RESUMO
BACKGROUND: We conducted the multicenter, prospective, open-label study in type 2 diabetic (T2DM) patients with renal dysfunction, to clarify the efficacy and the safety in relation to renal function and glycemic control, and the economic effect when other dipeptidyl peptidase-4 (DPP-4) inhibitors were switched to a small dose of sitagliptin depending on their renal function. METHODS: Vildagliptin, alogliptin, or linagliptin received for more than 2 months were changed to sitagliptin at 25 or 12.5 mg/day depending on their renal function in 49 T2DMs. Renal function and glycemic control, and the drug cost were assessed during 6 months. RESULTS: Estimated glomerular filtration rate was not changed in patients not on hemodialysis (n = 29). The HbA1c levels were not altered in all of the patients including those on hemodialysis (n = 20). The active glucagon-like peptide-1 levels or other renal parameters were not altered significantly. There were no adverse events to be related to the drugs. The daily drug expense was reduced by 88.1 yen per patient. CONCLUSION: Switching to a small dose of sitagliptin according to the renal function in T2DM patients with renal dysfunction demonstrated the same efficacy and safety as those with other full-dose DPP-4 inhibitors, indicating a therapeutic option with a high cost performance.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Nefropatias/tratamento farmacológico , Fosfato de Sitagliptina/uso terapêutico , Idoso , Feminino , Humanos , Hipoglicemiantes , Japão , Nefropatias/etiologia , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Here, we describe the isolation of two nickel-induced genes in Paramecium caudatum, NCI16 and PcGST1, by subtractive hybridization. NCI16 encoded a predicted four-transmembrane domain protein (â¼16 kDa) of unknown function, and PcGST1 encoded glutathione S-transferase (GST; â¼25 kDa) with GST and glutathione peroxidase (GPx) activities. Exposing cells to cobalt chloride also caused the moderate upregulation of NCI16 and PcGST1 mRNAs. Both nickel sulfate and cobalt chloride dose dependently induced NCI16 and PcGST1 mRNAs, but with different profiles. Nickel treatment caused a continuous increase in PcGST1 and NCI16 mRNA levels for up to 3 and 6 days, respectively, and a notable increase in H2O2 concentrations in P. caudatum. NCI16 expression was significantly enhanced by incubating cells with H2O2, implying that NCI16 induction in the presence of nickel ions is caused by reactive oxygen species (ROS). On the other hand, PcGST1 was highly induced by the antioxidant tert-butylhydroquinone (tBHQ) but not by H2O2, suggesting that different mechanisms mediate the induction of NCI16 and PcGST1. We introduced a luciferase reporter vector with an â¼0.42-kb putative PcGST1 promoter into cells and then exposed the transformants to nickel sulfate. This resulted in significant luciferase upregulation, indicating that the putative PcGST1 promoter contains a nickel-responsive element. Our nickel-inducible system also may be applicable to the efficient expression of proteins that are toxic to host cells or require temporal control.
Assuntos
Glutationa Transferase/isolamento & purificação , Proteínas de Membrana/genética , Níquel/metabolismo , Paramecium caudatum/metabolismo , Proteínas de Protozoários/genética , Antioxidantes/metabolismo , Glutationa Transferase/biossíntese , Glutationa Transferase/genética , Peróxido de Hidrogênio/metabolismo , Íons/metabolismo , Estresse Oxidativo/genética , Paramecium caudatum/genética , RNA Mensageiro/genética , Espécies Reativas de Oxigênio/metabolismoRESUMO
Osteoclast formation is regulated by balancing between the receptor activator of nuclear factor-κB ligand (RANKL) expressed in osteoblasts and extracellular negative regulatory cytokines such as interferon-γ (IFN-γ) and interferon-ß (IFN-ß), which can suppress excessive bone destruction. However, relatively little is known about intrinsic negative regulatory factors in RANKL-mediated osteoclast differentiation. Here, we show the paired-box homeodomain transcription factor Pax6 acts as a negative regulator of RANKL-mediated osteoclast differentiation. Electrophoretic mobility shift and reporter assays found that Pax6 binds endogenously to the proximal region of the tartrate acid phosphatase (TRAP) gene promoter and suppresses nuclear factor of activated T cells c1 (NFATc1)-induced TRAP gene expression. Introduction of Pax6 retrovirally into bone marrow macrophages attenuates RANKL-induced osteoclast formation. Moreover, we found that the Groucho family member co-repressor Grg6 contributes to Pax6-mediated suppression of the TRAP gene expression induced by NFATc1. These results suggest that Pax6 interferes with RANKL-mediated osteoclast differentiation together with Grg6. Our results demonstrate that the Pax6 pathway constitutes a new aspect of the negative regulatory circuit of RANKL-RANK signaling in osteoclastogenesis and that the augmentation of Pax6 might therefore represent a novel target to block pathological bone resorption.
