452 results on '"Oxepins"'
Search Results
152. Serum MMP-7 is increased in diabetic renal disease and diabetic diastolic dysfunction
- Author
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David S. Celermajer, Dennis K. Yue, Stephen M. Twigg, C. R. Ban, Belinda A. Brooks, Susan V. McLennan, and B. Franjic
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Male ,Cardiac function curve ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Diastole ,Enzyme-Linked Immunosorbent Assay ,Type 2 diabetes ,Naphthalenes ,Gastroenterology ,Endocrinology ,Diabetic cardiomyopathy ,Internal medicine ,Diabetes mellitus ,Matrix Metalloproteinases, Secreted ,Internal Medicine ,medicine ,Humans ,Diabetic Nephropathies ,Prospective cohort study ,Aged ,Tissue Inhibitor of Metalloproteinase-1 ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,Diabetes Mellitus, Type 2 ,Echocardiography ,Renal physiology ,Oxepins ,Albuminuria ,Female ,medicine.symptom ,Cardiomyopathies ,business - Abstract
Circulating matrix metalloproteinase (MMP) levels may correlate with diabetic complications. Whether they are changed in early diabetic cardiomyopathy is not known and was examined in this study. TIMP-1 and collagen degradation products were also measured. Results from subjects with and without diastolic dysfunction were compared with those obtained for patients with varying stages of diabetic renal disease. Patients with type 2 diabetes with or without diastolic dysfunction with varying degrees of renal disease were recruited for this study. Age-matched non-diabetic subjects served as controls. MMPs (-1, -3 and -7) and TIMP-1 were measured by ELISA, MMP-2 and -9 by zymography and collagen degradation products by radioimmunoassay. Differences in the pattern of MMPs/TIMPs and collagen degradation products were observed. The most consistent change was in totalMMP-7, which was increased in those with diastolic dysfunction and those with macroalbuminuria. MMP-7 correlated with cardiac function (p
- Published
- 2010
153. Modeling the formation and reactions of benzene metabolites
- Author
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Christine Bleasdale, Hannah J. Petty, Alistair P. Henderson, Xin Li, Martine L. Barnes, Bernard T. Golding, Majid M. Sadeghi, Dong Jiang, and Esra Mutlu
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Aldehydes ,Diene ,Stereochemistry ,Diastereomer ,Benzene ,General Medicine ,Toxicology ,Models, Biological ,Adduct ,chemistry.chemical_compound ,chemistry ,Cyclohexanes ,Hexafluorophosphate ,Oxepins ,Proton NMR ,Oxidation-Reduction ,Diels–Alder reaction ,Pyrrole - Abstract
One or more of the muconaldehyde isomers is a putative product of benzene metabolism. As muconaldehydes are highly reactive dienals and potentially mutagenic they might be relevant to the carcinogenicity of benzene. Muconaldehydes may be derived through the action of a cytochrome P450 mono-oxygenase on benzene oxide–oxepin, which are established metabolites of benzene. Oxidation of benzene oxide–oxepin either by the one-electron oxidant cerium(IV) ammonium nitrate (CAN) or by iron(III) tris (1,10-phenanthroline) hexafluorophosphate in acetone at −78 °C or acetonitrile at −40 °C gave ( E , Z )-muconaldehyde, which was a single diastereoisomer according to analysis by 1 H NMR spectroscopy. Reaction of toluene-1,2-oxide/2-methyloxepin with CAN gave (2 E ,4 Z )-6-oxo-hepta-2,4-dienal. Similarly, the action of CAN on 1,6-dimethylbenzene oxide-2,7-dimethyloxepin gave (3 Z ,5 E )-octa-3,5-diene-2,7-dione. In vivo , benzene oxide–oxepin could suffer one-electron oxidation by cytochrome P450 mono-oxygenase giving ( E , Z )-muconaldehyde. The observations presented may be relevant to the toxicology of benzene oxide–oxepin and other arene oxide–oxepins as we have previously shown that ( E , Z )-muconaldehyde, analogously to ( Z , Z )-muconaldehyde, affords pyrrole adducts with the exocyclic amino groups of the DNA bases adenine and guanine. Independent of their possible toxicological significance, the experiments described provide preparatively useful routes to ( E , Z )-muconaldehyde and its congeners. Methods are also described for the trapping and analysis of reactive benzene metabolites, e.g. using the Diels–Alder reaction with the dienophile 4-phenyl-1,2,4-triazoline-3,5-dione to trap arene oxides and with the diene 1,3-diphenylisobenzofuran to trap enals.
- Published
- 2010
154. Synthesis of Oxepines and 2-Branched Pyranosides from a <scp>d</scp>-Glucal-Derived gem-Dibromo-1,2-cyclopropanated Sugar
- Author
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Russell J. Hewitt and Joanne E. Harvey
- Subjects
Cyclopropanes ,chemistry.chemical_classification ,Magnetic Resonance Spectroscopy ,Molecular Structure ,Glycal ,Cyclopropanation ,Stereochemistry ,Organic Chemistry ,Carbohydrates ,Stereoisomerism ,Deoxyglucose ,Carbohydrate ,Ring (chemistry) ,Chemical synthesis ,Cyclopropane ,chemistry.chemical_compound ,chemistry ,Oxepins ,Epoxy Compounds ,Glucal - Abstract
The conversion of cyclopropane-fused carbohydrates into oxepines is an attractive method for accessing diverse members of the septanoside family of carbohydrate mimetics. 2-Bromooxepines are obtained through silver(I)-promoted thermal ring expansion of a d-glucal-derived gem-dihalocyclopropanated sugar. In contrast, cyclopropane ring cleavage under basic conditions leads to 2-C-branched pyranosides, not the 2-bromooxepine structures assigned in an earlier report.
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- 2010
155. Omigapil Ameliorates the Pathology of Muscle Dystrophy Caused by Laminin-α2 Deficiency
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Lazar T. Sumanovski, Sarina Meinen, Markus A. Rüegg, Thomas Meier, Patrizia Barzaghi, Michael Erb, and I. Courdier-Fruh
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Pathology ,medicine.medical_specialty ,Apoptosis Inhibitor ,Ubiquitin-Protein Ligases ,Apoptosis ,Motor Activity ,Mice ,Laminin ,Omigapil ,medicine ,Animals ,p300-CBP Transcription Factors ,Muscular dystrophy ,Muscle, Skeletal ,Mice, Knockout ,Pharmacology ,biology ,Body Weight ,Glyceraldehyde-3-Phosphate Dehydrogenases ,Nuclear Proteins ,Muscular Dystrophy, Animal ,medicine.disease ,Neonatal hypotonia ,Peripheral neuropathy ,Oxepins ,biology.protein ,Congenital muscular dystrophy ,Molecular Medicine ,Tumor Suppressor Protein p53 ,Signal Transduction ,medicine.drug - Abstract
Laminin alpha2-deficient congenital muscular dystrophy, called MDC1A, is a rare, devastating genetic disease characterized by severe neonatal hypotonia ("floppy infant syndrome"), peripheral neuropathy, inability to stand or walk, respiratory distress, and premature death in early life. Transgenic overexpression of the apoptosis inhibitor protein BCL-2, or deletion of the proapoptotic Bax gene in a mouse model for MDC1A prolongs survival and mitigates pathology, indicating that apoptotic events are involved in the pathology. Here we demonstrate that the proapoptotic glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-Siah1-CBP/p300-p53 pathway is activated in a mouse model for MDC1A. Moreover, we show that omigapil, which inhibits GAPDH-Siah1-mediated apoptosis, ameliorates several pathological hallmarks in the MDC1A mouse model. Specifically, we demonstrate that treatment with omigapil inhibits apoptosis in muscle, reduces body weight loss and skeletal deformation, increases locomotive activity, and protects from early mortality. These data qualify omigapil, which is in late phase of clinical development for human use, as a drug candidate for the treatment of MDC1A.
- Published
- 2009
156. Heptanosides from Galactose-Derived Oxepenes via Stereoselective Addition Reactions
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Rhys Batchelor, John O. Hoberg, Joanne E. Harvey, Peter T. Northcote, and Paul H. Teesdale-Spittle
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chemistry.chemical_classification ,Addition reaction ,Molecular Structure ,Cyclopropanation ,Organic Chemistry ,Galactose ,Stereoisomerism ,Carbon-13 NMR ,Oligosaccharide ,Heptoses ,Chemical synthesis ,chemistry.chemical_compound ,Aldose ,chemistry ,Oxepins ,Organic chemistry ,Stereoselectivity - Abstract
Addition reactions to a 3,4-anhydroheptanose gave heptanoside analogues of carbohydrate derivatives in good to excellent stereochemical purity. Characterization of the products by (1)H and (13)C NMR, COSY, HSQC-DEPT, HMBC, 1D TOCSY, and NOE experiments were performed to obtain the stereochemistry of addition. The 3,4-anhydroheptanose used in this study is obtained from the ring-expansion of a cyclopropanated galactal and thus demonstrates the synthetic utility of heptanose synthesis via cyclopropanated carbohydrates.
- Published
- 2009
157. The effects of calorie restriction olfactory cues on conspecific anxiety-like behaviour
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Elizabeth A. Levay, Jim Penman, Jacenta D. Abbott, Rachel Tucker, Antonio G. Paolini, Stephen Kent, and Amanda H. Tammer
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Male ,medicine.medical_specialty ,Elevated plus maze ,Calorie restriction ,Olfactory cues ,Olfaction ,Anxiety ,Naphthalenes ,Pheromones ,Statistics, Nonparametric ,Open field ,Random Allocation ,Behavioral Neuroscience ,chemistry.chemical_compound ,Neurochemical ,Corticosterone ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Caloric Restriction ,Olfactory Perception ,Rats ,Animal Communication ,Endocrinology ,Anti-Anxiety Agents ,chemistry ,Oxepins ,Exploratory Behavior ,Psychology ,Glucocorticoid ,medicine.drug - Abstract
Olfactory stimuli and calorie restriction (CR) have both been found to reduce anxiety-like behaviour and alter anxiety-related neurochemical mechanisms in rats. The aim of this study was to determine if exposure to olfactory cues from 25% CR male rats leads to anxiolytic-like behaviour in male rats fed ad libitum. Animals were divided into four groups: control (fed ad libitum and given new bedding every 5 days), control olfactory group (fed ad libitum and given the bedding from the control group every 5 days), CR (fed a 25% CR regime and given new bedding every 5 days), and CR olfaction (fed ad libitum and given the bedding from the CR group every 5 days). All animals were assessed on two measures of anxiety-like behaviour: the open field and the elevated plus maze. The CR group demonstrated anxiolytic-like behavioural responses in the open field test, characterised by more time spent in the aversive central zone and a higher frequency of central and middle zone entries compared to all other groups. Intriguingly, the CR olfaction group demonstrated anxiolytic-like behaviour in the elevated plus maze test, characterised by more time spent on the open arms, and a higher ratio of open compared to total arm entries relative to the control and control olfaction groups. After the completion of behavioural testing, serum corticosterone assays were conducted on trunk blood. However, only the CR group demonstrated an increase in corticosterone. Olfactory cues from conspecifics on a CR regime significantly reduced anxiety-like behaviour in rats fed ad libitum, similar to the reduction in anxiety-like behaviour following CR. This may have implications for the development of more efficacious novel treatments for anxiety disorders.
