Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D3.
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BACKGROUND: The secosteroid 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) acts through the vitamin D receptor (VDR) to elicit many activities that make it a promising drug candidate for the treatment of a number of diseases, including cancer and psoriasis. Clinical use of 1,25(OH)2D3 has been limited by hypercalcemia elicited by pharmacologically effective doses. We hypothesized that structurally distinct, nonsecosteroidal mimics of 1,25(OH)2D3 might have different activity profiles from vitamin D analogs, and set out to discover such compounds by screening small-molecule libraries. RESULTS: A bis-phenyl derivative was found to activate VDR in a transactivation screening assay. Additional related compounds were synthesized that mimicked various activities of 1,25(OH)2D3, including growth inhibition of cancer cells and keratinocytes, as well as induction of leukemic cell differentiation. In contrast to 1, 25(OH)2D3, these synthetic compounds did not demonstrate appreciable binding to serum vitamin D binding protein, a property that is correlated with fewer calcium effects in vivo. Two mimics tested in mice showed greater induction of a VDR target gene with less elevation of serum calcium than 1,25(OH)2D3. CONCLUSIONS: These novel VDR modulators may have potential as therapeutics for cancer, leukemia and psoriasis with less calcium mobilization side effects than are associated with secosteroidal 1,25(OH)2D3 analogs. (+info)
Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice.
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BACKGROUND: Extracellular matrix synthesis and degradation contribute to the morphological changes that occur after myocardial infarction (MI). METHODS AND RESULTS: We tested the hypothesis that inhibition of matrix metalloproteinases (MMPs) attenuates left ventricular remodeling in experimental MI. Seventy-one male FVB mice that survived ligation of the left anterior coronary artery were randomized to a broad-spectrum MMP inhibitor (CP-471,474) or placebo by gavage. Echocardiographic studies were performed before randomization (within 24 hours of surgery) and 4 days later and included short-axis imaging at the midpapillary and apical levels. Infarction as defined by wall motion abnormality was achieved in 79% of the procedures (n=56), and mortality rate during the 4-day protocol was 23% (9 of 36 on treatment vs 7 of 35 on placebo; P=NS). Baseline end-diastolic and end-systolic dimensions and areas were similar (P=NS) between treated and placebo groups. At follow-up, infarcted mice allocated to MMP inhibitor had significantly smaller increases in end-systolic and end-diastolic dimensions and areas at both midpapillary and apical levels compared with infarcted mice allocated to placebo (all P<0.05). In addition, infarcted animals that received MMP inhibitor had no change in fractional shortening (-3+/-13%), whereas animals that received placebo had a decrease in fractional shortening (-12+/-12%) (P<0.05). In an analysis stratified by baseline end-diastolic area, the effects of MMP inhibition on the changes in end-systolic area and end-diastolic area were most prominent in animals that had more initial left ventricular dilatation (both P<0.05). CONCLUSIONS: -Administration of an MMP inhibitor attenuates early left ventricular dilation after experimental MI in mice. Further studies in genetically altered mice and other models will improve understanding of the role of MMPs in left ventricular remodeling. (+info)
Flame retardant exposure: polybrominated diphenyl ethers in blood from Swedish workers.
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Polybrominated diphenyl ethers (PBDEs) are used as additives in polymers and textiles to prohibit the development of fires. Because of the production and use of PBDEs, their lipophilic characteristics, and persistence, these compounds have become ubiquitous environmental contaminants. The aim of the present study was to determine potential exposures of PBDEs to clerks working full-time at computer screens and personnel at an electronics-dismantling plant, with hospital cleaners as a control group. Five PBDE congeners--2,2',4,4'-tetraBDE; 2,2',4,4',5,5'-hexaBDE; 2,2',4,4',5, 6'-hexaBDE; 2,2',3,4,4',5',6-heptaBDE; and decaBDE--were quantified in blood serum from all three categories of workers. Subjects working at the dismantling plant showed significantly higher levels of all PBDE congeners in their serum as compared to the control group. Decabromodiphenyl ether is present in concentrations of 5 pmol/g lipid weight (lw) in the personnel dismantling electronics; these concentrations are comparable to the concentrations of 2,2',4, 4'-tetraBDE. The latter compound was the dominating PBDE congener in the clerks and cleaners. The major compound in personnel at the dismantling plant was 2,2',3,4,4',5',6-heptaBDE. Concentrations of this PBDE congener are almost twice as high as for 2,2',4, 4'-tetraBDE in these workers and seventy times the level of this heptaBDE in cleaners. The total median PBDE concentrations in the serum from workers at the electronics-dismantling plant, clerks, and cleaners were 37, 7.3, and 5.4 pmol/g lw, respectively. The results show that decabromodiphenyl ether is bioavailable and that occupational exposure to PBDEs occurs at the electronics-dismantling plant. (+info)
Vitamin A decreases the incidence and severity of nitrofen-induced congenital diaphragmatic hernia in rats.
