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Introduction: The incidence of steatotic liver disease has increased in recent years. Thus, steatotic liver disease is a major public health issue in Japan. This study investigated the association between weight reduction and the remission of metabolic dysfunction-associated steatotic liver disease (MASLD)/Metabolic and alcohol related/associated liver disease (MetALD) in Japanese individuals undergoing health checkups. Methods: This retrospective observational study included 8,707 Japanese patients with MASLD/MetALD who underwent health checkups from May 2015 to March 2023. The participants were monitored for its remission at their subsequent visit. MASLD was diagnosed on abdominal ultrasonography and based on the presence of at least one of five metabolic abnormalities. The impact of body mass index (BMI) reduction on MASLD/MetALD remission was assessed via logistic regression analysis and using receiver operating characteristic curves. Results: Logistic regression analysis revealed that weight loss was significantly associated with MASLD/MetALD remission. Other factors including exercise habits and reduced alcohol consumption were significant predictors of MASLD/MetALD remission in the overall cohort and in male patients. The optimal BMI reduction cutoff values for MASLD/MetALD remission were 0.9 kg/m2 and 4.0% decrease in the overall cohort, 0.85 kg/m2 and 3.9% decrease in males, and 1.2 kg/m2 and 4.5% decrease in females. In participants with a BMI of 23 kg/m2, the cutoff values were 0.75 kg/m2 and 2.7% BMI reduction. Discussion: Weight reduction plays an important role in both MASLD and MetALD remission among Japanese individuals. That is, targeting specific BMI reduction is effective. This underscores the importance of targeted weight management strategies in preventing and managing MASLD/MetALD in the Japanese population.
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Índice de Masa Corporal , Pérdida de Peso , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Japón/epidemiología , Adulto , Hígado Graso/epidemiología , Anciano , Enfermedades Metabólicas/epidemiología , Enfermedades Metabólicas/etiología , Pueblos del Este de AsiaRESUMEN
We investigated the influence of repeated intravenous administration of dextrans (DEXs) to rats. Seven-week-old Sprague Dawley rats (6 males/group) were given intravenously 10% saline solutions of dextrans (DEXs), 40 kDa or 200-300 kDa, at a dose level of 5 mL/kg/day for 28 days and they were examined histopathologically. Another group (3 males/group) was administered saline in a similar manner and served as the control. Histopathological changes indicating accumulation of DEXs in the mononuclear phagocyte system (MPS) and the liver were noted in the treated groups. The incidence and severity of the findings were molecular weight-dependent, except for the lungs. These results are considered useful in interpreting data from preclinical studies, in which DEXs or their derivatives are administered as test or control substances.
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AIM: Increased levels of small dense low-density lipoproteins (sd-LDL) have been reported more atherogenic compared to total low-density lipoprotein (LDL); however, no definitive experiments using macrophages have examined this concept in vitro. METHOD AND RESULT: In this study, we isolated fractions of total LDL (density 1.019-1.063 g/ml) and sd-LDL (density 1.044-1.063 g/ml) from the plasma of subjects with modest hypertriglycidemia. Oxidizabilty as assessed by copper-induced generation (1.6 µmol/L CuSO(4),12 h) of thiobarbituric acid reactive substances (TBARS) was significantly greater (7-fold higher, p < 0.01) for sd-LDL (4.3 ± 1.1 nmol/mg) than for total LDL (0.6 ± 0.2 nmol/mg) at the same cholesterol concentrations. Moreover, oxidized sd-LDL induced more lipid staining in macrophages than oxidized total LDL. When non-oxidized sd-LDL were incubated with THP1 macrophages, there was much greater lipid accumulation as assessed by oil red O staining, and more than a 2-fold increase (p < 0.05) in intracellular triglyceride content as compared to non-oxidized total LDL. Furthermore, non-oxidized sd-LDL in contrast to non-oxidized total LDL enhanced macrophage lectin-like oxidized LDL receptor-1 (LOX-1) protein expression and significantly LOX-1 mRNA levels (+158%, p < 0.05), with no effect on scavenger receptor A or CD36 gene expression. These effects of non-oxidized sd-LDL on LOX-1 gene expression were suppressed when Toll-like receptor 4 was inactivated either by RNAi or antibody. CONCLUSION: Our data indicate for the first time that sd-LDL is much more effective in promoting macrophage triglyceride accumulation and LOX-1 gene expression than total LDL.
