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Biomedical subjects

D Heber

Publications and source records attributed to D Heber.

At least 19 recordsLinked to original sources
PubMed1999

Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial.

CONTEXT: Orlistat, a gastrointestinal lipase inhibitor that reduces dietary fat absorption by approximately 30%, may promote weight loss and reduce cardiovascular risk factors. OBJECTIVE: To test the hypothesis that orlistat combined with dietary intervention is more effective than placebo plus diet for weight loss and maintenance over 2 years. DESIGN: Randomized, double-blind, placebo-controlled study conducted from October 1992 to October 1995. SETTING AND PARTICIPANTS: Obese adults (body mass index [weight in kilograms divided by the square of height in meters], 30-43 kg/m2) evaluated at 18 US research centers. INTERVENTION: Subjects received placebo plus a controlled-energy diet during a 4-week lead-in. On study day 1, the diet was continued and subjects were randomized to receive placebo 3 times a day or orlistat, 120 mg 3 times a day, for 52 weeks. After 52 weeks, subjects began a weight-maintenance diet, and the placebo group (n = 133) continued to receive placebo and orlistat-treated subjects were rerandomized to receive placebo 3 times a day (n = 138), orlistat, 60 mg (n = 152) or 120 mg (n = 153) 3 times a day, for an additional 52 weeks. MAIN OUTCOME MEASURES: Body weight change and changes in blood pressure and serum lipid, glucose, and insulin levels. RESULTS: A total of 1187 subjects entered the protocol, and 892 were randomly assigned on day 1 to double-blind treatment. For intent-to-treat analysis, 223 placebo-treated subjects and 657 orlistat-treated subjects were evaluated. During the first year orlistat-treated subjects lost more weight (mean +/- SEM, 8.76+/-0.37 kg) than placebo-treated subjects (5.81+/-0.67 kg) (P<.001). Subjects treated with orlistat, 120 mg 3 times a day, during year 1 and year 2 regained less weight during year 2 (3.2+/-0.45 kg; 35.2% regain) than those who received orlistat, 60 mg (4.26+/-0.57 kg; 51.3% regain), or placebo (5.63+/-0.42 kg; 63.4% regain) in year 2 (P<.001). Treatment with orlistat, 120 mg 3 times a day, was associated with improvements in fasting low-density lipoprotein cholesterol and insulin levels. CONCLUSIONS: Two-year treatment with orlistat plus diet significantly promotes weight loss, lessens weight regain, and improves some obesity-related disease risk factors.

Adult↗
PubMed1999

Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement.

BACKGROUND: We examined the cholesterol-lowering effects of a proprietary Chinese red-yeast-rice supplement in an American population consuming a diet similar to the American Heart Association Step I diet using a double-blind, placebo-controlled, prospectively randomized 12-wk controlled trial at a university research center. OBJECTIVE: We evaluated the lipid-lowering effects of this red-yeast-rice dietary supplement in US adults separate from effects of diet alone. DESIGN: Eighty-three healthy subjects (46 men and 37 women aged 34-78 y) with hyperlipidemia [total cholesterol, 5.28-8.74 mmol/L (204-338 mg/dL); LDL cholesterol, 3.31-7.16 mmol/L (128-277 mg/dL); triacylglycerol, 0.62-2.78 mmol/L (55-246 mg/dL); and HDL cholesterol 0.78-2.46 mmol/L (30-95 mg/dL)] who were not being treated with lipid-lowering drugs participated. Subjects were treated with red yeast rice (2.4 g/d) or placebo and instructed to consume a diet providing 30% of energy from fat, <10% from saturated fat, and <300 mg cholesterol daily. Main outcome measures were total cholesterol, total triacylglycerol, and HDL and LDL cholesterol measured at weeks 8, 9, 11, and 12. RESULTS: Total cholesterol concentrations decreased significantly between baseline and 8 wk in the red-yeast-rice-treated group compared with the placebo-treated group [(x+/-SD) 6.57+/-0.93 mmol/L (254+/-36 mg/dL) to 5.38+/-0.80 mmol/L (208+/-31 mg/dL); P < 0.001]. LDL cholesterol and total triacylglycerol were also reduced with the supplement. HDL cholesterol did not change significantly. CONCLUSIONS: Red yeast rice significantly reduces total cholesterol, LDL cholesterol, and total triacylglycerol concentrations compared with placebo and provides a new, novel, food-based approach to lowering cholesterol in the general population.