- Published
- 2009
158. CoMFA, CoMSIA and Eigenvalue Analysis on Dibenzodioxepinone and Dibenzodioxocinone Derivatives as Cholesteryl Ester Transfer Protein Inhibitors
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Dongmei Zhao, Jian Wang, Xu-Qiong Xiong, Yang Liu, Peng-fei Bu, Jinhong Ren, and Maosheng Cheng
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Models, Molecular ,CoMFA ,eigenvalue analysis ,dibenzodioxepinone and dibenzodioxocinone analogues ,Stereochemistry ,Quantitative Structure-Activity Relationship ,Pharmaceutical Science ,Article ,Analytical Chemistry ,lcsh:QD241-441 ,lcsh:Organic chemistry ,Eigenvalue analysis ,Drug Discovery ,Cholesterylester transfer protein ,Enzyme Inhibitors ,Physical and Theoretical Chemistry ,chemistry.chemical_classification ,biology ,Chemistry ,Hydrogen bond ,Oxocins ,Organic Chemistry ,Hydrogen Bonding ,Cetp inhibition ,Cholesterol Ester Transfer Proteins ,Chemistry (miscellaneous) ,Oxepins ,biology.protein ,Molecular Medicine ,cholesteryl ester transfer protein inhibitors ,Hydrophobic and Hydrophilic Interactions ,Lactone ,CoMSIA - Abstract
CoMFA, CoMSIA and eigenvalue analysis (EVA) were performed to study the structural features of 61 diverse dibenzodioxepinone and dibenzodioxocinone analogues to probe cholesteryl ester transfer protein (CETP) inhibitory activity. Three methods yielded statistically significant models upon assessment of cross-validation, bootstrapping, and progressive scrambling. This was further validated by an external set of 13 derivatives. Our results demonstrate that three models have a good interpolation as well as extrapolation. The hydrophobic features were confirmed to contribute significantly to inhibitor potencies, while a pre-oriented hydrogen bond provided by the hydroxyl group at the 3-position indicated a good correlation with previous SAR, and a hydrogen bond acceptor may play a crucial role in CETP inhibition. These derived models may help us to gain a deeper understanding of the binding interaction of these lactone-based compounds and aid in the design of new potent compounds against CETP.
- Published
- 2008
159. The effect of early maternal separation on brain derived neurotrophic factor and monoamine levels in adult heterozygous reeler mice
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Elisa Ognibene, Giovanni Laviola, Antonio Caprioli, Luigi Aloe, Syed F. Ali, Walter Adriani, and Orlando Ghirardi
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Heterozygote ,medicine.medical_specialty ,Motor Activity ,Naphthalenes ,Benzodiazepines ,Mice ,Mice, Neurologic Mutants ,Reeler ,Neurotrophic factors ,Internal medicine ,Glial cell line-derived neurotrophic factor ,medicine ,Animals ,Biogenic Monoamines ,Glial Cell Line-Derived Neurotrophic Factor ,Reelin ,Social Behavior ,Biological Psychiatry ,Pharmacology ,Brain-derived neurotrophic factor ,Maternal deprivation ,Behavior, Animal ,biology ,Brain-Derived Neurotrophic Factor ,Maternal Deprivation ,Brain ,Mice, Inbred C57BL ,Reelin Protein ,Endocrinology ,Monoamine neurotransmitter ,Olanzapine ,Oxepins ,Exploratory Behavior ,biology.protein ,Hypoactivity ,Psychology ,Neuroscience ,Antipsychotic Agents - Abstract
Objective and methods The reeler heterozygous (HZ) mice have provided a model for studying the relationship between reelin (a protein of extracellular matrix) haploinsufficiency and the emergence of neuropsychiatric diseases. In a neurodevelopmental framework, the enduring consequences of early maternal separation (5 h/day during the first postnatal week, or handling controls, H) were studied in reeler HZ and wild type (WT) mice at adulthood. The modulatory effects of a chronic treatment with the atypical antipsychotic olanzapine (OLZ, 1.5 mg/kg for 40 days) were also investigated. Results Early maternal separation had long-term effects on brain plasticity, with a reduction of brain- and glial- derived neurotrophic factor (BDNF and GDNF) in several brain areas of mice, but such a consequence was less marked in the HZ genotype. On the other hand, treatment with OLZ did not affect at all the GDNF but led to an increase of BDNF levels in maternally separated (SEP) mice, an effect which was far more marked in the HZ genotype. Brain levels of serotonin (5-HT) were markedly increased, striatal dopamine (DA) was increased, whereas metabolites and turnover were decreased, in SEP mice of both genotypes. The spontaneous home-cage activity was generally lower in HZ than WT mice, and OLZ treatment contrasted this hypoactivity profile. Maternal separation also decreased the interest toward an unknown mouse proposed as a social stimulus, but only in WT mice. Conclusion We investigated the interplay between genetic vulnerability (reelin haploinsufficiency), the outcome of early stressful experiences, and the efficacy of the antipsychotic drug therapy. The reeler HZ genotype exhibited a slightly lower sensitivity to the environmental insult as well as an enhanced response to the atypical antipsychotic treatment.
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- 2008
160. Task-dependent and task-independent neurovascular responses to syntactic processing
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Gloria Waters, Evan C. Chen, and David Caplan
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Adult ,Male ,Cognitive Neuroscience ,Inferior frontal gyrus ,Experimental and Cognitive Psychology ,Proposition ,Naphthalenes ,Verbal learning ,Article ,Task (project management) ,Discrimination, Psychological ,Reference Values ,Humans ,Set (psychology) ,Evoked Potentials ,Brain Mapping ,Cognition ,Verbal Learning ,Magnetic Resonance Imaging ,Frontal Lobe ,Comprehension ,Neuropsychology and Physiological Psychology ,Regional Blood Flow ,Oxepins ,Female ,Psychology ,Sentence ,Cognitive psychology - Abstract
The neural basis for syntactic processing was studied using event-related fMRI to determine the locations of BOLD signal increases in the contrast of syntactically complex sentences with center-embedded, object-extracted relative clauses and syntactically simple sentences with right-branching, subject-extracted relative clauses in a group of 15 participants in three tasks. In a sentence verification task, participants saw a target sentence in one of these two syntactic forms, followed by a probe in a simple active form, and determined whether the probe expressed a proposition in the target. In a plausibility judgment task, participants determined whether a sentence in one of these two syntactic forms was plausible or implausible. Finally, in a non-word detection task, participants determined whether a sentence in one of these two syntactic forms contained only real words or a non-word. BOLD signal associated with the syntactic contrast increased in the left posterior inferior frontal gyrus in non-word detection and in a widespread set of areas in the other two tasks. We conclude that the BOLD activity in the left posterior inferior frontal gyrus reflects syntactic processing independent of concurrent cognitive operations and the more widespread areas of activation reflect the use of strategies and the use of the products of syntactic processing to accomplish tasks.
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- 2008
161. ALPHA.-Glucosidase Inhibitors from Garcinia brevipedicellata (Clusiaceae)
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Muhammad Shaiq Ali, Joseph Ngoupayo, Turibio Kuiate Tabopda, and Etienne Tsamo
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Spectrometry, Mass, Electrospray Ionization ,Magnetic Resonance Spectroscopy ,Spectrophotometry, Infrared ,Damnacanthal ,chemistry.chemical_compound ,Scopoletin ,Drug Discovery ,Botany ,Benzopyrans ,Glycoside Hydrolase Inhibitors ,Cameroon ,Enzyme Inhibitors ,Stem bark ,Stigmasterol ,biology ,Depsidone ,α glucosidase ,Clusiaceae ,General Chemistry ,General Medicine ,Garcinia brevipedicellata ,biology.organism_classification ,Plant Leaves ,chemistry ,Oxepins ,Plant Bark ,Indicators and Reagents ,Spectrophotometry, Ultraviolet ,Garcinia - Abstract
In our continuous search for alpha-glucosidase inhibitors from plants, four new depsidones named brevipsidones A-D (1-4) were isolated from stem bark of Garcinia brevipedicellata together with known damnacanthal, scopoletin and a mixture of stigmasterol and beta-sitosterol. Structural elucidations were made by spectroscopic analyses including 2D-NMR data.
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- 2008
162. An auditory brain–computer interface (BCI)
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Andrea Kübler, Dennis J. McFarland, Ingo Gunst, Niels Birbaumer, Femke Nijboer, Juergen Mellinger, and Adrian Furdea
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Adult ,Male ,medicine.medical_specialty ,Visual perception ,genetic structures ,Brain activity and meditation ,Speech recognition ,Emotions ,Naphthalenes ,Electroencephalography ,Audiology ,Article ,Communication Aids for Disabled ,User-Computer Interface ,Reaction Time ,medicine ,Humans ,Brain–computer interface ,Auditory feedback ,medicine.diagnostic_test ,General Neuroscience ,Brain ,Biofeedback, Psychology ,Mood ,Acoustic Stimulation ,Sensorimotor rhythm ,Oxepins ,Evoked Potentials, Auditory ,Evoked Potentials, Visual ,Feasibility Studies ,Female ,Auditory Physiology ,Psychology ,Photic Stimulation - Abstract
Brain-computer interfaces (BCIs) translate brain activity into signals controlling external devices. BCIs based on visual stimuli can maintain communication in severely paralyzed patients, but only if intact vision is available. Debilitating neurological disorders however, may lead to loss of intact vision. The current study explores the feasibility of an auditory BCI. Sixteen healthy volunteers participated in three training sessions consisting of 30 2-3 min runs in which they learned to increase or decrease the amplitude of sensorimotor rhythms (SMR) of the EEG. Half of the participants were presented with visual and half with auditory feedback. Mood and motivation were assessed prior to each session. Although BCI performance in the visual feedback group was superior to the auditory feedback group there was no difference in performance at the end of the third session. Participants in the auditory feedback group learned slower, but four out of eight reached an accuracy of over 70% correct in the last session comparable to the visual feedback group. Decreasing performance of some participants in the visual feedback group is related to mood and motivation. We conclude that with sufficient training time an auditory BCI may be as efficient as a visual BCI. Mood and motivation play a role in learning to use a BCI.
- Published
- 2008
163. Theoretical Study of Reaction Mechanisms of OH Radical with Toluene 1,2-Epoxide/2-Methyloxepin
- Author
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Rocío Cartas-Rosado and Miguel Castro
- Subjects
Reaction mechanism ,Hydroxyl Radical ,Chemistry ,Epoxide ,Photochemistry ,Toluene ,Transition state ,chemistry.chemical_compound ,Reaction rate constant ,Yield (chemistry) ,Oxepins ,Epoxy Compounds ,Thermodynamics ,Physical chemistry ,Molecule ,Physical and Theoretical Chemistry ,Ground state ,Oxidation-Reduction - Abstract
In this study, the reaction mechanism of toluene 1,2-epoxide/2-methyloxepin with OH radical was studied by means of quantum chemical computations performed using B3LYP/6-31G(d,p), B3LYP/6-311G(2df,2p), and BHandHLYP/6-31G(d,p) methods. Ground state, intermediate, and transition states were determined. The results indicated that the 2-methyloxepin, A, isomer is more stable, by 2.4 kcal/mol, than toluene 1,2-epoxide, B. Two reaction pathways were studied, RP-A and RP-B, corresponding to the reaction of OH with toluene 1,2-epoxide and 2-methyloxepin, respectively. The localization of a pre-reactive complex for RP-A is crucial for the accurate estimation of the rate constant, k=1.0x10(-10) cm3 molecule(-1) s(-1), which is in good agreement with that determined experimentally, whereas for RP-B the rate constant is 1.3x10(-14) cm3 molecule(-1) s(-1). Under atmospheric conditions, both pathways yield 6-oxohepta-2,4-dienal as a main product, and from the energetic and kinetic results it was found that RP-A is the preferred pathway. The study of the oxide/oxepin mechanism is relevant because, aside from its relatively high concentration in the troposphere, this compound has carcinogenic and mutagenic properties.
- Published
- 2007
164. Synthesis and Properties of Oligonucleotides Containing A 7-Membered (Oxepane) Sugar Ring
- Author
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David Sabatino and Masad J. Damha
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RNase P ,Stereochemistry ,Ribonuclease H ,Oligonucleotides ,Nucleic Acid Denaturation ,Biochemistry ,chemistry.chemical_compound ,Oxepane ,Organophosphorus Compounds ,Escherichia coli ,Genetics ,RNase H ,Molecular Structure ,biology ,Oligonucleotide ,Chemistry ,Circular Dichroism ,RNA ,General Medicine ,Thymine ,Drug Design ,Oxepins ,Nucleic acid ,biology.protein ,Thermodynamics ,Molecular Medicine ,DNA - Abstract
Herein we describe the synthesis of novel 7-membered ring (oxepane) thymine and adenine nucleosides (oT and oA) and their corresponding 5'-O-phosphoramidite derivatives. Two homopolymeric sequences (oT(15) and oA(15)) were prepared via conventional solid-phase synthesis. The mutually complementary strands had the ability to form a duplex (oT(15):oA(15)) exhibiting a transition temperature of 12 degrees C. The oxepane oligonucleotides were also found to associate with their respective complementary RNA strands thus forming oT(15):rA(15) (13 degrees C) and oA(15):rU(15) (12 degrees C) hybrids. The corresponding native duplexes, namely dT(15):dA(15), dT(15):rA(15) and dA(15):rU(15) had melting temperatures of 37 degrees C, 32 degrees C and 16 degrees C, respectively. The CD spectrum of oT(15):rA(15) closely resembled that of the native dT(15):rA(15) hybrid and, in fact, both were found to be substrates for E. Coli RNase H. Thus the oxepane nucleic acids reported here are one of only a handful of DNA mimics capable of activating RNase H when bound to RNA.
