Biomedical subjects
Publications and source records attributed to David Heber.
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BACKGROUND: In some studies, high calcium intake has been associated with an increased risk of prostate cancer, but no randomized studies have investigated this issue. METHODS: We randomly assigned 672 men to receive either 3 g of calcium carbonate (1,200 mg of calcium), or placebo, daily for 4 years in a colorectal adenoma chemoprevention trial. Participants were followed for up to 12 years and asked periodically to report new cancer diagnoses. Subject reports were verified by medical record review. Serum samples, collected at randomization and after 4 years, were analyzed for 1,25-(OH)2 vitamin D, 25-(OH) vitamin D, and prostate-specific antigen (PSA). We used life table and Cox proportional hazard models to compute rate ratios for prostate cancer incidence and generalized linear models to assess the relative risk of increases in PSA levels. RESULTS: After a mean follow-up of 10.3 years, there were 33 prostate cancer cases in the calcium-treated group and 37 in the placebo-treated group [unadjusted rate ratio, 0.83; 95% confidence interval (95% CI), 0.52-1.32]. Most cases were not advanced; the mean Gleason's score was 6.2. During the first 6 years (until 2 years post-treatment), there were significantly fewer cases in the calcium group (unadjusted rate ratio, 0.52; 95% CI, 0.28-0.98). The calcium risk ratio for conversion to PSA >4.0 ng/mL was 0.63 (95% CI, 0.33-1.21). Baseline dietary calcium intake, plasma 1,25-(OH)2 vitamin D and 25-(OH) vitamin D levels were not materially associated with risk. CONCLUSION: In this randomized controlled clinical trial, there was no increase in prostate cancer risk associated with calcium supplementation and some suggestion of a protective effect.
The prevention of breast cancer through dietary modification is an active area of clinical and epidemiological research. It has been proposed that dietary supplementation of vitamin E may reduce a woman's risk of developing breast cancer. However, the exact mechanism remains unknown. alpha-Tocopherol is the most biologically active form of vitamin E. We investigated the effect of vitamin E (alpha-tocopherol) on breast cancer cell growth. A dose-dependent inhibition of cell proliferation was found in estrogen receptor (ER)-positive cells showing a potent suppression of growth at 100 microM vitamin E in MCF-7 (53%) and T47D (75%) cells. Vitamin E reduced significantly the response of both cell lines to estrogen (10 nM), and cell proliferation was decreased in MCF-7 and T47D cells by 69% and 84%, respectively. No growth inhibition was observed when cells were grown in the absence of estrogen. Vitamin E altered and decreased the growth inhibition induced by tamoxifen (10 microM) in MCF-7 (33%) and T47D (54%) cells. In addition, the immunostaining of ER of MCF-7 cells was reduced by 30% in the presence of vitamin E, suggesting an effect of vitamin E on the expression of ER. This provides evidence that vitamin E may inhibit ER-positive cell growth by altering the cellular response to estrogen.
Investigators have shown that PC-SPES is a potent herbal mixture which has often been used by prostate cancer patients. In this study, we examined the inhibitory effects of certain individual components of PC-SPES on the in vitro proliferation of the human breast cancer cells MDA-MB231 and the human umbilical vein endothelial cells (HUVEC). Our data showed that individual components of PC-SPES had varying suppressive effects on cellular proliferation, and that Rabdosia rubescens appeared to be the most potent agent in these assays. Apoptosis was up-regulated by Rabdosia rubescens, as seen in the caspase-9 and TUNEL assays. These effects may be mediated via both the MAPK (mitogen-activated protein kinase) and the Akt kinase pathways. In mouse experiments, the extract from Rabdosia rubescens suppressed breast cancer xenograft size and decreased the tumor vessel density. We conclude that Rabdosia rubescens may potentially be used to treat or prevent breast cancer, and that the extract from this herbal source deserves further studies.
This study was conducted to investigate chemopreventive effects of Ganoderma lucidum using a unique in vitro human urothelial cell (HUC) model consisted of HUC-PC cells and MTC-11 cells. Ethanol and water extracts of fruiting bodies and spores of the G. lucidum were used to examine growth inhibition, actin polymerization status, and impact of actin remodeling on cell migration and adhesion. Results showed that ethanol extracts had a stronger growth inhibition effect than water extracts. Cell cycle analysis showed that the growth inhibition effect was associated with G2/M arrest. At non-cytotoxic concentrations (40-80 microg/ml), these extracts induced actin polymerization, which in turn inhibited carcinogen 4-aminobiphenyl induced migration in both cell lines. The increased actin polymerization was associated with increased stress fibers and focal adhesion complex formation, however, expression of matrix metalloproteinase-2 and focal adhesion kinase (total and phospholated) were unchanged, which suggests that other mechanisms may be involved.
