RESUMEN
BACKGROUND: Voriconazole concentrations display a large variability, which cannot completely be explained by known factors. We investigated the relationships of voriconazole concentration with patient-specific variables and concomitant medication to identify clinical factors affecting voriconazole clearance. METHODS: A retrospective chart review of voriconazole trough concentration, laboratory data, and concomitant medication in patients was performed. The concentration/dose ratio (C/D-ratio) was assessed as a surrogate marker of total clearance by dividing voriconazole concentration by daily dose per kg of body weight. RESULTS: A total of 77 samples from 63 patients were obtained. In multiple linear regression analysis, increased C-reactive protein (CRP) level (p < 0.05) and decreased albumin (Alb) level (p < 0.05) were associated with significantly increased C/D-ratio of voriconazole, and coadministration with a glucocorticoid was associated with significantly (p < 0.05) decreased C/D-ratio of voriconazole (adjusted r (2) = 0.31). Regarding CRP and Alb, receiver operating characteristic curve analysis indicated that increased CRP level and decreased Alb level were significant predictors of toxic trough concentration of voriconazole. For CRP, area under the curve (AUC) and cutoff value were 0.71 (95 % confidence interval (CI), 0.57-0.86, p < 0.01) and 4.7 mg/dl, respectively. For Alb, AUC and cutoff value were 0.68 (95 % CI, 0.53-0.82, p < 0.05) and 2.7 g/dl, respectively. A significant difference was seen in voriconazole trough concentration between patients with hepatotoxicity and those without (5.69 µg/ml vs 3.0 µg/ml, p < 0.001). CONCLUSION: Coadministration of glucocorticoid and inflammation, reflected by elevated CRP level and hypoalbuminemia, are associated with voriconazole clearance. We propose that early measurement of voriconazole concentration before the plateau phase will lead to avoidance of a toxic voriconazole level in patients with elevated CRP level and hypoalbuminemia, although further studies are needed to confirm our findings.
RESUMEN
BACKGROUND: The Huntingtin-interacting protein HYPK possesses chaperone-like activity. We hypothesized that the expression of HYPK could be regulated by heat shock factor HSF1, a transcriptional regulator of chaperone genes. METHODS: HYPK expression in HeLa cells was assessed by RT-PCR and Western blot analysis. In vivo binding of HSF1 to the HYPK promoter was analyzed by chromatin immunoprecipitation assays. The requirement for HYPK in heat-shocked cells was examined using HYPK-knockdown cells. RESULTS: Levels of HYPK mRNA were slightly increased by heat treatment; however, the levels decreased in HSF1-silenced cells. The HYPK promoter was bound by HSF1 in a heat-inducible manner; however, its core promoter activity was notably suppressed upon heat shock. When cells were exposed to heat shock, silencing HYPK caused a decrease in cell viability. CONCLUSIONS: HYPK is a novel target gene of HSF1. HSF1 maintains HYPK expression in heat-shocked cells. GENERAL SIGNIFICANCE: The maintenance of HYPK expression by HSF1 is necessary for the survival of cells under thermal stress conditions.
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Proteínas Portadoras/genética , Proteínas de Unión al ADN/fisiología , Factores de Transcripción/fisiología , Regulación de la Expresión Génica , Células HeLa , Factores de Transcripción del Choque Térmico , Calor , Humanos , Regiones Promotoras Genéticas , Estrés FisiológicoRESUMEN
The transcription factor activator protein-1 (AP-1) participates in many aspects of cell physiology, such as cellular proliferation, transformation, and death. AP-1 is a dimeric complex that primarily contains Jun and Fos family members. Here, we report that JUN is a target of heat shock transcription factor HSF1. HSF1 is the master regulator of genes encoding molecular chaperones, and is involved in cellular processes such as the stress response, cell differentiation, aging and carcinogenesis. In HeLa cells, JUN transcription was rapidly induced by heat treatment. We found that HSF1 bound to the JUN promoter and was necessary for its efficient response to heat shock. In heat-shocked cells, c-Jun-mediated gene expression was induced slowly following accumulation of c-Jun protein. Forced expression of active HSF1 in cells resulted in an increase in c-Jun expression and activation of c-Jun target genes. These results show that HSF1 regulates JUN expression, thereby modulating AP-1 activity.
