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OBJECTIVE: The perioperative chemotherapy with fluorouracil, leucovorin, oxaliplatin plus docetaxel (FLOT) was recommended by the Chinese Society of Clinical Oncology Guidelines for gastric cancer (2018 edition) for patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (class IIA). However, the economic impact of FLOT chemotherapy in China remains unclear. The analysis aimed to compare the cost-effectiveness of FLOT versus epirubicin, cisplatin plus fluorouracil or capecitabine (ECF/ECX) in patients with locally advanced resectable tumours. DESIGN: We developed a Markov model to compare the healthcare and economic outcomes of FLOT and ECF/ECX in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma. Costs were estimated from the perspective of Chinese healthcare system. Clinical and utility inputs were derived from the FLOT4 phase II/III clinical trial and published literature. Sensitivity analyses were employed to assess the robustness of our result. The annual discount rate for costs and health outcomes was set at 5%. OUTCOME MEASURES: The primary outcome of incremental cost-effectiveness ratios (ICERs) was calculated as the cost per quality-adjusted life years (QALYs). RESULTS: The base-case analysis found that compared with ECF/ECX, the use of FLOT chemotherapy was associated with an additional 1.08 QALYs, resulting in an ICER of US$851/QALY. One-way sensitivity analysis results suggested that the HR of overall survival and progression-free survival had the greatest impact on the ICER. Probabilistic sensitivity analysis demonstrated that FLOT was more likely to be cost-effective compared with ECF/ECX at a willingness-to-pay threshold of US$31 513/QALY. CONCLUSIONS: For patients with locally advanced resectable tumours, the FLOT chemotherapy is a cost-effective treatment option compared with ECF/ECX in China. TRIAL REGISTRATION NUMBER: NCT01216644.
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Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/cirugía , Adenocarcinoma/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/uso terapéutico , Análisis Costo-Beneficio , Docetaxel/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/cirugía , Neoplasias Esofágicas/patología , Fluorouracilo/uso terapéutico , Leucovorina/uso terapéutico , Oxaliplatino/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/patologíaRESUMEN
WHAT IS KNOWN AND OBJECTIVE: Drug fever is frequently misdiagnosed, especially during concurrent infection. Celecoxib causes various adverse effects; however, celecoxib-induced drug fever is rarely reported. CASE SUMMARY: A 32-year-old man presented with pyrexia after 17 days of celecoxib therapy, which was reintroduced following 3-day total drug cessation. His fever recurred after this unsuspected rechallenge, which aided in the ultimate identification of the offending drug. A Naranjo Score of 8 led us to infer that drug fever was "probably" caused by celecoxib. WHAT IS NEW AND CONCLUSION: This is the first report of celecoxib-induced drug fever, aimed at assisting its diagnosis, particularly with rarely suspected causative drugs.
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Pirazoles , Sulfonamidas , Adulto , Antiinflamatorios no Esteroideos/efectos adversos , Celecoxib/efectos adversos , Inhibidores de la Ciclooxigenasa 2/efectos adversos , Fiebre/inducido químicamente , Humanos , Masculino , Pirazoles/efectos adversos , Sulfonamidas/efectos adversosRESUMEN
Aims: To explore the interactive influence of glucocorticoids and cytochrome P450 (CYP450) polymorphisms on voriconazole (VRC) plasma trough concentrations (Cmin) and provide a reliable basis for reasonable application of VRC. Methods: A total of 918 VRC Cmin from 231 patients was collected and quantified using high-performance liquid chromatography in this study. The genotypes of CYP2C19, CYP3A4, and CYP3A5 were detected by DNA sequencing assay. The effects of different genotypes and the coadministration of glucocorticoids on VRC Cmin were investigated. Furthermore, the interactive effects of glucocorticoids with CYP450s on VRC Cmin were also analyzed. Results: The median Cmin of oral administration was lower than that of intravenous administration (1.51 vs. 4.0 mg l-1). Coadministration of glucocorticoids (including dexamethasone, prednisone, prednisolone, and methylprednisolone) reduced the VRC Cmin/dose, respectively, among which dexamethasone make the median of the VRC Cmin/dose ratio lower. As a result, when VRC was coadministrated with glucocorticoids, the proportion of VRC Cmin/dose in the subtherapeutic window was increased. Different CYP450 genotypes have different effects on the Cmin/dose of VRC. Mutations of CYP2C19*2 and *3 increased Cmin/dose of VRC, while CYP2C19*17 and CYP3A4 rs4646437 polymorphisms decreased Cmin/dose of VRC. The mutation of CYP3A5 has no significant effect. Furthermore, CYP2C19*17 mutants could strengthen the effects of glucocorticoids and decrease VRC Cmin/dose to a larger extent. Conclusion: Our study revealed that glucocorticoids reduced the Cmin/dose levels of VRC and different SNPs of CYP450 have different effects on the Cmin/dose ratio of VRC. Glucocorticoids and CYP2C19*17 mutants had a synergistic effect on reducing VRC Cmin/dose. The present results suggested that when VRC is combined with glucocorticoids, we should pay more attention to the clinical efficacy of VRC, especially when CYP2C19*17 mutants exist.
