RESUMO
Betatrophin is a protein which is produced by the liver and by adipose tissue. There are no clear data about serum betatrophin's cardiovascular role and it is unknown, whether betatrophin is associated with the risk of cardiovascular death. This article provides additional data on the association of betatrophin with its power to predict cardiovascular death in coronary patients. In addition, this data article demonstrates the performance of betatrophin as a biomarker using c-statistics. Analyzed data was derived from 553 coronary patients. Betatrophin was measured in serum samples and cardiovascular deaths were recorded for a median of 7.1 years. This data article is related to a research article titled "High betatrophin in coronary patients protects from cardiovascular events" [1].
RESUMO
BACKGROUND AND AIMS: Betatrophin, also known as angiopoietin-like protein 8 (ANGPTL8) or lipasin, is a nutritionally-regulated mammalian-specific protein secreted by the liver and adipose tissue. Many conflicting data exist with respect to its association with type 2 diabetes mellitus (T2DM), insulin resistance, and lipid markers, but no data are available on its association with cardiovascular risk. METHODS: We measured betatrophin in 553 coronary patients undergoing coronary angiography for the evaluation of established or suspected stable coronary artery disease (CAD) and prospectively recorded cardiovascular events during a follow-up of up to 8 years. RESULTS: During follow-up, 201 patients suffered a cardiovascular event and 64 died from cardiovascular causes. High betatrophin (upper tertile) was significantly and inversely associated with cardiovascular events both univariately (HR = 0.64 [95%CI 0.47-0.87], p = 0.004) and after full adjustment including the status of CAD and T2DM (adj. HR = 0.55 [95%CI 0.40-0.76], p < 0.001). The inclusion of betatrophin into a basic prediction model for the cardiovascular event risk significantly improved the model performance (NRI = 0.728, p < 0.001). CONCLUSIONS: This study is the first to show that betatrophin predicts cardiovascular events independently of conventional risk factors including the presence of CAD and T2DM.
Assuntos
Proteínas Semelhantes a Angiopoietina/sangue , Doença da Artéria Coronariana/sangue , Hormônios Peptídicos/sangue , Idoso , Proteína 8 Semelhante a Angiopoietina , Biomarcadores/sangue , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Fatores de TempoRESUMO
BACKGROUND: Uromodulin is the most abundant protein in urine. Low uromodulin has been found associated with diabetes as well as with chronic kidney disease (CKD). Whether it also predicts a future decline in kidney function is not known. METHODS: We evaluated the association between serum uromodulin and kidney function in 529 patients and performed a genome-wide association study. Clinical parameters including renal function were determined at baseline and reassessed at a 4-year follow-up visit. RESULTS: Patients' serum uromodulin levels were highest associated with a polymorphism in the UMOD coding region and were significantly correlated with estimated glomerular filtration rate (eGFR) (râ=â0.242, Pâ<â0.001) and, in an inverse way, with the albumin-creatinine ratio (râ=â-0.120, Pâ=â0.012). Serum uromodulin concentrations were significantly lower in patients with CKD (eGFRâ<â60âml/min per 1.73âm) than in patients with normal kidney function (71.9â±â29.0 vs. 169.1â±â76.1âng/ml, Pâ<â0.001) and the same applied to patients with albuminuria (148.7â±â72.2 vs. 167.9â±â77.6âng/ml, Pâ=â0.008) or hypertension (160.9â±â74.0 vs. 181.8â±â87.8âng/ml, Pâ=â0.037). Prospectively, patients who developed CKD during the follow-up had significantly less uromodulin in serum than those who did not (126.8â±â42.3 vs. 180.2â±â79.1âng/ml, Pâ=â0.003). Serum uromodulin concentration was inversely associated with the development of CKD, even after adjustment for patients age, sex, genotype of the identified polymorphism, hypertension and diabetes status, and eGFR (odds ratioâ=â0.263, Pâ=â0.019), and it significantly increased the performance of a prediction model for CKD (C-statistics 0.844 vs. 0.804, Pâ=â0.049). CONCLUSION: The current study is the first evaluating the value of uromodulin in serum as a novel predictive biomarker for renal function and for the incidence of CKD.