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Células Espumosas/citología , Lipoproteínas LDL/metabolismo , Macrófagos/citología , Antígenos CD36/biosíntesis , Línea Celular , Cobre/química , Relación Dosis-Respuesta a Droga , Humanos , Lectinas/metabolismo , Lípidos/química , Macrófagos/metabolismo , Interferencia de ARN , Receptores Depuradores de Clase A/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Factores de Tiempo , Receptor Toll-Like 4/metabolismoAsunto(s)
Aterosclerosis/etiología , Inflamación/etiología , Adiponectina , Quimiocina CCL2 , Citocinas , Células Endoteliales , Productos Finales de Glicación Avanzada , Humanos , Mediadores de Inflamación , Lipoproteínas , Macrófagos , Monocitos , Estrés Oxidativo , Receptores CCR2 , Receptores CXCR3 , Linfocitos TRESUMEN
OBJECTIVE: To examine the direct effect of apolipoprotein CIII (apoCIII) on adipokine expressions that are involved in obesity, insulin resistance, or metabolic syndrome. METHODS AND RESULTS: ApoCIII in triglyceride-rich lipoproteins is elevated in patients with obesity, insulin resistance, or metabolic syndrome. Its level is also associated with proinflammatory adipokines. Fully differentiated mouse 3T3L1 adipocytes were incubated with apoCIII. ApoCIII activated nuclear factor κB of 3T3L1 adipocytes and induced the expression of monocyte chemoattractant protein (MCP) 1 and interleukin (IL) 6. ApoCIII also activated extracellular signal-regulated kinase and p38. Mitogen-activated protein kinase kinase (MEK)-1 inhibitor PD98059, but not p38 inhibitor SB203580, inhibited apoCIII-induced upregulation of MCP-1 and IL-6. Previously, it was shown that apoCIII activates proinflammatory signals through toll-like receptor (TLR) 2. TLR2-blocking antibody abolished activation of nuclear factor κB and extracellular signal-regulated kinase induced by apoCIII and inhibited apoCIII-induced upregulation of MCP-1 and IL-6. ApoCIII also reduced adiponectin expression of 3T3L1 adipocytes, which was recovered by TLR2-blocking antibody. ApoCIII induced the expression of MCP-1 and IL-6 in TLR2-overexpressed human embryonic kidney 293 cells but not wild-type human embryonic kidney 293 cells without TLR2. ApoCIII induced the expression of MCP-1 and IL-6 and decreased adiponectin expression in white adipose tissue of wild-type mice but not of TLR2-deficient mice in vivo. CONCLUSIONS: ApoCIII may activate extracellular signal-regulated kinase and nuclear factor kB through TLR2 and induce proinflammatory adipokine expression in vitro and in vivo. Thus, apoCIII links dyslipidemia to inflammation in adipocytes, which, in turn, may contribute to atherosclerosis.