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We report a case of Listeria meningitis related to mantle cell lymphoma. A clinical pharmacist adjusted repeatedly the patient's anti-infective therapeutic regimen by analyzing the pharmacologic and pharmacokinetic characteristics of antibacterial drugs (such as cefotaxime, meropenem, etc.) due to the patient's repeated fever during hospitalization. To the best of our knowledge, this is the first case of Listeria meningitis related to mantle cell lymphoma treated successfully with meropenem reported in China. This case aims to optimize the anti-infection treatment regimen of Listeria meningitis and to provide a reference for clinicians and clinical pharmacists to use drugs rationally.
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Antibacterianos/uso terapéutico , Listeria monocytogenes/efectos de los fármacos , Linfoma de Células del Manto/microbiología , Meningitis por Listeria/diagnóstico , Meningitis por Listeria/tratamiento farmacológico , Meropenem/uso terapéutico , China , Quimioterapia Combinada , Fiebre/tratamiento farmacológico , Fiebre/microbiología , Humanos , Linfoma de Células del Manto/complicaciones , Masculino , Persona de Mediana Edad , Tienamicinas/uso terapéutico , Resultado del TratamientoRESUMEN
A 66-year-old male patient with a 10-year course of Parkinson's disease (PD) was admitted for hallucination lasting a half a month. After treatment with levodopa/carbidopa, selegiline, and piribedil, the patient's motor symptoms were improved while no significant effects were observed on psychotic symptoms. A clinical pharmacist analyzed the pharmacologic and pharmacokinetic characteristics of selegiline and piribedil, summarized the scheme of PD with psychotic symptoms in the literature, and discovered that selegiline might potentiate psychotic side effects of piribedil, while the use of levodopa/carbidopa cannot be ruled out either. Finally, the clinical pharmacist proposed to reduce the dosage of levodopa/carbidopa, increase the dosage of selegiline and quetiapine, and discontinue piribedil. The clinician accepted this suggestion. After the adjustment of medication, the patient's motor symptoms were absolutely improved and the psychotic symptoms were notably improved. This case study suggests that long-term treatment with levodopa/carbidopa and piribedil, along with the progression of the disease itself, could contribute to the emergence of psychotic symptoms in PD. Additionally, selegiline could potentiate psychotic side effects of piribedil. Neurology clinical pharmacists should work alongside neurology clinicians at the bedside to optimize pharmacotherapy, improve patient safety, and contribute to scholarly efforts.
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OBJECTIVES: To investigate whether there are aberrant acetylation modifications in global histone and monocyte chemoattractant protein-1 (MCP-1) promoter in monocytes from patients with coronary artery disease (CAD) and demonstrate the potential mechanisms. METHODS: CD14+ monocytes were isolated from 13 patients with CAD and 18 confirmed non-CAD controls using magnetic beads. Global histone H3/H4 acetylation and H3K4/H3K27 tri-methylation levels were measured with enzyme-linked immunosorbent assay. Quantitative real time-PCR was performed to detect the mRNA expression levels of MCP-1 and enzymes involved in histone modification processes. Histone modification levels in MCP-1 promoter were assessed by ChIP-qPCR assay. RESULTS: Our results showed a markedly lower global histone H3 acetylation level in monocytes from CAD patients. Global H3K27 tri-methylation level was significantly increased in monocytes from CAD patients. Furthermore, the mRNA expression levels of epigenetic modification enzymes HDAC3, SIRT1, P300, JMJD3 and SUV39H1 were decreased significantly in monocytes from CAD patients, while HDAC7 mRNA expression level was markedly increased. MCP-1 mRNA expression level was increased histone H3/H4 acetylation levels in MCP-1 promoter were markedly increased in monocytes of CAD patients. CONCLUSION: Aberrant histone modifications, including acetylation and tri-methylation, were found both in global histone and specific MCP-1 gene locos in monocytes from patients with CAD. Aberrant epigenetic modification enzymes expressions may be the regulatory mechanism responsible for aberrant histone modifications.