Assuntos
Fosfatase Ácida/metabolismo , Células da Medula Óssea/metabolismo , Diferenciação Celular/fisiologia , Proteínas do Olho/metabolismo , Proteínas de Homeodomínio/metabolismo , Isoenzimas/metabolismo , Osteoclastos/metabolismo , Fatores de Transcrição Box Pareados/metabolismo , Ligante RANK/metabolismo , Proteínas Repressoras/metabolismo , Elementos de Resposta/fisiologia , Fosfatase Ácida/genética , Animais , Células da Medula Óssea/citologia , Células Cultivadas , Proteínas Correpressoras , Proteínas do Olho/genética , Regulação Enzimológica da Expressão Gênica/fisiologia , Proteínas de Homeodomínio/genética , Humanos , Isoenzimas/genética , Camundongos , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/citologia , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/genética , Ligante RANK/genética , Proteínas Repressoras/genética , Fosfatase Ácida Resistente a TartaratoRESUMO
Phosphatase and tensin homolog (PTEN) dephosphorylates phosphatidylinositol (PI) 3,4,5-triphosphate and antagonizes PI 3-kinase. Insulin acts in the mediobasal hypothalamus (MBH) to not only suppress food intake and weight gain but also improve glucose metabolism via PI 3-kinase activation. Thus, the blocking of hypothalamic PTEN is a potential target for treating obesity as well as diabetes. However, genetic modification of PTEN in specific neuronal populations in the MBH yielded complex results, and no postnatal intervention for hypothalamic PTEN has been reported yet. To elucidate how postnatal modification of hypothalamic PTEN influences food intake as well as glucose metabolism, we bidirectionally altered PTEN activity in the MBH of rats by adenoviral gene delivery. Inhibition of MBH PTEN activity reduced food intake and weight gain, whereas constitutive activation of PTEN tended to induce the opposite effects. Interestingly, the effects of MBH PTEN intervention on food intake and body weight were blunted by high-fat feeding. However, MBH PTEN blockade improved hepatic insulin sensitivity even under high-fat-fed conditions. On the other hand, constitutive activation of MBH PTEN induced hepatic insulin resistance. Hepatic Akt phosphorylation and the G6Pase expression level were modulated bidirectionally by MBH PTEN intervention. These results demonstrate that PTEN in the MBH regulates hepatic insulin sensitivity independently of the effects on food intake and weight gain. Therefore, hypothalamic PTEN is a promising target for treating insulin resistance even in states of overnutrition.
Assuntos
Regulação do Apetite/fisiologia , Gorduras na Dieta/metabolismo , Ingestão de Alimentos/fisiologia , Glucose/metabolismo , Hipotálamo/fisiologia , Fígado/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Animais , Retroalimentação Fisiológica/fisiologia , Resistência à Insulina/fisiologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Microalbuminuria is an early predictor of diabetic nephropathy and premature cardiovascular disease. We investigated whether treatment with an angiotensin-receptor blocker (ARB) would delay or prevent the occurrence of microalbuminuria in patients with type 2 diabetes and normoalbuminuria. METHODS: In a randomized, double-blind, multicenter, controlled trial, we assigned 4447 patients with type 2 diabetes to receive olmesartan (at a dose of 40 mg once daily) or placebo for a median of 3.2 years. Additional antihypertensive drugs (except angiotensin-converting-enzyme inhibitors or ARBs) were used as needed to lower blood pressure to less than 130/80 mm Hg. The primary outcome was the time to the first onset of microalbuminuria. The times to the onset of renal and cardiovascular events were analyzed as secondary end points. RESULTS: The target blood pressure (<130/80 mm Hg) was achieved in nearly 80% of the patients taking olmesartan and 71% taking placebo; blood pressure measured in the clinic was lower by 3.1/1.9 mm Hg in the olmesartan group than in the placebo group. Microalbuminuria developed in 8.2% of the patients in the olmesartan group (178 of 2160 patients who could be evaluated) and 9.8% in the placebo group (210 of 2139); the time to the onset of microalbuminuria was increased by 23% with olmesartan (hazard ratio for onset of microalbuminuria, 0.77; 95% confidence interval, 0.63 to 0.94; P=0.01). The serum creatinine level doubled in 1% of the patients in each group. Slightly fewer patients in the olmesartan group than in the placebo group had nonfatal cardiovascular events--81 of 2232 patients (3.6%) as compared with 91 of 2215 patients (4.1%) (P=0.37)--but a greater number had fatal cardiovascular events--15 patients (0.7%) as compared with 3 patients (0.1%) (P=0.01), a difference that was attributable in part to a higher rate of death from cardiovascular causes in the olmesartan group than in the placebo group among patients with preexisting coronary heart disease (11 of 564 patients [2.0%] vs. 1 of 540 [0.2%], P=0.02). CONCLUSIONS: Olmesartan was associated with a delayed onset of microalbuminuria, even though blood-pressure control in both groups was excellent according to current standards. The higher rate of fatal cardiovascular events with olmesartan among patients with preexisting coronary heart disease is of concern. (Funded by Daiichi Sankyo; ClinicalTrials.gov number, NCT00185159.).