Adult↗
PubMed1998

Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice.

Induction of differentiation and apoptosis in cancer cells through ligands of nuclear hormone receptors (NHRs) is a novel and promising approach to cancer therapy. All-trans-retinoic acid (ATRA), an RA receptor-specific NHR ligand, is now used for selective cancers. The NHR, peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed in breast cancer cells. Activation of PPARgamma through a synthetic ligand, troglitazone (TGZ), and other PPARgamma-activators cause inhibition of proliferation and lipid accumulation in cultured breast cancer cells. TGZ (10(-5) M, 4 days) reversibly inhibits clonal growth of MCF7 breast cancer cells and the combination of TGZ (10(-5) M) and ATRA (10(-6) M, 4 days) synergistically and irreversibly inhibits growth and induces apoptosis of MCF7 cells, associated with a dramatic decrease of their bcl-2 protein levels. Similar effects are noted with in vitro cultured breast cancer tissues from patients, but not with normal breast epithelial cells. The observed apoptosis mediated by TGZ and ATRA may be related to the striking down-regulation of bcl-2, because forced over-expression of bcl-2 in MCF7 cells cultured with TGZ and ATRA blocks their cell death. TGZ significantly inhibits MCF7 tumor growth in triple immunodeficient mice. Combined administration of TGZ and ATRA causes prominent apoptosis and fibrosis of these tumors without toxic effects on the mice. Taken together, this combination may provide a novel, nontoxic and selective therapy for human breast cancers.

Adenocarcinoma↗
PubMed1998

Preadipocytes stimulate breast cancer cell growth.

Mammary fat may affect human breast cancer development. In this study a novel coculture system was used to investigate stromal-epithelial cell interactions in vitro. The extent of differentiation of a feeder layer of 3T3-L1 preadipocytes affected the clonal growth of breast cancer cells under anchorage-independent conditions. When the feeder-layer preadipocytes were proliferating, the clonal growth of estrogen receptor-positive MCF-7 and estrogen receptor-negative MDA-MB-231 and MDA-MB-436 cells was stimulated by 100%, 43%, and 60%, respectively. In contrast, after differentiation the feeder layer of mature adipocytes inhibited clonal growth of breast cancer cell lines by 60%. No clonal growth stimulation of human pancreatic (Panc-1) or prostatic (PC-3) cancer cells was noted when these cells were grown under identical conditions with a proliferating 3T3-L1 cell feeder layer. These findings suggest that proliferating preadipocytes may be associated with factors that specifically stimulate breast cancer cell growth.

3T3 Cells↗
PubMed1997

Dietary modulation of omega-3/omega-6 polyunsaturated fatty acid ratios in patients with breast cancer.

