RESUMEN
Patients with diabetes mellitus (DM) often experience complications such as peripheral arterial disease (PAD), which is thought to be caused by vascular damage resulting from increased oxidative stress. Dipeptidyl peptidase-4 inhibitors have been reported to reduce oxidative stress, although the exact mechanism remains unclear. This study aimed to investigate the impact of long-term (6 weeks) anagliptin treatment at a dose of 200 mg/kg/d against oxidative stress in the femoral artery of Otsuka Long-Evans Tokushima Fatty (OLETF) rats using a well-established animal model for type 2 DM. Serum toxic advanced glycation end-products concentrations and blood glucose levels after glucose loading were significantly elevated in OLETF rats compared to Long-Evans Tokushima Otsuka (LETO) rats but were significantly suppressed by anagliptin administration. Plasma glucagon-like peptide-1 concentrations after glucose loading were significantly increased in anagliptin-treated rats. Superoxide production and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in femoral arteries were significantly increased in OLETF rats compared to LETO rats but were significantly decreased by anagliptin administration. The expressions of NADPH oxidase components (p22phox in the intima region and p22phox and gp91phox in the media region) in the femoral artery were significantly increased in OLETF rats compared to LETO rats but were significantly suppressed by anagliptin administration. Furthermore, the femoral artery showed increased wall thickness in OLETF rats compared to LETO rats, but anagliptin administration reduced the thickening. This study suggests that long-term anagliptin administration can reduce oxidative stress in femoral arteries and improve vascular injury.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Pirimidinas , Lesiones del Sistema Vascular , Humanos , Ratas , Animales , Arteria Femoral , Lesiones del Sistema Vascular/tratamiento farmacológico , Ratas Endogámicas OLETF , Ratas Long-Evans , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , GlucosaRESUMEN
Advanced glycation end-products (AGEs) form through non-enzymatic glycation of various proteins. Optic nerve degeneration is a frequent complication of diabetes, and retinal AGE accumulation is strongly linked to the development of diabetic retinopathy. Type 2 diabetes mellitus is a major risk factor for Alzheimer's disease (AD), with patients often exhibiting optic axon degeneration in the nerve fiber layer. Notably, a gap exists in our understanding of how AGEs contribute to neuronal degeneration in the optic nerve within the context of both diabetes and AD. Our previous work demonstrated that glyceraldehyde (GA)-derived toxic advanced glycation end-products (TAGE) disrupt neurite outgrowth through TAGE-ß-tubulin aggregation and tau phosphorylation in neural cultures. In this study, we further illustrated GA-induced suppression of optic nerve axonal elongation via abnormal ß-tubulin aggregation in mouse retinas. Elucidating this optic nerve degeneration mechanism holds promise for bridging the knowledge gap regarding vision loss associated with diabetes mellitus and AD.
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Axones , Productos Finales de Glicación Avanzada , Nervio Óptico , Tubulina (Proteína) , Animales , Tubulina (Proteína)/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Ratones , Nervio Óptico/metabolismo , Nervio Óptico/patología , Nervio Óptico/efectos de los fármacos , Axones/metabolismo , Axones/efectos de los fármacos , Axones/patología , Ratones Endogámicos C57BL , Agregado de Proteínas/efectos de los fármacosRESUMEN
Glyceraldehyde-derived advanced glycation end products (glycer-AGEs) could contribute to colorectal cancer development and progression due to their pro-oxidative and pro-inflammatory properties. However, the association of glycer-AGEs with mortality after colorectal cancer diagnosis has not been previously investigated. Circulating glycer-AGEs were measured by competitive ELISA. Multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for associations of circulating glycer-AGEs concentrations with CRC-specific and all-cause mortality among 1034 colorectal cancer (CRC) cases identified within the European Prospective Investigation into Cancer and Nutrition (EPIC) study between 1993 and 2013. During a mean of 48 months of follow-up, 529 participants died (409 from CRC). Glycer-AGEs were statistically significantly positively associated with CRC-specific (HRQ5 vs Q1 = 1.53, 95% CI: 1.04-2.25, Ptrend = .002) and all-cause (HRQ5 vs Q1 = 1.62, 95% CI: 1.16-2.26, Ptrend < .001) mortality among individuals with CRC. There was suggestion of a stronger association between glycer-AGEs and CRC-specific mortality among patients with distal colon cancer (per SD increment: HRproximal colon = 1.02, 95% CI: 0.74-1.42; HRdistal colon = 1.51, 95% CI: 1.20-1.91; Peffect modification = .02). The highest HR was observed among CRC cases in the highest body mass index (BMI) and glycer-AGEs category relative to lowest BMI and glycer-AGEs category for both CRC-specific (HR = 1.78, 95% CI: 1.02-3.01) and all-cause mortality (HR = 2.15, 95% CI: 1.33-3.47), although no statistically significant effect modification was observed. Our study found that prediagnostic circulating glycer-AGEs are positively associated with CRC-specific and all-cause mortality among individuals with CRC. Further investigations in other populations and stratifying by tumor location and BMI are warranted.