Assuntos
Albuminúria/prevenção & controle , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Imidazóis/uso terapêutico , Tetrazóis/uso terapêutico , Adolescente , Adulto , Idoso , Albuminúria/epidemiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Doença das Coronárias/complicações , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Feminino , Seguimentos , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Tetrazóis/efeitos adversos , Adulto JovemRESUMO
The role of low-frequency variants in type 1 diabetes (T1D) susceptibility still remains to be clarified. In the present study, we analyzed low-frequency variants of the T1D candidate genes in Japanese. We first screened for protein-changing variants of 24 T1D candidate genes in 96 T1D patients and 96 control subjects, and then the association with T1D was tested in 706 T1D patients and 863 control subjects recruited from the collaborating institutions in Japan. In total, 56 protein-changing variants were discovered; among them, 34 were low-frequency variants (allele frequency < 5%). The association analysis of the low-frequency variants revealed that only the A908V variant of GLIS3 was strongly associated with resistance to T1D (Haldane's odds ratio = 0.046, p = 8.21 × 10(-4), and pc=2.22 × 10(-2)). GLIS3 is a zinc finger transcription factor that is highly expressed in pancreatic beta cells, and regulates beta cell development and insulin gene expression. GLIS3 mRNA is also moderately expressed in the human thymus. The precise mechanism responsible for the association is unclear at present, but the A908V variant may affect autoimmunity to the GLIS3 protein itself; the 908V containing epitope may induce central or peripheral tolerance more efficiently than that of 908A.
Assuntos
Diabetes Mellitus Tipo 1/genética , Regulação da Expressão Gênica , Predisposição Genética para Doença , Fatores de Transcrição/genética , Adolescente , Adulto , Alelos , Povo Asiático , Estudos de Casos e Controles , Proteínas de Ligação a DNA , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Variação Genética , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Japão , Masculino , Pessoa de Meia-Idade , Proteínas Repressoras , Timo/metabolismo , Transativadores , Adulto Jovem , Dedos de ZincoRESUMO
OBJECTIVE: Diabetic retinopathy (DR) is linked to cardiovascular risk in diabetic patients. This study examined whether mild-stage DR is associated with risk of coronary heart disease (CHD) and stroke in type 2 diabetic patients of the Japan Diabetes Complications Study (JDCS). DESIGN: Prospective cohort study. PARTICIPANTS: In the JDCS, there were 2033 Japanese persons with type 2 diabetes free of cardiovascular diseases at baseline. METHODS: Diabetic retinopathy was ascertained from clinical and photographic grading (70%) following the international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Incident CHD and stroke were followed up prospectively annually up to 8 years. MAIN OUTCOME MEASURES: Eight-year incidence of CHD and stroke compared between persons with or without DR. RESULTS: After adjusting for traditional cardiovascular risk factors, persons with mild to moderate nonproliferative DR had a higher risk of CHD (hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.17-2.97) and stroke (HR, 2.69; 95% CI, 1.03-4.86). Presence of retinal hemorrhages or microaneurysms was associated with risk of CHD (HR, 1.63; 95% CI, 1.04-2.56) but was not associated with stroke (P = 0.06). Presence of cotton-wool spots was associated with risk of incident stroke (HR, 2.39; 95% CI, 1.35-4.24) but was not associated with CHD (P = 0.66). When information about DR was added in the prediction models for CHD and stroke based on traditional cardiovascular risk factors, the area under the receiver operating curve improved from 0.682 to 0.692 and 0.640 to 0.677, and 9% and 13% of persons were reclassified correctly for CHD and stroke, respectively. CONCLUSIONS: Type 2 diabetic patients with even a mild stage of DR, such as dot hemorrhages, are already at higher risk of CHD and stroke independent of traditional risk factors.