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- 2007
165. Adjunctive therapy of uncontrolled partial seizures with levetiracetam in Australian patients
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Samuel F. Berkovic, Ernest Somerville, Martin K. Robinson, and Daniel B. McLaughlin
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Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Levetiracetam ,Adolescent ,Population ,Naphthalenes ,Behavioral Neuroscience ,Epilepsy ,medicine ,Humans ,Adverse effect ,education ,Aged ,education.field_of_study ,Dose-Response Relationship, Drug ,business.industry ,Australia ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Piracetam ,Discontinuation ,Clinical trial ,Treatment Outcome ,Neurology ,Tolerability ,Anesthesia ,Oxepins ,Adjunctive treatment ,Quality of Life ,Drug Evaluation ,Anticonvulsants ,Female ,Epilepsies, Partial ,Neurology (clinical) ,business ,medicine.drug - Abstract
Objective The goal of the work described here was to explore the efficacy, safety, and tolerability of adjunctive therapy with levetiracetam and associated changes in health-related quality of life in Australian patients with uncontrolled partial seizures. Methods A phase IV open-label 16-week clinical trial was undertaken. Patients received adjunctive levetiracetam, adjusted according to clinical response to a final daily dose of 1000–3000 mg. Seizure frequency and adverse events were recorded. A quality-of-life questionnaire (QOLIE-10-P) was administered at the start and end of therapy. Results The intention-to-treat population ( N = 152) experienced a median reduction in total seizure frequency of 57.7%. The 50% responder rate was 56.6%, and 12.5% of patients were free of seizures throughout the trial. Adverse events were mostly mild or moderate, leading to discontinuation in 9.9%. The most common adverse events were somnolence, fatigue, headache, and dizziness. Behavioral adverse events occurred in approximately one-quarter of patients, including two-thirds of those who withdrew because of adverse events. There was an improvement in the QOLIE-10-P score. Conclusion Levetiracetam is effective and well tolerated when added to existing therapy in patients with uncontrolled partial seizures.
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- 2007
166. A Diastereoselective Intermolecular Heck Reaction of 1,3-Dioxepins
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Tomislav Rovis, Nathan T. Jui, Christopher G. Nasveschuk, and Jeffrey D. Frein
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chemistry.chemical_classification ,Olefin fiber ,Molecular Structure ,Chemistry ,Alkene ,Organic Chemistry ,Intermolecular force ,Stereoisomerism ,Biochemistry ,Medicinal chemistry ,Kinetic control ,Adduct ,Ethers, Cyclic ,Heck reaction ,Yield (chemistry) ,Oxepins ,Physical and Theoretical Chemistry - Abstract
A highly diastereoselective intermolecular Heck reaction of 1,3-dioxepins is reported. Substitution at both the 2- and 4-positions of the dioxepin directs the Pd coordination and subsequent olefin insertion to provide the trans-disubstituted adduct in good yield and high diastereoselectivity. Chemoselective Heck reaction occurs at the dioxepin alkene in the presence of other olefinic functional groups. A labeling study has been conducted which suggests that the reaction is under kinetic control.
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- 2007
167. New dibenz[b, f]oxepins from Cercis chinensis Bunge
- Author
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Li-Hua Mu, Jian-bei Li, Dong-Ming Zhang, and Jing-Zhi Yang
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Pharmacology ,Folk medicine ,Spectrometry, Mass, Electrospray Ionization ,Magnetic Resonance Spectroscopy ,biology ,Chemistry ,Stereochemistry ,Cercis ,Organic Chemistry ,Pharmaceutical Science ,Cercis chinensis ,Fabaceae ,General Medicine ,Nuclear magnetic resonance spectroscopy ,biology.organism_classification ,Analytical Chemistry ,Complementary and alternative medicine ,Oxepins ,Drug Discovery ,Molecular Medicine ,Spectrophotometry, Ultraviolet - Abstract
Three new dibenz[b,f]oxepins: 6-methoxy-7-methyl-8-hydroxydibenz[b, f]oxepin (1), 1,8-dimethoxy-6-hydroxy-7-methyldibenz[b, f]oxepin (2), and 1-hydroxy-6,8-dimethoxy-7-methyldibenz[b,f]oxepin (3), along with two known dibenz[b,f]oxepins pacharin (4) and bauhiniastatin 4 (5), were isolated from Cercis chinensis Bunge (Leguminosae). Their structures were elucidated on the basis of spectroscopic evidence (EI-MS, UV, IR, (1)H, (13)C and 2D NMR). Compounds 1-5 were isolated from the Cercis genus for the first time.
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- 2007
168. Post-translational protein modifications in type 1 diabetes: a role for the repair enzyme protein-l-isoaspartate (d-aspartate) O-methyltransferase?
- Author
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Paul A C Cloos, A. M. Wagner, R. Bergholdt, D. B. Henriksen, Thomas Levin Andersen, Flemming Pociot, Stephan Christgau, Claus Christiansen, Patrice Boissy, and Jørn Nerup
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Methyltransferase ,Endocrinology, Diabetes and Metabolism ,Gene Expression Regulation, Enzymologic ,Epitope ,Isoaspartate ,Reference Values ,Protein D-Aspartate-L-Isoaspartate Methyltransferase ,Internal Medicine ,Animals ,Humans ,Rats, Inbred BB ,Pancreas ,Gene ,Oligonucleotide Array Sequence Analysis ,chemistry.chemical_classification ,Regulation of gene expression ,biology ,Immunohistochemistry ,O-methyltransferase ,Rats ,Protein L ,Diabetes Mellitus, Type 1 ,Enzyme ,chemistry ,Biochemistry ,Oxepins ,biology.protein ,Protein Processing, Post-Translational - Abstract
Udgivelsesdato: 2007-Mar AIMS/HYPOTHESIS: Post-translational modifications, such as isomerisation of native proteins, may create new antigenic epitopes and play a role in the development of the autoimmune response. Protein-L-isoaspartate (D-aspartate) O-methyltransferase (PIMT), encoded by the gene PCMT1, is an enzyme that recognises and repairs isomerised Asn and Asp residues in proteins. The aim of this study was to assess the role of PIMT in the development of type 1 diabetes. MATERIALS AND METHODS: Immunohistochemical analysis of 59 normal human tissues was performed with a monoclonal PIMT antibody. CGP3466B, which induces expression of Pcmt1, was tested on MIN6 and INS1 cells, to assess its effect on Pcmt1 mRNA and PIMT levels (RT-PCR and western blot) and apoptosis. Forty-five diabetes-prone BioBreeding (BB) Ottawa Karlsburg (OK) rats were randomised to receive 0, 14 or 500 microg/kg (denoted as the control, low-dose and high-dose group, respectively) of CGP3466B from week 5 to week 20. RESULTS: A high level of PIMT protein was detected in beta cells. CGP3466B induced a two- to threefold increase in Pcmt1 mRNA levels and reduced apoptosis by 10% in MIN6 cells. No significant effect was seen on cytokine-induced apoptosis or PIMT protein levels in INS1 cells. The onset of diabetes in the BB/OK rats was significantly delayed (85.6+/-9.0 vs 84.3+/-6.8 vs 106.6+/-13.5 days, respectively; p
- Published
- 2007
169. Molecular basis for metabolite channeling in a ring opening enzyme of the phenylacetate degradation pathway.
- Author
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Sathyanarayanan, Nitish, Cannone, Giuseppe, Gakhar, Lokesh, Katagihallimath, Nainesh, Sowdhamini, Ramanathan, Ramaswamy, Subramanian, and Vinothkumar, Kutti R.
- Subjects
METABOLITES ,PHENYLACETATES ,ELECTRON cryomicroscopy ,SMALL-angle X-ray scattering ,OXEPINS - Abstract
Substrate channeling is a mechanism for the internal transfer of hydrophobic, unstable or toxic intermediates from the active site of one enzyme to another. Such transfer has previously been described to be mediated by a hydrophobic tunnel, the use of electrostatic highways or pivoting and by conformational changes. The enzyme PaaZ is used by many bacteria to degrade environmental pollutants. PaaZ is a bifunctional enzyme that catalyzes the ring opening of oxepin-CoA and converts it to 3-oxo-5,6-dehydrosuberyl-CoA. Here we report the structures of PaaZ determined by electron cryomicroscopy with and without bound ligands. The structures reveal that three domain-swapped dimers of the enzyme form a trilobed structure. A combination of small-angle X-ray scattering (SAXS), computational studies, mutagenesis and microbial growth experiments suggests that the key intermediate is transferred from one active site to the other by a mechanism of electrostatic pivoting of the CoA moiety, mediated by a set of conserved positively charged residues. The bacterial enzyme PaaZ is involved in the breakdown of environmental pollutants via the aerobic-anaerobic hybrid pathway but its substrate transfer mechanism is not fully understood. Here, the authors present cryoEM structures of free and ligand-bound PaaZ that suggest a mechanism for internal substrate channeling. [ABSTRACT FROM AUTHOR]
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- 2019
- Full Text
- View/download PDF
170. Dibenz[b,f]oxepin and Antimycobacterial Chalcone Constituents of Empetrum nigrum
- Author
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Stéphanie Jean, John A. Johnson, Haoxin Li, Duncan Webster, Christopher A. Gray, Larry A. Calhoun, and Gilles A. Robichaud
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Chalcone ,Canada ,medicine.drug_class ,Stereochemistry ,Antitubercular Agents ,Pharmaceutical Science ,Microbial Sensitivity Tests ,Antimycobacterial ,01 natural sciences ,Analytical Chemistry ,Mycobacterium tuberculosis ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Drug Discovery ,medicine ,Ic50 values ,Inhibitory concentration 50 ,Animals ,Benzoxepins ,Humans ,Nuclear Magnetic Resonance, Biomolecular ,Pharmacology ,biology ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,HEK 293 cells ,biology.organism_classification ,0104 chemical sciences ,3. Good health ,010404 medicinal & biomolecular chemistry ,HEK293 Cells ,Complementary and alternative medicine ,chemistry ,Ericaceae ,Oxepins ,Molecular Medicine ,Empetrum nigrum - Abstract
Two new dibenz[b,f]oxepins, empetroxepins A and B (1 and 2), and seven known compounds (3-9) were isolated from an extract of the Canadian medicinal plant Empetrum nigrum that significantly inhibited the growth of Mycobacterium tuberculosis H37Ra. The structures of 1 and 2 were established through analysis of NMR and MS data. The antimycobacterial activity of the plant extract was attributed primarily to the presence of two chalcone derivatives (6 and 7) that exhibited selective antimycobacterial activity (IC50 values of 23.8 and 32.8 μM, respectively) in comparison to mammalian (HEK 293) cells (IC50 values of 109 and 249 μM, respectively).