Assuntos
Insuficiência Renal Crônica/sangue , Uromodulina/sangue , Idoso , Albuminúria , Biomarcadores/sangue , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/fisiopatologia , Uromodulina/genéticaRESUMO
Uromodulin is a protein which is produced by the tubular cells of the thick ascending limb in the kidneys and the creatinine to uromodulin ratio in serum recently has attracted interest as a marker of kidney disease. Whether this ratio also is associated with cardiovascular event risk is unknown. This article provides additional data on the association of the creatinine to uromodulin ratio with its power to predict cardiovascular events and major cardiovascular events in coronary patients. In addition, this data article demonstrates the performance of the creatinine to uromodulin ratio as a biomarker using c-statistics. Analyzed data was derived from 529 coronary patients. Uromodulin and creatinine were measured and cardiovascular events were recorded for up to 8 years. This data article is related to a research article titled "Serum Uromodulin is a predictive biomarker for cardiovascular events and overall mortality in coronary patients" [1].
RESUMO
Uromodulin is the most abundant urine protein under physiological conditions. It has recently been described as a serum and plasma marker for kidney disease. Whether uromodulin is associated with impaired glucose metabolism is unknown.We therefore measured serum uromodulin and glucose traits in a cohort of 529 consecutively recruited patients.Serum uromodulin was significantly and inversely correlated with fasting plasma glucose (râ=â-0.161; Pâ<â0.001), with plasma glucose 2 hours after an oral 75âg glucose challenge (râ=â-0.158; Pâ=â0.001), and with HbA1c (râ=â-0.103; Pâ=â0.018). A total of 146 (27.6%) of our patients had type 2 diabetes mellitus (T2DM). Analysis of covariance confirmed that T2DM was an independent determinant of serum uromodulin (Fâ=â5.5, Pâ=â0.020) after multivariate adjustment including hypertension and glomerular filtration rate. Prospectively, uromodulin was lowest in patients with T2DM at baseline, higher in initially nondiabetic subjects who developed diabetes during follow-up (FU) and highest among nondiabetic patients (147.7â±â69.9 vs 164â±â67 vs 179.9â±â82.2âng/mL, Ptrendâ<â0.001). Similar results were seen with respect to prediabetes (168.0â±â81.2 vs 172.8â±â66.3 vs 188.2â±â74.0âng/mL, Pâ=â0.011).We conclude that serum uromodulin is significantly associated with impaired glucose metabolism and the development of prediabetes and diabetes.
Assuntos
Diabetes Mellitus Tipo 2/sangue , Estado Pré-Diabético/sangue , Uromodulina/sangue , Idoso , Biomarcadores , Glicemia , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Jejum/sangue , Feminino , Taxa de Filtração Glomerular , Teste de Tolerância a Glucose , Humanos , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/epidemiologia , Estado Pré-Diabético/metabolismo , Estudos Prospectivos , Fatores de Risco , Fumar/epidemiologia , Uromodulina/metabolismoRESUMO
BACKGROUND: Uromodulin is a protein produced exclusively by the kidneys and present in urine and blood. In contrast to weak and in part contradictory study data on uromodulin in urine samples, the analysis of serum samples recently proved uromodulin's value as superior biomarker for ongoing kidney disease. Whether serum uromodulin is associated with cardiovascular event risk and whether it has predictive power for overall mortality is still unknown and has been evaluated in the present study. METHODS: We measured uromodulin in a series of 529 patients without acute coronary syndrome undergoing coronary angiography for the evaluation of established or suspected stable coronary artery disease (CAD) and prospectively recorded mortality as well as cardiovascular events in our patients during a follow-up of up to 8years. RESULTS: We recorded 95 deaths and 145 cardiovascular events over 8years. Serum uromodulin proved protective for overall mortality (HR=0.56 [95%CI 0.43-0.72]; p<0.001), even after full adjustment including eGFR, current smoking, diabetes, and CAD status (adj. HR=0.57 [95%CI 0.37-0.89]; p=0.014). Patients in the lowest tertile of serum uromodulin had a significantly higher cardiovascular event risk compared to patients in the medium and highest tertile (HR=of 1.45 (95%CI 1.04-2.02, p=0.027). The ratio between creatinine and uromodulin was significantly associated with kidney function (r=-0.322; p<0.001) and significantly predicted the incidence of cardiovascular events (HR of 1.26 [95%CI 1.12-1.41], p<0.001) and major cardiovascular events (HR of 1.37 [95%CI 1.21-1.56], p<0.001). CONCLUSION: We conclude that serum uromodulin is a valuable biomarker to predict overall mortality and cardiovascular events.