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Adipocitos/metabolismo , Apolipoproteína C-III/farmacología , Quimiocina CCL2/metabolismo , Interleucina-6/metabolismo , Lipoproteínas VLDL/farmacología , Receptor Toll-Like 2/metabolismo , Adipocitos/efectos de los fármacos , Animales , Células Cultivadas , Humanos , Masculino , Ratones , FN-kappa B/metabolismoRESUMEN
The present study attempted to define the role of hepatic Niemann-Pick C1-like 1 (NPC1L1), a cholesterol transporter, in hepatic insulin resistance as well as hepatic steatosis. The inhibition of NPC1L1 and its molecular consequences were examined in Zucker obese fatty (ZOF) rats and cultured steatotic hepatocytes using ezetimibe, a pharmacoloigcal inhibitor of NPC1L1, and short hairpin RNA (shRNA) of NPC1L1. Ezetimibe improved hepatic insulin signaling as well as hepatic steatosis in ZOF rats. It also restored insulin sensitivity in steatotic hepatocytes in vitro through a reduction in hepatic reactive oxygen species (ROS) generation, JNK activation, and ER stress. In addition, ezetimibe recovered insulin-induced Akt activation and reduced gluconeogenic genes in the liver of ZOF rats and cultured steatotic hepatocytes. Transfection of NPC1L1 shRNA into hepatocytes also reduced ROS generation and ER stress. These results indicate that NPC1L1 contributes to hepatic insulin resistance through cholesterol accumulation, and its inhibition could be a potential therapeutic target of hepatic insulin resistance.
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Anticolesterolemiantes/farmacología , Azetidinas/farmacología , Resistencia a la Insulina/fisiología , Hígado/metabolismo , Proteínas de Transporte de Membrana/fisiología , Animales , Western Blotting , Células Cultivadas , Colesterol/metabolismo , Cartilla de ADN , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Ezetimiba , Hígado Graso/metabolismo , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Masculino , Ácido Pirúvico/metabolismo , Interferencia de ARN , ARN Mensajero/biosíntesis , Ratas , Especies Reactivas de Oxígeno , Reacción en Cadena en Tiempo Real de la Polimerasa , Superóxidos/metabolismo , Triglicéridos/metabolismoRESUMEN
Plasma levels of lipoproteins that contain apolipoprotein (apo) CIII predict coronary heart disease (CHD), and associate with contributors to metabolic syndrome such as type 2 diabetes and hypertriglyceridemia. ApoCIII causes hypertriglyceridemia by inhibiting the catabolism and the clearance of TG-rich lipoproteins (TLRs), and the association of apoCIII with CHD has been commonly attributed to these properties; however, it has been untested whether apoCIII itself or in association with lipoproteins directly affects atherogenic mechanisms in vascular cells. This review describes the proatherogenic effect of apoCIII-containing lipoproteins. In brief, apoCIII-rich VLDL (VLDL CIII+) increased the adhesion of human monocytes to vascular endothelial cells (ECs). ApoCIII alone also increased monocyte adhesion to vascular ECs. Interestingly, apoCIII-rich HDL did not reduce the adhesion of monocytes to vascular ECs, whereas HDL without apoCIII decreased their adhesion, suggesting that apoCIII in HDL counteracts the anti-inflammatory property of HDL. ApoCIII alone as well as VLDL CIII+also activated vascular ECs through the activation of NF-kappaB, and induced the recruitment of monocytes to vascular ECs. Moreover, apoCIII induced insulin resistance in vascular ECs and caused endothelial dysfunction. These findings indicate that apoCIII in TLRs not only modulates their metabolism, but also may directly contribute to the development of atherosclerosis by activating the proinflammatory signal transduction of vascular cells. Here, we propose a novel role for apoCIII that links dyslipidemia with atherosclerosis.