- Published
- 2015
171. Lichen Secondary Metabolite, Physciosporin, Inhibits Lung Cancer Cell Motility
- Author
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Cheol Moon, Min-Hye Jeong, Eun Gene Sun, Thanh Thi Nguyen, Tru Van Nguyen, Kyung Keun Kim, Iris Pereira, Hyung-Ho Ha, Jayalal Udeni, So-Yeon Park, Jae-Seoun Hur, Young Hyun Yu, Hangun Kim, and Yi Yang
- Subjects
rho GTP-Binding Proteins ,Epithelial-Mesenchymal Transition ,Lung Neoplasms ,Lichens ,lcsh:Medicine ,Motility ,RAC1 ,Antineoplastic Agents ,Secondary metabolite ,Biology ,Kangai-1 Protein ,Metastasis ,Acetone ,Tetraspanin ,Cell Movement ,Cell Line, Tumor ,medicine ,Humans ,Neoplasm Invasiveness ,Epithelial–mesenchymal transition ,Neoplasm Metastasis ,lcsh:Science ,Multidisciplinary ,Plant Extracts ,lcsh:R ,Membrane Proteins ,medicine.disease ,Molecular biology ,Gene Expression Regulation, Neoplastic ,Transcription Factor AP-1 ,Metastasis Suppressor Gene ,Cell culture ,Immunology ,Oxepins ,lcsh:Q ,Carrier Proteins ,medicine.drug ,Research Article - Abstract
Lichens produce various unique chemicals that can be used for pharmaceutical purposes. To screen for novel lichen secondary metabolites showing inhibitory activity against lung cancer cell motility, we tested acetone extracts of 13 lichen samples collected in Chile. Physciosporin, isolated from Pseudocyphellaria coriacea (Hook f. & Taylor) D.J. Galloway & P. James, was identified as an effective compound and showed significant inhibitory activity in migration and invasion assays against human lung cancer cells. Physciosporin treatment reduced both protein and mRNA levels of N-cadherin with concomitant decreases in the levels of epithelial-mesenchymal transition markers such as snail and twist. Physciosporin also suppressed KITENIN (KAI1 C-terminal interacting tetraspanin)-mediated AP-1 activity in both the absence and presence of epidermal growth factor stimulation. Quantitative real-time PCR analysis showed that the expression of the metastasis suppressor gene, KAI1, was increased while that of the metastasis enhancer gene, KITENIN, was dramatically decreased by physciosporin. Particularly, the activity of 3'-untranslated region of KITENIN was decreased by physciosporin. Moreover, Cdc42 and Rac1 activities were decreased by physciosporin. These results demonstrated that the lichen secondary metabolite, physciosporin, inhibits lung cancer cell motility through novel mechanisms of action.
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- 2015
172. Surface-Functionalized Biodegradable Nanoparticles Consisting of Amphiphilic Graft Polymers Prepared by Radical Copolymerization of 2-Methylene-1,3-Dioxepane and Macromonomers
- Author
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Akihiko Kikuchi, Taka-Aki Asoh, Takahito Nakajima, and Takuya Matsuyama
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Free Radicals ,Polymers ,Surface Properties ,Nanoparticle ,chemistry.chemical_compound ,Surface-Active Agents ,Polymer chemistry ,Amphiphile ,Electrochemistry ,Copolymer ,General Materials Science ,Alkaline hydrolysis ,Spectroscopy ,chemistry.chemical_classification ,Molecular Structure ,Hydrolysis ,Surfaces and Interfaces ,Polymer ,Condensed Matter Physics ,Grafting ,Polyester ,chemistry ,Cyclization ,Oxepins ,Nanoparticles ,Ethylene glycol - Abstract
Biodegradable polyester-based nanoparticles were prepared by the precipitation of amphiphilic graft copolymers, which were prepared by the ring-opening radical copolymerization of 2-methylene-1,3-dioxepane (MDO) and amphiphilic macromonomers. The diameter of the nanoparticles was controlled by the degree of grafting and the molecular weight of the grafting oligomer. PMDO-g-poly(ethylene glycol) nanoparticles were degraded by the alkaline hydrolysis of the polyester backbone. Although the colloidal stability of nanoparticles was retained due to the reorientation of the PEG chains during hydrolysis, the size of the nanoparticles decreased with increasing hydrolysis time. We also prepared PMDO-g-poly(N-isopropylacrylamide) nanoparticles, which show aggregation in response to increasing temperature.
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- 2015
173. Seven-membered ring scaffolds for drug discovery: Access to functionalised azepanes and oxepanes through diazocarbonyl chemistry
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Christopher J. Moody and Andrew Nortcliffe
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Models, Molecular ,Ketone ,Alkylation ,Clinical Biochemistry ,Pharmaceutical Science ,Ring (chemistry) ,Biochemistry ,Enamine ,chemistry.chemical_compound ,Luche reduction ,Oxepane ,Azepane ,Drug Discovery ,Organic chemistry ,Molecular Biology ,chemistry.chemical_classification ,Molecular Structure ,Organic Chemistry ,Stereoisomerism ,Azepines ,Seven-Membered Rings, Azepane, Oxepane, Diazocarbonyl, Medicinal Chemistry ,Amino acid ,chemistry ,Oxepins ,Molecular Medicine ,Amine gas treating ,Azo Compounds - Abstract
© 2015 Elsevier Ltd. All rights reserved. Functionalised azepane and oxepane scaffolds were prepared using diazocarbonyl chemistry and elaborated to show their potential use in library synthesis. Key dicarbonyl containing seven-membered rings were functionalised via diastereoselective Luche reduction of the ketone followed by manipulation of the ester and amine groups. Further scaffolds could be accessed by C-alkylation of the dicarbonyl compounds. In addition, an oxepane containing amino acid could be prepared via a diastereoselective enamine reduction.
- Published
- 2015
174. Solid state structure of p-bromo phenyl 4,5,7-tri-O-benzyl-β-D-glycero-D-talo-septanoside and an analysis of non-covalent interactions
- Author
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Narayanaswamy Jayaraman, Supriya Dey, and Krishnayan Basuroy
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chemistry.chemical_classification ,Stereochemistry ,Organic Chemistry ,Molecular Conformation ,General Medicine ,Crystallography, X-Ray ,Biochemistry ,Analytical Chemistry ,Crystal ,chemistry.chemical_compound ,Oxepane ,Crystallography ,Organophosphorus Compounds ,Sugar Alcohols ,chemistry ,Oxepins ,Molecule ,Non-covalent interactions ,Methacrylates ,Pi interaction ,Center (algebra and category theory) ,Single crystal ,Derivative (chemistry) ,Solid-Phase Synthesis Techniques - Abstract
The solid state structure of a new seven-membered sugar oxepane derivative, namely, p-bromo phenyl 4,5,7-tri-O-benzyl-beta-D-glycero-D-talo-septanoside is discussed, as determined through single crystal X-ray structural determination and in relation to their conformational features. The molecule adopts twist-chair as the preferred conformation, with conformational descriptor (TC2,3)-T-0,1. The solid state packing of molecules is governed by a rich network of non-covalent bonding originating from O-H center dot center dot center dot O, C-H center dot center dot center dot pi, C-H center dot center dot center dot Br and aromatic pi center dot center dot center dot pi interactions that stabilize the packing of molecules in the crystal. (C) 2015 Elsevier Ltd. All rights reserved.
- Published
- 2015
175. Synthesis of 1,2,4-trioxepanes via application of thiol-olefin Co-oxygenation methodology
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Jean-Francois Rossignol, Gael Labat, Richard Amewu, Paul M. O'Neill, Stephen A. Ward, Neil G. Berry, Andrew V. Stachulski, and Jill Davies
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Models, Molecular ,Allylic rearrangement ,Ketone ,Iron ,Plasmodium falciparum ,Clinical Biochemistry ,Pharmaceutical Science ,Alkenes ,Biochemistry ,Peroxide ,Chemical synthesis ,Ferrous ,Antimalarials ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,Animals ,Moiety ,Organic chemistry ,Sulfhydryl Compounds ,Molecular Biology ,chemistry.chemical_classification ,Olefin fiber ,Molecular Structure ,Organic Chemistry ,General Medicine ,Combinatorial chemistry ,Oxygen ,chemistry ,1,2,4-Trioxane ,Oxepins ,Thiol ,Degradation (geology) ,Molecular Medicine - Abstract
Thiol-olefin co-oxygenation (TOCO) of substituted allylic alcohols generates beta-hydroxy peroxides that can be condensed in situ with various ketones, to afford a series of functionalised 1,2,4-trioxepanes in good yields. Manipulation of the phenylsulfenyl group in 8a-8c allows for convenient modification to the spiro-trioxepane substituents. Surprisingly, and in contrast to the 1,2,4-trioxanes examined, 1,2,4-trioxepanes are inactive as antimalarials up to 1000 nM and we rationalize this observation based on the inherent stability of these systems to ferrous mediated degradation. FMO calculations clearly show that the sigma* orbital of the peroxide moiety of 1,2,4-trioxane derivatives 4a and 14b are lower in energy and more accessible to attack by Fe(II) compared to their trioxepane analogues 8b and 9b. (c) 2006 Published by Elsevier Ltd.
- Published
- 2006
176. Design, Synthesis, and Biological Evaluation of Phenylamino-Substituted 6,11-Dihydro-dibenzo[b,e]oxepin-11-ones and Dibenzo[a,d]cycloheptan-5-ones: Novel p38 MAP Kinase Inhibitors
- Author
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Solveigh C. Karcher, Gabriele M. Ahrens, Raimund Niess, Stefan Laufer, and Jörg S. Hering
- Subjects
Stereochemistry ,p38 Mitogen-Activated Protein Kinases ,Chemical synthesis ,Proinflammatory cytokine ,Structure-Activity Relationship ,Cytochrome P-450 Enzyme System ,Drug Discovery ,Cytochrome P-450 Enzyme Inhibitors ,Humans ,heterocyclic compounds ,Protein kinase A ,Protein Kinase Inhibitors ,chemistry.chemical_classification ,Molecular Structure ,biology ,Chemistry ,food and beverages ,Biological activity ,Enzyme ,Enzyme inhibitor ,Drug Design ,Mitogen-activated protein kinase ,Oxepins ,biology.protein ,Molecular Medicine ,Signal transduction - Abstract
The pathogenesis of chronic inflammatory diseases is promoted by various pro-inflammatory cytokines. p38 MAP kinase seems to be a valid target as it controls proinflammatory cytokine levels on both transcriptional and translational levels. Starting from benzophenone-type inhibitors, a rigidisation strategy lead to 3-amino-6,11-dihydro-dibenzo[b,e]thiepin-11-one, phenylamino-substituted 6,11-dihydro-dibenzo[b,e]oxepin-11-ones, and dibenzo[a,d]cyclohepten-5-ones. Synthesis, p38 inhibition, and CYP-inhibition of selected compounds are described.
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- 2006
177. The Role of Asynchronous Bond Formation in the Diastereoselective Epoxidation of Cyclic Enol Ethers: A Density Functional Theory Study
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Jon D. Rainier, Anita M. Orendt, and S. W. Roberts
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Models, Molecular ,chemistry.chemical_classification ,Cyclic compound ,Molecular Structure ,Stereochemistry ,Organic Chemistry ,Substitution (logic) ,Stereoisomerism ,Bond formation ,Enol ,chemistry.chemical_compound ,Models, Chemical ,chemistry ,Cyclization ,Ethers, Cyclic ,Computational chemistry ,Oxepins ,Enol ether ,Epoxy Compounds ,Thermodynamics ,Density functional theory ,Dimethyldioxirane ,Basis set ,Pyrans - Abstract
Density functional theory (DFT) (Becke3LYP functional and the D95** basis set) was used to study the influence of substitution on the dimethyldioxirane epoxidation reaction of six- and seven-membered cyclic enol ethers. In agreement with our previously reported experimental results, the calculations predict that substitution on the cyclic enol ether influences the level of diastereoselectivity. Apparent only from the calculations is that the degree of synchronicity in the transition state is important in the diastereoselectivity.