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Quimiocina CCL2/genética , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/metabolismo , Histonas/metabolismo , Receptores de Lipopolisacáridos/genética , Receptores de Lipopolisacáridos/metabolismo , Monocitos/metabolismo , Acetilación , Femenino , Histonas/química , Histonas/genética , Humanos , Masculino , Persona de Mediana Edad , Monocitos/enzimología , Regiones Promotoras Genéticas , Procesamiento Proteico-PostraduccionalRESUMEN
DNA hypomethylation plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Here we investigated whether 3-hydroxy butyrate dehydrogenase 2 (BDH2), a modulator of intracellular iron homeostasis, was involved in regulating DNA hypomethylation and hyper-hydroxymethylation in lupus CD4+ T cells. Our results showed that BDH2 expression was decreased, intracellular iron was increased, global DNA hydroxymethylation level was elevated, while methylation level was reduced in lupus CD4+ T cells compared with healthy controls. The decreased BDH2 contributed to DNA hyper-hydroxymethylation and hypomethylation via increasing intracellular iron in CD4+ T cells, which led to overexpression of immune related genes. Moreover, we showed that BDH2 was the target gene of miR-21. miR-21 promoted DNA demethylation in CD4+ T cells through inhibiting BDH2 expression. Our data demonstrated that the dysregulation of iron homeostasis in CD4+ T cells induced by BDH2 deficiency contributes to DNA demethylation and self-reactive T cells in SLE.
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Linfocitos T CD4-Positivos/metabolismo , Hidroxibutirato Deshidrogenasa/metabolismo , Hierro/metabolismo , Lupus Eritematoso Sistémico/genética , Adulto , Animales , Western Blotting , Estudios de Casos y Controles , Desmetilación del ADN , Metilación de ADN , Regulación hacia Abajo , Epigénesis Genética , Femenino , Técnicas de Silenciamiento del Gen , Células HEK293 , Homeostasis , Humanos , Lupus Eritematoso Sistémico/metabolismo , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , MicroARNs/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto JovenRESUMEN
Atherosclerosis is a chronic inflammatory disease. Recently, a growing body of evidence emphasizes that the monocyte and macrophage differentiation and activation are key processes in the development of atherosclerosis. However, the regulatory mechanism that manipulates the function of monocyte and macrophage is still unclear. Recent years, epigenetic mechanisms have received a wide attention and bring us a new field of vision. More and more evidence shows that epigenetics weighs heavily in atherosclerosis by regulating the function and differentiation states of monocyte and macrophage. In this review, we illuminate the epigenetic regulation mechanisms in monocyte and macrophage and their contributions to inflammatory processes of atherosclerosis to provide new thoughts and find novel targets or biomarkers for atherosclerosis.
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Arterias/metabolismo , Aterosclerosis/genética , Ensamble y Desensamble de Cromatina , Metilación de ADN , Epigénesis Genética , Macrófagos/metabolismo , Monocitos/metabolismo , Animales , Arterias/patología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Diferenciación Celular , Humanos , Macrófagos/patología , Monocitos/patología , Fenotipo , Placa Aterosclerótica , Factores de Riesgo , Transducción de SeñalRESUMEN
Significant progress has been made in understanding in the pathogenesis of atherosclerosis. Nevertheless, atherosclerosis remains a great threat to human health worldwide. Epigenetic mechanisms, which involve DNA methylation, histone modification, and microRNA, have significantly enhanced our understanding of the pathological process of atherosclerosis. More importantly, epigenetic processes (in contrast to genetic alterations) are reversible and thus provide a potential therapeutic target in atherosclerosis treatment. Both in vitro and in vivo studies using drugs targeting enzymes involved in epigenetic modifications have shown considerable promise in atherosclerosis treatment. This review aims to present an overview of current epigenetic mechanisms involved in the pathogenesis of atherosclerosis, and discuss points in these processes where therapeutic interventions likely bear fruition.
