Cyclohexanes: Six-carbon alicyclic hydrocarbons.Cyclohexanecarboxylic AcidsCrotonates: Derivatives of BUTYRIC ACID that include a double bond between carbon 2 and 3 of the aliphatic structure. Included under this heading are a broad variety of acid forms, salts, esters, and amides that include the aminobutryrate structure.trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride: An anticholesteremic agent that inhibits sterol biosynthesis in animals.Octanes: Eight-carbon saturated hydrocarbon group of the methane series. Include isomers and derivatives.Deltaproteobacteria: A group of PROTEOBACTERIA represented by morphologically diverse, anaerobic sulfidogens. Some members of this group are considered bacterial predators, having bacteriolytic properties.Methanospirillum: The sole genus in the family Methanospirillaceae whose organisms are progressively motile by means of polar, tufted flagella. They have been isolated from sewage-sludge and pear waste digesters as well as marine and non-marine habitats.Solvents: Liquids that dissolve other substances (solutes), generally solids, without any change in chemical composition, as, water containing sugar. (Grant & Hackh's Chemical Dictionary, 5th ed)HydrocarbonsHexanes: Six-carbon saturated hydrocarbon group of the methane series. Include isomers and derivatives. Various polyneuropathies are caused by hexane poisoning.Dioctyl Sulfosuccinic Acid: All-purpose surfactant, wetting agent, and solubilizer used in the drug, cosmetics, and food industries. It has also been used in laxatives and as cerumenolytics. It is usually administered as either the calcium, potassium, or sodium salt.tert-Butyl AlcoholCyclohexanols: Monohydroxy derivatives of cyclohexanes that contain the general formula R-C6H11O. They have a camphorlike odor and are used in making soaps, insecticides, germicides, dry cleaning, and plasticizers.Serotonin 5-HT1 Receptor Antagonists: Drugs that bind to but do not activate SEROTONIN 5-HT1 RECEPTORS, thereby blocking the actions of SEROTONIN 5-HT1 RECEPTOR AGONISTS. Included under this heading are antagonists for one or more of the specific 5-HT1 receptor subtypes.Amines: A group of compounds derived from ammonia by substituting organic radicals for the hydrogens. (From Grant & Hackh's Chemical Dictionary, 5th ed)Benzoates: Derivatives of BENZOIC ACID. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the carboxybenzene structure.Respiratory Protective Devices: Respirators to protect individuals from breathing air contaminated with harmful dusts, fogs, fumes, mists, gases, smokes, sprays, or vapors.Gas Chromatography-Mass Spectrometry: A microanalytical technique combining mass spectrometry and gas chromatography for the qualitative as well as quantitative determinations of compounds.Alkanes: The generic name for the group of aliphatic hydrocarbons Cn-H2n+2. They are denoted by the suffix -ane. (Grant & Hackh's Chemical Dictionary, 5th ed)Stereoisomerism: The phenomenon whereby compounds whose molecules have the same number and kind of atoms and the same atomic arrangement, but differ in their spatial relationships. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed)Hydroxybenzoates: Benzoate derivatives substituted by one or more hydroxy groups in any position on the benzene ring.Molecular Conformation: The characteristic three-dimensional shape of a molecule.Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight [1.00784; 1.00811]. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are PROTONS. Besides the common H1 isotope, hydrogen exists as the stable isotope DEUTERIUM and the unstable, radioactive isotope TRITIUM.Salmonella enterica: A subgenus of Salmonella containing several medically important serotypes. The habitat for the majority of strains is warm-blooded animals.Quantum Theory: The theory that the radiation and absorption of energy take place in definite quantities called quanta (E) which vary in size and are defined by the equation E=hv in which h is Planck's constant and v is the frequency of the radiation.Biodegradation, Environmental: Elimination of ENVIRONMENTAL POLLUTANTS; PESTICIDES and other waste using living organisms, usually involving intervention of environmental or sanitation engineers.Organic Chemicals: A broad class of substances containing carbon and its derivatives. Many of these chemicals will frequently contain hydrogen with or without oxygen, nitrogen, sulfur, phosphorus, and other elements. They exist in either carbon chain or carbon ring form.Magnetic Resonance Spectroscopy: Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (MAGNETIC RESONANCE IMAGING).Water: A clear, odorless, tasteless liquid that is essential for most animal and plant life and is an excellent solvent for many substances. The chemical formula is hydrogen oxide (H2O). (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds.Mixed Function Oxygenases: Widely distributed enzymes that carry out oxidation-reduction reactions in which one atom of the oxygen molecule is incorporated into the organic substrate; the other oxygen atom is reduced and combined with hydrogen ions to form water. They are also known as monooxygenases or hydroxylases. These reactions require two substrates as reductants for each of the two oxygen atoms. There are different classes of monooxygenases depending on the type of hydrogen-providing cosubstrate (COENZYMES) required in the mixed-function oxidation.X-Ray Diffraction: The scattering of x-rays by matter, especially crystals, with accompanying variation in intensity due to interference effects. Analysis of the crystal structure of materials is performed by passing x-rays through them and registering the diffraction image of the rays (CRYSTALLOGRAPHY, X-RAY). (From McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)