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- 2006
178. Inhibition of Human Acetyl- and Butyrylcholinesterase by Novel Carbamates of (−)- and (+)-Tetrahydrofurobenzofuran and Methanobenzodioxepine
- Author
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and Arnold Brossi, Harold W. Holloway, Damon A. Parrish, David Tweedie, Qian-sheng Yu,†,‡, Debomoy K. Lahiri, Weiming Luo, Nigel H. Greig, Avigdor Shafferman, and Santosh S. Kulkarni
- Subjects
Models, Molecular ,Stereochemistry ,Stereoisomerism ,Crystallography, X-Ray ,Torpedo ,Article ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,Furans ,Butyrylcholinesterase ,Benzofurans ,Cholinesterase ,chemistry.chemical_classification ,biology ,Acetophenones ,Acetylcholinesterase ,Enzyme ,chemistry ,Biochemistry ,Enzyme inhibitor ,Oxepins ,biology.protein ,Molecular Medicine ,Carbamates ,Cholinesterase Inhibitors ,Enantiomer ,Heterocyclic Compounds, 3-Ring - Abstract
A new enantiomeric synthesis utilizing classical resolution provided two novel series of optically active inhibitors of cholinesterase: (-)- and (+)-O-carbamoyl phenols of tetrahydrofurobenzofuran and methanobenzodioxepine. An additional two series of (-)- and (+)-O-carbamoyl phenols of pyrroloindole and furoindole were obtained by known procedures, and their anticholinesterase actions were similarly quantified against freshly prepared human acetyl- (AChE) and butyrylcholinesterase (BChE). Both enantiomeric forms of each series demonstrated potent cholinesterase inhibitory activity (with IC(50) values as low as 10 nM for AChE and 3 nM for BChE), with the exception of the (+)-O-carbamoyl phenols of pyrroloindole, which lacked activity (IC(50) values >1 microM). Based on the biological data of these four series, a structure-activity relationship (SAR) analysis was provided by molecular volume calculations. In addition, a probable transition-state model was established according to the known X-ray structure of a transition-state complex of Torpedo californica AChE-m-(N,N,N-trimethylammonio)-2,2,2-trifluoroacetophenone (TcAChE-TMTFA). This model proved valuable in explaining the enantioselectivity and enzyme subtype selectivity of each series. These carbamates are more potent than, or similarly potent to, anticholinesterases in current clinical use, providing not only inhibitors of potential clinical relevance but also pharmacological tools to define drug-enzyme binding interactions within an enzyme crucial in the maintenance of cognition and numerous systemic physiological functions in health, aging, and disease.
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- 2006
179. High-resolution structure of human<scp>D</scp>-glyceraldehyde-3-phosphate dehydrogenase
- Author
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Jermaine L. Jenkins and John J. Tanner
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Models, Molecular ,Protein Conformation ,Stereochemistry ,Placenta ,Ubiquitin-Protein Ligases ,Dehydrogenase ,Biology ,X-Ray Diffraction ,stomatognathic system ,Structural Biology ,Oxidoreductase ,Humans ,Cloning, Molecular ,Binding site ,Glyceraldehyde 3-phosphate dehydrogenase ,chemistry.chemical_classification ,Binding Sites ,Ubiquitin ,Glyceraldehyde-3-Phosphate Dehydrogenases ,Nuclear Proteins ,Active site ,General Medicine ,Ubiquitin ligase ,chemistry ,Docking (molecular) ,Oxepins ,biology.protein ,Female ,NAD+ kinase - Abstract
GAPDH (D-glyceraldehyde-3-phosphate dehydrogenase) is a multifunctional protein that is a target for the design of antitrypanosomatid and anti-apoptosis drugs. Here, the first high-resolution (1.75 Angstroms) structure of a human GAPDH is reported. The structure shows that the intersubunit selectivity cleft that has been leveraged in the design of antitrypanosomatid compounds is closed in human GAPDH. Modeling of an anti-trypanosomatid GAPDH inhibitor in the human GAPDH active site provides insights into the basis for the observed selectivity of this class of inhibitor. Moreover, the high-resolution data reveal a new feature of the cleft: water-mediated intersubunit hydrogen bonds that assist closure of the cleft in the human enzyme. The structure is used in a computational ligand-docking study of the small-molecule compound CGP-3466, which inhibits apoptosis by preventing nuclear accumulation of GAPDH. Plausible binding sites are identified in the adenosine pocket of the NAD(+)-binding site and in a hydrophobic channel located in the center of the tetramer near the intersection of the three molecular twofold axes. The structure is also used to build a qualitative model of the complex between GAPDH and the E3 ubiquitin ligase Siah1. The model suggests that the convex surface near GAPDH Lys227 interacts with a large shallow groove of the Siah1 dimer. These results are discussed in the context of the recently discovered NO-S-nitrosylation-GAPDH-Siah1 apoptosis cascade.
- Published
- 2006
180. The use of LC/MS, GC/MS, and LC/NMR hyphenated techniques to identify a drug degradation product in pharmaceutical development
- Author
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Donald Drinkwater, Changkang Pan, Frances Liu, Wei Wang, Qin Ji, and Richard Victor Vivilecchia
- Subjects
Chemical ionization ,Magnetic Resonance Spectroscopy ,Chromatography ,Chemistry ,Electrospray ionization ,Clinical Biochemistry ,Pharmaceutical Science ,Stereoisomerism ,Atmospheric-pressure chemical ionization ,Mass spectrometry ,Gas Chromatography-Mass Spectrometry ,Mass Spectrometry ,Analytical Chemistry ,Pharmaceutical Preparations ,Liquid chromatography–mass spectrometry ,Oxepins ,Selegiline ,Drug Discovery ,Solid phase extraction ,Direct electron ionization liquid chromatography–mass spectrometry interface ,Gas chromatography–mass spectrometry ,Drug Contamination ,Spectroscopy ,Chromatography, Liquid - Abstract
Understanding drug degradation in the formulated product is critical in pharmaceutical development as it has significant impacts on drug efficacy, safety profile and storage conditions. As a result, identification of degradation compounds has taken an important role in the drug development process. In this study, various hyphenated analytical techniques, such as liquid chromatography mass spectrometry (LC/MS), gas chromatography mass spectrometry (GC/MS), and liquid chromatography nuclear magnetic resonance with a solid phase extraction interface (LC/SPE/NMR), have been applied to the identification of a drug degradation product which grew over time in the stability study of the drug product. The target unknown is less polar and more unsaturated than the drug substance based upon reverse phase HPLC relative retention time and UV spectra. It is not ionizable by electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI) in either a positive or a negative mode. The unknown was isolated by an HPLC fraction collector and enriched by solid phase extraction. GC/MS with chemical ionization (CI) was employed to determine the molecular weight of this compound. Its fragmentation pattern was determined by CI-MS/MS using an ion trap mass spectrometer. The isolated material was also analyzed by LC/SPE/NMR, from which the structure of this compound was further characterized. The study utilizes a combination of various hyphenated analytical techniques to obtain complimentary information for structure elucidation of the unknown. The combination approach is critical for unambiguous impurity structure elucidation in drug degradation studies of pharmaceutical drug products.
- Published
- 2006
181. Boron Trifluoride-Induced, New Stereospecific Rearrangements of Chiral Epoxy Ethers. Ready Access to Enantiopure 4-(Diarylmethyl)-1,3-dioxolanes and 4,5-Disubstituted Tetrahydrobenzo[c]oxepin-4-ols
- Author
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Gabriela Islas‐Gonzalez, Jordi Benet-Buchholz, Antoni Riera, Miquel A. Pericàs, and Miguel A. Maestro
- Subjects
Aryl ,Organic Chemistry ,Epoxide ,Dioxolanes ,Stereoisomerism ,Ether ,Medicinal chemistry ,chemistry.chemical_compound ,Enantiopure drug ,chemistry ,Oxepins ,Benzene Derivatives ,Polar effect ,Benzyl group ,Epoxy Compounds ,Boranes ,Friedel–Crafts reaction ,Boron trifluoride ,Ethers - Abstract
Upon treatment with BF3·Et2O at low temperature, enantiopure benzyl-type ethers of arylglycidols with electron withdrawing substituents at the skeletal aryl group and electron donating substituents at the benzyl group undergo stereospecific rearrangements of Friedel−Crafts type, leading to enantiopure 4-diarylmethyl-1,3-dioxolanes (2) or to enantiopure trans-4,5 disubstituted tetrahydrobenzo[c]oxepin-4-ols (5). The course of the reactions is controlled by the substitution pattern at the benzyl ether: While benzylic systems activated toward ipso substitution afford diarylmethanes 2 through a Friedel−Crafts reaction followed by fragmentation, benzylic systems activated toward ortho attack lead to enantiopure oxepinols 5 through a 7-endo-tet ring closure of Friedel−Crafts type.
- Published
- 2006
182. Investigation of Selective Mono-deallylation of O,O'-Diallylcatechols and 3-Methylene-1,5-benzodioxepanes
- Author
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Miyuki Ishizaki, Hiroshi Hara, and Maiko Hayashida
- Subjects
Alkylation ,Molecular Structure ,Chemistry ,Catechols ,Regioselectivity ,Stereoisomerism ,Ether ,General Chemistry ,General Medicine ,Ring (chemistry) ,Medicinal chemistry ,Carbon ,Allyl Compounds ,chemistry.chemical_compound ,Oxepins ,Drug Discovery ,Polymer chemistry ,Methylene ,Selectivity ,Benzene ,Palladium - Abstract
Selective mono-deallylation of O,O'-diallylcatechols using 10% Pd/C was investigated to give the correspond-ing allylphenols. A similar reaction of 3-methylene-1,5-benzodioxepanes afforded O-methacryl catecohols. When substrates bearing various substituents on the benzene ring were subjected to the reaction, regioselective cleavage of an ether bond occurred at the side of para position to an electron-withdrawing group on the aromatic ring. On the other hand, an electron-donating group did not cause any selectivity.
- Published
- 2006
183. Nitric Oxide-GAPDH Transcriptional Signaling Mediates Behavioral Actions of Cocaine
- Author
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Solomon H. Snyder and Maged M. Harraz
- Subjects
medicine.medical_treatment ,Ubiquitin-Protein Ligases ,Pharmacology ,CREB ,Nitric Oxide ,Article ,Nitric oxide ,chemistry.chemical_compound ,Cocaine ,Dopamine Uptake Inhibitors ,Dopamine ,medicine ,Animals ,Humans ,biology ,General Neuroscience ,Nitrosylation ,Neurotoxicity ,Glyceraldehyde-3-Phosphate Dehydrogenases ,Nuclear Proteins ,medicine.disease ,Stimulant ,Monoamine neurotransmitter ,chemistry ,Oxepins ,biology.protein ,Signal transduction ,medicine.drug ,Signal Transduction - Abstract
Psychotropic actions of cocaine are generally thought to involve its blockade of monoamine transporters leading to increased synaptic levels of monoamines, especially dopamine. Subsequent intracellular events have been less well characterized. We describe a signaling system wherein lower behavioral stimulant doses of cocaine, as well as higher neurotoxic doses, activate a cascade wherein nitric oxide nitrosylates glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to generate a complex with the ubiquitin-E3-ligase Siah1 which translocates to the nucleus. With lower cocaine doses, nuclear GAPDH augments CREB signaling, while at higher doses p53 signaling is enhanced. The drug CGP3466B very potently blocks GAPDH nitrosylation, hindering both signaling cascades and inhibits both behavioral activating and neurotoxic effects of cocaine. This system affords potentially novel approaches to the therapy of cocaine abuse.