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Aterosclerosis/genética , Epigénesis Genética , Aterosclerosis/terapia , Biomarcadores/metabolismo , HumanosRESUMEN
New Onset Diabetes after Transplantation (NODAT) is defined as sustained hyperglycemia developing in patients without diabetes history before transplantation. A cohort study was performed to access the effects of tacrolimus on insulin secretion and insulin sensitivity and consequently in the development of NODAT in kidney transplant recipients. Then, we further investigated the association between NODAT and single-nucleotide polymorphisms of IRS-1 and IRS-2 in renal allograft recipients. One hundred and fifty-eight kidney transplant patients, receiving tacrolimus as the base immunosuppressant, were divided into two groups: with or without NODAT. Plasma levels of fasting insulin concentration (FINS) and C-peptide were determined by enhanced chemiluminescence immunoassay and ADVIA Centaur C peptide assay, respectively. The genotypes of Gly1057Asp in IRS-2 and Gly972Arg in IRS-1 were detected through polymerase chain reaction fragment length polymorphism in NODAT and non-NODAT patients. It was found that the concentrations of fasting plasma insulin and C-peptide in NODAT and non-NODAT patients treated with tacrolimus were higher than that in healthy volunteers (p < 0.05). Fasting plasma insulin concentration in NODAT was significantly elevated compared with than that in non-NODAT group (p < 0.05). But there are no statistical differences in fasting plasma C-peptide concentrations between NODAT and non-NODAT groups. The allele and genotype frequencies of IRS-2 Gly1057Asp and IRS-1 Gly972Arg in NODAT patients were not significantly different from non-NODAT patients (p > 0.05). In conclusion, insulin resistance is the primary cause of tacrolimus-induced NODAT. The IRS-2 Gly1057Asp and IRS-1 Gly972Arg genotypes are not related to NODAT.
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Diabetes Mellitus/inducido químicamente , Diabetes Mellitus/epidemiología , Ayuno/sangre , Resistencia a la Insulina , Insulina/sangre , Trasplante de Riñón , Complicaciones Posoperatorias/inducido químicamente , Complicaciones Posoperatorias/epidemiología , Tacrolimus/efectos adversos , Adulto , Estudios de Cohortes , Diabetes Mellitus/genética , Femenino , Estudios de Seguimiento , Humanos , Inmunosupresores , Masculino , Complicaciones Posoperatorias/genética , Factores de Riesgo , Factores de TiempoRESUMEN
Atherosclerosis has been widely considered as a chronic inflammation process, which triggers a wide range of cardiovascular diseases such as ischemic coronary artery disease (CAD). Toll-like receptor 4 (TLR4), a primary receptor of the innate immune system, plays a pivotal role in the initiation and progression of atherosclerosis. Here we summarize recent progress on understanding the activation and function of TLR4 signaling in the initiation and development of CAD, with the focus on the role of TLR4 as a link between CAD and other inflammatory diseases. Furthermore, we list a variety of drugs which exert anti-atherosclerosis effects via targeting TLR4 signaling. Finally, we discuss the promise of TLR4 signaling as a therapeutic target for CAD.
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Antiinflamatorios/uso terapéutico , Enfermedad de la Arteria Coronaria/terapia , Terapia Molecular Dirigida , Receptor Toll-Like 4/inmunología , Animales , Antiinflamatorios/farmacología , Enfermedad de la Arteria Coronaria/inmunología , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inmunidad Innata/efectos de los fármacos , Sistema Renina-Angiotensina/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/antagonistas & inhibidoresRESUMEN
BACKGROUND: Circulating endothelial progenitor cells (EPCs) may be a biomarker for vascular function and cardiovascular risk in patients with coronary artery disease (CAD). Dimethylarginine dimethylaminohydrolase 2 (DDAH2) regulates the function of EPCs. This study aimed to examine whether hypermethylation of DDAH2 promoter contributes to impaired function of EPCs in CAD patients. METHODS: Peripheral blood mono-nuclear cells from 25 CAD patients and 15 healthy volunteers were collected and differentiated into EPCs. EPCs were tested for their adhesive capability. DDAH2 mRNA expression was analyzed by real-time PCR, and the methylation of DDAH2 promoter was detected by bisulfite genomic sequencing. RESULTS: DDAH2 promoter in EPCs from CAD patients was hypermethylated and the methylation level was negatively correlated to DDAH2 mRNA level and adhesion function of EPCs. Homocysteine impaired the adhesion function of EPCs, accompanied by lower DDAH2 expression and higher methylation level of DDAH2 promoter, compared to controls. These effects of homocysteine were reversed by pretreatment with Aza, an inhibitor of DNA methyltransferase. CONCLUSION: Hypermethylation in DDAH2 promoter is positively correlated to the dysfunction of EPCs in CAD patients. Homocysteine disrupts EPCs function via inducing the hypermethylation of DDAH2 promoter, suggesting a key role of epigenetic mechanism in the progression of atherosclerosis.