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Neoplasias Colorrectales , Productos Finales de Glicación Avanzada , Humanos , Gliceraldehído , Estudios Prospectivos , Índice de Masa CorporalRESUMEN
Objectives: Glyceraldehyde-derived advanced glycation end-products (Glycer-AGEs) have a strong binding affinity for their cognate receptor and elicit oxidative stress and inflammation. However, it remains unknown whether the levels of Glycer-AGEs correlate with the severity of cardiac function and heart failure in patients with diabetic adverse cardiac remodeling (DbCR). Fourteen heart failure patients with type 2 diabetes mellitus (DM) without other cardiac disorders (DbCR group) were enrolled. Another 14 patients with idiopathic dilated cardiomyopathy (DCM) without DM were served as a control (DCM group). All patients were assessed for serum Glycer-AGEs, nitrotyrosine (NT), and tumor necrosis factor alpha (TNFα) and for plasma brain natriuretic peptide (BNP). The left ventricular ejection fraction (LVEF) was evaluated by echocardiography. Results: The mean serum levels of Glycer-AGEs, NT, and TNFα in the DbCR group were significantly higher than those in the DCM group (for Glycer-AGEs, p = .0073; for NT, p = .005; for TNFα, p < .0001, respectively). In the patients with DbCR, the levels of serum Glycer-AGEs and TNFα were closely associated with LVEF and BNP values. Conclusions: Both Glycer-AGEs and TNFα showed close associations with LVEF and the levels of BNP in patients with DbCR. Glycer-AGEs and TNFα may play a pathological role in the development of DbCR.
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Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Gliceraldehído , Humanos , Péptido Natriurético Encefálico , Volumen Sistólico , Factor de Necrosis Tumoral alfa , Función Ventricular Izquierda , Remodelación VentricularRESUMEN
BACKGROUND: Advanced glycation end-products (AGE), which accumulate with insulin resistance and aging, impair folliculogenesis and may decrease endometrial receptivity. Hishi (Trapa bispinosa Roxb.) extract, a safe herbal medicine, strongly inhibits AGE formation in vitro. We determined whether Hishi lowers AGE and increases live births in older assisted reproductive technology (ART) patients. METHODS: This prospective randomized open-label controlled trial included 64 patients 38 to 42 years old undergoing ART with or without Hishi extract between June 11, 2015 and July 12, 2019. None had over 2 ART failures, diabetes, uterine anomalies, or exhausted ovarian reserve. After allocation, the Hishi group received Hishi extract (100 mg/day) until late pregnancy or failure. The control group received no extract. Both groups underwent 1 cycle of conventional infertility treatment; 1 long-protocol cycle of ovarian stimulation, oocyte retrieval, in vitro fertilization/intracytoplasmic sperm injection, and fresh embryo transfer (ET); and, if needed, cryopreserved ET until live birth or embryo depletion. Serum AGE were measured before and during ART, as were AGE in follicular fluid (FF). RESULTS: Cumulative live birth rate among 32 Hishi patients was 47%, significantly higher than 16% among 31 controls (p<0.01; RR, 4.6; 95% CI, 1.4 - 15.0; 1 control dropped out). Live birth rate per ET, including fresh and cryopreserved, was significantly higher with Hishi (28% in 47 ET vs. 10% in 49 ET; p<0.05; RR, 3.4; 95% CI, 1.1-10.4). Among variables including age, day-3 FSH, anti-Müllerian hormone, and Hishi, logistic regression identified only Hishi as significantly associated with increased cumulative live birth (p<0.05; OR, 5.1; 95% CI, 1.4 - 18.3). Hishi significantly enhanced oocyte developmental potential, improved endometrial receptivity in natural cycles, and decreased AGE in serum and FF. Larger serum AGE decreases with Hishi were associated with more oocytes becoming day-2 embryos. CONCLUSIONS: Hishi decreased AGE in serum and FF and improved oocyte developmental potential and endometrial receptivity, increasing live births in older patients. Treatment of infertility by AGE reduction represents a new addition to infertility treatment. Therapeutic trials of Hishi for other AGE-associated diseases might be considered. TRIAL REGISTRATION: UMIN registration in Japan ( UMIN000017758 ) on June 1, 2015. https://www.umin.ac.jp/ctr/index.htm.