BACKGROUND: Polyunsaturated fatty acids of the omega-6 (omega-6) class, as found in corn and safflower oils, can act as precursors for intermediates involved in the growth of mammary tumors when fed to animals, whereas polyunsaturated fatty acids of the omega-3 (omega-3) class, as found in fish oil, can inhibit these effects. The effects of dietary intervention on the ratios of these fatty acids in breast and other adipose tissues have not previously been prospectively studied. PURPOSE: The present investigation was conducted to study the impact on the ratio of omega-3 and omega-6 polyunsaturated fatty acid in plasma and in adipose tissue of the breast and buttocks when women with breast cancer consume a low-fat diet and fish oil supplements. METHODS: Twenty-five women with high-risk localized breast cancer were enrolled in a dietary intervention program that required them to eat a low-fat diet and take a daily fish oil supplement throughout a 3-month period. Breast and gluteal fat biopsy specimens were obtained from each woman before and after dietary intervention. The fatty acid compositions of specimens of plasma, breast fat, and gluteal fat were determined by gas-liquid chromatography. Statistical analysis involved use of a two-sided paired t test. RESULTS: After dietary intervention, a reduction in the level of total omega-6 polyunsaturated fatty acids in the plasma was observed (P<.0003); moreover, total omega-3 polyunsaturated fatty acids increased approximately three-fold (P<.0001) and the omega-3/omega-6 polyunsaturated fatty acids ratio increased approximately fourfold (i.e., mean values increased from 0.09 to 0.41; P = .0001). An increase in total omega-3 polyunsaturated fatty acids in breast adipose tissue was observed following dietary intervention (P = .04); the omega-3/omega-6 polyunsaturated fatty acid ratio increased from a mean value of 0.05 to 0.07 (P = .0001). An increase in total omega-3 polyunsaturated fatty acids was observed in gluteal adipose tissue following the intervention (P = .05); however, the ratio of omega-3 to omega-6 polyunsaturated fatty acids (mean ratio values of 0.036-0.045; P = .06) was unchanged. CONCLUSION: Short-term dietary intervention can lead to statistically significant increases in omega-3/omega-6 polyunsaturated fatty acid ratios in plasma and breast adipose tissue. Breast adipose tissue changed more rapidly than gluteal adipose tissue in response to the dietary modification tested in this study. Therefore, gluteal adipose tissue may not be a useful surrogate to study the effect of diet on breast adipose tissue.

Adipose Tissue↗
PubMed1997

Effects of potent vitamin D3 analogs on clonal proliferation of human prostate cancer cell lines.

BACKGROUND: Management of prostate cancer that has spread outside of the prostate capsule is a difficult problem. Innovative, non-toxic approaches to the disease are required. New, relatively non-toxic vitamin D3 analogs have recently been synthesized. We report that several of these compounds have marked antiproliferative effects on prostate cells. METHODS: The clonal antiproliferative activity of five novel analogs of 1,25 dihydroxyvitamin D3 [1,25(OH)2D3, (cmpd C)] as well as 1,25(OH)2D3 itself was tested on three human prostate cancer cell lines (PC-3, LNCaP, and DU-145). The analogs were 20-epi-22oxa-24a,26a,27a-tri-homo-1 alpha,25(OH)2D3 (code name: KH 1060); 24a26a27a-tri-homo-22,24-diene-1 alpha,25(OH)2D3 (code name: EB 1089); 1,25(OH)2-16ene-D3 (code name: HM); 1,25(OH)2-16ene-23yne-D3 (code name: V); 1,25(OH)2-20-epi-D3 (code name: MC 1288)]. RESULTS: With the parent compound [1,25(OH)2D3], the effective dose that inhibited 50% clonogenic growth of PC-3 and LNCaP was 10(-8)M and 7 x 10(-9)M, respectively. For these prostate cancer cell lines, KH 1060 was the most potent analog by an order of 25- to 35-fold as compared to cmpd C. The second and third most potent analogs were HM and MC 1288. DU-145 was resistant to all the vitamin D3 analogs. The major side-effect of 1,25(OH)2D3 is the production of hypercalcemia. The relative inhibitory index (RII) was determined by comparing the antiproliferative activity of the analog to its ability to produce hypercalcemia in mice injected intraperitoneally every other day. The KH 1060 had the best RTI: 50- to 70-fold greater than 1,25(OH)2D3 for PC-3 and LNCaP, respectively. CONCLUSIONS: A trial of one or more of these innovative compounds should be considered for treatment of minimal residual disease of prostate cancer.

Animals↗
PubMed1997

NADPH-cytochrome P-450 reductase, cytochrome P-450 2C11 and P-450 1A1, and the aryl hydrocarbon receptor in livers of rats fed methyl-folate-deficient diets.