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Amidohidrolasas/genética , Enfermedad de la Arteria Coronaria/patología , Metilación de ADN , Células Progenitoras Endoteliales/patología , Regiones Promotoras Genéticas , Anciano , Secuencia de Bases , Estudios de Casos y Controles , Adhesión Celular , Células Cultivadas , Cartilla de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Our previous study showed that hypermethylation of dimethylarginine dimethylaminohydrolase 2 contributes to homocysteine-induced apoptosis of human umbilical vein endothelial cells. Epigallocatechin-3-gallate is a green tea-derived phenol which has been proved beneficial on atherosclerosis. It was demonstrated that epigallocatechin-3-gallate inhibits DNA methyltransferase activity and reactivates methylation-silenced genes in cancer cells. The aim of this study was to address whether epigallocatechin-3-gallate could induce DNA demethylation of the dimethylarginine dimethylaminohydrolase 2 gene, contributing to prevent endothelial cells from apoptosis induced by homocysteine. Human umbilical vein endothelial cells (ATCC, CRL-2480) were treated with homocysteine (1 mM) for 48 hours with or without epigallocatechin-3-gallate (20 µM) or 5-Aza (DNA methyltransferase inhibitor, 5 µM). Apoptosis rate of human umbilical vein endothelial cells was assayed by flow cytometry with an annexin V-FITC apoptosis detection kit. The mRNA and protein expression level of dimethylarginine dimethylaminohydrolase 2 and DNA methyltransferase 1 were detected by real-time PCR and Western blot, respectively. DNA methylation level of dimethylarginine dimethylaminohydrolase 2 was assayed by methylation specific PCR. The binding level of DNA methyltransferase 1 in the promoter of dimethylarginine dimethylaminohydrolase 2 was determined by chromatin immunoprecipitation-quantitative real-time PCR. It was shown that the apoptosis rate was decreased significantly in human umbilical vein endothelial cells treated with homocysteine compared with the control. Furthermore, the mRNA and protein level of dimethylarginine dimethylaminohydrolase 2 were downregulated, the dimethylarginine dimethylaminohydrolase 2 gene promoter was hypermethylated, and the DNA methyltransferase 1 mRNA and protein level were increased in human umbilical vein endothelial cells treated with homocysteine. Chromatin immunoprecipitation-quantitative real-time PCR revealed that homocysteine-induced binding of DNA methyltransferase 1 to the dimethylarginine dimethylaminohydrolase 2 promoter was increased. Pretreatment with epigallocatechin-3-gallate or 5-Aza inhibited such effects of homocysteine. In conclusion, epigallocatechin-3-gallate exerted protective effects on homocysteine-induced apoptosis in human umbilical vein endothelial cells by inhibiting promoter hypermethylation of the dimethylarginine dimethylaminohydrolase 2 gene and inducing dimethylarginine dimethylaminohydrolase 2 expression. These effects may be due to the decreased DNA methyltransferase 1 expression and binding of DNA methyltransferase 1 to the dimethylarginine dimethylaminohydrolase 2 promoter induced by epigallocatechin-3-gallate. This research suggests that modulating the epigenetic processes might be a novel plausible way for treatment of atherosclerosis.