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Productos Finales de Glicación Avanzada , Nacimiento Vivo , Lythraceae , Extractos Vegetales , Técnicas Reproductivas Asistidas , Adulto , Femenino , Humanos , Recién Nacido , Embarazo , Terapia Combinada , Regulación hacia Abajo/efectos de los fármacos , Productos Finales de Glicación Avanzada/efectos de los fármacos , Productos Finales de Glicación Avanzada/metabolismo , Japón/epidemiología , Nacimiento Vivo/epidemiología , Edad Materna , Medicina Tradicional de Asia Oriental , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fitoterapia/métodos , Extractos Vegetales/uso terapéutico , Resultado del Embarazo/epidemiología , Índice de Embarazo , Técnicas Reproductivas Asistidas/estadística & datos numéricos , Resultado del Tratamiento , Lythraceae/químicaRESUMEN
Nonalcoholic steatohepatitis (NASH), the aggressive form of the most common chronic liver disease nonalcoholic fatty liver disease, is characterized by inflammation and damage in the liver. Although hepatocyte injury and cell death have been identified as cardinal pathological features of NASH, its pathogenesis has not yet been elucidated in detail. Immortalized cell lines and primary cultured cells have been used as in vitro models of NASH. However, these cells have several disadvantages, such as specialized characteristics by immortalization or limited growth potential. To overcome these difficulties and develop a strategy to analyze the pathology of NASH, we employed hepatocyte-like cells differentiated from human induced pluripotent stem cells (hiPSC-HLCs) as an in vitro model of NASH to clarify the intracellular effects of glyceraldehyde-derived advanced glycation end-products (AGEs), also named toxic AGEs (TAGE). The viability of hiPSC-HLCs decreased with the accumulation of TAGE in the cells, which was consistent with previous findings on human hepatocellular carcinoma cells and human primary cultured hepatocytes. In addition, the TAGE accumulation up-regulated the expression of inflammation-related genes (interleukin 6, interleukin 8, and monocyte chemoattractant protein-1) in hiPSC-HLCs. These results indicated that the accumulation of TAGE induced hiPSC-HLC cytotoxicity and inflammation, which are features of the pathology of NASH. Therefore, we suggest the use of hiPSC-HLCs as an important strategy for analyses of the pathology of NASH.
Asunto(s)
Productos Finales de Glicación Avanzada/metabolismo , Hepatocitos/patología , Enfermedad del Hígado Graso no Alcohólico/inmunología , Diferenciación Celular , Hepatocitos/inmunología , Humanos , Células Madre Pluripotentes Inducidas , Enfermedad del Hígado Graso no Alcohólico/patologíaRESUMEN
Advanced glycation end-products (AGEs) are produced by the non-enzymatic reaction of sugars with proteins. It has been revealed that glyceraldehyde-derived toxic AGEs (TAGE) are elevated in the serum of non-alcoholic steatohepatitis (NASH) patients. NASH causes liver fibrosis and progresses to cirrhosis and hepatocellular carcinoma. However, the impact of TAGE in liver fibrosis caused by extracellular matrix accumulation remains poorly understood. In this study, we examined the effect of TAGE on the activation of hepatic stellate cells that are involved in liver fibrosis. LX-2 cells treated with transforming growth factor-ß1 (TGF-ß1) significantly reduced cell viability by apoptosis. However, the decrease in cell viability with TGF-ß1 treatment was significantly suppressed by TAGE co-treatment. The levels of α-smooth muscle actin (α-SMA) and platelet-derived growth factor (PDGF)-Rß and its ligand PDGF-B were increased in LX-2 cells following TGF-ß1 treatment, suggesting that these cells were activated; however, these increases were unaffected by TAGE co-treatment. Moreover, collagen I level was increased with TGF-ß1 treatment, and this increase was further increased by TAGE co-treatment. These results suggested that the suppression of apoptosis in activated LX-2 cells by TGF-ß1 and TAGE co-treatment is related to an increase in the production of the extracellular matrix such as collagen I. Therefore, it was suggested that TAGE might aggravate the liver fibrosis of chronic hepatitis, such as NASH.
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Supervivencia Celular/efectos de los fármacos , Productos Finales de Glicación Avanzada/toxicidad , Células Estrelladas Hepáticas/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Células Estrelladas Hepáticas/patología , Células Estrelladas Hepáticas/fisiología , HumanosRESUMEN
Hepatocyte cell death is a key process in the pathogenesis of nonalcoholic steatohepatitis (NASH). However, the factors responsible for and mechanisms underlying NASH-related cell death have not yet been elucidated in detail. We herein investigated the effects of intracellular glyceraldehyde (GA)-derived advanced glycation end-products (AGEs), named toxic AGEs (TAGE), on the production of reactive oxygen species (ROS), which have been implicated in the pathogenesis of NASH. Cell death related to intracellular TAGE accumulation was eliminated in the hepatocyte carcinoma cell line HepG2 by the antioxidant effects of N-acetyl-L-cysteine. The intracellular accumulation of TAGE increased ROS production and the expression of Nrf2, including its downstream gene. These results suggest that ROS are produced in association with the accumulation of TAGE and are a direct trigger for cell death. We also investigated the factors responsible for these increases in ROS. Catalase activity did not decrease with the accumulation of TAGE, while mitochondrial membrane depolarization was enhanced in cells treated with GA. These results indicate that TAGE play an important role in mitochondrial abnormalities and increases in ROS production, both of which are characteristic features of NASH. The suppression of TAGE accumulation has potential as a new therapeutic target in the progression of NASH.