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Congenital diaphragmatic hernia (CDH) is a major cause of refractory respiratory failure in the newborn. Pulmonary hypoplasia often limits survival. Vitamin A (Vit A) is an important signal for lung growth. We hypothesized that antenatal treatment with Vit A would stimulate lung growth and decrease mortality in experimental CDH induced in rats by ingestion of the herbicide nitrofen (2, 4-dichlorophenyl-p-nitrophenyl ether). Nitrofen was administered to pregnant rats on day 12 of gestation (term 22 days). Rats were assigned to five groups: three groups received one dose of oral antenatal Vit A (15,000 IU) before (day 10), concomitant with (day 12), or after (day 14) nitrofen administration; one group received only nitrofen; and a control group received vehicle (olive oil). The incidence of CDH was markedly lower in all groups receiving Vit A (day 10, 44%; day 12, 20%; and day 14, 40%) compared with the nitrofen-treated group (84%; P < 0.05). The 72-h survival was higher in all 3 Vit A-treated groups (day 10, 40%; day 12, 58%; and day 14, 70%) compared with the nitrofen-treated group (16%; P < 0.05). Lung-to-body weight ratio and radial saccular count were significantly increased by Vit A. Antenatal treatment with Vit A lowers the incidence and severity of experimental CDH and increases lung growth and maturation. (+info)
Fetal tracheal occlusion in the rat model of nitrofen-induced congenital diaphragmatic hernia.
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Prenatal tracheal occlusion (TO) consistently accelerates lung growth in the sheep model of congenital diaphragmatic hernia (CDH). However, significant variability in lung growth has been observed in early clinical trials of TO. We hypothesized that lung hypoplasia created at relatively late stages of lung development may not be equivalent to human CDH-induced lung hypoplasia, which begins early in gestation. To test this hypothesis, we performed TO in the rat model of nitrofen-induced CDH. Left-sided CDH was induced by administering 100 mg of nitrofen to timed pregnant rats on day 9 of gestation. On day 19 of gestation, four to five fetuses per dam underwent surgical ligation of the trachea. At death (day 21.5), lungs from non-CDH (non-CDH group), left-CDH (CDH group), and trachea-occluded left-CDH fetuses (CDH-TO group) were harvested and compared by weight, DNA and protein content, and stereological morphometry. Wet and dry lung weight-to-body weight ratio, total lung DNA and protein contents, the volume of lung parenchyma, and the total saccular surface area of the CDH-TO group were significantly increased relative to the CDH group and were either greater than or comparable to the non-CDH controls. We conclude that TO accelerates lung growth and increases lung parenchyma in an early-onset model of CDH-induced lung hypoplasia. (+info)
Selective inhibition of sweetness by the sodium salt of +/-2-(4-methoxyphenoxy)propanoic acid.
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The purpose of this study was to determine the degree to which the sodium salt of +/-2-(4-methoxyphenoxy)propanoic acid (Na-PMP) reduced sweet intensity ratings of 15 sweeteners in mixtures. Na-PMP has been approved for use in confectionary/frostings, soft candy and snack products in the USA at concentrations up to 150 p.p.m. A trained panel evaluated the effect of Na-PMP on the intensity of the following 15 sweeteners: three sugars (fructose, glucose, sucrose), three terpenoid glycosides (monoammonium glycyrrhizinate, rebaudioside-A, stevioside), two dipeptide derivatives (alitame, aspartame), two N-sulfonylamides (acesulfame-K, sodium saccharin), two polyhydric alcohols (mannitol, sorbitol), 1 dihydrochalcone (neohesperidin dihydrochalcone), one protein (thaumatin) and one sulfamate (sodium cyclamate). Sweeteners were tested at concentrations isosweet with 2.5, 5, 7.5 and 10% sucrose in mixtures with two levels of Na-PMP: 250 and 500 p.p.m. In addition, the 15 sweeteners were tested either immediately or 30 s after a pre-rinse with 500 p.p.m. Na-PMP. In mixtures, Na-PMP at both the 250 and 500 p.p.m. levels significantly blocked sweetness intensity for 12 of the 15 sweeteners. However, when Na-PMP was mixed with three of the 15 sweeteners (monoammonium glycyrrhizinate, neohesperidin dihydrochalcone and thaumatin), there was little reduction in sweetness intensity. Pre-rinsing with Na-PMP both inhibited and enhanced sweetness with the greatest enhancements found for monoammonium glycyrrhizinate, neohesperidin dihydrochalcone and thaumatin, which were not suppressed by Na-PMP in mixtures. The mixture data suggest that Na-PMP is a selective competitive inhibitor of sweet taste. The finding that pre-treatment can produce enhancement may be due to sensitization of sweetener receptors by Na-PMP. (+info)
Phase II trial of N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine.HCl and doxorubicin chemotherapy in metastatic breast cancer: A National Cancer Institute of Canada clinical trials group study.