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Amidohidrolasas/metabolismo , Apoptosis/efectos de los fármacos , Catequina/análogos & derivados , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Inhibidores Enzimáticos/farmacología , Amidohidrolasas/genética , Azacitidina/farmacología , Catequina/farmacología , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/genética , Metilación de ADN/efectos de los fármacos , Regulación de la Expresión Génica , Homocisteína/farmacología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Regiones Promotoras Genéticas/genética , ARN Mensajero/genéticaRESUMEN
Homocysteine (Hcy) could induce apoptosis of endothelial cells (ECs). Dimethylarginine dimethylaminohydrolase 2 (DDAH2) is recognized as a protective factor to improve the endothelial function. Defect of DDAH2 has been confirmed to be involved in the Hcy-induced dysfunction of endothelial NO system. This study was to determine whether Hcy could inhibit DDAH2 expression and induce apoptosis of ECs via increasing DNA methylation level of DDAH2 promoter and whether DNA methylation inhibitor 5-azacytidine (5-aza) could attenuate the effect of Hcy on ECs. Firstly, human umbilical vein endothelial cells (HUVECs) were treated by Hcy with or without 5-aza for 48 h. MTT assay showed that Hcy reduced the viability of HUVECs in a dose-dependent manner. The level of asymmetric dimethylarginine (ADMA) and the apoptosis rate of HUVECs treated with Hcy at 1.0 mM were increased significantly compared with that of control. Moreover, we found that mRNA level of DDAH2 was down-regulated and DNA methylation level of DDAH2 promoter was increased significantly in HUVECs treated with Hcy, in concomitance with up-regulated protein level of DNA methyltransferase 1 (DNMT1). Furthermore, we also found that 5-aza could neutralize the effect of Hcy on ECs through up-regulating mRNA level of DDAH2 and inducing demethylation of DDAH2 promoter. In conclusion, hypermethylation of DDAH2 contributes to Hcy induced apoptosis of ECs. Modulating DNA methylation status of DDAH2 promoter may be a potential strategy for treatment of endothelial dysfunction.
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Amidohidrolasas/metabolismo , Apoptosis/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Homocisteína/farmacología , Amidohidrolasas/genética , Anexina A5/metabolismo , Antimetabolitos Antineoplásicos/farmacología , Azacitidina/farmacología , Supervivencia Celular/efectos de los fármacos , Colorantes , Metilación , Regiones Promotoras Genéticas/efectos de los fármacos , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Represoras/biosíntesis , Proteínas Represoras/genética , Sales de Tetrazolio , TiazolesRESUMEN
To observe the direct effects of 3,4,5,6-tetrahydroxyxanthone on connexin43 (Cx43) expression in cultured endothelial cells, cells were treated with lysophosphatidylcholine (LPC, 10 mg/l) for 24 h in the presence or absence of different concentrations of 3,4,5,6-tetrahydroxyxanthone (1, 3, or 10 µmol l(- 1)). The reactive oxygen species (ROS) production, cell viability, asymmetric dimethylarginine (ADMA) levels, and Cx43 expression were detected. 3,4,5,6-Tetrahydroxyxanthone significantly inhibited the increase in ROS production and ADMA level, increased cell viability and up-regulated Cx43 mRNA and protein expression induced by LPC. 3,4,5,6-Tetrahydroxyxanthone has protective effect in LPC-induced atherosclerotic lesions, which is at least partly related to the reduction of ADMA level and downregulation of Cx43 expression.
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Lisofosfatidilcolinas/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Xantonas/farmacología , Arginina/análogos & derivados , Arginina/análisis , Supervivencia Celular/efectos de los fármacos , Conexina 43/genética , Conexina 43/metabolismo , Estructura Molecular , Óxido Nítrico Sintasa/análisis , Especies Reactivas de Oxígeno/metabolismoRESUMEN
AIM: It has been reported that Ginkgo biloba extract (GBE) is an inducer or inhibitor of microsomal cytochrome P450 (CYP) 2C19, and diazepam is a substrate of CYP2C19. Thus, it could be expected that GBE may alter the metabolism of diazepam. METHODS: The pharmacokinetic parameters of diazepam and one of its metabolites, N-demethyldiazepam, were compared after oral administration of diazepam (10 mg) in the absence or presence of oral GBE (120 mg bid, for 28 days) in 12 healthy volunteers. The pharmacokinetic analysis was performed using a noncompartmental method. RESULTS: The 90% confidence intervals (CIs) of the ratios of mean pharmacokinetic parameters of diazepam presence and absence of GBE were well within the 80-125% bioequivalence range, indicating no pharmacokinetic interaction. The ratio of AUC(0-408) with GBE to AUC(0-408) without GBE was 95.2 (90%CI: 91.6-98.8) and 101.8 (90%CI: 99.4-104.1) for diazepam and N-desmethyldiazepam, respectively. The two drugs were well tolerated, and no drug-related serious adverse events were reported. CONCLUSION: The above data suggest that GBE, when taken in normally recommended doses over a 4-week time period, may not affect the pharmacokinetics of diazepam via CYP2C19 and the excretion of N-desmethyldiazepam in healthy volunteers. No drug-drug interaction was observed between GBE and diazepam.