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Doença da Artéria Coronariana/sangue , Medição de Risco , Uromodulina/sangue , Idoso , Áustria/epidemiologia , Biomarcadores/sangue , Doenças Cardiovasculares , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Incidência , Masculino , Valor Preditivo dos Testes , Prevalência , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Fatores de TempoRESUMO
Obesity is characterized by the rapid expansion of visceral adipose tissue, resulting in a hypoxic environment in adipose tissue which leads to a profound change of gene expression in adipocytes. As a consequence, there is a dysregulation of metabolism and adipokine secretion in adipose tissue leading to the development of systemic inflammation and finally resulting in the onset of metabolic diseases. The flavonoid quercetin as well as other secondary plant metabolites also referred to as phytochemicals have anti-oxidant, anti-inflammatory, and anti-diabetic effects known to be protective in view of obesity-related-diseases. Nevertheless, its underlying molecular mechanism is still obscure and thus the focus of this study was to explore the influence of quercetin on human SGBS (Simpson Golabi Behmel Syndrome) adipocytes' gene expression. We revealed for the first time that quercetin significantly changed expression of adipokine (Angptl4, adipsin, irisin and PAI-1) and glycolysis-involved (ENO2, PFKP and PFKFB4) genes, and that this effect not only antagonized but in part even overcompensated the effect mediated by hypoxia in adipocytes. Thus, these results are explained by the recently proposed hypothesis that the protective effect of quercetin is not solely due to its free radical-scavenging activity but also to a direct effect on mitochondrial processes, and they demonstrate that quercetin might have the potential to counteract the development of obesity-associated complications.
Assuntos
Adipócitos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Obesidade/metabolismo , Quercetina/farmacologia , Proteína 4 Semelhante a Angiopoietina , Angiopoietinas/genética , Angiopoietinas/metabolismo , Linhagem Celular , Fibronectinas/genética , Fibronectinas/metabolismo , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Oxigênio/metabolismo , Fosfofrutoquinases/genética , Fosfofrutoquinases/metabolismo , Fosfopiruvato Hidratase , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
One of the first strategies for cancer gene therapy was the use of suicide gene/prodrug combinations, originally delivered to tumor cells using viral vectors. A major limitation of this approach was the inefficiency of suicide gene delivery. An alternative strategy, in which the suicide genes are physically juxtaposed to the tumor, involves the implantation of encapsulated, genetically modified cells. Cell encapsulation technologies were originally developed for the treatment of acquired and genetic diseases, such as diabetes. In the application of this technology for the treatment of tumors, cells that are genetically modified to overexpress suicide genes are encapsulated and implanted near solid tumors; this process is then followed by systemic prodrug administration. This review discusses the various cells types, suicide genes and prodrugs that have been used in preclinical and clinical trials, as well as the data that have been obtained from these studies. Future improvements for the production of second-generation approaches are also discussed.
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Antineoplásicos/farmacocinética , Animais , Antineoplásicos/farmacologia , Biotransformação/efeitos dos fármacos , Células Imobilizadas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Genes Transgênicos Suicidas , Humanos , Neoplasias/terapiaRESUMO
Acetylation is the most prominent modification on core histones that strongly affects nuclear processes such as DNA replication, DNA repair and transcription. Enzymes responsible for the dynamic equilibrium of histone acetylation are histone acetyltransferases (HATs) and histone deacetylases (HDACs). In this paper we describe the identification of novel HDACs from the filamentous fungi Aspergillus nidulans and the maize pathogen Cochliobolus carbonum. Two of the enzymes are homologs of Saccharomyces cerevisiae HOS3, an enzyme that has not been identified outside of the established yeast systems until now. One of these homologs, HosB, showed intrinsic HDAC activity and remarkable resistance against HDAC inhibitors like trichostatin A (TSA) when recombinant expressed in an Escherichia coli host system. Phylo genetic analysis revealed that HosB, together with other fungal HOS3 orthologs, is a member of a separate group within the classical HDACs. Immunological investigations with partially purified HDAC activities of Aspergillus showed that all classical enzymes are part of high molecular weight complexes and that a TSA sensitive class 2 HDAC constitutes the major part of total HDAC activity of the fungus. However, further biochemical analysis also revealed an NAD(+)-dependent activity that could be separated from the other activities by different types of chromatography and obviously represents an enzyme of the sirtuin class.