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Apolipoproteína C-III/sangre , Aterosclerosis/sangre , Dislipidemias/sangre , Humanos , Síndrome Metabólico/sangreRESUMEN
Apolipoprotein (apo)CIII predicts risk for coronary heart disease. We recently reported that apoCIII directly activates human monocytes. Recent evidence indicates that toll-like receptor (TLR)2 can contribute to atherogenesis through transduction of inflammatory signals. Here, we tested the hypothesis that apoCIII activates human monocytoid THP-1 cells through TLR2. ApoCIII induced the association of TLR2 with myeloid differentiation factor 88, activated nuclear factor (NF)-kappaB in THP-1 cells, and increased their adhesion to human umbilical vein endothelial cells (HUVECs). Anti-TLR2 blocking antibody, but not anti-TLR4 blocking antibody or isotype-matched IgG, inhibited these processes (P<0.05). ApoCIII bound with high affinity to human recombinant TLR2 protein and showed a significantly higher (P<0.05) and saturable binding to 293 cells overexpressing human TLR2 than to parental 293 cells with no endogenous TLR2. Overexpression of TLR2 in 293 cells augmented apoCIII-induced NF-kappaB activation and beta(1) integrin expression, processes inhibited by anti-apoCIII antibody as well as anti-TLR2 antibody. Exposure of peripheral blood monocytes isolated from C57BL/6 (wild-type) mice to apoCIII activated their NF-kappaB and increased their adhesiveness to HUVECs. In contrast, apoCIII did not activate monocytes from TLR2-deficient mice. Finally, intravenous administration to C57BL/6 mice of apoCIII-rich very-low-density lipoprotein (VLDL), but not of apoCIII-deficient VLDL, activated monocytes and increased their adhesiveness to HUVECs, processes attenuated by anti-TLR2 or anti-apoCIII antibody. ApoCIII-rich VLDL did not activate monocytes from TLR2-deficient mice. In conclusion, apoCIII activated monocytes at least partly through a TLR2-dependent pathway. The present study identifies a novel mechanism for proinflammatory and proatherogenic effects of apoCIII and a role for TLR2 in atherosclerosis induced by atherogenic lipoproteins.
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Apolipoproteína C-III/fisiología , Monocitos/metabolismo , Receptor Toll-Like 2/fisiología , Animales , Apolipoproteína C-III/metabolismo , Apolipoproteínas B/metabolismo , Aterosclerosis/etiología , Aterosclerosis/metabolismo , Línea Celular , Humanos , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Unión Proteica/fisiología , Receptor Toll-Like 2/metabolismoRESUMEN
Metabolic conditions affect hypothalamo-pituitary-adrenal responses to stressful stimuli. Here we examined effects of food deprivation, leptin and ghrelin upon noradrenaline release in the hypothalamic paraventricular nucleus (PVN) and plasma adrenocorticotropic hormone (ACTH) concentrations after stressful stimuli. Food deprivation augmented both noradrenaline release in the PVN and the increase in plasma ACTH concentration following electrical footshocks (FSs). An intracerebroventricular injection of leptin attenuated the increases in hypothalamic noradrenaline release and plasma ACTH concentrations after FSs, while ghrelin augmented these responses. These data suggest that leptin inhibits and ghrelin facilitates neuroendocrine stress responses via noradrenaline release and indicate that a decrease in leptin and an increase in ghrelin release after food deprivation might contribute to augmentation of stress-induced ACTH release in a fasting state.
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Ghrelina/farmacología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Leptina/farmacología , Norepinefrina/metabolismo , Estrés Psicológico/fisiopatología , Hormona Adrenocorticotrópica/sangre , Animales , Estimulación Eléctrica , Privación de Alimentos , Inyecciones Intraventriculares , Masculino , Microdiálisis , Ratas , Ratas WistarRESUMEN
BACKGROUND: Apolipoprotein CIII (apoCIII) is a component of some triglyceride-rich very-low-density and low-density lipoprotein and is elevated in dyslipidemia with insulin resistance and the metabolic syndrome. We previously reported that apoCIII directly activates proinflammatory and atherogenic signaling in vascular endothelial cells through protein kinase C-beta (PKCbeta). Because PKCbeta impairs the response of vascular endothelial cells to insulin, we tested the hypothesis that apoCIII affects insulin signaling in vascular endothelial cells and its function in vitro and in vivo. METHODS AND RESULTS: ApoCIII inhibited insulin-induced tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), decreasing phosphatidylinositol 3-kinase (PI3K)/Akt activation in human umbilical vein endothelial cells. These effects of apoCIII led to reduced endothelial nitric oxide synthase (eNOS) activation and NO release into the media. ApoCIII activated PKCbeta in human umbilical vein endothelial cells, resulting in IRS-1 dysfunction via serine phosphorylation. ApoCIII also activated mitogen-activated protein kinase through PKCbeta. The impaired insulin signaling was restored by PKCbeta inhibitor or MEK1 inhibitor. ApoCIII-rich very-low-density lipoprotein and apoCIII impaired insulin signaling in the aorta of C57BL/6J mice and in human umbilical vein endothelial cells, which was recovered by PKCbeta inhibitor. They also inhibited endothelium-dependent relaxation of the aortas of C57BL/6J mice. In summary, apoCIII in very-low-density lipoprotein impaired insulin stimulation of NO production by vascular endothelium and induced endothelial dysfunction in vivo. This adverse effect of apoCIII was mediated by its activation of PKCbeta, which inhibits the IRS-1/PI3K/Akt/eNOS pathway. CONCLUSIONS: Our results suggest that apoCIII is a crucial link between dyslipidemia and insulin resistance in vascular endothelial cells with consequential deleterious effects on their atheroprotective functions.