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Diazepam/farmacocinética , Ginkgo biloba , Interacciones de Hierba-Droga , Extractos Vegetales/efectos adversos , Pueblo Asiatico , Humanos , Hidrocortisona/análogos & derivados , Hidrocortisona/orina , Masculino , Quercetina/sangre , Adulto JovenRESUMEN
Asymmetric dimethylarginine (ADMA), a major endogenous inhibitor of nitric oxide synthase, is recently defined as a novel atherogenic factor. Communication via gap junction (GJIC) is involved in the regulation of a variety of endothelial activities, such as cell differentiation and senescence. The aim of this study is to explore the effects of ADMA on connexin43 (Cx43) mediated endothelial GJIC. Lysophosphatidylcholine (LPC) caused the downregulation of Cx43 expression and GJIC dysfunction in cultured human umbilical vein endothelial cells (HUVECs), which were significantly ameliorated by decreasing ADMA accumulation. Furthermore, we found that ADMA (10 micromol x L(-1), 24 h) markedly downregulated Cx43 expression and damaged GJIC function in HUVECs. ADMA also increased production of intracellular reactive oxygen species (ROS) and induced phosphorylation of p38 MAPK. Furthermore, the inhibitory effect of ADMA on Cx43-mediated GJIC could be attenuated by NADPH oxidase inhibitor diphenyleneiodonium and apocynin as well as p38 MAPK inhibitor SB203580, respectively. In conclusion, our present results suggest that ADMA inhibits endothelial GJIC function via downregulating Cx43 expression, which suggesting a novel mechanism linking between elevated ADMA level and progression of atherosclerosis.
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Arginina/análogos & derivados , Comunicación Celular/fisiología , Conexina 43/metabolismo , Células Endoteliales/metabolismo , Inhibidores Enzimáticos/metabolismo , Uniones Comunicantes/metabolismo , Amidohidrolasas/metabolismo , Animales , Arginina/metabolismo , Células Cultivadas , Células Endoteliales/citología , Recuperación de Fluorescencia tras Fotoblanqueo , Humanos , Lisofosfatidilcolinas/metabolismo , NADPH Oxidasas/antagonistas & inhibidores , NADPH Oxidasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/fisiología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
The aim of this study was to investigate the effect of demethylbellidifolin (DMB), a major xanthone compound of Swertia davidi franch, on nitroglycerin (NTG) tolerance. In the in vivo portion of the study, pretreatment of Sprague-Dawley rats with NTG (10 mg/kg) for 8 days caused tolerance to the depressor effect of NTG. This was evident because the depressor effect of NTG (150 microg/kg, I. V.) was almost completely abolished in the tolerant rats. The tolerance could be diminished by treatment with DMB. In the in vitro study, the exposure of aortic rings of Sprague-Dawley rats to NTG (10 microM) for 30 min caused tolerance to the vasodilating effect of NTG. The tolerance is evident because of a substantial right shift of the NTG concentration-relaxation curves. This shift was reduced by pretreatment of the aortic rings with DMB. In cultured human umbilical vein endothelial cells (HUVECs), incubation of NTG for 16 h increased reactive oxygen species (ROS) production, attenuated cyclic guanosine monophosphate (cGMP) levels and decreased the activity of aldehyde dehydrogenase 2 (ALDH-2), the main enzyme responsible for NTG bioactivation. All the effects mentioned above were prevented by co-incubation with DMB. In conclusion, DMB prevents NTG tolerance via increasing ALDH-2 activity through decreasing ROS production.