The growing popularity of botanical dietary supplements (BDS) has been accompanied by concerns regarding the quality of commercial products. Health care providers, in particular, have an interest in knowing about product quality, in view of the issues related to herb-drug interactions and potential side effects. This study assessed whether commercial formulations of saw palmetto, kava kava, echinacea, ginseng and St. John's wort had consistent labeling and whether quantities of marker compounds agreed with the amounts stated on the label. We purchased six bottles each of two lots of supplements from nine manufacturers and analyzed the contents using established commercial methodologies at an independent laboratory. Product labels were found to vary in the information provided, such as serving recommendations and information about the herb itself (species, part of the plant, marker compound, etc.) With regard to marker compound content, little variability was observed between different lots of the same brand, while the content did vary widely between brands (e.g. total phenolic compounds in Echinacea ranged from 3.9-15.3 mg per serving; total ginsenosides in ginseng ranged from 5.3-18.2 mg per serving). Further, the amounts recommended for daily use also differed between brands, increasing the potential range of a consumer's daily dose. Echinacea and ginseng were the most variable, while St. John's wort and saw palmetto were the least variable. This study highlights some of the key issues in the botanical supplement market, including the importance of standardized manufacturing practices and reliable labeling information. In addition, health care providers should keep themselves informed regarding product quality in order to be able to appropriately advise patients utilizing both conventional and herbal medicines.
Cranberries (Vaccinium macrocarpon Ait.) are an excellent dietary source of phytochemicals that include flavonol glycosides, anthocyanins, proanthocyanidins (condensed tannins), and organic and phenolic acids. Using C-18 and Sephadex Lipophilic LH-20 column chromatography, HPLC, and tandem LC-ES/MS, the total cranberry extract (TCE) has been analyzed, quantified, and separated into fractions enriched in sugars, organic acids, total polyphenols, proanthocyanidins, and anthocyanins (39.4, 30.0, 10.6, 5.5, and 1.2% composition, respectively). Using a luminescent ATP cell viability assay, the antiproliferative effects of TCE (200 microg/mL) versus all fractions were evaluated against human oral (KB, CAL27), colon (HT-29, HCT116, SW480, SW620), and prostate (RWPE-1, RWPE-2, 22Rv1) cancer cell lines. The total polyphenol fraction was the most active fraction against all cell lines with 96.1 and 95% inhibition of KB and CAL27 oral cancer cells, respectively. For the colon cancer cells, the antiproliferative activity of this fraction was greater against HCT116 (92.1%) than against HT-29 (61.1%), SW480 (60%), and SW620 (63%). TCE and all fractions showed >/=50% antiproliferative activity against prostate cancer cells with total polyphenols being the most active fraction (RWPE-1, 95%; RWPE-2, 95%; 22Rv1, 99.6%). Cranberry sugars (78.8 microg/mL) did not inhibit the proliferation of any cancer cell lines. The enhanced antiproliferative activity of total polyphenols compared to TCE and its individual phytochemicals suggests synergistic or additive antiproliferative interactions of the anthocyanins, proanthocyanidins, and flavonol glycosides within the cranberry extract.
An isocaloric low-fat diet has been shown to slow androgen-sensitive Los Angeles Prostate Cancer-4 (LAPC-4) tumor growth in a mouse xenograft model. LAPC-4 cells were injected into male severe combined immunodeficient mice. After palpable tumors developed, the mice were divided into three groups, high-fat intact, high-fat castration, and low-fat castration. Tumor latency (18 versus 9 weeks; P < 0.001) and mouse survival (20.8 +/- 1.3 versus 13 +/- 0.7 weeks; P < 0.01) were significantly longer in the low-fat castration versus high-fat castration group. Reduced dietary fat intake delayed conversion from androgen-sensitive to -insensitive prostate cancer and significantly prolonged survival of severe combined immunodeficient mice bearing LAPC-4 xenografts.