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Productos Finales de Glicación Avanzada/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Carcinoma Hepatocelular/metabolismo , Muerte Celular/fisiología , Línea Celular Tumoral , Progresión de la Enfermedad , Células Hep G2 , Hepatocitos/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Potencial de la Membrana Mitocondrial/fisiología , Mitocondrias/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
A complication of diabetes mellitus is the over-production of vascular superoxides, which contribute to the development of arteriosclerosis and peripheral arterial disease (PAD). Hyperglycemia induces the formation and accumulation of advanced glycation end-products (AGEs), which in turn stimulate vascular superoxide production. The mechanism underlying AGE-mediated vascular superoxide production remains to be clarified in lower limb complications associated with diabetes. In the present study, we investigated the role of AGEs and the mitochondrial respiratory complex in superoxide production in femoral arteries using the type 2 diabetes model Otsuka Long-Evans Tokushima Fatty (OLETF) rats [vs. non-diabetic Long-Evans Tokushima Otsuka (LETO) rats]. The effects of in vivo administration of pravastatin on superoxide production in femoral arteries were also examined. Using chemiluminescent assays, luminescence microscopy, and competitive enzyme-linked immunosorbent assay (ELISA), we determined that vascular superoxide production and serum glyceraldehyde-derived AGEs (Glycer-AGEs) increased in OLETF rats. Pravastatin inhibited these responses without changing serum total cholesterol concentrations. The mitochondrial complex II inhibitor thenoyltrifluoroacetone (TTFA) also inhibited vascular superoxide production. Application of Glycer-AGEs in situ increased superoxide production in the vascular wall of femoral arteries from pravastatin-treated OLETF rats, which was then inhibited by TTFA. These results suggest that hyperglycemia increases serum Glycer-AGEs, which subsequently induce superoxide production in the femoral artery of OLETF rats in a mitochondrial complex II-dependent manner. Collectively, our results have partially elucidated the pathological mechanisms leading to diabetes-related PAD, and indicate dual beneficial actions of pravastatin for the prevention of oxidative damage to the vascular wall.
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Arteria Femoral/efectos de los fármacos , Productos Finales de Glicación Avanzada/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Pravastatina/farmacología , Superóxidos/metabolismo , Animales , Glucemia/análisis , Colesterol/sangre , Arteria Femoral/metabolismo , Gliceraldehído , Masculino , Mitocondrias/metabolismo , Ratas Endogámicas OLETF , Ratas Long-EvansRESUMEN
Trimethylamine (TMA), an intestinal microflora-dependent metabolite formed from phosphatidylcholine- and L-carnitine-rich food, such as red meat, is further converted to trimethylamine-N-oxide (TMAO), which could play a role in cardiometabolic disease. Red meat-derived products are one of the major environmental sources of advanced glycation end products (AGEs) that may also contribute to the pathogenesis of cardiometabolic disorders through the interaction with receptor for AGEs (RAGE). However, the relationship among AGEs, soluble form of RAGE (sRAGE) and TMAO in humans remains unclear. Non-diabetic subjects underwent a physical examination, determination of blood chemistry and anthropometric variables, including AGEs, sRAGE, TMA and TMAO. Multiple regression analyses revealed that HbA1c, uric acid and AGEs were independently associated with log TMA, whereas log AGEs to sRAGE ratio and statin non-use were independently correlated with log TMAO. Our present findings indicated that AGEs to sRAGE ratio was correlated with log TMAO, a marker of cardiometabolic disorders.
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Productos Finales de Glicación Avanzada/sangre , Metilaminas/sangre , Receptor para Productos Finales de Glicación Avanzada/sangre , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Experimental ischemia-reperfusion models have shown that 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, have cardioprotective effects. SAMIT (Statin Acute Myocardial Infarction Trial) is a multicenter prospective open randomized trial, designed to evaluate the effects of statin treatment from the earliest stage on cardioprotection in patients with acute myocardial infarction (AMI). Patients were randomly assigned to receive atorvastatin (initial dose of 40 mg at admission followed by the maintenance dose of 10 mg/day for 30 days) or not (control), and then immediately underwent percutaneous coronary intervention (PCI) for the culprit lesion. The primary endpoints were infarct size and left ventricular function. The secondary endpoints were major adverse cardiac and cerebrovascular events (MACCE) and various biomarkers. There were no significant differences in baseline characteristics between 2 groups of the statin treatment group and the control group. The left ventricular ejection fraction increased at 6 months after the onset of AMI, compared with the baseline level in the atorvastatin group (P < 0.05), while it did not change in the control group. Although there were no significant differences in the MACCE, the changes in the levels of angiopoietin-like protein 2 (ANGPTL2) (P < 0.05), and glyceraldehyde-derived advanced glycation end-products, (TAGE) (P < 0.01) were suppressed at 2 weeks in the atorvastatin group, compared with the control group. Statin therapy started early after the onset reduced the levels of ANGPTL2 and TAGE, and thus, might have cardioprotective effects in patients with AMI.
