ABSTRACT
PURPOSE: Intestinal perforation (IP) is a fatal complication in extremely low birth weight infants (ELBWI). We started administrating enteral miconazole (MCZ) to ELBWI in 2002. Since then, the incidence of IP has significantly decreased. The aim of this study was to elucidate the prophylactic effect of MCZ for the treatment of neonatal IP, and to establish a new prophylactic concept for this disease. METHODS: In in vivo experiments, the effects of MCZ were examined histopathologically using a mouse model of intestinal ischemia. In in vitro experiments, the cytoprotective effect of MCZ against hypoxia was evaluated using Caco-2 intestinal cells, and its anti-inflammatory potential using a co-culture model of Caco-2 and HL60 cells. RESULTS: MCZ showed a tissue protective effect against intestinal ischemia. MCZ reduced high mobility group-box 1 (HMGB1) release in Caco-2 cells under hypoxic stress and attenuated the potential to activate co-cultured HL60 leukocytes with Caco-2 cells by suppressing interleukin-8 (IL-8). CONCLUSION: MCZ may have preventive roles in the clinical management of IP in ELBWI by the suppression of IL-8 and HMGB-1.
Subject(s)
Cytochrome P-450 CYP2C9 Inhibitors/therapeutic use , Intestinal Perforation/prevention & control , Miconazole/therapeutic use , Animals , Caco-2 Cells/drug effects , Cytochrome P-450 CYP2C9 Inhibitors/administration & dosage , Disease Models, Animal , Humans , Intestines/drug effects , Male , Mice , Mice, Inbred BALB C , Miconazole/administration & dosage , Treatment OutcomeABSTRACT
The first total synthesis of citridone A has been achieved through regioselective intramolecular iodocyclization and regio- and stereoselective Pd(0)-catalyzed coupling as key reactions.
Subject(s)
Biological Products/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Palladium/chemistry , Biological Products/chemistry , Catalysis , Heterocyclic Compounds, 4 or More Rings/chemistry , Molecular Structure , Penicillium/chemistry , StereoisomerismABSTRACT
A new fungal metabolite designated calpinactam (1) was isolated from the culture broth of Mortierella alpina FKI-4905, and its structure was elucidated by spectroscopic analyses including NMR experiments. Calpinactam was found to be a hexapeptide with a caprolactam ring at its C-terminal. Its absolute stereochemistry was determined by amino acid analysis and total synthesis. Calpinactam selectively inhibited the growth of mycobacteria among various microorganisms. The MIC values of calpinactam against Mycobacterium smegmatis and M. tuberculosis were 0.78 and 12.5 microg/mL, respectively.
Subject(s)
Anti-Bacterial Agents , Caprolactam , Mycobacterium smegmatis/drug effects , Mycobacterium tuberculosis/drug effects , Oligopeptides , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Caprolactam/analogs & derivatives , Caprolactam/chemical synthesis , Caprolactam/chemistry , Caprolactam/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Mortierella/chemistry , Nuclear Magnetic Resonance, Biomolecular , Oligopeptides/chemical synthesis , Oligopeptides/chemistry , Oligopeptides/pharmacologyABSTRACT
The total synthesis of (-)-amidepsine B, a potent diacylglycerol acyltransferase inhibitor, has been achieved. This synthetic study resulted in the revision of the previously assigned stereostructure of the natural amidepsine B and determined the absolute configuration.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Hydroxybenzoates/chemical synthesis , Chromatography, High Pressure Liquid , Chromatography, Thin Layer , Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Hydroxybenzoates/chemistry , Indicators and Reagents , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Conformation , Spectrophotometry, Infrared , Spectrophotometry, UltravioletABSTRACT
The total synthesis of salinosporamide A has been achieved through enzymatic desymmetrization, diastereoselective aldol reaction, intramolecular aldol reaction, and intermolecular Reformatsky-type reaction followed by 1,4-reduction as key reactions.
Subject(s)
Lactones/chemical synthesis , Pyrroles/chemical synthesis , Cyclohexenes/chemistry , Lactones/chemistry , Pyrroles/chemistry , Stereoisomerism , Substrate SpecificityABSTRACT
OBJECTIVE: Tissue hypoxia is closely associated with arthritis pathogenesis, and extracellular high mobility group box chromosomal protein 1 (HMGB-1) released from injured cells also has a role in arthritis development. This study was thus undertaken to investigate the hypothesis that extracellular HMGB-1 may be a coupling factor between hypoxia and inflammation in arthritis. METHODS: Concentrations of tumor necrosis factor alpha, interleukin-6, vascular endothelial growth factor, lactic acid, lactate dehydrogenase, and HMGB-1 were measured in synovial fluid (SF) samples from patients with inflammatory arthropathy (rheumatoid arthritis and pseudogout) and patients with noninflammatory arthropathy (osteoarthritis). The localization of tissue hypoxia and HMGB-1 was also examined in animal models of collagen-induced arthritis (CIA). In cell-based experiments, the effects of hypoxia on HMGB-1 release and its associated cellular events (i.e., protein distribution and cell viability) were studied. RESULTS: In SF samples from patients with HMGB-1-associated inflammatory arthropathy (i.e., samples with HMGB-1 levels >2 SD above the mean level in samples from patients with noninflammatory arthropathy), concentrations of HMGB-1 were significantly correlated with those of lactic acid, a marker of tissue hypoxia. In CIA models in which the pathologic phenotype could be attenuated by HMGB-1 neutralization, colocalization of HMGB-1 with tissue hypoxia in arthritis lesions was also observed. In cell-based experiments, hypoxia induced significantly increased levels of extracellular HMGB-1 by the cellular processes of secretion and/or apoptosis-associated release, which was much more prominent than the protein release in necrotic cell injury potentiated by oxidative stress. CONCLUSION: These findings indicate that tissue hypoxia and its resultant extracellular HMGB-1 might play an important role in the development of arthritis.