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Proteínas de Unión al ADN/metabolismo , Regulación Neoplásica de la Expresión Génica , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-jun/genética , Factor de Transcripción AP-1/metabolismo , Factores de Transcripción/metabolismo , Western Blotting , Proliferación Celular , Inmunoprecipitación de Cromatina , Ciclina D1/genética , Ciclina D1/metabolismo , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/genética , Ensayo de Cambio de Movilidad Electroforética , Células HeLa , Factores de Transcripción del Choque Térmico , Respuesta al Choque Térmico , Calor , Humanos , Receptores de Hialuranos/genética , Receptores de Hialuranos/metabolismo , Luciferasas/metabolismo , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-jun/metabolismo , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Elementos de Respuesta/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción AP-1/genética , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genéticaRESUMEN
Heat shock transcription factor (HSF) regulates the expression of genes encoding molecular chaperones and stress-responsive proteins. Conversion of HSF from a monomer to a homotrimer or heterotrimer is essential for its binding to heat shock elements (HSEs) comprised of inverted repeats of the pentamer nGAAn. Here, we constructed various human HSF1 derivatives and analyzed their transcriptional activity through the continuously and discontinuously arranged nGAAn units. We identified a short stretch of amino acids that inhibits the activation ability of HSF1, especially through discontinuous HSEs. This stretch is conserved in HSFs of various organisms, interacts with the hydrophobic repeat regions that mediate HSF oligomerization, and impedes homotrimer formation and DNA binding. This conserved domain plays an important role in maintaining HSF in an inactive monomeric form.
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Evolución Biológica , Biopolímeros/química , Proteínas de Unión al ADN/fisiología , ADN/metabolismo , Factores de Transcripción/fisiología , Secuencia Conservada , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/metabolismo , Factores de Transcripción del Choque Térmico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción/química , Factores de Transcripción/metabolismoRESUMEN
Expression of the RGS2 gene modulates RGS2 activity toward G protein-coupled signaling in diverse cellular processes. In this study, RGS2 transcription was induced in HeLa and rat aorta smooth muscle cells by exposure to febrile temperatures or proteotoxic stress. The promoter region of RGS2 contained a binding sequence of HSF1, which is an activator of the heat shock protein gene, and was inducibly bound by stress-activated HSF1. A single nucleotide change identified in the RGS2 promoter of hypertensive patients abolished HSF1-regulated expression of RGS2, suggesting that activated HSF1 is involved in blood pressure regulation via modulation of RGS2 expression.
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Proteínas de Unión al ADN/metabolismo , Proteínas RGS/genética , Estrés Fisiológico/fisiología , Factores de Transcripción/metabolismo , Transcripción Genética , Animales , Proteínas de Unión al ADN/genética , Células HeLa , Factores de Transcripción del Choque Térmico , Humanos , Miocitos del Músculo Liso/metabolismo , Regiones Promotoras Genéticas , Proteínas RGS/metabolismo , Ratas , Factores de Transcripción/genéticaRESUMEN
Fifty two outpatients, who showed signs of school-refusal-withdrawal at the Shiga Prefectural Psychiatric Institution have been analyzed according to their age, gender, ICD-10 diagnosis, medical evolution, and total number of consultations. A total of 61.5% of the population were male, and they showed a higher average and a wider range of age than female patients. According to the ICD-10 diagnosis, 67.3% were in the group of F40-48 neurotic, stress-related and somatoform disorders, and 11.5% were in the group of F30-39 mood [affective] disorders. Twenty five % of the patients were assumed to have show medical improvement, and 42.3% of the patients continued to have further consultations. This article discusses the possible role of psychiatric medical institutions in supporting cases of school-refusal and social-withdrawal.