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Angioplastia Coronaria con Balón , Angiopoyetinas/sangre , Atorvastatina/administración & dosificación , Productos Finales de Glicación Avanzada/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Infarto del Miocardio/terapia , Enfermedad Aguda , Anciano , Proteína 2 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Estrés Oxidativo/efectos de los fármacos , Estudios Prospectivos , Resultado del Tratamiento , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
OBJECTIVES: Food or supplement-derived L-carnitine is changed to trimethylamine (TMA) by interstinal microbiota, which is further metabolized to trimethylamine-N-oxide (TMAO), being involved in the promotion of atherosclerosis in animal models. Meanwhile, carnitine deficiency has played a role in accelerated atherosclerosis in hemodialysis (HD) patients. However, effects of oral L-carnitine supplementation on circulating levels of TMAO and markers of vascular injury and oxidative stress in patients on HD remain unclear. In this study, we addressed the issue. METHODS: Thirty-one HD patients with carnitine deficiency were treated with oral L-carnitine (900 mg/d) for 6 months. At baseline and after treatment, clinical variables including circulating levels of carnitine fractions, TMA, TMAO, advanced glycation end products (AGE), soluble forms of intracellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and malondialdehyde (MDA) were measured. RESULTS: Oral L-carnitine supplementation significantly increased total, free, acyl carnitine, and plasma TMA and TMAO levels, whereas it decreased markers of vascular injury and oxidative stress such as sICAM-1, sVCAM-1, and MDA levels. TMA and TMAO levels at baseline were correlated with each other, and free carnitine was independently associated with TMAO levels. Furthermore, change in AGE values from baseline ([INCREMENT]AGE) was positively correlated with [INCREMENT]sICAM-1 (P = 0.043) and was a sole independent determinant of [INCREMENT]sICAM-1 (R = 0.133, P = 0.043). CONCLUSIONS: This study demonstrated that although oral L-carnitine supplementation was associated with increased TMAO levels, it might be beneficial on vascular injury in patients on HD. Vasculoprotective properties of L-carnitine supplementation in HD patients might be ascribed partly to its inhibitory actions on AGE.
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Carnitina/administración & dosificación , Carnitina/deficiencia , Enfermedades Carenciales/tratamiento farmacológico , Suplementos Dietéticos , Enfermedades Renales/terapia , Metilaminas/sangre , Diálisis Renal , Lesiones del Sistema Vascular/prevención & control , Administración Oral , Anciano , Biomarcadores/sangre , Carnitina/efectos adversos , Carnitina/sangre , Estudios de Casos y Controles , Enfermedades Carenciales/sangre , Enfermedades Carenciales/complicaciones , Enfermedades Carenciales/diagnóstico , Suplementos Dietéticos/efectos adversos , Femenino , Productos Finales de Glicación Avanzada/sangre , Humanos , Molécula 1 de Adhesión Intercelular/sangre , Japón , Enfermedades Renales/sangre , Enfermedades Renales/complicaciones , Enfermedades Renales/diagnóstico , Masculino , Malondialdehído/sangre , Persona de Mediana Edad , Estrés Oxidativo/efectos de los fármacos , Diálisis Renal/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Molécula 1 de Adhesión Celular Vascular/sangre , Lesiones del Sistema Vascular/sangre , Lesiones del Sistema Vascular/diagnóstico , Lesiones del Sistema Vascular/etiologíaRESUMEN
BACKGROUND: The prevalence of non-B or non-C hepatocellular carcinoma (NBNC-HCC) has been increasing all over the world. Advanced glycation end products (AGE) play a role in the pathogenesis of alcoholic liver injury or nonalcoholic steatohepatitis (NASH). METHODS: We examined here whether serum levels of AGE were elevated in NBNC-HCC patients compared with NASH subjects without HCC and investigated which anthropometric and clinical variables were independent determinants of AGE. RESULTS: Ninety NBNC-HCC, 56 NASH, and 27 control subjects underwent a complete history and physical examination, determination of blood chemistries, including AGE levels. Serum levels of AGE were significantly higher in NBNC-HCC patients compared with NASH and control subjects [9.1 ± 2.7, 5.2 ± 1.7, 3.5 ± 1.2 (U/ml), respectively, P < 0.05]. Univariate analysis showed that AGE levels were associated with male (P < 0.05), age (P < 0.01), aspartate aminotransferase (P < 0.05), γ-glutamyl transpeptidase (GGT) (P < 0.01), HDL-cholesterol (inversely, P < 0.01), fasting plasma glucose (P < 0.01), and HbA1c (P < 0.05). By the use of multiple stepwise regression analysis, age, GGT, and HDL-cholesterol (inversely) remained significant and were independently related to AGE levels (R(2) = 0.406). CONCLUSION: The present results suggest that AGE might be involved in the pathogenesis of NBNC-HCC, thereby being a biomarker that could discriminate NBNC-HCC from NASH.