We investigated three hepatic cytochrome P-450 isozymes and the aryl hydrocarbon (Ah) receptor in rats fed one of the following three diets for 15 months: a diet containing the AIN vitamin mixture (control), the control diet devoid of choline and folate (CFD), or the CFD diet devoid of niacin (CFND). Hepatic tumors developed in all CFD- and CFND-fed rats. Western blot analyses of nontumor hepatic tissue showed that NADPH-cytochrome P-450 reductase (P-450 reductase) increased significantly in the CFD and CFND groups compared with the control group. Hepatic cytochrome P-450 2C11 (CYP2C11) was not detectable in the CFD and CFND groups compared with the control group. Ah receptor and cytochrome P-450 1A1 (CYP1A1) were detected in higher amounts in livers of both deficient groups. CYP1A1 is an enzyme associated with bioactivation of exogenous genotoxins. To our knowledge, this is the first time it has been shown that CYP1A1 and the Ah receptor are induced by dietary deficiencies.

Animals↗
PubMed1996

Effects of novel retinoid X receptor-selective ligands on myeloid leukemia differentiation and proliferation in vitro.

The biologic effects of retinoids such as all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid on proliferation and differentiation of hematopoietic cells are mediated by binding and activating two distinct families of transcription factors: the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). The RARs require heterodimerization with RXRs; in addition, RXRs can form homodimers, which can bind to DNA response elements that are either distinct or the same as those bound by the RAR/RXR heterodimers. Therefore, the two retinoid pathways provide sequences that are specific for effective DNA binding and activation of target genes. We have developed several series of novel synthetic retinoids that selectively interact with RXR/RXR homodimers and RAR/RXR heterodimers. We show here that SR11236 and SR11246, which are RXR-selective analogs, had little ability to inhibit clonal growth and induce differentiation of leukemic cells (HL-60 cells and fresh acute myeloid leukemia cells). However, SR11249, SR11256, and LGD1069, which activated both RXR/RXR homodimers and RAR/RXR heterodimers, could inhibit clonal growth and induce differentiation of HL-60 cells as well as leukemic cells from patients, including those with acute promyelocytic leukemia (APL). This is similar to results observed with RAR/RXR-specific ligands. Interestingly, the combination of ATRA and either SR11249, SR11256, or LGD1069 showed synergistic effects in inducing differentiation of HL-60 cells. A retinoid (SR11238) with strong anti-AP-1 activity that did not activate the RARs and RXRs for gene transcription from the response element TREpal was inactive in our assay systems, suggesting that the antiproliferative effects of retinoids on leukemic cells is not mediated by inhibiting the AP-1 pathway. We conclude that the RAR/RXR pathway is more important than RXR/RXR pathway for differentiation and proliferation of acute myeloid leukemic cells, and certain retinoids or combination of retinoids with both RAR and RXR specificities may synergistically enhance the differentiation activity of ATRA, which may be relevant in several clinical situations.

Bexarotene↗
PubMed1996

Synthesis, opioid receptor affinity, and enzymatic hydrolysis of sterically hindered morphine 3-esters.

With the intention of preparing prodrugs, 10 morphine 3-esters were synthesized and evaluated in vitro for opioid receptor binding and enzymatic hydrolysis. The results of binding assays performed on homogenates of guinea pig brain demonstrate a loss in affinity of morphine to mu-, delta-, and kappa-receptors by esterification at the 3-position. The conversion of the esters to morphine was determined in human plasma by HPLC analysis. The half-lives of hydrolysis ranged from 0.5 to > 300 h. The investigations indicate that esterification at the 3-position results in morphine prodrugs with variable hydrolytic stability. Sterically hindered morphine 3-esters may be a promising approach to manipulate the rate of release of morphine.

Animals↗
PubMed1996

Clinical detection of sarcopenic obesity by bioelectrical impedance analysis.