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PURPOSE: This multicenter phase II trial investigated the efficacy and toxicity of a combination of the novel intracellular histamine antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine.HCl (DPPE), and doxorubicin in patients with anthracycline-naive metastatic breast cancer. Preclinical models and early single institutional studies suggested DPPE could potentiate the cytotoxicity of doxorubicin. PATIENTS AND METHODS: Forty-two women, 32 to 77 years old (median, 59 years), with anthracycline-naive metastatic breast cancer were treated. Patients may have had one previous regimen of nonanthracycline chemotherapy, either in the adjuvant or metastatic disease treatment setting. DPPE (6 mg/kg) was administered as an 80 minute intravenous infusion with doxorubicin (60 mg/m(2)) given intravenously over the last 20 minutes of the DPPE infusion. Patients were premedicated with an antiemetic and sedating regimen. The DPPE/doxorubicin treatment was given every 21 days for a maximum of seven cycles. RESULTS: All 42 patients were assessable. Overall, toxicity was comparable to that expected with doxorubicin alone, with the exception of DPPE-related motion sickness, mild hallucinations, and cerebellar signs at the time of the infusion. These CNS side effects were manageable in an ambulatory care setting, improved with subsequent cycles of treatment, and did not usually require hospitalization. Four patients developed febrile neutropenia. Thirty-five patients received four or more cycles of chemotherapy. The overall response rate was 52.5% (95% confidence interval, 36% to 68%), with 9.5% complete responses (n = 4), 43% partial responses (n = 18), and 38% of patients with stable disease (n = 16). CONCLUSION: The antitumour effects of DPPE/doxorubicin the 52.5% response rate seems encouraging, particularly in consideration of the fact that a recently reported randomized National Cancer Institute of Canada Clinical Trials Group trial using single-agent doxorubicin 60 mg/m(2) in one of the treatment arms achieved a 31% response rate. Thus, a randomized phase III trial of doxorubicin versus doxorubicin plus DPPE is being conducted in this clinical setting. (+info)
Bastadin 10 stabilizes the open conformation of the ryanodine-sensitive Ca(2+) channel in an FKBP12-dependent manner.
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The marine sponge Ianthella basta synthesizes at least 25 tetrameric bromotyrosine structures that possess a stringent structural requirement for modifying the gating behavior of ryanodine-sensitive Ca(2+) channels (ryanodine receptors) (RyR)). Bastadin 5 (B5) was shown to stabilize open and closed channel states with little influence on the sensitivity of the channel to activation by Ca(2+) (Mack, M. M., Molinski, T. F., Buck, E. D., and Pessah, I. N. (1994) J. Biol. Chem. 269, 23236-23249). In the present paper, we utilize single channel analysis and measurements of Ca(2+) flux across the sarcoplasmic reticulum to identify bastadin 10 (B10) as the structural congener responsible for dramatically stabilizing the open conformation of the RyR channel, possibly by reducing the free energy associated with closed to open channel transitions (DeltaG*c --> o). The stability of the channel open state induced by B10 sensitized the channel to activation by Ca(2+) to such an extent that it essentially obviated regulation by physiological concentrations of Ca(2+) and relieved inhibition by physiological Mg(2+). These actions of B10 were produced only on the cytoplasmic face of the channel, were selectively eliminated by pretreatment of channels with FK506 or rapamycin, and were reconstituted by human recombinant FKBP12. The actions of B10 were found to be reversible. A structure-activity model is proposed by which substitutions on the Eastern and Western hemispheres of the bastarane macrocycle may confer specificity toward the RyR1-FKBP12 complex to stabilize either the closed or open channel conformation. These results indicate that RyR1-FKBP12 complexes possesses a novel binding domain for phenoxycatechols and raise the possibility of molecular recognition of an endogenous ligand. (+info)