- Published
- 2014
184. Expressions of cytokines and chemokines in the dorsal motor nucleus of the vagus nerve after right vagotomy
- Author
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Bei Ping He, S. Thameem Dheen, Jun Feng Ji, Samuel Sam Wah Tay, and S Dinesh Kumar
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Male ,Chemokine ,medicine.medical_specialty ,Time Factors ,medicine.medical_treatment ,Cell Count ,Naphthalenes ,Vagotomy ,Functional Laterality ,Cellular and Molecular Neuroscience ,Parasympathetic nervous system ,Lectins ,Internal medicine ,medicine ,Animals ,RNA, Messenger ,Rats, Wistar ,Molecular Biology ,Medulla Oblongata ,biology ,Microglia ,Reverse Transcriptase Polymerase Chain Reaction ,Immunohistochemistry ,Rats ,Vagus nerve ,medicine.anatomical_structure ,Endocrinology ,Cytokine ,Dorsal motor nucleus ,Gene Expression Regulation ,Oxepins ,Immunology ,biology.protein ,Cytokines ,Tumor necrosis factor alpha ,Chemokines - Abstract
The aim of this study was to investigate the expression of cytokines, tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1beta), interleukin-6 (IL-6) and transforming growth factor-beta 1 (TGF-beta1) and chemokines, fractalkine, monocyte chemoattractant protein 1 (MCP-1) and stromal cell-derived factor 1 (SDF-1) in the dorsal motor nucleus of the vagus nerve (DMV) after right vagotomy. Results showed that the immunoreactivities of IL-1beta, IL-6, TGF-beta1, fractalkine and MCP-1 were upregulated in the DMV at 14 days and the upregulation persisted at least until 28 days following right vagotomy. Quantification analysis revealed significant increases in the number of their immunopositive cells in the right DMV at 14 and 28 days after right vagotomy. Moreover, the upregulation of TNF-alpha immunoreactivity and significantly increased number of TNF-alpha-immunopositive cells were observed in the injured DMV at 7 and 14 days, and the increase in SDF-1-immunopositive cells at 14 days, after right vagotomy. Real time RT-PCR analysis showed the significant increase in the mRNA expression of IL-1beta, fractalkine and MCP-1 at 7 days, and the upregulation of TNF-alpha mRNA expression at 1 day after vagotomy. However, the peak increase in TGF-beta1 mRNA expression was observed at 1 day and the significant increase persisted at least until 14 days following right vagotomy. Double immunofluorescence analysis showed co-localization of lectin, a marker for microglia with CX3CR1 but not with IL-1beta at 14 days following right vagotomy. This study suggests that cytokines and chemokines involved in neuroprotection and neurodestruction could be activated in the axotomized DMV. However, it warrants further investigation to understand the neurodestructive and neuroprotective mechanisms that determine the fate of the vagal motoneurons after vagotomy.
- Published
- 2005
185. Anticipating the Effects of Gravity When Intercepting Moving Objects: Differentiating Up and Down Based on Nonvisual Cues
- Author
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Myrka Zago, Francesco Lacquaniti, Patrice Senot, and Joseph McIntyre
- Subjects
visual field ,Male ,Gravity (chemistry) ,Physiology ,Computer science ,proprioception ,Acoustics ,Motion Perception ,Naphthalenes ,volunteer ,Gravitational acceleration ,Settore BIO/09 ,Motion (physics) ,human experiment ,Gravitation ,Acceleration ,Racket ,Reaction Time ,Humans ,Attention ,Computer Simulation ,human ,normal human ,computer.programming_language ,stereoscopic vision ,vestibular system ,General Neuroscience ,article ,acceleration ,deceleration ,microgravity ,gravity ,female ,priority journal ,kinematics ,Oxepins ,Ball (bearing) ,virtual reality ,Cues ,Falling (sensation) ,male ,mathematical model ,Female ,Proprioception ,Psychomotor Performance ,computer - Abstract
Intercepting an object requires a precise estimate of its time of arrival at the interception point (time to contact or “TTC”). It has been proposed that knowledge about gravitational acceleration can be combined with first-order, visual-field information to provide a better estimate of TTC when catching falling objects. In this experiment, we investigated the relative role of visual and nonvisual information on motor-response timing in an interceptive task. Subjects were immersed in a stereoscopic virtual environment and asked to intercept with a virtual racket a ball falling from above or rising from below. The ball moved with different initial velocities and could accelerate, decelerate, or move at a constant speed. Depending on the direction of motion, the acceleration or deceleration of the ball could therefore be congruent or not with the acceleration that would be expected due to the force of gravity acting on the ball. Although the best success rate was observed for balls moving at a constant velocity, we systematically found a cross-effect of ball direction and acceleration on success rate and response timing. Racket motion was triggered on average 25 ms earlier when the ball fell from above than when it rose from below, whatever the ball's true acceleration. As visual-flow information was the same in both cases, this shift indicates an influence of the ball's direction relative to gravity on response timing, consistent with the anticipation of the effects of gravity on the flight of the ball.
- Published
- 2005
186. Serotonergic 5-HT2A receptor stimulation induces steroid 5α-reductase gene expression in rat C6 glioma cells via transcription factor Egr-1
- Author
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Hideki Arimochi, Song Her, and Kyoji Morita
- Subjects
Serotonin ,medicine.medical_specialty ,Time Factors ,Neuroactive steroid ,Blotting, Western ,Gene Expression ,Stimulation ,Naphthalenes ,Biology ,Serotonergic ,Reuptake ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,3-Oxo-5-alpha-Steroid 4-Dehydrogenase ,Cell Line, Tumor ,Internal medicine ,medicine ,Animals ,Receptor, Serotonin, 5-HT2A ,RNA, Messenger ,Neurotransmitter ,Molecular Biology ,Early Growth Response Protein 1 ,Regulation of gene expression ,Dose-Response Relationship, Drug ,Reverse Transcriptase Polymerase Chain Reaction ,Glioma ,Blotting, Northern ,Rats ,Endocrinology ,medicine.anatomical_structure ,Gene Expression Regulation ,chemistry ,Oxepins ,Neuroglia ,Oligoribonucleotides, Antisense - Abstract
Selective serotonin reuptake inhibitors (SSRIs) are widely used for the treatment of depressive mood disorders and well known to inhibit the reuptake of neurotransmitter serotonin into nerve terminals. Thus, it seems conceivable that these drugs may induce the outflow of serotonin from the synapse as a consequence of inhibiting the reuptake, resulting in the stimulation of glial cells surrounding nerve terminals. On this hypothesis, the effect of serotonin on steroid 5alpha-reductase type 1 (5alpha-R) gene expression in rat C6 glioma cells was examined as one of the in vitro model experiments for investigating the indirect influence of SSRIs on glial cells. Serotonin elevated 5alpha-R mRNA and protein levels through the stimulation of serotonin 5-HT2A receptors, and also elevated Egr-1 mRNA and protein levels prior to 5alpha-R gene expression in the glioma cells. Furthermore, serotonin failed to significantly increase 5alpha-R mRNA levels in the cells preloaded with the antisense oligodeoxynucleotide targeted on Egr-1 gene. These results indicate that serotonin may stimulate 5alpha-R gene expression via transcription factor Egr-1 in glial cells, thus suggesting that serotonin flowing out of the serotonergic synapse may be implicated in SSRI-induced changes in neurosteroid metabolism in brain.
- Published
- 2005
187. Neuronal cell loss accompanies the brain tissue response to chronically implanted silicon microelectrode arrays
- Author
-
Patrick A. Tresco, Roy Biran, and David C. Martin
- Subjects
Diagnostic Imaging ,Male ,Silicon ,Time Factors ,Central nervous system ,Cell Count ,Nerve fiber ,Naphthalenes ,Biology ,Developmental Neuroscience ,Neurofilament Proteins ,Glial Fibrillary Acidic Protein ,medicine ,Animals ,Premovement neuronal activity ,Gliosis ,Neuroinflammation ,Inflammation ,Neurons ,Cell Death ,Macrophages ,Brain ,Membrane Proteins ,Multielectrode array ,Ectodysplasins ,Immunohistochemistry ,Rats, Inbred F344 ,Electrodes, Implanted ,Rats ,Cortex (botany) ,Microelectrode ,medicine.anatomical_structure ,Neurology ,Astrocytes ,Phosphopyruvate Hydratase ,Oxepins ,Cytokines ,Implant ,Neuroscience ,Biomedical engineering - Abstract
Implantable silicon microelectrode array technology is a useful technique for obtaining high-density, high-spatial resolution sampling of neuronal activity within the brain and holds promise for a wide range of neuroprosthetic applications. One of the limitations of the current technology is inconsistent performance in long-term applications. Although the brain tissue response is believed to be a major cause of performance degradation, the precise mechanisms that lead to failure of recordings are unknown. We observed persistent ED1 immunoreactivity around implanted silicon microelectrode arrays implanted in adult rat cortex that was accompanied by a significant reduction in nerve fiber density and nerve cell bodies in the tissue immediately surrounding the implanted silicon microelectrode arrays. Persistent ED1 up-regulation and neuronal loss was not observed in microelectrode stab controls indicating that the phenotype did not result from the initial mechanical trauma of electrode implantation, but was associated with the foreign body response. In addition, we found that explanted electrodes were covered with ED1/MAC-1 immunoreactive cells and that the cells released MCP-1 and TNF-alpha under serum-free conditions in vitro. Our findings suggest a potential new mechanism for chronic recording failure that involves neuronal cell loss, which we speculate is caused by chronic inflammation at the microelectrode brain tissue interface.
- Published
- 2005
188. The role of prolactin and testosterone in mediating seasonal differences in the self-grooming behavior of male meadow voles, Microtus pennsylvanicus
- Author
-
Michael H. Ferkin, Stuart T. Leonard, Reza Alizadeh-Naderi, and Kristen Stokes
- Subjects
Male ,medicine.medical_specialty ,Time Factors ,medicine.drug_class ,Photoperiod ,Zoology ,Experimental and Cognitive Psychology ,Naphthalenes ,Behavioral Neuroscience ,Internal medicine ,medicine ,Seasonal breeder ,Animals ,Testosterone ,Castration ,Microtus ,photoperiodism ,Behavior, Animal ,biology ,Arvicolinae ,biology.organism_classification ,Androgen ,Grooming ,Prolactin ,Endocrinology ,Odor ,Odorants ,Oxepins ,Female ,Vole ,Seasons ,psychological phenomena and processes - Abstract
Self-grooming in response to the odors of conspecifics is a form of olfactory communication among meadow voles. The amount of time meadow voles spend self-grooming when they encounter the odors of conspecifics varies seasonally, with males targeting the odors of reproductively active females only during the breeding season. Other odor related behaviors in male voles such as odor preferences for conspecifics and the attractiveness of their odors to conspecifics vary seasonally as well. For male meadow voles, these behaviors are mediated by seasonal variations in testosterone (T) and prolactin (PRL) titers. The objective of this study was to determine whether seasonal differences in the amount of time male meadow voles self-groom in response to odors of conspecifics are mediated by seasonal rhythms in their circulating T and PRL titers. We tested the hypothesis that high titers of both T and PRL are necessary for reproductively active (long-photoperiod; LP) males and sufficient for reproductively quiescent (short-photoperiod; SP) male voles to spend more time self-grooming in response to odors of LP females than to those of other conspecifics. Results of this study demonstrate that high titers of PRL and T are necessary for LP male meadow vole to self-groom more in response to odors of LP females as compared to those of other conspecifics, but were not sufficient to induce SP males to preferentially self-groom to odors of LP females. The endocrine control of self-grooming by LP males appears to depend upon high titers of both PRL and T, which matches the endocrine mediation of other odor related behaviors in male voles. In contrast, the endocrine tissues that underlie self-grooming in SP male meadow voles appear to be refractory to the effects of LP-equivalent titers of PRL and T.
- Published
- 2005
189. Syntheses of Tetrahydrofurobenzofurans and Dihydromethanobenzodioxepines from 5-Hydroxy-3-methyl-3H-benzofuran-2-one. Rearrangement and Ring Expansion under Reductive Conditions on Treatment with Hydrides
- Author
-
Damon A. Parrish, Arnold Brossi, Nigel H. Greig, Weiming Luo, Harold W. Holloway, and Qian-Sheng Yu
- Subjects
Hot Temperature ,Magnetic Resonance Spectroscopy ,Molecular Structure ,Stereochemistry ,Organic Chemistry ,General Medicine ,Nuclear magnetic resonance spectroscopy ,Ring (chemistry) ,Acetylcholinesterase ,Medicinal chemistry ,Chemical synthesis ,chemistry.chemical_compound ,chemistry ,Oxepins ,Cholinesterases ,Hemiacetal ,Reactivity (chemistry) ,Cholinesterase Inhibitors ,Pyruvic acid ,Phenols ,Benzofuran ,Butyrylcholinesterase ,Benzofurans - Abstract
5-Hydroxy-3-methyl-3H-benzofuran-2-one, 5, easily obtained from pyruvic acid and 1,4-cyclohexanedione, was used as a starting material to prepare (+/-)-5-hydroxy-3a-methyl-2,3,3a,8a-tetrahydro-furo[2,3-b]benzofuran, 10, and (+/-)-7-hydroxy-5-methyl-4,5-dihydro-2,5-methano-1,3-benzodioxepine, 14. Reduced reactivity relative to 5-hydroxy-3-methoxycarbonylmethylene-3-methyl-3H-benzofuran-2-one, 6, was preliminarily studied. Meanwhile, a plausible mechanism with regard to the formation of 10 and 14, which included cyclization, rearrangement, and ring expansion of hemiacetal, 15, is proposed. Specific carbamates of phenols, 10 and 14, have shown impressive inhibitory activities against human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) ex vivo.