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Biomarcadores de Tumor/sangre , Carcinoma Hepatocelular/diagnóstico , Productos Finales de Glicación Avanzada/sangre , Neoplasias Hepáticas/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Anciano , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/etiología , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/etiología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , PronósticoRESUMEN
Epidemiological studies have suggested that diabetes is associated with an increased risk of cancer. However, the underlying molecular mechanism remains unclear. We investigated here whether DNA aptamer directed against advanced glycation end products (AGE-aptamer) inhibited melanoma growth in nude mice. G361 melanoma cells were injected intradermally into the upper flank of athymic nude mice. Mice received continuous intraperitoneal infusion (0.136 µg/day) of either AGE-aptamer (n=9) or Control-aptamer (n=8) by an osmotic mini pump. Tumor volume was measured at 4-day interval, and G361 melanoma was excised at day 43 after the aptamer treatment. We further examined the effects of AGE-aptamer on proliferation of AGE-exposed endothelial cells and G361 cells. AGE-aptamer significantly inhibited the in vivo-tumor growth of G361 melanoma. Immunohistochemical and western blotting analyses of G361 melanoma revealed that AGE-aptamer decreased expression levels of proliferating nuclear antigen, CD31 and Mac-3, markers of endothelial cells and macrophages, respectively. AGE-aptamer significantly decreased the number of tumor-associated vessels. AGE, receptor for AGE (RAGE) and vascular endothelial growth factor levels were also reduced in AGE-aptamer-treated G361 melanoma. AGE-aptamer inhibited the AGE-induced proliferation and tube formation of endothelial cells as well as the growth of G361 cells in vitro. The present findings suggest that AGE-aptamer could inhibit the AGE-RAGE axis in G361 melanoma and resultantly suppress the tumor growth in nude mice by blocking the angiogenesis. AGE-aptamer might be a novel therapeutic strategy for preventing the progression of malignant melanoma in diabetes.
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Aptámeros de Nucleótidos/uso terapéutico , Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Melanoma Experimental/tratamiento farmacológico , Animales , Antígenos de Diferenciación/metabolismo , Aptámeros de Nucleótidos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Células Endoteliales/efectos de los fármacos , Femenino , Productos Finales de Glicación Avanzada/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Melanoma Experimental/metabolismo , Ratones , Ratones Desnudos , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Antígeno Nuclear de Célula en Proliferación/metabolismo , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, contributes to diabetic nephropathy. We have found that glucagon-like peptide-1 (GLP-1) inhibits the AGE-induced inflammatory reactions in endothelial cells. However, effects of GLP-1 on the AGE-RAGE-ADMA axis are unknown. This study examined the effects of GLP-1 on reactive oxygen species (ROS) generation, gene expression of protein arginine methyltransfetase-1 (PRMT-1), an enzyme that mainly generates ADMA, and ADMA levels in human proximal tubular cells. Streptozotocin-induced diabetic rats received continuous i.p. infusion of 0.3 µg of vehicle or 1.5 µg of the GLP-1 analog exendin-4 per kilogram of body weight for 2 weeks. We further investigated whether and how exendin-4 treatment reduced ADMA levels and renal damage in streptozotocin-induced diabetic rats. GLP-1 inhibited the AGE-induced RAGE and PRMT-1 gene expression, ROS, and ADMA generation in tubular cells, which were blocked by small-interfering RNAs raised against GLP-1 receptor. Exendin-4 treatment decreased gene expression of Rage, Prmt-1, Icam-1, and Mcp-1 and ADMA level; reduced urinary excretions of 8-hydroxy-2'-deoxyguanosine and albumin; and improved histopathologic changes of the kidney in diabetic rats. Our present study suggests that GLP-1 receptor agonist may inhibit the AGE-RAGE-mediated ADMA generation by suppressing PRMT-1 expression via inhibition of ROS generation, thereby protecting against the development and progression of diabetic nephropathy.