CyclohexaneDicycloverineCrotonyl-CoAOctaneDesulfococcus oleovorans Strain Hxd3: Desulfococcus oleovorans Strain Hxd3 was isolated from the saline water phase of an oil-water separator from a northern German oil field.Aeckersberg, F.Chronic solvent-induced encephalopathy: Chronic solvent induced encephalopathy (CSE) is a condition induced by long-term exposure to organic solvents, typically in the workplace, that lead to a wide variety of persisting sensorimotor polyneuropathies and neurobehavioral deficits even after solvent exposure has been removed. This syndrome can also be referred to as "psycho-organic syndrome", "organic solvent syndrome", "chronic painter's syndrome", "occupational solvent encephalopathy", "solvent intoxication", "toxic solvent syndrome", "painters disease", "psycho-organic syndrome", "chronic toxic encephalopathy", and "neurasthenic syndrome".Unsaturated hydrocarbon: Unsaturated hydrocarbons are hydrocarbons that have double or triple covalent bonds between adjacent carbon atoms. Those with at least one carbon to carbon double bond are called alkenes and those with at least one carbon to carbon triple bond are called alkynes.HexaneDioctyl terephthalateMycobacterium austroafricanum: Mycobacterium austroafricanum is a species of the phylum actinobacteria (Gram-positive bacteria with high guanine and cytosine content, one of the dominant phyla of all bacteria), belonging to the genus mycobacterium.Mycosporine-like amino acid: Mycosporine-like amino acids (MAAs) are small secondary metabolites produced by organisms that live in environments with high volumes of sunlight, usually marine environments. So far there are up to 20 known MAAs identified.ElzasonanOrganic base: An organic base is an organic compound which acts as a base. Organic bases are usually, but not always, proton acceptors.Propyl benzoateBreathing tube (breathing apparatus): A breathing tube is a flexible tube for breathing through, as part of a scuba set or other breathing apparatus or a medical oxygen apparatus or anaesthetic apparatus (Here they are distinguished from the medium-pressure hoses which are often found as parts of modern breathing apparatus.)Gas chromatography–mass spectrometry: right|300 px|Example of a GC-MS instrument|thumbDodecaneSharpless asymmetric dihydroxylation: Sharpless asymmetric dihydroxylation (also called the Sharpless bishydroxylation) is the chemical reaction of an alkene with osmium tetroxide in the presence of a chiral quinine ligand to form a vicinal diol.Phenolic acid: Phenolic acids or phenolcarboxylic acids are types of aromatic acid compound. Included in that class are substances containing a phenolic ring and an organic carboxylic acid function (C6-C1 skeleton).Hydrogen gas porosity: Hydrogen gas porosity is an aluminium casting defect under the form of a porosity or void in an aluminium casting caused by a high level of hydrogen gas (H2) dissolved in the aluminium at liquid phase. Because the solubility of hydrogen in solid aluminium is much smaller than in liquid aluminium, when the aluminium freezes, the dissolved hydrogen gas creates porosity in solid aluminium.George Albert II, Margrave of BrandenburgTrapped ion quantum computer: A trapped ion quantum computer is one proposed approach to a large-scale quantum computer. Ions, or charged atomic particles, can be confined and suspended in free space using electromagnetic fields.BiodegradationPrinomastatSpin–lattice relaxation in the rotating frame: Spin–lattice relaxation in the rotating frame is the mechanism by which Mxy, the transverse component of the magnetization vector, exponentially decays towards its equilibrium value of zero, under the influence of a radio frequency (RF) field in nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI). It is characterized by the spin–lattice relaxation time constant in the rotating frame, T1ρ.Outline of water: The following outline is provided as an overview of and topical guide to water:Clavaminate synthase: Clavaminate synthase (, clavaminate synthase 2, clavaminic acid synthase) is an enzyme with system name deoxyamidinoproclavaminate,2-oxoglutarate:oxygen oxidoreductase (3-hydroxylating). This enzyme catalyses the following chemical reactionPowder diffraction: Powder diffraction is a scientific technique using X-ray, neutron, or electron diffraction on powder or microcrystalline samples for structural characterization of materials.B.