BACKGROUND: Ellagic acid (EA) and hydrolyzable ellagitannins (ETs) are dietary polyphenols found in fruits and nuts and implicated with potent antioxidant, anticancer and antiatherosclerotic biological properties. Unfortunately, there are no reports on the bioavailability studies of EA or ETs in the human body. We conducted in vivo studies whereby a human subject consumed pomegranate juice (PJ) (180 ml) containing EA (25 mg) and ETs (318 mg, as punicalagins, the major fruit ellagitannin). METHODS: A rapid plasma extraction procedure utilizing acidic precipitation of proteins, followed by HPLC-UV analyses, was employed. RESULTS: EA was detected in human plasma at a maximum concentration (31.9 ng/ml) after 1 h post-ingestion but was rapidly eliminated by 4 h. The calibration curve for quantification of EA was linear (r2 = 0.9975) over the concentration range from 1000 to 15.6 ng/ml. CONCLUSIONS: Since EA has reportedly strong affinity for proteins and poor absorption in small animals, further studies to investigate whether the presence of free EA in human plasma may be due to its release from the hydrolysis of ETs, facilitated by physiological pH and/or gut microflora action, is warranted. EA can be considered as a biomarker for future human bioavailability studies involving consumption of ETs from food sources.
OBJECTIVES: To investigate the relationship between diet and prostate cancer (CaP) among native Japanese (NJ) and second-generation or third-generation Japanese-American (J-A) men--focusing on the effects of animal fat and soy on prostatic tissues. METHODS: The subjects were 50 Japanese men undergoing radical prostatectomy, 25 NJ living in Nagoya, Japan and 25 U.S.-born J-A men, living in Los Angeles, California. A priori, the NJ men were believed to be a low-fat, high-soy group and the J-A men, a high-fat, low-soy group. The studies included postoperative measurements of diet (Block questionnaire), body fat (bioimpedance), blood, urine, and prostatic biomarkers in malignant and adjacent normal tissue, using a tissue microarray made from the original paraffin blocks. RESULTS: The NJ and J-A men were similar in age (65 to 70 years old; P <0.05), prostate-specific antigen level (7.1 to 8.6 ng/mL), prostate volume (35 to 38 cm3), and Gleason score (5.6 to 6.6), but their body composition differed. J-A men had more body fat (24% versus 19%), higher serum triglyceride levels (245 versus 106 mg/dL), lower estradiol levels (27 versus 31 ng/mL), and much lower urinary soy-metabolite levels (1:3) than NJ men (P <0.02). In both NJ and J-A groups, expression of numerous tissue biomarkers separated normal from CaP tissue, including markers for apoptosis (Bcl-2, caspase-3), growth factor receptors (epidermal growth factor receptor), racemase, 5-lipoxygenase, kinase inhibition (p27), and cell proliferation (Ki-67; all P <0.02). Furthermore, within both normal and CaP tissues, caspase-3 and 5-lipoxygenase were expressed more in NJ than in J-A men (P <0.01). Nuclear morphometry showed that the chromatin in each of the four groups (normal versus CaP, NJ versus J-A) was different (area under the curve 85% to 94%, P <0.01), despite fundamental genetic homogeneity. CONCLUSIONS: NJ and J-A men, products of similar genetics but differing environments, were shown to have differences in body composition that could influence CaP evolution. The CaP specimens from the NJ and J-A men were histologically similar, but tissue biomarker expression, especially of lipoxygenase and the caspase family, suggested differing mechanisms of carcinogenesis. Differences in nuclear morphometry suggested the additional possibility of gene-nutrient interactions.
BACKGROUND: Green and black tea polyphenols have been extensively studied as cancer chemopreventive agents. Many in vitro experiments have supported their strong antioxidant activity. Additional in vivo studies are needed to examine the pharmacokinetic relation of absorption and antioxidant activity of tea polyphenols administered in the form of green or black tea or tea extract supplements. OBJECTIVE: The purpose of this study was to compare the pharmacokinetic disposition of tea polyphenols and their effect on the antioxidant capacity in plasma 8 h after a bolus consumption of either green tea, black tea, or a green tea extract supplement. DESIGN: Thirty healthy subjects were randomly assigned to 3 different sequences of green tea, black tea, or a green tea extract supplement in a 3 x 3 crossover design with a 1-wk washout period in between treatments. RESULTS: Flavanol absorption was enhanced when tea polyphenols were administered as a green tea supplement in capsule form and led to a small but significant increase in plasma antioxidant activity compared with when tea polyphenols were consumed as black tea or green tea. All 3 interventions provided similar amounts of (-)-epigallocatechin-3-gallate. CONCLUSIONS: Our observations suggest that green tea extract supplements retain the beneficial effects of green and black tea and may be used in future chemoprevention studies to provide a large dose of tea polyphenols without the side effects of caffeine associated with green and black tea beverages.