Asunto(s)
Aldehído Deshidrogenasa/metabolismo , Antioxidantes/farmacología , Tolerancia a Medicamentos , Células Endoteliales/efectos de los fármacos , Proteínas Mitocondriales/metabolismo , Nitroglicerina/uso terapéutico , Swertia/química , Xantenos/farmacología , Aldehído Deshidrogenasa Mitocondrial , Animales , Antioxidantes/aislamiento & purificación , Aorta , GMP Cíclico/metabolismo , Interacciones de Hierba-Droga , Humanos , Masculino , Extractos Vegetales/química , Extractos Vegetales/farmacología , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Venas Umbilicales , Vasodilatadores , Xantenos/aislamiento & purificaciónRESUMEN
CD38 contains an ADP ribosylcyclase domain that mediates intracellular Ca(2+) signaling by the production of cyclic ADP-ribose (cADPR), but the mechanisms by which the agonists activate this enzyme remain unclear. The present study tested a hypothesis that a special lipid-raft (LR) form, ceramide-enriched lipid platform, contributes to CD38 activation to produce cADPR in response to muscarinic type 1 (M(1)) receptor stimulation in bovine coronary arterial myocytes (CAMs). By confocal microscopic analysis, oxotremorine (Oxo), an M(1) receptor agonist, was found to increase LR clustering on the membrane with the formation of a complex of CD38 and LR components such as GM(1), acid sphingomyelinase (ASMase), and ceramide, a typical ceramide-enriched macrodomain. At 80 microM, Oxo increased LR clustering by 78.8%, which was abolished by LR disruptors, methyl-beta-cyclodextrin (MCD), or filipin. With the use of a fluorescence resonance energy transfer (FRET) technique, 15.5+/-1.9% energy transfer rate (vs. 5.3+/-0.9% of control) between CD38 and LR component, ganglioside M(1) was detected, further confirming the proximity of both molecules. In the presence of MCD or filipin, there were no FRET signals detected. In floated detergent-resistant membrane fractions, CD38 significantly increased in LR fractions of CAMs treated by Oxo. Moreover, MCD or filipin attenuated Oxo-induced production of cADPR via CD38. Functionally, Oxo-induced intracellular Ca(2+) release and coronary artery constriction via cADPR were also blocked by LR disruption or ASMase inhibition. These results provide the first evidence that the formation of ceramide-enriched lipid macrodomains is crucial for Oxo-induced activation of CD38 to produce cADPR in CAMs, and these lipid macrodomains mediate transmembrane signaling of M(1) receptor activation to produce second messenger cADPR.
Asunto(s)
ADP-Ribosil Ciclasa 1/metabolismo , Ceramidas/metabolismo , Microdominios de Membrana/efectos de los fármacos , Agonistas Muscarínicos/farmacología , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Oxotremorina/farmacología , Receptor Muscarínico M1/agonistas , Animales , Señalización del Calcio/efectos de los fármacos , Bovinos , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/inmunología , Vasos Coronarios/metabolismo , ADP-Ribosa Cíclica/metabolismo , Relación Dosis-Respuesta a Droga , Filipina/farmacología , Transferencia Resonante de Energía de Fluorescencia , Microdominios de Membrana/inmunología , Microdominios de Membrana/metabolismo , Microscopía Confocal , Músculo Liso Vascular/inmunología , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/inmunología , Miocitos del Músculo Liso/metabolismo , Receptor Muscarínico M1/metabolismo , Esfingomielina Fosfodiesterasa/metabolismo , Vasoconstricción/efectos de los fármacos , beta-Ciclodextrinas/farmacologíaRESUMEN
OBJECTIVES: To investigate role of endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) in down-regulation of the expression of endothelial SK3 in atherosclerosis. METHODS: Apolipoprotein E deficient (apo E(-/-)) mice aged 11 approximately 12 weeks were treated with ADMA (5 mg/kg per day, subcutaneous injection) for 4 weeks. Cultured human umbilical venous endothelial cells (HUVECs) were treated with different concentrations of lysophosphatidylcholine (LPC) or ADMA for 48 h. Plasma levels of ADMA were determined by high performance liquid chromatogram (HPLC); protein and mRNA levels of SK3 in the aortas of mice and cultured cells were detected by immunofluorescence, western blot and RT-PCR, respectively. RESULTS: Concomitantly with the elevated plasma levels of ADMA, the expressions of both SK3 protein and mRNA in aortas of apo E(-/-) mice were significantly reduced in comparison to those of the wild-type mice. Moreover, 4-week treatment of ADMA made levels of SK3 expression even lower. In cultured HUVECs, either LPC or ADMA notably decreased the expressions of both SK3 protein and mRNA in a concentration dependent manner. CONCLUSIONS: Endogenous ADMA may be an important factor for down-regulation of the expression of endothelial SK3 in atherosclerotic animals.