- Published
- 2005
190. Stereoselective Lewis Acid Mediated [1,3] Ring Contraction of 2,5-Dihydrooxepins as a Route to Polysubstituted Cyclopentenes
- Author
-
Tomislav Rovis and Christopher G. Nasveschuk
- Subjects
Contraction (grammar) ,Molecular Structure ,Extramural ,Chemistry ,Stereochemistry ,Stereoisomerism ,Cyclopentanes ,General Chemistry ,General Medicine ,Catalysis ,chemistry.chemical_compound ,Cyclization ,Oxepins ,Cyclopentene ,Stereoselectivity ,Lewis acids and bases - Published
- 2005
191. Neuronal nitric oxide synthase inhibition differentially affects oxytocin and vasopressin secretion in salt loaded rats
- Author
-
Alexandre Giusti-Paiva, José Antunes-Rodrigues, Dayane Aparecida Gomes, Lucila Leico Kagohara Elias, and Renato Rizo Ventura
- Subjects
Male ,endocrine system ,Vasopressin ,medicine.medical_specialty ,Indazoles ,Time Factors ,7-Nitroindazole ,Vasopressins ,Radioimmunoassay ,Neuropeptide ,Naphthalenes ,Oxytocin ,Tritium ,Supraoptic nucleus ,Nitric oxide ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Drug Interactions ,Rats, Wistar ,Sodium Chloride, Dietary ,biology ,Chemistry ,General Neuroscience ,Osmolar Concentration ,Rats ,Nitric oxide synthase ,Endocrinology ,nervous system ,Vasopressin secretion ,Oxepins ,biology.protein ,Citrulline ,Nitric Oxide Synthase ,Supraoptic Nucleus ,hormones, hormone substitutes, and hormone antagonists ,Paraventricular Hypothalamic Nucleus ,medicine.drug - Abstract
Nitric oxide, an endogenous gas produced by nitric oxide synthase (NOS), has been described as a neuromodulator of hormone secretion, including the neurohypophysial peptides oxytocin (OT) and vasopressin (AVP), hormones involved in the sodium and water homeostasis. The presence of NOS in the hypothalamic nuclei as well as in the circumventricular organs suggests a nitrergic regulation of OT and AVP secretion. Thus, the aim of this study was to evaluate the effect of 7-nitroindazole (7-NI), a selective inhibitor of neuronal NOS, in the plasma OT and AVP levels in rats submitted to a short and long-term salt loading. We also evaluated the NOS activity in the supraoptic (SON) and paraventricular (PVN) hypothalamic nuclei. Our data showed an increase of plasma OT and AVP levels in both short and long-term salt loading. The augment of plasma OT and AVP levels was accompanied by an increase of NOS activity in the SON and PVN. The injection of 7-NI potentiated the increase of plasma OT induced by salt loading, but inhibited the increase of plasma AVP in the same experimental conditions. These results indicate that, under short and prolonged osmotic stimulation, nitric oxide may differentially control the neurohypophysial secretion.
- Published
- 2005
192. Effect of cell-density on in-vitro dopaminergic differentiation of mesencephalic precursor cells
- Author
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Ji Yun Ko, Sang-Hun Lee, Chang-Hwan Park, and Ji-Yeon Lee
- Subjects
medicine.medical_specialty ,Time Factors ,Tyrosine 3-Monooxygenase ,Dopamine ,Cellular differentiation ,Blotting, Western ,Population ,Cell Count ,Naphthalenes ,Biology ,chemistry.chemical_compound ,Mesencephalon ,Tubulin ,Precursor cell ,Internal medicine ,Glial Fibrillary Acidic Protein ,medicine ,Animals ,RNA, Messenger ,education ,Neurotransmitter ,Cells, Cultured ,Cell Proliferation ,Neurons ,education.field_of_study ,Reverse Transcriptase Polymerase Chain Reaction ,Stem Cells ,General Neuroscience ,Dopaminergic ,Brain ,Cell Differentiation ,Embryo, Mammalian ,Immunohistochemistry ,Coculture Techniques ,Neural stem cell ,Rats ,Cell biology ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Culture Media, Conditioned ,Oxepins ,Neuron ,medicine.drug - Abstract
Neural precursor cells isolated from early embryonic mesencephalon are in-vitro expanded and differentiated toward dopamine neurons. However, conditions for controlled conversion of the precursors into dopamine neurons largely remained to be determined. We here examined the effects of plating cell density and duration of in-vitro cell expansion on the precursors-derived dopamine differentiation. The yield of dopamine neurons from cultured mesencephalic precursors was greater when the cells were initially plated at higher density. Soluble factors secreted from the precursors appeared to be responsible for the cell density effect. We further demonstrated that the dopamine differentiation potential of the precursors was lost after a long-term cell expansion. Therefore, in order to attain high percentage of dopamine neuron population in mesencephalic precursor cultures, cultures need to be seeded at high cell density and to be expanded for a short period of time.
- Published
- 2005
193. Sequential Cyclization−Elimination Route to Carbohydrate-Based Oxepines
- Author
-
Mark W. Peczuh and Steve Castro
- Subjects
chemistry.chemical_classification ,Magnetic Resonance Spectroscopy ,Molecular Structure ,Stereochemistry ,Organic Chemistry ,Acetal ,Carbohydrates ,Metathesis ,Aldehyde ,Chemical synthesis ,Catalysis ,chemistry.chemical_compound ,Hydroboration ,Elimination reaction ,Pyranose ,chemistry ,Cyclization ,Oxepins ,Swern oxidation ,Organic chemistry ,Indicators and Reagents ,Oxidation-Reduction - Abstract
A five-step preparation of carbohydrate-based oxepines from hept-1-enitols is presented. The hept-1-enitols were subjected to silyl protection and hydroboration/oxidation to give the protected heptan-1-itols. Swern oxidation of the homologated alcohols followed by sequential acetal formation/cyclization provided methyl 2-deoxyseptanosides that underwent elimination reactions to give the carbohydrate-based oxepines. The new sequence is an alternative to the ring-closing metathesis for the synthesis of carbohydrate-based oxepines from protected pyranose sugars. The product oxepines can serve as glycosyl donors in the synthesis of novel septanose carbohydrates. In addition, C-methylenealdehydo arabinofuranoside 16 was formed from 2-deoxyseptanoside 10 as the only product during protic acid mediated elimination reactions. This novel ring contraction complements other reported preparations of C-methylenaldehydo furanosides and underscores the acid-mediated reactivity introduced by competing eliminations between the C-1/C-2 and C-2/C-3 bonds.
- Published
- 2005
194. Endothelial Nitric Oxide Synthase Regulates Brain-Derived Neurotrophic Factor Expression and Neurogenesis after Stroke in Mice
- Author
-
Chunling Zhang, Alex Zacharek, Mei Lu, Hao Jiang, Cynthia Roberts, Michael Chopp, Alissa Kapke, Jieli Chen, and Yi Li
- Subjects
Doublecortin Domain Proteins ,Male ,Vascular Endothelial Growth Factor A ,Time Factors ,Angiogenesis ,Basic fibroblast growth factor ,Gene Expression ,Blood Pressure ,Cell Count ,Nestin ,Mice ,chemistry.chemical_compound ,Intermediate Filament Proteins ,Cell Movement ,Neurotrophic factors ,Telomerase ,Mice, Knockout ,Neurologic Examination ,General Neuroscience ,Brain ,Infarction, Middle Cerebral Artery ,Immunohistochemistry ,Vascular endothelial growth factor ,Endothelial stem cell ,Vascular endothelial growth factor A ,medicine.anatomical_structure ,Microtubule-Associated Proteins ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Subventricular zone ,Enzyme-Linked Immunosorbent Assay ,Nerve Tissue Proteins ,Naphthalenes ,Biology ,Article ,Internal medicine ,Neurites ,medicine ,Animals ,Corneal Neovascularization ,Cell Proliferation ,Brain-derived neurotrophic factor ,Brain-Derived Neurotrophic Factor ,Neuropeptides ,Endothelial Cells ,Recovery of Function ,Mice, Inbred C57BL ,Disease Models, Animal ,Ki-67 Antigen ,Endocrinology ,Bromodeoxyuridine ,nervous system ,chemistry ,Oxepins ,Immunology ,Psychomotor Performance - Abstract
Here, we investigate the effects of endothelial nitric oxide synthase (eNOS) on angiogenesis, neurogenesis, neurotrophic factor expression, and neurological functional outcome after stroke. Wild-type and eNOS knock-out (eNOS-/-) mice were subjected to permanent occlusion of the right middle cerebral artery.eNOS-/-mice exhibited more severe neurological functional deficit after stroke than wild-type mice. Decreased subventricular zone (SVZ) progenitor cell proliferation and migration, measured using bromodeoxyuridine, Ki-67, nestin, and doublecortin immunostaining in the ischemic brain, and decreased angiogenesis, as demonstrated by reduced endothelial cell proliferation, vessel perimeter, and vascular density in the ischemic border, were evident ineNOS-/-mice compared with wild-type mice. eNOS-deficient mice also exhibited a reduced response to vascular endothelial growth factor (VEGF)-induced angiogenesis in a corneal assay. ELISAs showed thateNOS-/-mice have decreased brain-derived neurotrophic factor (BDNF) expression but not VEGF and basic fibroblast growth factor in the ischemic brain compared with wild-type mice. In addition, cultured SVZ neurosphere formation, proliferation, telomerase activity, and neurite outgrowth but not cell viability fromeNOS-/-mice were significantly reduced compared with wild-type mice. BDNF treatment of SVZ cells derived fromeNOS-/-mice restored the decreased neurosphere formation, proliferation, neurite outgrowth, and telomerase activity in culturedeNOS-/-SVZ neurospheres. SVZ explant cell migration also was significantly decreased ineNOS-/-mice compared with wild-type mice. These data indicate that eNOS is not only a downstream mediator for VEGF and angiogenesis but also regulates BDNF expression in the ischemic brain and influences progenitor cell proliferation, neuronal migration, and neurite outgrowth and affects functional recovery after stroke.
- Published
- 2005
195. Early Alcohol Exposure Induces Persistent Alteration of Cortical Columnar Organization and Reduced Orientation Selectivity in the Visual Cortex
- Author
-
Alexandre E. Medina, Ary S. Ramoa, and Thomas E. Krahe
- Subjects
Diagnostic Imaging ,Male ,Time Factors ,Physiology ,Fetal alcohol syndrome ,Action Potentials ,Cell Count ,Sensory system ,Naphthalenes ,Alcohol exposure ,Orientation (mental) ,Orientation ,medicine ,Animals ,Cerebral Cortex ,Neurons ,Brain Mapping ,Neuronal Plasticity ,Ethanol ,Critical Period, Psychological ,General Neuroscience ,Age Factors ,Ferrets ,Central Nervous System Depressants ,medicine.disease ,Visual cortex ,medicine.anatomical_structure ,Animals, Newborn ,Oxepins ,Female ,Psychology ,Neuroscience - Abstract
Fetal alcohol syndrome (FAS) is a major cause of learning and sensory deficits in children. The visual system in particular is markedly affected, with an elevated prevalence of poor visual perceptual skills. Developmental problems involving the neocortex are likely to make a major contribution to some of these abnormalities. Neuronal selectivity to stimulus orientation, a functional property thought to be crucial for normal vision, may be especially vulnerable to alcohol exposure because it starts developing even before eye opening. To address this issue, we examined the effects of early alcohol exposure on development of cortical neuron orientation selectivity and organization of cortical orientation columns. Ferrets were exposed to ethanol starting at postnatal day (P) 10, when the functional properties and connectivity of neocortical neurons start to develop. Alcohol exposure ended at P30, just before eye opening at P32. Following a prolonged alcohol-free period (15–35 days), long-term effects of early alcohol exposure on cortical orientation selectivity were examined at P48–P65, when orientation selectivity in normal ferret cortex has reached a mature state. Optical imaging of intrinsic signals revealed decreased contrast of orientation maps in alcohol- but not saline-treated animals. Moreover, single-unit recordings revealed that early alcohol treatment weakened neuronal orientation selectivity while preserving robust visual responses. These findings indicate that alcohol exposure during a brief period of development disrupts cortical processing of sensory information at a later age and suggest a neurobiological substrate for some types of sensory deficits in FAS.