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Many laboratory-based studies have shown that soy can suppress breast cancer proliferation. However, given the recent controversy generated by animal experiments that soy may under certain conditions stimulate breast cancer growth, we decided to carry out a pilot clinical trial in order to elucidate any interaction(s) between short-term isoflavone supplement administration and breast cancer growth. After a core-needle biopsy established the diagnosis of breast cancer, 17 patients were administered soy isoflavone tablets for two weeks. This surgically based study provided the unique opportunity to make objective observations based on human breast cancer tissues and blood obtained prior to and after isoflavone supplement treatment in the same patient. Twenty-six historical control cases with similar characteristics to the experimental patients were selected for comparison. We observed that the apoptosis/mitosis ratios in isoflavone-treated cancer specimens were not significantly different from those of control untreated cancer specimens. Furthermore, there appeared to be a statistically nonsignificant trend towards cancer growth inhibition in the isoflavone treatment group, as manifested by higher apoptosis/mitosis ratios compared with those from the control untreated group. Ex vivo/in vitro assays using serum from breast cancer patients prior to and at the conclusion of soy treatment reveal no significant proliferative changes on both breast cancer cells and endothelial cells. We concluded that the effect of soy on breast cancer deserves further studies in larger clinical trials.
Green tea may prevent cancer, partially by inhibiting tumor angiogenesis. Our previous studies showed that green tea extract was effective in inhibiting breast cancer and endothelial cell proliferation in vitro, and suppressed xenograft size and decreased the tumor vessel density in vivo. Here, we set out to further investigate the molecular mechanisms of this observed angiogenesis suppression. We utilized cDNA microarray technology to profile the global changes in endothelial cellular gene expression in response to green tea. HUVEC (human umbilical vein endothelial cells) were exposed in vitro to green tea for either 6 or 48 h. Only statistically significantly differentially expressed genes were analyzed. Gene profiling demonstrated a global down-regulation of multiple genes involved in endothelial cell growth, signal transduction and oxidation, accompanied by up-regulation of several apoptotic genes. We validated these observations by showing positive correlations with biological assays of cellular proliferation, cell cycle, and apoptosis. The anti-oxidant characteristics of green tea and its metabolites were confirmed in the ORAC (oxygen radical absorbance capacity) assay. cDNA microarray revealed that green tea has an overall suppressive effect on multiple pathways in endothelial cells. This study contributes to the comprehensive analysis of the molecular effects of green tea on endothelial cells, and provides insight into genes that may be important in chemoprevention.
This study was conducted to investigate the anti-proliferative activities of medicinal mushroom Ganoderma lucidum (Rei-shi or Mannentake). We have identified an alcohol extract from the spore of Ganoderma lucidum that inhibits the in vitro proliferation of human umbilical vein endothelial cells and MDA-MB231 human breast cancer cells. Further fractionation of the alcohol extract revealed that the ethyl acetate fraction inhibited both cell lines in a dose-dependent manner from 2 to 40 micro g/ml. Our results suggest that the alcohol extract from the spore of Ganoderma lucidum may possess potential anti-tumor and anti-angiogenic activities.
BACKGROUND: Calcium and vitamin D both appear to have antineoplastic effects in the large bowel. Although these nutrients are inter-related metabolically in bone and in the normal intestine, their potential interactions in large-bowel carcinogenesis are not well understood. METHODS: We assessed independent and joint effects of calcium supplementation and vitamin D status on adenoma recurrence in 803 subjects in a multi-center, placebo-controlled randomized clinical trial of calcium supplementation for the prevention of colorectal adenoma recurrence. Serum levels of 25-hydroxy [25-(OH)] vitamin D and 1,25-dihydroxy [1,25-(OH)2] vitamin D levels were determined, and the Taq I and Fok I polymorphisms in the vitamin D receptor (VDR) gene were analyzed by polymerase chain reaction. Risk ratios (RRs) for any adenoma recurrence were computed for calcium supplementation within groups defined by serum vitamin D levels and for serum vitamin D levels within treatment groups. Associations of VDR polymorphisms with recurrence risk were also evaluated. All statistical tests were two-sided. RESULTS: Among subjects with baseline 25-(OH) vitamin D levels at or below the median (29.1 ng/mL), calcium supplementation was not associated with adenoma recurrence, whereas among those with levels above the median, calcium supplementation was associated with a reduced risk (RR = 0.71, 95 % confidence interval [CI] = 0.57 to 0.89, P for interaction =.012). Conversely, serum 25-(OH) vitamin D levels were associated with a reduced risk only among subjects receiving calcium supplements (RR per 12 ng/mL increase of vitamin D = 0.88, 95% CI = 0.77 to 0.99, P for interaction =.006). VDR polymorphisms were not related to adenoma recurrence and did not modify the associations with vitamin D or calcium. CONCLUSIONS: Calcium supplementation and vitamin D status appear to act largely together, not separately, to reduce the risk of colorectal adenoma recurrence. VDR genotype does not appear to be associated with risk.