Assuntos
Doença das Coronárias/etiologia , Retinopatia Diabética/complicações , Aneurisma/complicações , Glicemia/metabolismo , Colesterol/sangue , Doença das Coronárias/diagnóstico , Complicações do Diabetes , Diabetes Mellitus Tipo 2/complicações , Retinopatia Diabética/diagnóstico , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Incidência , Japão , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Hemorragia Retiniana/complicações , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologiaRESUMO
BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD) has become a common liver disease, as its prevalence has increased markedly in recent decades. The aim of the present study was to examine the improving effect of Clostridium butyricum MIYAIRI 588 (CBM588), a probiotic in clinical use for antibiotic-associated diarrhea, against high-fat diet (HFD)-induced fatty liver in rats. METHODS: After feeding HFD or HFD coated with CBM588 (HFD-CBM) for 12 weeks, we evaluated the hepatic mRNA levels related to lipid metabolism, and then assessed the hepatic protein levels of several transcription factors regulating these lipogenic gene expressions. RESULTS: The HFD-CBM group had decreased accumulation of lipid droplets in the liver compared with the HFD group. The HFD-CBM group had significantly decreased diacylglycerol acyltransferase (DGAT) 2 mRNA in the liver compared with the HFD group, whereas DGAT1 mRNA did not change between the HFD group and the HFD-CBM group. Moreover, the HFD-CBM group had significantly increased hepatic mRNA regulating cholesterol catabolism enzymes and excretion transporters. Correspondingly, the HFD-CBM588 groups had increased hepatic protein levels of peroxisome proliferator-activated receptor α/γ and liver X receptor α compared with the HFD group. The HFD-CBM group had accelerated excretion of total bile acid and non-esterified fatty acid in the feces. CONCLUSIONS: CBM588 intake may have novel potential for improving NAFLD.
Assuntos
Clostridium butyricum , Fígado Gorduroso/terapia , Metabolismo dos Lipídeos , Animais , Peso Corporal , Diacilglicerol O-Aciltransferase/metabolismo , Ingestão de Alimentos , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado/enzimologia , Fígado/patologia , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-DawleyRESUMO
Amyotrophic lateral sclerosis (ALS) is an incurable degenerative disorder of motoneurons. We recently reported that reduced expression of Vegfa causes ALS-like motoneuron degeneration in Vegfa(delta/delta) mice. In a meta-analysis of over 900 individuals from Sweden and over 1,000 individuals from Belgium and England, we now report that subjects homozygous with respect to the haplotypes -2,578A/-1,154A/-634G or -2,578A/-1,154G/-634G in the VEGF promoter/leader sequence had a 1.8 times greater risk of ALS (P = 0.00004). These 'at-risk' haplotypes lowered circulating VEGF levels in vivo and reduced VEGF gene transcription, IRES-mediated VEGF expression and translation of a novel large-VEGF isoform (L-VEGF) in vivo. Moreover, SOD1(G93A) mice crossbred with Vegfa(delta/delta) mice died earlier due to more severe motoneuron degeneration. Vegfa(delta/delta) mice were unusually susceptible to persistent paralysis after spinal cord ischemia, and treatment with Vegfa protected mice against ischemic motoneuron death. These findings indicate that VEGF is a modifier of motoneuron degeneration in human ALS and unveil a therapeutic potential of Vegfa for stressed motoneurons in mice.
Assuntos
Esclerose Lateral Amiotrófica/genética , Fatores de Crescimento Endotelial/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Linfocinas/genética , Idoso , Alelos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/etiologia , Esclerose Lateral Amiotrófica/patologia , Animais , Morte Celular/efeitos dos fármacos , Criança , Pré-Escolar , Fatores de Crescimento Endotelial/fisiologia , Fatores de Crescimento Endotelial/uso terapêutico , Feminino , Variação Genética , Haplótipos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Isquemia/patologia , Linfocinas/fisiologia , Linfocinas/uso terapêutico , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/patologia , Degeneração Neural/genética , Paralisia/etiologia , Isquemia do Cordão Espinal/tratamento farmacológico , Isquemia do Cordão Espinal/patologia , Suécia , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
Recent studies have shown colestimide, a bile acid-binding resin, to also exert a glucose-lowering effect via amelioration of insulin resistance. To evaluate the effects of colestimide on glucose metabolism and to elucidate the underlying mechanism, we conducted a 6-month, open-label pilot study on 43 type 2 diabetic patients with obesity (BMI ≥ 25). The subjects were randomized to either treatment with colestimide 4g/day (T group, n=23) or continuation of their current therapy (C group, n=20). In the T group patients, mean HbA1c and fasting glucose improved markedly (from 7.71 ± 0.32% to 6.97 ± 0.20%; from 147.4 ± 7.3mg/dL to 127.0 ± 5.0mg/dL, respectively), while obesity-related parameters, i.e. body weight, waist circumference, and visceral fat and subcutaneous fat as determined by umbilical slice abdominal CT, showed no significant changes. Fractionation analyses of serum bile acids revealed significantly increased cholic acids (CA) and decreased chenodeoxycholic acids (CDCA) in the T group patients. However, no correlation was observed between these changes and ΔHbA1c. According to logistic regression analysis, baseline HbA1c was the only variable predicting the decrease of HbA1c (>0.5%) among sex, age, BMI, total cholesterol, ΔCA and ΔCDCA. The index of insulin resistance, i.e. HOMA-R, did not improve, and the index of ß cell function, i.e. HOMA-ß, actually increased significantly. These results suggests that, in obese patients with type 2 diabetes, the mechanism underlying improved glycemic control with colestimide treatment involves enhanced ß cell activity rather than improved insulin resistance.
Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Epicloroidrina/farmacologia , Hipoglicemiantes/farmacologia , Imidazóis/farmacologia , Resistência à Insulina , Obesidade/sangue , Resinas Sintéticas/farmacologia , Peso Corporal/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Resultado do TratamentoRESUMO
Interstitial fibrosis and hypoxia accelerate the progression of CKD, but clinical tools to quantitate these factors in patients are lacking. Here, we evaluated the use of two magnetic resonance imaging (MRI) techniques, diffusion-weighted (DW)-MRI and blood oxygen level-dependent (BOLD)-MRI, to assess kidney fibrosis and hypoxia of the cortex in 142 patients with either diabetic nephropathy (n = 43), CKD without diabetes (n = 76), or acute kidney injury (AKI) (n = 23). Apparent diffusion coefficient (ADC) values of DW-MRI correlated with estimated glomerular filtration rates (eGFR) in the diabetic nephropathy and CKD groups (r(2) = 0.56 and r(2) = 0.46, respectively). Although the T2* values of BOLD-MRI and eGFR displayed good correlation in the CKD group (r(2) = 0.38), we did not observe a significant correlation between these values in the diabetic nephropathy group, suggesting that factors other than tubulointerstitial alteration determine the degree of hypoxia in the renal cortex. In the AKI group, neither the T2* nor ADC values correlated with eGFR. Renal biopsies from patients with CKD demonstrated that the T2* and ADC MRI values correlated with renal pathology. Taken together, ADC and T2* values appear to serve as accurate indices for evaluating renal tubulointerstitial alterations and parenchymal hypoxia, respectively, in the cortex. Functional MRI can thus contribute to multilateral, noninvasive, in vivo assessment of kidney function.
Assuntos
Fibrose/patologia , Hipóxia/patologia , Rim/patologia , Imageamento por Ressonância Magnética/métodos , Adulto , Biópsia , Nefropatias Diabéticas/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Fibrose/diagnóstico , Taxa de Filtração Glomerular , Humanos , Hipóxia/diagnóstico , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/patologia , Masculino , Oxigênio/metabolismo , Cintilografia/métodosRESUMO
The increasing number of patients with metabolic syndrome is a critical global problem. In this study, we describe a novel geometrical electrophoretic separation method using a bioformulated-fiber matrix to analyze high-density lipoprotein (HDL) particles. HDL particles are generally considered to be a beneficial component of the cholesterol fraction. Conventional electrophoresis is widely used but is not necessarily suitable for analyzing HDL particles. Furthermore, a higher HDL density is generally believed to correlate with a smaller particle size. Here, we use a novel geometrical separation technique incorporating recently developed nanotechnology (Nata de Coco) to contradict this belief. A dyslipidemia patient given a 1-month treatment of fenofibrate showed an inverse relationship between HDL density and size. Direct microscopic observation and morphological observation of fractionated HDL particles confirmed a lack of relationship between particle density and size. This new technique may improve diagnostic accuracy and medical treatment for lipid related diseases.
Assuntos
Acetobacter/química , Eletroforese Capilar/métodos , Lipoproteínas HDL/análise , Nanotecnologia/métodos , Tamanho da PartículaRESUMO
PURPOSE: To assess modifiable environmental risk factors and protective factors for age-related macular degeneration (AMD) in a native Japanese population. DESIGN: A case-control study. PARTICIPANTS: We included 422 case-control samples composed of 279 consecutive AMD cases and 143 controls. METHODS: Information regarding systemic conditions and lifestyle were documented in each subject by standardized questionnaire including age, gender, smoking history, body mass index (BMI), and history of cardiovascular disease, hypertension, and diabetes. Serum fatty acids profiles were analyzed by gas chromatography performed on blood samples taken from each study participant. Logistic regression and multiple comparison analyses were utilized in this study. MAIN OUTCOME MEASURES: Population-specific information assessing systemic conditions, lifestyle, and serum fatty acid profiles. RESULTS: Among environmental factors analyzed cigarette smoking showed the most significant association with development of all AMD (P<0.00001; odds ratio [OR], 4.06; 95% confidence interval [CI], 2.22-7.43), typical neovascular AMD (P<0.0001, OR, 4.59; 95% CI, 2.29-9.18), and polypoidal choroidal vasculopathy (P<0.001; OR, 4.87; 95% CI, 1.96-12.1). Hypertension and BMI showed a mild association with AMD. Although male prevalence was significantly higher in all case groups than in controls with conventional Scheffe correction, there was no association of gender with AMD development when logistic regression analysis was used to adjust for cigarette smoking. There was no difference in fatty acid profiles, except for a mild association of eicosapentaenoic acid concentration in the all AMD group. CONCLUSIONS: In the Japanese population studied, cigarette smoking influenced the risk of AMD but fractionated serum fatty acid levels did not. Although prior reports indicate a male predominance in Japanese patients with AMD, this study demonstrates that cigarette smoking accounts for this confounding bias. In addition, our population-specific data do not demonstrate significant differences in serum fatty acid composition, including ω-3 and ω-6 long chain polyunsaturated fatty acids, in Japanese patients with and without AMD. These results are consistent with the high proportion of smokers in aged Japanese men and the high fish oil intake in this population. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.