(1/763) Inhibition of angiogenesis induces chromaffin differentiation and apoptosis in neuroblastoma.
Inhibition of angiogenesis has been shown to reduce tumor growth, metastasis, and tumor microvascular density in experimental models. To these effects we would now like to add induction of differentiation, based on biological analysis of xenografted human neuroblastoma (SH-SY5Y, WAG rnu/rnu) treated with the angiogenesis inhibitor TNP-470. Treatment with TNP-470 (10 mg/kg s.c., n = 15) reduced the tumor growth by 66% and stereological vascular parameters (Lv, Vv, Sv) by 36-45%. The tumor cell apoptotic fraction increased more than threefold, resulting in a decrease in viable tumor cells by 33%. In contrast, the mean vascular diameter (29 microm) and the mean tumor cell proliferative index (49%) were unaffected. TNP-470-treated tumors exhibited striking chromaffin differentiation of neuroblastoma cells, observed as increased expression of insulin-like growth factor II gene (+88%), tyrosine hydroxylase (+96%), chromogranin A, and cellular processes. Statistical analysis revealed an inverse correlation between differentiation and angiogenesis. It is suggested that by inhibiting angiogenesis, TNP-470 induces metabolic stress, resulting in chromaffin differentiation and apoptosis in neuroblastoma. Such agonal differentiation may be the link between angiostatic therapy and tumor cell apoptosis. (+info)
(2/763) Increased transcriptional activity of prostate-specific antigen in the presence of TNP-470, an angiogenesis inhibitor.
Prostate-specific antigen, PSA, is regarded as a reliable surrogate marker for androgen-independent prostate cancer (AIPC). Concern has been raised that investigational agents may affect PSA secretion without altering tumour growth or volume. In a phase I trial, several patients with AIPC had elevated serum PSA levels while receiving TNP-470 that reversed upon discontinuation. TNP-470 inhibits capillary growth in several angiogenesis models. These observations prompted us to determine if TNP-470, or its metabolite, AGM-1883, altered PSA secretion. Intracellular protein and transcriptional levels of PSA and androgen receptor were also determined. The highest TNP-470 concentration produced a 40.6% decrease in cell number; AGM-1883 had minimal effects on cell viability. PSA secretion per cell was induced 1.1- to 1.5-fold following TNP-470 exposure. The same trend was observed for AGM-1883. PSA and AR were transcriptionally up-regulated within 30 min after exposure to TNP-470. PSA transcription was increased 1.4-fold, while androgen receptor (AR) transcription was induced 1.2-fold. The increased PSA transcriptional activity accounts for the increased PSA secretion. Increased AR transcription was also reflected at the protein level. In conclusion, TNP-470 and AGM-1883 both up-regulated PSA making clinical utilization of this surrogate marker problematic. (+info)
(3/763) Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice.