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Apolipoproteína C-III/metabolismo , Células Endoteliales/metabolismo , Hiperlipidemias/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Aorta/fisiopatología , Apolipoproteína C-III/farmacología , Células Cultivadas , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Humanos , Hiperlipidemias/fisiopatología , Insulina/farmacología , Proteínas Sustrato del Receptor de Insulina , Resistencia a la Insulina/fisiología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteína Quinasa C/metabolismo , Proteína Quinasa C beta , Proteínas Proto-Oncogénicas c-akt/metabolismo , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
Both experimental and epidemiological studies suggest that leptin is one of the molecules responsible for accelerated atherosclerosis in obese humans. To confirm the notion, we studied whether leptin accelerates atherosclerosis in apoE(-/-) mice. Leptin deficient hyperlipidemic mice (ob/ob;apoE(-/-) mice) developed significantly less atherosclerosis than apoE(-/-) mice, when fed an atherogenic diet for 16 weeks from 8 weeks of age. Histological analysis revealed that most of the atherosclerotic lesions in ob/ob;apoE(-/-) mice remained as fatty streaks, while those in apoE(-/-) mice were mainly fibrous plaques. The decrease in atherosclerosis was not due to changes in the serum levels of cholesterol, TNF-alpha, or adiponectin. Exogenous leptin significantly increased atherosclerotic areas in apoE(-/-) mice, even though it decreased food intake and body weight. Our findings support the notion that leptin accelerates atherosclerosis.
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Apolipoproteínas E/genética , Aterosclerosis/fisiopatología , Leptina/deficiencia , Leptina/fisiología , Obesidad/fisiopatología , Animales , Aterosclerosis/genética , Aterosclerosis/patología , Dieta Aterogénica , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones NoqueadosRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is associated with the metabolic syndrome characterized by dislipidemia and insulin resistance. We hypothesized that ezetimibe, an inhibitor of NPC1L1, improves these metabolic disorders in Zucker obese fatty rats (ZOF). Ezetimibe significantly lowered total cholesterol and triglycerides in ZOF with prominent reduction in the remnant lipoprotein fraction and small dense low density lipoprotein fraction. Moreover, lipid deposition and fibrosis of liver were decreased by ezetimibe. Interestingly, ezetimibe improved insulin and plasma glucose response after intraperitoneal glucose injection. Further, ezetimibe enhanced insulin signaling in cultured hepatocytes. Our results indicate the potential of ezetimibe in treating the metabolic syndrome and NAFLD.
