RESUMO
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.
Assuntos
Inibidores do Citocromo P-450 CYP2C9/uso terapêutico , Perfuração Intestinal/prevenção & controle , Miconazol/uso terapêutico , Animais , Células CACO-2/efeitos dos fármacos , Inibidores do Citocromo P-450 CYP2C9/administração & dosagem , Modelos Animais de Doenças , Humanos , Intestinos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miconazol/administração & dosagem , Resultado do TratamentoRESUMO
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.
Assuntos
Artrite/metabolismo , Proteína HMGB1/análise , Hipóxia/metabolismo , Inflamação/metabolismo , Articulações/metabolismo , Líquido Sinovial/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Artrite/patologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Western Blotting , Células Cultivadas , Feminino , Imunofluorescência , Humanos , Hipóxia/patologia , Inflamação/patologia , Interleucina-1/análise , L-Lactato Desidrogenase/análise , Ácido Láctico/análise , Masculino , Camundongos , Pessoa de Meia-Idade , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Índice de Gravidade de Doença , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Fator de Necrose Tumoral alfa/análise , Fator A de Crescimento do Endotélio Vascular/análiseRESUMO
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.
Assuntos
Dopaminérgicos/uso terapêutico , Levodopa/uso terapêutico , Dor/tratamento farmacológico , Animais , Comportamento Animal , Benserazida/farmacologia , Benzazepinas/farmacologia , Dopamina/administração & dosagem , Dopaminérgicos/administração & dosagem , Relação Dose-Resposta a Droga , Interações Medicamentosas , Inibidores Enzimáticos/farmacologia , Injeções Espinhais/métodos , Levodopa/administração & dosagem , Masculino , Camundongos , Dor/induzido quimicamente , Medição da Dor/métodos , Medula Espinal/efeitos dos fármacos , Medula Espinal/microbiologia , Substância P , Fatores de TempoRESUMO
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]
Assuntos
Antibacterianos/síntese química , Álcoois Graxos/síntese química , Antibacterianos/química , Antimaláricos/síntese química , Antimaláricos/química , Ciclização , Álcoois Graxos/química , Estrutura Molecular , Estereoisomerismo , Streptomyces/químicaRESUMO
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.
Assuntos
Produtos Biológicos/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Paládio/química , Produtos Biológicos/química , Catálise , Compostos Heterocíclicos de 4 ou mais Anéis/química , Estrutura Molecular , Penicillium/química , EstereoisomerismoRESUMO
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.
Assuntos
Antibacterianos , Caprolactama , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Oligopeptídeos , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Caprolactama/análogos & derivados , Caprolactama/síntese química , Caprolactama/química , Caprolactama/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mortierella/química , Ressonância Magnética Nuclear Biomolecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Oligopeptídeos/farmacologiaRESUMO
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.
Assuntos
Inibidores Enzimáticos/síntese química , Hidroxibenzoatos/síntese química , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Inibidores Enzimáticos/química , Hidroxibenzoatos/química , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Conformação Molecular , Espectrofotometria Infravermelho , Espectrofotometria UltravioletaRESUMO
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.
Assuntos
Lactonas/síntese química , Pirróis/síntese química , Cicloexenos/química , Lactonas/química , Pirróis/química , Estereoisomerismo , Especificidade por SubstratoRESUMO
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.
Assuntos
Ciclização , Álcoois Graxos/síntese química , Álcoois Graxos/química , Estrutura Molecular , EstereoisomerismoRESUMO
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.