BACKGROUND: Neovascularization within the intima of human atherosclerotic lesions is well described, but its role in the progression of atherosclerosis is unknown. In this report, we first demonstrate that intimal vessels occur in advanced lesions of apolipoprotein E-deficient (apoE -/-) mice. To test the hypothesis that intimal vessels promote atherosclerosis, we investigated the effect of angiogenesis inhibitors on plaque growth in apoE -/- mice. METHODS AND RESULTS: ApoE -/- mice were fed a 0.15% cholesterol diet. At age 20 weeks, mice were divided into 3 groups and treated for 16 weeks as follows: group 1, recombinant mouse endostatin, 20 mg. kg-1. d-1; group 2, fumagillin analogue TNP-470, 30 mg/kg every other day; and group 3, control animals that received a similar volume of buffer. Average cholesterol levels were similar in all groups. Plaque areas were quantified at the aortic origin. Median plaque area before treatment was 0.250 mm2 (range, 0.170 to 0.348; n=10). Median plaque areas were 0.321 (0.238 to 0.412; n=10), 0.402 (0.248 to 0.533; n=15), and 0.751 mm2 (0.503 to 0.838; n=12) for the endostatin, TNP-470, and control groups, respectively (P=0.0001). Therefore, endostatin and TNP-470 inhibited plaque growth during the treatment period by 85% and 70%. Intimal smooth muscle cell contents of plaques from control and treated mice were similar. CONCLUSIONS: Prolonged treatment with either angiogenesis inhibitor reduced plaque growth and intimal neovascularization in apoE -/- mice. Although the mechanism of plaque inhibition induced by these agents is not established, these results suggest that intimal neovascularization may promote plaque development. (+info)
(4/763) Inhibition of secretion by 1,3-Cyclohexanebis(methylamine), a dibasic compound that interferes with coatomer function.
We noted previously that certain aminoglycoside antibiotics inhibit the binding of coatomer to Golgi membranes in vitro. The inhibition is mediated in part by two primary amino groups present at the 1 and 3 positions of the 2-deoxystreptamine moiety of the antibiotics. These two amines appear to mimic the epsilon-amino groups present in the two lysine residues of the KKXX motif that is known to bind coatomer. Here we report the effects of 1, 3-cyclohexanebis(methylamine) (CBM) on secretion in vivo, a compound chosen for study because it contains primary amino groups that resemble those in 2-deoxystreptamine and it should penetrate lipid bilayers more readily than antibiotics. CBM inhibited coatomer binding to Golgi membranes in vitro and in vivo and inhibited secretion by intact cells. Despite depressed binding of coatomer in vivo, the Golgi complex retained its characteristic perinuclear location in the presence of CBM and did not fuse with the endoplasmic reticulum (ER). Transport from the ER to the Golgi was also not blocked by CBM. These data suggest that a full complement of coat protein I (COPI) on membranes is not critical for maintenance of Golgi integrity or for traffic from the ER to the Golgi but is necessary for transport through the Golgi to the plasma membrane. (+info)
(5/763) Effects of NTE-122, a novel acyl-CoA:cholesterol acyltransferase inhibitor, on cholesterol esterification and secretions of apolipoprotein B-containing lipoprotein and bile acids in HepG2.
We studied the effect of NTE-122 (trans-1,4-bis[[1-cyclohexyl-3-(4-dimethylamino phenyl) ureido]methyl]cyclohexane), a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on intracellular cholesterol esterification and the secretion of apolipoprotein B100 (apoB)-containing lipoprotein and bile acids in the human hepatoma cell line HepG2. NTE-122 markably inhibited [3H]oleate incorporation into cholesteryl esters in HepG2 cells incubated with 5 microg/ml 25-hydroxycholesterol as a stimulus for ACAT (IC50=6.0 nM). On the other hand, NTE-122 did not affect [3H]oleate incorporation into triglycerides and phospholipids and [14C]acetate incorporation into cholesterol. The stimulation of ACAT by 25-hydroxycholesterol caused significant increases in the secretion of radiolabeled cholesteryl esters, radiolabeled triglycerides and apoB mass. NTE-122 pronouncedly inhibited the secretion of radiolabeled cholesteryl esters in proportion to the inhibition of cellular cholesterol esterification, and it significantly reduced the secretion of radiolabeled triglycerides and apoB mass in HepG2 cells incubated with 25-hydroxycholesterol. Furthermore, NTE-122 increased the secretion of bile acids synthesized from [14C]-cholesterol. These results suggest that NTE-122 is capable of exhibiting anti-hyperlipidemic effects by reducing both the cholesterol content and the amount of secreted very low-density lipoprotein and enhancing the excretion of bile acid from the liver. (+info)
(6/763) Effects of NTE-122, a novel acyl-CoA:cholesterol acyltransferase inhibitor, on cholesterol esterification and high-density lipoprotein-induced cholesterol efflux in macrophages.