Assuntos
Ácidos Graxos/sangue , Degeneração Macular/etiologia , Vigilância da População , Fumar/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Índice de Massa Corporal , Progressão da Doença , Feminino , Seguimentos , Humanos , Incidência , Japão/epidemiologia , Degeneração Macular/sangue , Degeneração Macular/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fumar/sangue , Fumar/epidemiologiaRESUMO
PURPOSE: To determine whether there is an association between complement factor H (CFH), high-temperature requirement A-1 (HTRA1), vascular endothelial growth factor (VEGF), and pigment epithelium-derived factor (PEDF) genotypes and response to treatment with photodynamic therapy (PDT) for age-related macular degeneration (AMD) in a Japanese population. DESIGN: Prospective, case-control study. PARTICIPANTS: One hundred ten patients with exudative AMD treated by verteporfin PDT were recruited prospectively at the Department of Ophthalmology, Saitama Medical University Hospital, Saitama, Japan. METHODS: The patients were genotyped for 4 single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996, rs2274700) in the CFH gene, a rs11200638-SNP in the HTRA1 gene, 3 SNPs (rs699947, rs1570360, rs2010963) in the VEGF gene, and 4 SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the PEDF gene using a TaqMan assay. MAIN OUTCOME MEASURES: The treatment outcomes and genotypes of CFH, HTRA1, VEGF, and PEDF polymorphisms. RESULTS: Best-corrected visual acuity 1 year after PDT was significantly increased in patients with the HTRA1-rs11200638 GG genotype as compared with patients with the GA or AA genotypes (P = 2.9 × 10⻲, 7.0 × 10â»4, respectively). The rate of recurrence in the 12-month period after PDT was also associated with HTRA1-rs11200638 genotype (P = 3.12 × 10⻲). Patients with the AA genotype of HTRA1-rs11200638 had an approximately 6-fold greater risk of the recurrence than patients with the GG genotype (P = 5.58 × 10⻳). Significant differences were demonstrated in the mean time interval from the initial treatment to the time of recurrence for the genotypes of CFH-rs1410996/-rs2274700 (P = 8.50 × 10⻳). CONCLUSIONS: The HTRA1-rs11200638 and CFH-rs1410996/-rs2274700 variants were associated with response to PDT in this study population. These variants may be used for genetic biomarkers to estimate visual outcomes and recurrences in the response to PDT with significant predictive power.
Assuntos
Degeneração Macular/tratamento farmacológico , Degeneração Macular/genética , Fotoquimioterapia , Polimorfismo de Nucleotídeo Único , Serina Endopeptidases/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Fator H do Complemento/genética , Proteínas do Olho/genética , Feminino , Genótipo , Serina Peptidase 1 de Requerimento de Alta Temperatura A , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Crescimento Neural/genética , Fármacos Fotossensibilizantes/uso terapêutico , Reação em Cadeia da Polimerase , Porfirinas/uso terapêutico , Estudos Prospectivos , Serpinas/genética , Fator A de Crescimento do Endotélio Vascular/genética , Verteporfina , Acuidade Visual/fisiologiaRESUMO
BACKGROUND: We previously reported the associations of human leukocyte antigen (HLA) (DRB1 and DQB1), INS, CTLA4, IL2RA, ERBB3 and CLEC16A with Japanese type 1 diabetes (T1D). In this study, we jointly analysed these loci in addition to IFIH1 and IL7R. METHODS: A maximum of 790 T1D patients and 953 control subjects were analysed. HLA was determined by sequencing-based typing. Seven non-HLA single nucleotide polymorphisms were genotyped using TaqMan assay. RESULTS: HLA DRB1*0405, DRB1*0901 and DRB1*0802-DQB1*0302 haplotypes were positively associated with T1D, while the DRB1*15 haplotypes were negatively associated. Non-HLA single nucleotide polymorphisms, INS, IL2RA, ERBB3, CLEC16A and IL7R were associated with T1D. By a prediction model using the HLA loci alone (HLA model) or the non-HLA loci alone (non-HLA model), it was revealed that the cumulative effect of the non-HLA model was much weaker than that of the HLA model (average increase in odds ratio: 1.17 versus 3.14). Furthermore, the area under the receiver operating characteristic curve of the non-HLA model was also much smaller than that of the HLA model (0.65 versus 0.81, p<10(-11)). Finally, a patient-only analysis revealed the susceptible HLA haplotypes and the risk allele of INS to be negatively associated with slower onset of the disease. In addition, the DRB1*0901 haplotype and the risk alleles of ERBB3, CLEC16A and CTLA4 were positively associated with the co-occurrence of thyroid autoimmunity. CONCLUSIONS: Although several non-HLA susceptibility genes in Japanese were confirmed trans-racially and appear to contribute to the heterogeneity of the clinical phenotypes, the cumulative effect on the ability to predict the development of T1D was weak.