To assess whether bioelectrical impedance analysis (BIA) provides clinically useful information on body composition beyond that obtained from measuring height and weight, we clinically classified 306 obese patients (233 females and 73 males) into tertiles of increasing fat-free mass estimated by BIA. Because fat-free mass by BIA is an estimate of lean body mass, the lowest tertile was clinically defined as sarcopenic obesity (reduced lean body mass), as contrasted with proportionate or muscular obesity in the next two tertiles. Fat mass in patients in each of the above tertiles based on BIA was then compared with fat mass estimated by using the equations of Garrow and Webster with body mass index (weight/height2). BIA-estimated fat mass was 4.3 kg greater in the sarcopenic group (n = 102) than predicted from body mass index. Fat mass predicted by BIA in the proportionate (n = 102) and muscular (n = 102) groups differed by less than the SEE of fat mass predicted by BMI. In premenopausal women at increased risk of breast cancer BIA showed a high prevalence of sarcopenic obesity (28/30) in these women at normal body mass indexes. Thus, BIA may be clinically useful for demonstrating sarcopenic obesity, but additional studies are needed to determine the metabolic and clinical significance of sarcopenic obesity.

Adipose Tissue↗
PubMed1996

Metabolic effects of triiodothyronine replacement during fasting in obese subjects.

The adaptation to fasting reduces muscle protein breakdown by switching from a carbohydrate to fat fuel economy in normal man. With the discovery of T3 and the observation that its formation from T4 was reduced significantly during starvation, it was proposed that T3 mediated many of these changes. To examine this possibility, otherwise healthy, obese subjects were fasted for 10 days and supplemented with T3 the last 3 days of the fast to bring circulating T3 levels within normal prefasting (weight maintenance) levels. The effects of the same dose of T3 for 3 days were tested during the last 3 days of a 10-day weight maintenance diet for comparison. Both metabolic rate and CO2 production decreased as expected with fasting and did not increase after T3 supplementation. Hepatic glucose appearance rates fell with fasting and increased significantly during T4 supplementation, but not to prefasting levels. Urinary urea nitrogen excretion decreased significantly with fasting and decreased further with T3 supplementation. Lysine appearance did not change during fasting or T3 supplementation, but leucine appearance decreased with T3 supplementation during fasting. These observations suggest that the fall in serum T3 during fasting may not mediate the observed decreases in protein breakdown that occur during fasting and prolonged starvation, but may instead initiate the fall in hepatic glucose appearance.

Adult↗
PubMed1995

Effects of a very low fat, high fiber diet on serum hormones and menstrual function. Implications for breast cancer prevention.

BACKGROUND: Low fat, high fiber dietary interventions that decrease blood estrogen levels may reduce breast cancer risk. Asian women consuming their traditional low fat, high fiber diets have lower blood estrogen levels before and after menopause and lower rates of breast cancer compared with Western women. The current controlled feeding study of premenopausal women was designed to determine the effects of a very low fat (10% of calories) and high fiber (35-45 g/day) diet on blood estrogen levels and menstrual function. METHOD: Twelve healthy premenopausal women with regular ovulatory cycles were followed for 3 months. Subjects consumed a diet providing 30% of their energy from fat and 15-25 g of dietary fiber per day for 1 month, and they consumed a very low fat, high fiber and libitum diet providing 10% of their energy from fat and 25-35 g of dietary fiber per day for 2 months. RESULTS: At the end of the second month of the very low fat, high fiber diet, there was a significant reduction in serum estrone and estradiol levels during the early follicular and late luteal phases. There were no significant changes observed in serum estrone sulfate, sex hormone binding globulin, or progesterone. Despite a significant decrease in serum estradiol and estrone levels after 2 months of a very low fat, high fiber diet, there was no interference with ovulation or the magnitude of the mid-cycle leuteinizing hormone surge. Small changes in menstrual cycle length of up to 3 days were not ruled out due to the small sample size of the study. CONCLUSIONS: A very low fat, high fiber diet in healthy premenopausal women can reduce estradiol and estrone levels without affecting ovulation, thereby providing a rationale for the prevention of breast cancer through a very low fat, high fiber diet.

Adult↗