We investigated the effects of a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, NTE-122 (trans-1,4-bis[[1-cyclohexyl-3-(4-dimethylamino phenyl)ureido]methyl]cyclohexane), on ACAT activities in macrophages originating from several species and high-density lipoprotein (HDL)-induced cholesterol efflux in phorbol 12-myristate 13-acetate (PMA)-treated THP-1 cells. NTE-122 inhibited cell-free ACAT activities in human PMA-treated THP-1 cells and mouse J774.1 cells with IC50 values of 0.88 and 360 nM, respectively. NTE-122 competively inhibited the ACAT activity in PMA-treated THP-1 cells. NTE-122 also inhibited cellular ACAT activities in PMA-treated THP-1 cells, rat peritoneal macrophages and J774.1 cells with IC50 values of 3.5, 84 and 6800 nM, respectively. Furthermore, NTE-122 prevented cholesterol accumulation in PMA-treated THP-1 cells incubated with acetylated low density lipoprotein, simultaneously with HDL, while it caused accumulation of a significant amount of free cholesterol in the absence and even in the presence of HDL. NTE-122 also enhanced HDL-induced cholesterol efflux from established foam cells converted from PMA-treated THP-1 cells. These results suggest that NTE-122, capable of inhibiting macrophage ACAT activity in humans more strongly than those in the other species, exhibits anti-atherogenic effects by preventing the foam cell formation and enhancing the foam cell regression in humans. (+info)
(7/763) The loss in hydrophobic surface area resulting from a Leu to Val mutation at the N-terminus of the aldehyde dehydrogenase presequence prevents import of the protein into mitochondria.
An apparent conservative mutation, Leu to Val, at the second residue of the rat liver mitochondrial aldehyde dehydrogenase (ALDH) presequence resulted in a precursor protein that was not imported into mitochondria. Additional mutants were made to substitute various amino acids with nonpolar side chains for Leu2. The Ile, Phe, and Trp mutants were imported to an extent similar to that of the native precursor, but the Ala mutant was imported only about one-fourth as well. It was shown that the N-terminal methionine was removed from the L2V mutant in a reaction catalyzed by methionine aminopeptidase. The N-terminal methionine of native pALDH and the other mutant presequences was blocked, presumably by acetylation. Because of the difference in co-translational modification, the L2V mutant sustained a significant loss in the available hydrophobic surface of the presequence. Import competence was restored to the L2V mutant when it was translated using a system that did not remove Met1. The removal of an Arg-Gly-Pro helix linker segment (residues 11-14) from the L2V mutant, which shifted three leucine residues toward the N-terminus, also restored import competence. These results lead to the conclusion that a minimum amount of hydrophobic surface area near the N-termini of mitochondrial presequences is an essential property to determine their ability to be imported. As a result, both electrostatic and hydrophobic components must be considered when trying to understand the interactions between precursor proteins and proteins of the mitochondrial import apparatus. (+info)
(8/763) Metabolic drug interactions between angiogenic inhibitor, TNP-470 and anticancer agents in primary cultured hepatocytes and microsomes.
The potential metabolic drug interactions between TNP-470, a potent inhibitor of angiogenesis, and several commonly used anticancer agents, such as cyclophosphamide, taxol, and minocycline, were investigated in vitro using primary cultured hepatocytes and microsomes of rhesus monkeys. After incubation of hepatocytes with 5 microM [3H]TNP-470, rapid and extensive formation of six metabolites was observed, with M-II and M-IV being the predominant metabolites. After 30 min of incubation in the presence of 250 microM cyclophosphamide, concentrations of unchanged TNP-470 and M-IV were increased with values of 1.00 +/- 0.02 and 1.49 +/- 0.01 microM compared with control values of 0.67 +/- 0.09 (p =.02), 1.39 +/- 0. 03 microM (p <.01), respectively. In contrast, the concentration of M-II was substantially decreased from 1.69 +/- 0.86 to 1.02 +/- 0.16 microM (p =.01). Combination of taxol with TNP-470 led to a 50% decrease of M-II levels (p <.01), whereas unchanged TNP-470 and M-IV levels were increased by at least 2.5-fold compared with control (p =.08 and 0.01). Exposure of cells to TNP-470 with 250 microM minocycline had no effect on TNP-470 metabolism in monkey hepatocytes. In vitro studies with isolated monkey liver microsomes confirmed these drug-drug metabolic interactions detected at the cellular level. A detailed understanding of the potential drug interactions in TNP-470 metabolism occurring with taxol or cyclophosphamide is critical to fully elucidate the potentiation of the antitumor activity observed in vivo after coadministration of these two agents with TNP-470. (+info)