Assuntos
Diabetes Mellitus Tipo 1/genética , Antígenos de Histocompatibilidade Classe II/genética , Idade de Início , Povo Asiático/genética , Autoanticorpos/análise , Feminino , Predisposição Genética para Doença/genética , Antígenos HLA-DR/genética , Cadeias HLA-DRB1/genética , Haplótipos , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Insulina/genética , Subunidade alfa de Receptor de Interleucina-2/genética , Lectinas Tipo C/genética , Masculino , Proteínas de Transporte de Monossacarídeos/genética , Polimorfismo de Nucleotídeo Único , Glândula Tireoide/imunologiaRESUMO
Recent guidelines including Japanese Society of Hypertension 2009 (JSH2009) recommend the lower target blood pressure such as < 130/80 mmHg in patients with diabetes mellitus, although the recent clinical trials such as ACCORD, INVEST or ROADMAP study raised questions about that the current target BP might be too low in some diabetic patients associated with coronary artery disease. In JSH2009, when BP is more than 130/80 mmHg, renin-angiotenisn blocker such as ACE inhibitor or ARB will be given as the first line hypotensive agent. If the target BP is not achieved, the dosage of ACE inhibitor or ARB is maximized or calcium channel antagonist or thiazide diuretic is added. In patients with metabolic syndrome, the target BP is < 140/90 mmHg. If their glucose tolerance is diabetic, the target BP is < 130/80 mmHg as mentioned above. The first line hypotensive agent is ACE inhibitor or ARB, since these agents improve insulin resistance.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Síndrome Metabólica/complicações , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , HumanosRESUMO
Phospholipase A(2) (PLA(2)) not only plays a role in the membrane vesiculation system but also mediates membrane-raft budding and fission in artificial giant liposomes. This study aimed to demonstrate the same effects in living cells. Differentiated Caco-2 cells were cultured on filter membranes. MDCK cells were challenged with Influenza virus. The MDCK cultures were harvested for virus titration with a plaque assay. Alkaline phosphatase (ALP), a membrane-raft associated glycosylphosphatidylinositol (GPI)-anchored protein, was 70% released by adding 0.2 mmol/l lysophosphatidylcholine, which was abolished by treatment with a membrane-raft disrupter, methyl-beta-cyclodextrin. Activation of calcium-independent PLA(2) (iPLA(2)) by brefeldin A increased the apical release of ALP by approximately 1.5-fold (p<0.01), which was blocked by PLA(2) inhibitor bromoenol lactone (BEL). BEL also reduced Influenza virus production into the media (<10%) in the MDCK culture. These results suggest that cells utilize inverted corn-shaped lysophospholipids generated by PLA(2) to modulate plasma membrane structure and assist the budding of raft-associated plasma membrane particles, which virus utilizes for its budding. Brush borders are enriched with membrane-rafts and undergo rapid turnover; thus, PLA(2) may be involved in the regulatory mechanism in membrane dynamism. Further, iPLA(2) may provide a therapeutic target for viral infections.
Assuntos
Lisofosfolipídeos/química , Microdomínios da Membrana/química , Fosfolipases A2/química , Montagem de Vírus , Fosfatase Alcalina/metabolismo , Animais , Cálcio/metabolismo , Membrana Celular , Células Cultivadas/virologia , Cães , Humanos , Lisofosfolipídeos/metabolismo , Microdomínios da Membrana/efeitos dos fármacos , Microdomínios da Membrana/metabolismo , Orthomyxoviridae/fisiologia , Fosfolipases A2/metabolismo , Replicação Viral/efeitos dos fármacos , beta-Ciclodextrinas/farmacologiaRESUMO
The quantification of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) is currently one of the most important clinical measurements for characterizing metabolic syndrome. However, recent studies have revealed additional factors that may be more strongly associated with the coronary heart disease than simple measurement of LDL or HDL levels, such as small dense (sd) LDL particles and oxidized LDL or HDL particles. Although several methods using enzyme-antibody detection systems or fluorescent probes have been devised to characterize these factors, such methods are expensive to implement for clinical measurements. Here, we present a straightforward analytical method for direct quantitation of oxidized lipoproteins by fluorescence spectrometry, with excitation in the UV (365 +/- 10 nm) or visible (470 +/- 10 nm) range and emission detected at 450 +/- 30 nm or 535 +/- 15 nm. This method can be readily applied for clinical measurement in patients with dyslipidemia using only 1 microL of 1 mg/mL of lipoprotein and without the need for any expensive detection antibodies. Using this new technique, biological samples from patients with dyslipidemia showed higher fluorescence intensities than samples from normal subjects when detecting oxidized LDL and light HDL (d = 1.063-1.125 g/mL), whereas samples from patients with dyslipidemia showed lower fluorescence intensities than samples from normal subjects when measuring oxidized heavy HDL (d = 1.125-1.210 g/mL) levels.