Lipopolysaccharide (LPS) injected intraperitoneally (i.p.) is known to decrease food intake. Ghrelin is a peptide hormone produced by the stomach with a potent orexigenic effect and plasma levels that are inversely correlated with the fed state. We examined changes in plasma ghrelin levels 3 h after LPS (100 microg/kg, i.p.) in fasted rats with or without a 1 h re-feeding period. LPS injection decreased the fasting levels of ghrelin by 51+/-5% compared with preinjection values while i.p. vehicle did not modify ghrelin levels in fasted rats. LPS at this dose reduced fasting-induced food intake by 60% compared with the i.p. vehicle group. Re-feeding decreased plasma ghrelin levels by 58+/-3% compared with pre-feeding fasting values in i.p. vehicle group. These data provide the first evidence that LPS shifts fasting ghrelin levels to those observed postprandially.
The opportunities for additional research in this area are plentiful. Unfortunately, there has been relatively limited funding for research on herbal supplements compared with the amount of funding that is available for research on pharmaceuticals. Botanical dietary supplements often contain complex mixtures of phytochemicals that have additive or synergistic interactions. For example, the tea catechins include a group of related compounds with effects that are demonstrable beyond those that are seen with epigallocatechin gallate, the most potent catechin. The metabolism of families of related compounds may be different than the metabolism of purified crystallized compounds. In some cases, herbal medicines may simply be less purified forms of single active ingredients, but in other cases they represent unique formulations of multiple, related compounds that may have superior safety and efficacy compared with single ingredients. Obesity is a global epidemic, and traditional herbal medicines may have more acceptance than prescription drugs in many cultures with emerging epidemics of obesity. Several ethnobotanical studies found herbal treatments for diabetes, and similar surveys, termed bioprospecting, for obesity treatments may be productive. Beyond increasing thermogenesis, there are other biological rationales for the actions of several different alternative medical and herbal approaches to weight loss. For example, several supplements and herbs claim to result in nutrient partitioning so that ingested calories will be directed to muscle, rather than fat. These include an herb (Garcinia cambogia), and a lipid which is the product of bacterial metabolism (conjugated linoleic acid). Moreover, a series of approaches attempt to physically affect gastric satiety by filling the stomach. Fiber swells after ingestion and has was found to result in increased satiety. A binding resin (Chitosan) has the ability to precipitate fat in the laboratory and is touted for its ability to bind fat in the intestines so that it is not absorbed. In double-blind studies, however, this approach was found to be ineffective. There are two key attractions of alternative treatments to obese patients. First, they are viewed as being natural and are assumed by patients to be safer than prescription drugs. Second, there is no perceived need for professional assistance with these approaches. For obese individuals who cannot afford to see a physician, these approaches often represent a more accessible solution. Finally, for many others, these approaches represent alternatives to failed attempts at weight loss with the use of more conventional approaches. These consumers are often discouraged by previous failures, and are likely to combine approaches or use these supplements at doses higher than are recommended. It is vital that the primary care physician is aware of the herbal preparations that are being used by patients so that any potential interaction with prescription drugs or underlying medical conditions can be anticipated. Unfortunately, there have been several instances where unscrupulous profiteers have plundered the resources of the obese public. Although Americans spend $30 billion per year on weight loss aids, our regulatory and monitoring capability as a society are woefully inadequate. Without adequate resources, the FDA resorted to "guilt by association" adverse events reporting, which often results in the loss of potentially helpful therapies without adequate investigation of the real causes of the adverse events that are reported. Scientific investigations of herbal and alternative therapies represent a potentially important source for new discoveries in obesity treatment and prevention. Cooperative interactions in research between the Office of Dietary Supplements, the National Center for Complementary and Alternative Medicine, and the FDA could lead to major advances in research on the efficacy and safety of the most promising of these alternative approaches.