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Arginina/análogos & derivados , Diabetes Mellitus Experimental/metabolismo , Riñón/metabolismo , Péptidos/farmacología , Proteína-Arginina N-Metiltransferasas/biosíntesis , Receptores de Glucagón/agonistas , Ponzoñas/farmacología , Animales , Arginina/biosíntesis , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/patología , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Evaluación Preclínica de Medicamentos/métodos , Exenatida , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Péptido 1 Similar al Glucagón/farmacología , Receptor del Péptido 1 Similar al Glucagón , Productos Finales de Glicación Avanzada/fisiología , Humanos , Hipertrofia/prevención & control , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Glomérulos Renales/patología , Túbulos Renales/metabolismo , Macrófagos/patología , Masculino , Péptidos/uso terapéutico , Proteína-Arginina N-Metiltransferasas/genética , ARN Mensajero/genética , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Receptor para Productos Finales de Glicación Avanzada , Receptores de Glucagón/metabolismo , Receptores Inmunológicos/metabolismo , Proteínas Represoras/biosíntesis , Proteínas Represoras/genética , Ponzoñas/uso terapéuticoRESUMEN
BACKGROUND: The purpose of this study was to elucidate the effects of glimepiride on the levels of biomarkers related to cardiovascular regulation in patients with type 2 diabetes mellitus. METHODS AND RESULTS: Thirty-four patients with type 2 diabetes received glimepiride for 24 weeks. Significant decreases in the levels of glyceraldehyde-derived advanced glycation end products, (glycer-AGE: toxic AGE), eotaxin and fibroblast growth factor (FGF)-2 were recognized after the administration of glimepiride. Moreover, there were trends for there to be increases in the levels of granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF), and decreases in the levels of fractalkine, soluble CD40 ligand (sCD40L), macrophage inflammatory protein (MIP)-ß, vascular endothelial growth factor (VEGF) and soluble receptor for AGE (sRAGE). CONCLUSIONS: Glimepiride may have potent anti-oxidative, anti-inflammatory and angiogenic properties and it may potentially repair tissue damage by decreasing the levels of toxic AGE and increasing colony-stimulating factors.
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Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Índice Glucémico/fisiología , Hipoglucemiantes/uso terapéutico , Compuestos de Sulfonilurea/uso terapéutico , Anciano , Femenino , Índice Glucémico/efectos de los fármacos , Humanos , Hipoglucemiantes/farmacología , Masculino , Persona de Mediana Edad , Compuestos de Sulfonilurea/farmacología , Resultado del TratamientoRESUMEN
BACKGROUND: Basal and bolus insulin therapy is required for strict blood control in diabetic patients, which could lead to prevention of vascular complications in diabetes. However, the optimal combination regimen is not well established. METHODS: Fifty-nine diabetic patients (49 type 1 and 10 type 2; 52.9 ± 13.3 years old) whose blood glucose levels were uncontrolled (HbA1c > 6.2%) by combination treatment of basal insulin glargine with multiple daily pre-meal injections of bolus short-acting insulin [aspart (n = 19), lispro (n = 37) and regular human insulin (n = 3)] for at least 8 weeks were enrolled in this study. We examined whether glycaemic control and vascular injury were improved by replacement of short-acting insulin with glulisine. Patient satisfaction was assessed with Diabetes Treatment Satisfaction Questionnaire. RESULTS: Although bolus and basal insulin doses were almost unchanged before and after replacement therapy, switching to glulisine insulin for 24 weeks significantly decreased level of HbA1c , advanced glycation end products (AGEs), soluble receptor for AGEs (sRAGE), monocyte chemoattractant protein-1 (MCP-1) and urinary albumin excretion. In multiple stepwise regression analysis, change in MCP-1 values from baseline (ΔMCP-1) was a sole determinant of log urinary albumin excretion. ΔAGEs and ΔsRAGE were independently correlated with each other. The relationship between ΔMCP-1 and ΔsRAGE was marginally significant (p = 0.05). Replacement of short-acting insulin by glulisine significantly increased Diabetes Treatment Satisfaction Questionnaire scores. CONCLUSIONS: Our present study suggests that combination therapy of glargine with multiple daily pre-meal injections of glulisine might show superior efficacy in controlling blood glucose, preventing vascular damage and improving treatment satisfaction in diabetic patients.
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Angiopatías Diabéticas/prevención & control , Hiperglucemia/prevención & control , Hipoglucemiantes/administración & dosificación , Insulina/análogos & derivados , Satisfacción del Paciente , Adulto , Anciano , Biomarcadores/sangre , Biomarcadores/orina , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/orina , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/orina , Esquema de Medicación , Resistencia a Medicamentos , Quimioterapia Combinada/efectos adversos , Femenino , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemia/prevención & control , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Inyecciones Subcutáneas , Insulina/administración & dosificación , Insulina/efectos adversos , Insulina/uso terapéutico , Insulina Glargina , Insulina de Acción Prolongada/administración & dosificación , Insulina de Acción Prolongada/efectos adversos , Insulina de Acción Prolongada/uso terapéutico , Japón , Masculino , Persona de Mediana EdadRESUMEN
Advanced glycation end-products (AGEs) have recently been implicated in the onset/progression of lifestyle-related diseases (LSRDs); therefore, the suppression of AGE-induced effects may be used in both the prevention and treatment of these diseases. Various AGEs are produced by different biological pathways in the body. Glyceraldehyde (GA) is an intermediate of glucose and fructose metabolism, and GA-derived AGEs (GA-AGEs), cytotoxic compounds that accumulate and induce damage in mammalian cells, contribute to the onset/progression of LSRDs. The following GA-AGE structures have been detected to date: triosidines, GA-derived pyridinium compounds, GA-derived pyrrolopyridinium lysine dimers, methylglyoxal-derived hydroimidazolone 1, and argpyrimidine. GA-AGEs are a key contributor to the formation of toxic AGEs (TAGE) in many cells. The extracellular leakage of TAGE affects the surrounding cells via interactions with the receptor for AGEs. Elevated serum levels of TAGE, which trigger different types of cell damage, may be used as a novel biomarker for the prevention and early diagnosis of LSRDs as well as in evaluations of treatment efficacy. This review provides an overview of the structures of GA-AGEs.
