given, intravenous Ca-EDTA promoted the greatest output of lead in the urine, followed by intravenous and oral PCA. These three agents also had a very satisfactory effect on the output δ-aminolaevulinic acid (ALA) in urine. Oral Ca-EDTA was found to be greatly inferior in both these respects.

In order to study the absorption of the agents and the renal excretion of the formed lead complexes, the urine was collected quantitatively and fractionated in consecutive 4-hour periods, after which the lead excretion during each period was determined. It was found that the oral absorption of PCA was rapid and quantitatively great, whereas the oral absorption of Ca-EDTA was very slow and quantitatively small. The possible resorption of ligand-lead complexes is discussed and indications were found of resorption of the Ca-EDTA-lead complex but not of the PCA-lead complex. The renal excretion of the different ligand-lead complexes was very effective and reached its maximal level within four hours. However, in some subjects excretion of the Ca-EDTA-lead complex showed some delay. An investigation, in four subjects, of a blocking effect of probenecid on the renal excretion of PCA and/or PCA-lead complexes gave no conclusive results. It is concluded that oral PCA is satisfactory in most cases of lead poisoning. However, in more severe cases intravenous treatment is preferable. Which agent should be chosen, Ca-EDTA or PCA, appears to be unimportant as both are quite satisfactory from the point of view of treatment, but it seems that Ca-EDTA may cause more serious side-effects. Oral Ca-EDTA is quite unsatisfactory and there is good evidence to indicate that the agent causes a resorption of Ca-EDTA-lead complexes from the gastro-intestinal tract.

     

Orally administered isoflavones are present as glucuronides in the human prostate

Better knowledge of the bioavailability and metabolism of isoflavones in prostate tissue is needed to further investigate their mechanisms of action in the context of prostate cancer prevention. A total of 12 men with benign prostatic hyperplasia received soy extract supplementation (3 Evestrel capsules, providing a total of 112.5 mg isoflavones aglycone eq/day) for 3 days before prostate surgery. Blood and prostate tissues were sampled and metabolites were identified using electrospray ionization liquid chromatography tandem mass spectrometry (LC-ESI-MS/MS) and chemically synthesized standards of glucuronidated isoflavones. The main metabolites were the same in prostate tissue and in plasma, namely, 2 monoglucuronides of daidzein and 2 monoglucuronides of genistein. Concentrations of total isoflavones measured in prostate reached 1.05 +/- 0.62 nmol/g tissue (range 0.30-2.23) at the time of sampling, 12 h after the last isoflavone supplementation. At that time point, prostate concentrations were lower than plasma concentrations in all volunteers: 0.47 nmol/g vs. 0.66 microM for daidzein and 0.58 nmol/g vs. 0.78 microM for genistein. Isoflavone mechanisms of action should thus be investigated in in vitro cell studies using physiological conditions, intracellular concentrations below 5 nmol/g and no intracellular deconjugation of the monoglucuronide metabolites.     

Inhibition of α1-Adrenergic,Non-Adrenergic and Neurogenic Human Prostate Smooth Muscle Contraction and of Stromal Cell Growth by the Isoflavones Genistein and Daidzein

Isoflavone-rich legumes, including soy, are used for food production, as dietary supplements and in traditional medicine. Soy consumption correlates negatively with benign prostatic hyperplasia (BPH) and voiding symptoms. However, isoflavone effects on the prostate are hardly known. Here, we examined the effects on human prostate smooth muscle contractions and stromal cell growth, which are driving factors of voiding symptoms in BPH. Smooth muscle contractions were induced in prostate tissues from radical prostatectomy. Growth-related functions were studied in cultured stromal cells (WPMY-1). Neurogenic, α₁-adrenergic and non-adrenergic contractions were strongly inhibited with 50 µM and by around 50% with 10 µM genistein. Daidzein inhibited neurogenic contractions using 10 and 100 µM. Agonist-induced contractions were inhibited by 100 µM but not 10 µM daidzein. A combination of 6 µM genistein with 5 µM daidzein still inhibited neurogenic and agonist-induced contractions. Proliferation of WPMY-1 cells was inhibited by genistein (>50%) and daidzein (<50%). Genistein induced apoptosis and cell death (by seven-fold relative to controls), while daidzein induced cell death (6.4-fold) without apoptosis. Viability was reduced by genistein (maximum: 87%) and daidzein (62%). In conclusion, soy isoflavones exert sustained effects on prostate smooth muscle contractions and stromal cell growth, which may explain the inverse relationships between soy-rich nutrition, BPH and voiding symptoms.     

武汉市前列腺癌的流行病学研究

前列腺癌是欧美国家男性的主要死亡原因，我国还没有全面的发病率和死亡统计资料。为了解我国前列腺癌的流行情况，在武汉市１９９０～１９９２年前列腺癌的发病及死亡报告的基础上，收集了１９９０～１９９５年住院治疗的１０２例前列腺癌现患病例进行了１１配比的病例对照研究。结果显示：武汉市前列腺癌的发病率和死亡率分别为１．３７／１０万和０．７５／１０万，世界人口年平均标化发病率和死亡率分别为１．１０／１０万和０．６６／１０万。泌尿系统病史〔ＯＲ＝５．４２，９５％可信区间（ＣＩ）＝１．５６～１８．８３〕、子女数超过３个（ＯＲ＝２．４３，９５％ＣＩ＝１．１７～５．０２）、青壮年期每周性交超过３次（ＯＲ＝３．３８，９５％ＣＩ＝１．５１～７．５８）、滥用药物（ＯＲ＝４．１１，９５％ＣＩ＝１．６５～１０．２５）、体质指数高（ＯＲ＝２．５８，９５％ＣＩ＝１．３０～５．１１）等是前列腺癌的危险因素，而体力劳动（ＯＲ＝０．３５，９５％ＣＩ＝０．１７～０．７１）、初次遗精年龄晚于１８岁（ＯＲ＝０．２０，９５％ＣＩ＝０．０８～０．５２）等是其保护性因素。     

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.     

铁路公共厕所卫生状况的调查分析

为了解铁路公厕的卫生状况，笔者采用概率分布填表抽样调查的方法对全国１０个铁路局管辖的１００４座公厕进行了实地调查和分析，结果表明；１）水冲式厕所３４９座占３５％，旱式原则所６５５座占６５％。（２）８７％的水冲式厕所分布在二等以上客运车站，７４．４％贩旱厕分布在三及以下车站。（３）水冲式厕所卫生达标率为９１．７％，旱式厕所卫生达标率为３５．９％，４）公厕数量和蹲位不足，卫生设施不健全。这结果提示今后