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Anticolesterolemiantes/uso terapéutico , Azetidinas/uso terapéutico , Hígado Graso/tratamiento farmacológico , Resistencia a la Insulina/fisiología , Síndrome Metabólico/tratamiento farmacológico , Animales , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/farmacología , Azetidinas/administración & dosificación , Azetidinas/farmacología , Glucemia/metabolismo , Peso Corporal , Células Cultivadas , Modelos Animales de Enfermedad , Dislipidemias/metabolismo , Ezetimiba , Hígado Graso/metabolismo , Hígado Graso/patología , Hepatocitos/metabolismo , Lípidos/administración & dosificación , Obesidad/tratamiento farmacológico , Ratas , Ratas Zucker , Factores de TiempoRESUMEN
To elucidate an anti-inflammatory role of angiotensin-converting enzyme inhibitors (ACEIs) in cardiovascular disease, we studied the effect of ACEIs in monocyte adhesion to endothelial cells and underlying molecular mechanisms. Treatment of human monocytic THP-1 cells with monocyte chemoattractant protein-1 (MCP-1; 100 ng/ml; 10 min) significantly increased their adhesion to human umbilical vein endothelial cells (HUVECs) under flow condition (P < 0.001). Preincubation of THP-1 cells with imidaprilat (50 nM; 4 h), an active metabolite of imidapril, reduced MCP-1-triggered THP-1 cell adhesion (P < 0.01). Similar effects were obtained with experiments using human peripheral monocytes (P < 0.05). MCP-1 activated protein kinase C (PKC)alpha in THP-1 cells, resulting in the up-regulation of alpha4 and beta2 integrin. Imidaprilat attenuated MCP-1-induced PKC activation and integrin up-regulation in THP-1 cells. Imidaprilat also inhibited THP-1 cell adhesion induced by phorbol 12-myristate 13-acetate (PMA), a potent PKC activator. In attempt to elucidate the mechanisms for the modulation of PKC activity by imidaprilat, we found that MCP-1 or PMA increased labile zinc in THP-1 cells, which was canceled by imidaprilat. Indeed, zinc/pyrithione activated PKC and increased THP-1 cell adhesion. Zinc chelator as well as PKC inhibitor inhibited these processes, suggesting the role for labile zinc in PKC activation and THP-1 cell adhesion. Imidaprilat attenuated zinc/pyrithione-induced PKC activation and THP-1 cell adhesion. These data suggest that ACEI reduces MCP-1 or PMA-triggered monocyte adhesion to activated HUVECs by modulating labile zinc in monocytes. Our findings may point out a novel anti-inflammatory mechanism of ACEIs in atherogenesis.
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Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Células Endoteliales/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Imidazolidinas/farmacología , Monocitos/efectos de los fármacos , Peptidil-Dipeptidasa A/metabolismo , Adhesión Celular/efectos de los fármacos , Línea Celular , Células Endoteliales/citología , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Citometría de Flujo , Humanos , Immunoblotting , Monocitos/citologíaRESUMEN
Recent studies suggest that sphingosine 1-phosphate (S1P) protects against atherosclerosis. We assessed the effects of S1P on monocyte-endothelial interaction in the presence of inflammatory mediators. Pretreatment of THP-1 cells with S1P abolished Phorbol 12 myristate 13-acetate (PMA)-induced THP-1 cell adhesion to human umbilical vein endothelial cells (HUVECs). S1P inhibited PMA-induced activation of RhoA, but not PKCs. S1P activated p190Rho GTPase activation protein (GAP) only in the presence of PMA, suggesting an inhibitory effect of S1P and PMA to suppress RhoA. In conclusion, S1P inhibited monocyte-endothelial interactions by inhibiting RhoA activity which may explain its anti-atherogenic effects.