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Productos Finales de Glicación Avanzada , Gliceraldehído , Animales , Productos Finales de Glicación Avanzada/metabolismo , Gliceraldehído/metabolismo , Azúcares , Reacción de Maillard , Mamíferos/metabolismoRESUMEN
BACKGROUND: The Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome (JAPAN-ACS) trial demonstrated that early aggressive statin therapy in patients with ACS significantly reduces plaque volume (PV). Advanced glycation end products (AGEs) and the receptors of AGEs (RAGE) may lead to angiopathy in diabetes mellitus (DM) and may affect on the development of coronary PV. The present sub-study of JAPAN-ACS investigates the association between AGEs and RAGE, and PV. METHODS: Intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) was undertaken, followed by the initiation of statin treatment (either 4 mg/day of pitavastatin or 20 mg/day of atorvastatin), in patients with ACS. In the 208 JAPAN-ACS subjects, PV using IVUS in non-culprit segment > 5 mm proximal or distal to the culprit lesion and, serum levels of AGEs and soluble RAGE (sRAGE) were measured at baseline and 8-12 months after PCI. RESULTS: At baseline, no differences in the levels of either AGEs or sRAGE were found between patients with DM and those without DM. The levels of AGEs decreased significantly with statin therapy from 8.6 ± 2.2 to 8.0 ± 2.1 U/ml (p < 0.001), whereas the levels of sRAGE did not change. There were no significant correlations between changes in PV and the changes in levels of AGEs as well as sRAGE. However, high baseline AGEs levels were significantly associated with plaque progression (odds ratio, 1.21; 95% confidence interval, 1.01 - 1.48; p = 0.044) even after adjusting for DM in multivariate logistic regression models. CONCLUSIONS: High baseline AGEs levels were associated with plaque progression in the JAPAN-ACS trial. This relationship was independent of DM. These findings suggest AGEs may be related to long-term glucose control and other oxidative stresses in ACS. TRIAL REGISTRATION: NCT00242944.
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Síndrome Coronario Agudo/sangre , Síndrome Coronario Agudo/epidemiología , Progresión de la Enfermedad , Productos Finales de Glicación Avanzada/sangre , Placa Aterosclerótica/sangre , Placa Aterosclerótica/epidemiología , Síndrome Coronario Agudo/cirugía , Anciano , Femenino , Estudios de Seguimiento , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Intervención Coronaria Percutánea/métodos , Placa Aterosclerótica/cirugía , Estudios Prospectivos , Ultrasonografía Intervencional/métodosRESUMEN
Advanced glycation end products (AGEs) not only inhibit DNA synthesis of retinal pericytes, but also elicit vascular hyperpermeability, pathological angiogenesis, and thrombogenic reactions by inducing vascular endothelial growth factor (VEGF) and plasminogen activator inhibitor-1 (PAI-1) through the interaction with the receptor for AGEs (RAGE), thereby being involved in the pathogenesis of diabetic retinopathy. In this study, we screened novel phosphorothioate-modified aptamers directed against AGEs (AGEs-thioaptamers) using a combinatorial chemistry in vitro, and examined whether these aptamers could inhibit the AGE-induced damage in both retinal pericytes and human umbilical vein endothelial cells (HUVECs). We identified 11 AGEs-thioaptamers; among them, clones #4, #7s and #9s aptamers had higher binding affinity to AGEs-human serum albumin (HSA) than the others. Surface plasmon resonance analysis revealed that KD values of #4s, #7s and #9s were 0.63, 0.36, and 0.57nM, respectively. Furthermore, these 3 clones dose-dependently restored the decrease in DNA synthesis in AGE-exposed pericytes. AGEs significantly increased RAGE, VEGF and PAI-1 mRNA levels in HUVEC, all of which were completely blocked by the treatment with 20nM clone #4s aptamer. Quartz crystal microbalance analysis confirmed that #4s aptamer dose-dependently inhibited the binding of AGEs-HSA to RAGE. Our present study demonstrated that AGEs-thioaptamers could inhibit the harmful effects of AGEs in pericytes and HUVEC by suppressing the binding of AGEs to RAGE. Blockade by AGEs-thioaptamers of the AGEs-RAGE axis might be a novel therapeutic strategy for diabetic retinopathy.