Subject(s)
Arthritis/metabolism , HMGB1 Protein/analysis , Hypoxia/metabolism , Inflammation/metabolism , Joints/metabolism , Synovial Fluid/chemistry , Adult , Aged , Aged, 80 and over , Animals , Arthritis/pathology , Arthritis, Experimental/chemically induced , Arthritis, Experimental/metabolism , Arthritis, Experimental/pathology , Blotting, Western , Cells, Cultured , Female , Fluorescent Antibody Technique , Humans , Hypoxia/pathology , Inflammation/pathology , Interleukin-1/analysis , L-Lactate Dehydrogenase/analysis , Lactic Acid/analysis , Male , Mice , Middle Aged , Rats , Reverse Transcriptase Polymerase Chain Reaction , Severity of Illness Index , Synovial Membrane/metabolism , Synovial Membrane/pathology , Tumor Necrosis Factor-alpha/analysis , Vascular Endothelial Growth Factor A/analysisABSTRACT
The total synthesis of borrelidin has been achieved. The best feature of our synthetic route is macrocyclization at C11-C12 for the construction of an 18-membered ring after esterification between two segments. A detailed examination of the macrocyclization led us to the samarium(II) iodide-mediated intramolecular Reformatsky-type reaction as the most efficient synthetic approach. The two key segments were synthesized through regioselective methylation, directed hydrogenation, stereoselective Reformatsky-type reaction, and MgBr2.Et2O-mediated chelation-controlled allylation.
Subject(s)
Cyclization , Fatty Alcohols/chemical synthesis , Fatty Alcohols/chemistry , Molecular Structure , StereoisomerismABSTRACT
The p51 gene that encodes the major antigenic 51-kDa protein in Neorickettsia risticii was identified in strains of Neorickettsia sennetsu and the Stellantchasmus falcatus agent but not in Neorickettsia helminthoeca, suggesting that p51-based diagnosis would be useful to distinguish among them. groESL sequencing results delineated the phylogenic relationships among Neorickettsia spp.
Subject(s)
Antigens, Bacterial/analysis , Bacterial Proteins/analysis , Chaperonins/analysis , DNA-Binding Proteins/analysis , Mammals/microbiology , Neorickettsia/isolation & purification , Phosphoproteins , Trans-Activators , Trematoda/microbiology , Anaplasmataceae Infections/diagnosis , Anaplasmataceae Infections/veterinary , Animals , Genes, Tumor Suppressor , Humans , Neorickettsia/classification , Neorickettsia/genetics , Phylogeny , Restriction Mapping , Transcription Factors , Tumor Suppressor ProteinsABSTRACT
The mechanism of L-DOPA for antinociception was investigated. Nociceptive behaviors in mice after an intrathecal (i.t.) administration of substance P were evaluated. L-DOPA (i.t.) dose-dependently attenuated the substance P-induced nociceptive behaviors. Co-administration of benserazide (i.t.), a DOPA decarboxylase inhibitor, abolished the antinociceptive effect of L-DOPA. The L-DOPA-induced antinociception was antagonized by sulpiride, a D2 blocker, but not by SCH 23390, a D1 blocker. These results suggest that L-DOPA relieves pain after conversion to dopamine, with the dopamine sedating pain transmission by way of the dopamine D2 receptor.
Subject(s)
Dopamine Agents/therapeutic use , Levodopa/therapeutic use , Pain/drug therapy , Animals , Behavior, Animal , Benserazide/pharmacology , Benzazepines/pharmacology , Dopamine/administration & dosage , Dopamine Agents/administration & dosage , Dose-Response Relationship, Drug , Drug Interactions , Enzyme Inhibitors/pharmacology , Injections, Spinal/methods , Levodopa/administration & dosage , Male , Mice , Pain/chemically induced , Pain Measurement/methods , Spinal Cord/drug effects , Spinal Cord/microbiology , Substance P , Time FactorsABSTRACT
The total synthesis of borrelidin has been achieved. The best feature of our synthetic route is SmI(2)-mediated intramolecular Reformatsky-type reaction for macrocyclization after esterification between two segments. The two key segments were synthesized through chelation-controlled carbotitanation, chelation-controlled hydrogenation, stereoselective Reformatsky reaction, and MgBr(2).Et(2)O-mediated chelation-controlled allylation. [reaction: see text]