- Published
- 2005
196. Behavioral sensitization to binge-pattern cocaine administration is not associated with changes in protein levels of four major G-proteins
- Author
-
Joseph A. Schroeder, Shane A. Perrine, and Ellen M. Unterwald
- Subjects
Male ,Cingulate cortex ,medicine.medical_specialty ,Time Factors ,Gs alpha subunit ,G protein ,Blotting, Western ,In situ hybridization ,Motor Activity ,Naphthalenes ,Nucleus accumbens ,Biology ,Drug Administration Schedule ,Cellular and Molecular Neuroscience ,Cocaine ,Western blot ,Internal medicine ,Gene expression ,medicine ,Animals ,RNA, Messenger ,Anesthetics, Local ,Molecular Biology ,Sensitization ,Behavior, Animal ,medicine.diagnostic_test ,Reverse Transcriptase Polymerase Chain Reaction ,Heterotrimeric GTP-Binding Proteins ,Rats, Inbred F344 ,Rats ,medicine.anatomical_structure ,Endocrinology ,Gene Expression Regulation ,Oxepins ,Autoradiography ,Neuroscience - Abstract
Behavioral sensitization is a characteristic sequelae of repeated cocaine exposure. It likely occurs due to long-lasting neuroadaptations produced by cocaine, although the exact nature of these adaptations has yet to be defined. The goal of the present study was to determine if behavioral sensitization to cocaine is accompanied by alterations in G-protein levels. Adult male rats were administered cocaine or saline three times daily in a binge-pattern for 1, 3, or 14 days and activity monitored. Levels of four major G-protein alpha-subunits, Galphas, Galphaolf, Galphao and Galphai1, and their mRNAs were measured in the nucleus accumbens, caudate putamen, and cingulate/frontal cortex using Western blot analysis and in situ hybridization, respectively. Fourteen days of binge-pattern cocaine administration resulted in behavioral sensitization as evidenced by increased behavioral activity over the 14 days of drug exposure. Results demonstrated that Galphaolf mRNA expression was significantly reduced in the nucleus accumbens after 1, 3 or 14 days of cocaine, whereas Galphai1 mRNA was increased following 3, but not 1 or 14 days of cocaine in the caudate putamen, nucleus accumbens and cingulate cortex. Galphas and Galphao mRNA expression were not altered in any region investigated at any time point. In contrast to gene expression, protein levels of the four G-protein alpha-subunits were not significantly different from saline-injected rats in the caudate putamen, nucleus accumbens, or frontal cortex following 1, 3, or 14 days of cocaine administration. These results suggest that alterations in the level of G-proteins are not necessary for the development of cocaine-induced sensitization.
- Published
- 2005
197. Morphine withdrawal increases intrinsic excitability of oxytocin neurons in morphine-dependent rats
- Author
-
Javier E. Stern, Keshia Jackson, John A. Russell, Philip M. Bull, Gareth Leng, and Colin H. Brown
- Subjects
Narcotics ,Vasopressin ,medicine.medical_specialty ,Patch-Clamp Techniques ,Time Factors ,medicine.drug_class ,Narcotic Antagonists ,Hypothalamus ,Action Potentials ,(+)-Naloxone ,In Vitro Techniques ,Naphthalenes ,Oxytocin ,Supraoptic nucleus ,Rats, Sprague-Dawley ,Opioid receptor ,Internal medicine ,medicine ,Animals ,Drug Interactions ,Neurons ,Saline Solution, Hypertonic ,Morphine ,Naloxone ,Chemistry ,General Neuroscience ,Antagonist ,Rats ,Substance Withdrawal Syndrome ,medicine.anatomical_structure ,Endocrinology ,Oxepins ,Female ,Neuron ,Morphine Dependence ,medicine.drug - Abstract
To determine whether intrinsic mechanisms drive supraoptic nucleus oxytocin neuron excitation during morphine withdrawal, we calculated the probability of action potential (spike) firing with time after each spike for oxytocin neurons in morphine-naive and morphine-dependent rats in vivo and measured changes in intrinsic membrane properties in vitro. The opioid receptor antagonist, naloxone, increased oxytocin neuron post-spike excitability in morphine-dependent rats; this increase was greater for short interspike intervals (< 0.1 s). Naloxone had similar, but smaller (P = 0.04), effects in oxytocin neurons in morphine-naive rats. The increased post-spike excitability for short interspike intervals was specific to naloxone, because osmotic stimulation increased excitability without potentiating excitability at short interspike intervals. By contrast to oxytocin neurons, neither morphine dependence nor morphine withdrawal increased post-spike excitability in neighbouring vasopressin neurons. To determine whether increased post-spike excitability in oxytocin neurons during morphine withdrawal reflected altered intrinsic membrane properties, we measured the in vitro effects of naloxone on transient outward rectification (TOR) and after-hyperpolarization (AHP), properties mediated by K + channels and that affect supraoptic nucleus neuron post-spike excitability. Naloxone reduced the TOR and AHP (by 20% and 60%, respectively) in supraoptic nucleus neurons from morphine-dependent, but not morphine-naive, rats. In vivo, spike frequency adaptation (caused by activity-dependent AHP activation) was reduced by naloxone (from 27% to 3%) in vasopressin neurons in morphine-dependent, but not morphine-naive, rats. Thus, multiple K + channel inhibition increases post-spike excitability for short interspike intervals, contributing to the increased firing of oxytocin neurons during morphine withdrawal.
- Published
- 2005
198. HPA axis dysregulation following prenatal opiate exposure and postnatal withdrawal
- Author
-
Lisa M. Schrott, Kathryn L. Hamilton, Sheldon B. Sparber, Andrew C. Harris, and Jonathan C. Gewirtz
- Subjects
Lipopolysaccharides ,Male ,Narcotics ,Hypothalamo-Hypophyseal System ,medicine.medical_specialty ,Time Factors ,Pregnancy Rate ,Methadyl Acetate ,Pituitary-Adrenal System ,Levacetylmethadol ,Naphthalenes ,Toxicology ,Oral gavage ,Open field ,Rats, Sprague-Dawley ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Developmental Neuroscience ,Pregnancy ,Corticosterone ,Internal medicine ,medicine ,Animals ,Behavior, Animal ,Dose-Response Relationship, Drug ,Body Weight ,Stressor ,Organ Size ,medicine.disease ,Rats ,Substance Withdrawal Syndrome ,Prenatal treatment ,Endocrinology ,Animals, Newborn ,Social Isolation ,chemistry ,Prenatal Exposure Delayed Effects ,Oxepins ,Exploratory Behavior ,Female ,Opiate ,Psychology ,medicine.drug - Abstract
We examined the effects of prenatal exposure to the long acting opiate l-alpha-acetylmethadol (LAAM) followed by postnatal withdrawal on hypothalamic-pituitary-adrenal (HPA) axis reactivity in neonatal and adult rats and anxiety-like behavior in adult rats. Female rats were treated with LAAM (0, 0.2, or 1.0 mg/kg/day) via oral gavage for 28 days prior to and continuing throughout pregnancy. Pups were fostered at birth to nontreated, lactating dams and underwent opiate withdrawal. On postnatal day (PND) 18, prenatal opiate-exposed male and female rat pups displayed a decreased corticosterone response 2 h after the application of an immunological stressor and 15 min following a social stressor compared to controls. In contrast, in adulthood, prenatal opiate-treated rats showed a heightened corticosterone response compared to prenatal water-treated controls at 3 h, but not 8 h, following an immunological stressor. Males prenatally treated with 1.0 mg/kg LAAM displayed elevated startle responding compared to the other prenatally treated male groups, but there was no effect of prenatal treatment in females. There were no effects of prenatal treatment in the open field test in either sex. These results suggest that prenatal opiate exposure followed by postnatal withdrawal dysregulated the HPA axis response to stressors in the neonate and adult and differentially affected adult anxiety-like behavior in males and females.
- Published
- 2005
199. Clinical trials of neuroprotection for Parkinson's disease
- Author
-
Peter A. LeWitt
- Subjects
Monoamine Oxidase Inhibitors ,Parkinson's disease ,Ubiquinone ,Minocycline ,Nerve Tissue Proteins ,Substantia nigra ,Disease ,Neuroprotection ,Antiparkinson Agents ,Degenerative disease ,Double-Blind Method ,Selegiline ,medicine ,Humans ,Multicenter Studies as Topic ,Picolinic Acids ,Monoamine Oxidase ,Randomized Controlled Trials as Topic ,Clinical Trials as Topic ,Riluzole ,Pars compacta ,business.industry ,Parkinsonism ,Parkinson Disease ,Creatine ,medicine.disease ,Clinical trial ,Neuroprotective Agents ,Dopamine Agonists ,Indans ,Oxepins ,Neurology (clinical) ,business ,Neuroscience - Abstract
In the concluding pages of the first monograph to describe Parkinson’s disease (PD), we read that: … Until we are better informed respecting the nature of the disease, the employment of internal medicines is scarcely warrantable; unless analogy should point out some remedy the trial of which rational hope might authorize. Particular circumstances might arise in different cases, in which the aid of medicine may be demanded … James Parkinson, M.D. An Essay on the Shaking Palsy (1817)1 As in Parkinson’s day, the challenge is still with us to find rational therapeutic interventions for this disorder. Lacking evidence that points to the cause (or causes) of PD, contemporary efforts to slow or halt the disease are guided primarily by analogies to animal models and the few available insights into the pathophysiology of this disorder. Nevertheless, a long list of hypothetical targets for definitive treatment of PD has been developed. Reflecting this diversity of options, a recent initiative by the National Institutes of Health in the United States has considered 59 choices for protective therapies against the progression of PD.2 The range of possible anti-PD therapies is far greater today than the limited focus on antioxidant therapies two decades ago. This article reviews the results of several clinical trials along with comments regarding ongoing studies of neuroprotection in PD. The motor impairments of PD are generally progressive over time, and several types of evidence link the clinical deterioration to loss of dopaminergic neurons projecting to the striatum. The neuropathologic substrate of parkinsonism, whether resulting from the idiopathic disorder or from various neurotoxins that closely simulate the human motor impairments of PD, is the loss of most dopaminergic neurons in the substantia nigra pars compacta (SNpc).3 The severity of parkinsonian features appears to be in direct proportion to neuronal …
- Published
- 2004
200. Potential hypotensive agents: synthesis and hypotensive activity of oxime ethers derived from 1-naphthoxepines and related compounds
- Author
-
Hari O. Saxena, Gajendra K. Goswamy, Vishnu K. Tandon, Manoj Kumar, and Anoop K. Awasthi
- Subjects
Clinical Biochemistry ,Hypotensive drug ,Pharmaceutical Science ,Blood Pressure ,Ether ,Anaesthetized cats ,Pharmacology ,Biochemistry ,Chemical synthesis ,chemistry.chemical_compound ,Oximes ,Drug Discovery ,Animals ,Organic chemistry ,Molecular Biology ,Antihypertensive Agents ,Hypotensive agents ,biology ,Organic Chemistry ,Fissipedia ,General Medicine ,Oxime ,biology.organism_classification ,chemistry ,Oxepins ,Cats ,Molecular Medicine - Abstract
The synthesis and pharmacological evaluation of substituted oximino-ethers 1 and 2 of naphth[1,2- b ]- and naphth[2,1- b ]-oxepin-5-ones ( 4 and 8 ) were carried out. The hypotensive activity of oximino-ethers 1 and 2 was evaluated on anaesthetized cats. The results indicated that 1c caused a fall of 80 mm/Hg for >100′ at a dose of 5 mg/kg iv in anaesthetized cats.
- Published
- 2004
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