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Comunicación Celular/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/enzimología , Lisofosfolípidos/farmacología , Monocitos/efectos de los fármacos , Monocitos/enzimología , Esfingosina/análogos & derivados , Proteína de Unión al GTP rhoA/metabolismo , Adhesión Celular/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , Activación Enzimática/efectos de los fármacos , Humanos , Toxina del Pertussis/farmacología , Proteína Quinasa C/metabolismo , Esfingosina/farmacología , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
AIM: Hepatocyte growth factor (HGF) is known to stimulate endothelial cell proliferation. However, re-endothelialization is not enhanced when the native protein is administered to the injured artery, probably due to the short half-life of HGF at the site of injury. Therefore, the effects of an HGF fusion protein having collagen-binding activity (CBD-HGF) on re-endothelialization and neointimal formation was studied in the balloon-injured rat carotid artery. METHODS: The left common carotid artery of male Sprague-Dawley rats was injured with an inflated balloon catheter, and then treated with CBD-HGF 10 microg/mL), HGF (10 micro g/mL) or saline (control) for 15 min. After 14 days, the rats were injected with Evans blue and sacrificed. RESULTS: The re-endothelialized area was significantly greater in the CBD-HGF- treated rats than in the control or HGF -treated rats. Neointimal formation was significantly more pronounced in the CBD-HGF treated rats than in other rat groups. Both HGF and CBD-HGF stimulated proliferation of vascular smooth muscle cells as well as endothelial cells in vitro. Consistent with this, cultured smooth muscle cells were shown to express the HGF receptor (c-Met). CONCLUSION: CBD-HGF accelerates re-endothelialization and neointimal formation in vivo. CBD fusion protein is a useful vehicle to deliver vascular growth factors to injured arteries.
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Traumatismos de las Arterias Carótidas/tratamiento farmacológico , Traumatismos de las Arterias Carótidas/patología , Colágeno/metabolismo , Factor de Crecimiento de Hepatocito/farmacología , Proteínas Recombinantes de Fusión/farmacología , Animales , Aorta/citología , Cateterismo/efectos adversos , División Celular/efectos de los fármacos , Células Cultivadas , Sistemas de Liberación de Medicamentos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/patología , Factor de Crecimiento de Hepatocito/metabolismo , Hiperplasia , Masculino , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/patología , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes de Fusión/metabolismo , Túnica Íntima/efectos de los fármacos , Túnica Íntima/patologíaRESUMEN
AIM: Aim of this study was to directly detect increased permeability of vascular lesions by magnetic resonance imaging. METHODS: A novel contrast medium with a mean hydrodynamic diameter of 100 nm was prepared from monodispersed iron colloids incorporated into micelles of block copolymers composed of polyethylene glycol and polyamino acid. T2 mapping was applied to differentiate the minimal shortening of T2 relaxation time in balloon-injured rat carotid arteries. RESULTS: The novel contrast medium accumulated in deendothelialized arteries. T2 relaxation times of injured and uninjured arteries were 50.6 +/- 9.5 ms and 26.9 +/- 2.4 ms, respectively (the mean +/- SD, p< 0.01, n=5). The novel contrast medium, but not commercially available contrast media, shortened the T2 relaxation time of the injured artery to 35.5 +/- 9.7 ms (p< 0.01, n=4). CONCLUSION: A novel iron contrast medium enhanced the lesions with increased permeability. The contrast medium in combination with T2 mapping may be useful to detect unstable atherosclerotic plaques.
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Aterosclerosis/diagnóstico , Permeabilidad Capilar , Medios de Contraste , Animales , Aterosclerosis/patología , Sistemas de Liberación de Medicamentos , Endotelio Vascular/patología , Hierro , Imagen por Resonancia Magnética/métodos , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Autosomal dominant spinocerebellar ataxias (AD-SCAs) form a clinically and genetically heterogeneous group of neurodegenerative disorders. Recently, a single nucleotide substitution in the 5'-untranslated region of the puratrophin-1 gene was found to be associated with one type of AD-SCA linked to chromosome 16q (16q-SCA). To obtain further insight into the contribution of the C-to-T substitution in the puratrophin-1 gene to the clinical and genetic characteristics of patients with 16q-SCA, we analyzed 686 families with 719 individuals diagnosed with progressive ataxia. We found C-to-T substitution in the puratrophin-1 gene in 57 unrelated families with 65 affected individuals. The mean age at onset in the patients with 16q-SCA was 59.1 (range, 46-77). Ataxia is the most common initial symptom. The elderly patients over 65 occasionally showed other accompanying clinical features including abnormalities in tendon reflexes, involuntary movements, and reduced vibration sense. We also examined the frequency of the AD-SCA subtype, considering the effects of age at onset. In the 686 AD-SCA families, SCA6 and Machado-Joseph disease/SCA3 are frequent subtypes, followed by dentatorubral-pallidoluysian atrophy and 16q-SCA. 16q-SCA is not a rare subtype of Japanese AD-SCA, particularly in patients with ages at onset over 60.