Assuntos
Corantes Fluorescentes/química , Lipoproteínas HDL/análise , Lipoproteínas LDL/análise , Espectrometria de Fluorescência/métodos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxirredução , Piridinas/síntese química , Piridinas/químicaRESUMO
PURPOSE: To describe phenotype and genotype characteristics of age-related macular degeneration (AMD) in Japanese patients. DESIGN: A case-control study. PARTICIPANTS: A total of 550 case-control samples composed of 408 consecutive AMD cases and 142 controls. METHODS: Clinical information assessing age, gender, affected eyes, fundus features, and fluorescein/indocyanine green angiograms were systematically evaluated. Four single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996, rs2274700) in the complement factor H (CFH) gene, 1 SNP (rs11200638) in the high-temperature requirement factor A1 (HTRA1) gene, 3 SNPs (rs699947, rs1570360, rs2010963) in the vascular endothelial growth factor (VEGF) gene, and 4 SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the pigment epithelium-derived factor (PEDF) gene were assessed using TaqMan technology. MAIN OUTCOME MEASURES: The clinical phenotype information and genotypes of CFH, HTRA1, VEGF, and PEDF polymorphisms. RESULTS: Of Japanese patients with neovascular AMD (nAMD), 219 (58.7%) had typical nAMD and 154 (41.3%) had polypoidal choroidal vasculopathy (PCV). The frequency of bilateral exudative involvement was similar between typical nAMD (15.5%) and PCV (13.6%) (P = 0.613). Significant soft drusen were observed in the fellow eyes of 88 (47.6%) of 185 patients with unilateral typical nAMD and in 25 (18.8%) of 133 patients with unilateral PCV (P = 1.24x10(-7)). A serous pigment epithelium detachment was seen in 55 (25.1%) of 219 patients with typical nAMD and in 64 (41.6%) of 154 patients with PCV. A significant association was noted in CFH-rs800292, CFH-rs1410996, CFH-rs2274700, and HTRA1-rs11200638 with AMD development (P = 2.36x10(-5), 7.18x10(-5), 7.18x10(-5), 2.70x10(-7), respectively; population attributable risk = 57.3%, 57.8%, 57.8%, and 58.9%, respectively). We estimated the highest-risk group to have an approximately 70-fold greater risk of nAMD compared with the lowest-risk group when analyzing a combination of 4 SNPs in the CFH and HTRA1 genes. CONCLUSIONS: The Japanese AMD phenotype is characterized by a higher frequency of PCV, male predominance, and lower frequency of bilateral presentation compared with Caucasian AMD. Genotype analyses demonstrate a significant population attributable risk for SNPs in the CFH and HTRA1 genes and demonstrate joint effects for both genes. Gene variants in both CFH and HTRA1 contribute significantly to the AMD phenotype in a Japanese population.
Assuntos
Proteínas do Olho/genética , Degeneração Macular/genética , Fatores de Crescimento Neural/genética , Polimorfismo de Nucleotídeo Único , Serina Endopeptidases/genética , Serpinas/genética , Fator A de Crescimento do Endotélio Vascular/genética , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Estudos de Casos e Controles , Corantes , Fator H do Complemento/genética , Feminino , Angiofluoresceinografia , Genótipo , Serina Peptidase 1 de Requerimento de Alta Temperatura A , Humanos , Verde de Indocianina , Japão , Degeneração Macular/diagnóstico , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
Forty to sixty % of diabetic patients are associated with hypertension. Diabetics have been well known to be a high risk group for cardiovascular disease (CVD) such as myocardial infarction and stroke. Concomitant hypertension increases the risk of CVD furthermore by 2-3 times. Thus, recent guidelines for the management of hypertension such as Japanese Society of Hypertension 2009 (JSH2009) recommend to lower blood pressure in diabetics to less than 130/80 mmHg with ACE inhibitors on angiotensin receptor blocker. Long-acting Ca channel blocker or a small dosage of thiazide diuretic is recommended as the second line hypotensive agents in JSH2009.