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Cromosomas Humanos Par 16 , Factores de Intercambio de Guanina Nucleótido/genética , Espectrina/genética , Ataxias Espinocerebelosas/genética , Edad de Inicio , Anciano , Mapeo Cromosómico , ADN/genética , ADN/aislamiento & purificación , Femenino , Frecuencia de los Genes , Genes Dominantes , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Ataxias Espinocerebelosas/epidemiologíaRESUMEN
BACKGROUND: It is not clear how hyperbaric oxygen therapy (HBO) affects ischemia-induced pathophysiological responses such as angiogenesis and skeletal muscle regeneration. In the present study the effects of HBO on the functional and morphological recovery of ischemic hind limbs, blood perfusion and the local production of angiogenic growth factors were studied in a mouse model. METHODS AND RESULTS: Mice were placed in pure oxygen under 3 atm for 1 h/day for 14 days after the removal of a segment of the left femoral artery. HBO-treated mice showed better functional recovery and greater blood flow in the ischemic hind limb than untreated mice. Histological examination revealed unatrophied muscle fibers with islands of small regenerating muscle cells only in HBO-treated mice. Regeneration of muscle was confirmed by the increase in myf5 mRNA. The amount of mRNA for vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF) was slightly increased in the ischemic hind limbs. HBO eliminated the increase in VEGF mRNA. In contrast, the amount of mRNA for bFGF and HGF was further increased by HBO treatment. HBO transiently increased early growth response protein 1 (Egr-1) in the ischemic hind limbs. CONCLUSIONS: HBO accelerates the recovery of ischemic hind limbs by increasing the production of bFGF and HGF and by promoting muscle regeneration in mice.
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Factor 2 de Crecimiento de Fibroblastos/genética , Factor de Crecimiento de Hepatocito/genética , Oxigenoterapia Hiperbárica , Isquemia/terapia , Músculo Esquelético/fisiología , Reperfusión , Animales , Regulación de la Expresión Génica , Extremidad Inferior/irrigación sanguínea , Extremidad Inferior/fisiología , Ratones , Músculo Esquelético/irrigación sanguínea , Neovascularización Fisiológica , RegeneraciónRESUMEN
A 79-year old woman was admitted with disturbed consciousness (JCS II-30). She had been given a diagnosis of type 2 diabetes 7 years previously, and was being treated with oral hypoglycemic agents. She also suffered Alzheimer's disease and Parkinson's disease. Plasma glucose and HbA1c upon admission was 676mg/dl and 9.7%, respectively. Serum Na was 153mEq/l. Urine ketone body test was negative and metabolic acidosis was not observed. Hyperglycemic hyperosmolar non-ketotic coma (HHNC) was diagnosed, and treatment was started immediately with normal saline infusion. Continuous infusion of regular insulin was needed to lower blood glucose. Disturbed consciousness and dehydration improved by the third hospital day. However, she became bedridden afterwards and received tube feeding. Up to 46 units of insulin was needed daily to control blood glucose. Urine C-peptide secretion was very low (10microg/day), suggesting that insulin therapy was essential for glycemic control long before admission. It is thought that a number of elderly diabetic patients who need insulin therapy do not receive or continue it for various reasons. Discussion is necessary to grasp the actual situation and defensive actions that can be taken.