Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 17 de 17
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
Gan To Kagaku Ryoho ; 49(12): 1339-1342, 2022 Dec.
Artigo em Japonês | MEDLINE | ID: mdl-36539246

RESUMO

Palbociclib(PAL), which is a small molecule with inhibitory activity against cyclin-dependent kinase 4/6, is used in endocrine combined therapy for the treatment of estrogen receptor(ER)-positive and HER2-negative inoperable and recurrent breast cancer. We retrospectively investigated the factors associated with prolonged treatment in inoperable and recurrent breast cancer in a multicenter study. The median time-to-treatment failure(TTF)after PAL was 5.6 months(0.2-22.5). A total of 28 patients in the fulvestrant(FUL)group and 21 patients in the aromatase inhibitor(AI)group received concomitant endocrine therapy. The median TTF was 2.6 vs 6.7 months(p=0.015)for white blood cell(WBC), 3.7 vs 6.6 months (p=0.021)for neutrophils(Neu), and 2.8 vs 7.5 months(p=0.007)for lymphocytes(Lym). The treatment period tended to be prolonged in the group with higher WBC, Neu, and Lym levels than that of the standard values. The median treatment duration of the FUL group was 7.5 months vs 4.2 months(p=0.162); however, the difference was not statistically significant. The WBC, Neu, and Lym levels upon PAL introduction may be factors affecting the prolonged treatment. Further analysis of the data and further investigation of the prolongation-related factors of PAL treatment period are necessary.


Assuntos
Neoplasias da Mama , Duração da Terapia , Humanos , Feminino , Estudos Retrospectivos , Recidiva Local de Neoplasia , Neoplasias da Mama/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Receptor ErbB-2/análise
2.
Arterioscler Thromb Vasc Biol ; 38(5): 994-1006, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29496659

RESUMO

OBJECTIVE: Macrophages play a central role in various stages of atherosclerotic plaque formation and progression. The local macrophages reportedly proliferate during atherosclerosis, but the pathophysiological significance of macrophage proliferation in this context remains unclear. Here, we investigated the involvement of local macrophage proliferation during atherosclerosis formation and progression using transgenic mice, in which macrophage proliferation was specifically suppressed. APPROACH AND RESULTS: Inhibition of macrophage proliferation was achieved by inducing the expression of cyclin-dependent kinase inhibitor 1B, also known as p27kip, under the regulation of a scavenger receptor promoter/enhancer. The macrophage-specific human p27kip Tg mice were subsequently crossed with apolipoprotein E-deficient mice for the atherosclerotic plaque study. Results showed that a reduced number of local macrophages resulted in marked suppression of atherosclerotic plaque formation and inflammatory response in the plaque. Moreover, fewer local macrophages in macrophage-specific human p27kip Tg mice helped stabilize the plaque, as evidenced by a reduced necrotic core area, increased collagenous extracellular matrix, and thickened fibrous cap. CONCLUSIONS: These results provide direct evidence of the involvement of local macrophage proliferation in formation and progression of atherosclerotic plaques and plaque stability. Thus, control of macrophage proliferation might represent a therapeutic target for treating atherosclerotic diseases.


Assuntos
Aorta/patologia , Aortite/prevenção & controle , Aterosclerose/prevenção & controle , Proliferação de Células , Ativação de Macrófagos , Macrófagos Peritoneais/patologia , Placa Aterosclerótica , Animais , Aorta/metabolismo , Aortite/genética , Aortite/metabolismo , Aortite/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Cultivadas , Colágeno/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Modelos Animais de Doenças , Fibrose , Mediadores da Inflamação/metabolismo , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Camundongos Transgênicos , Necrose , Transdução de Sinais
3.
Int J Clin Pharmacol Ther ; 57(7): 353-361, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31094316

RESUMO

OBJECTIVE: In elderly patients, age-related, disease-related, and drug-related factors are associated with chronic kidney disease (CKD). Little is known about which factors are the best predictors for CKD in elderly patients. MATERIALS AND METHODS: The study was based on 784 patients aged 75 years or older for whom the clinical and serum creatinine on admission to our hospital were available. Impaired renal function, including CKD and transient renal insufficiency, was defined as a non-indexed glomerular filtration rate (GFR) below 60 mL/min. A logistic regression model was developed for predictors of CKD and was internally validated using bootstrapping. RESULTS: Approximately 61% of the patients, who had CKD (46%) and transient renal insufficiency (15%), had a non-indexed GFR < 60 mL/min. Synergistic use of 3 drugs potentially impairing renal function, diuretics, ACE-I/ARB, and NSAIDs (odds ratio (OR), 4.66; 95% confidence interval (CI), 1.48 - 17.7, p = 0.012) was a significantly associated factor for CKD in a multivariate logistic regression analysis. Age (OR 1.56, 95% CI 1.04 - 2.33, p = 0.03), female gender (OR 1.58, 95% CI 1.04 - 2.39, p = 0.03), any prescription ACE-I/ARB either alone or in combinations with diuretics or NSAIDs (OR 2.74, 95% CI 1.83 - 4.13, p = 0.0001), and proteinuria (OR 1.98, 95% CI 1.27 - 3.10, p = 0.003), were included as the best model for CKD. The area under the curve (AUC) of the best model and the bootstrapping validation were 0.68 and 0.71, respectively. CONCLUSION: Given the widespread use of ACE-I/ARB for elderly patients, our findings suggest that caution is needed when they are prescribed because of the possibility of the patient developing CKD.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Diuréticos/efeitos adversos , Prescrição Inadequada/estatística & dados numéricos , Insuficiência Renal Crônica/induzido quimicamente , Idoso , Creatinina/sangue , Estudos Transversais , Feminino , Taxa de Filtração Glomerular , Humanos , Pacientes Internados , Masculino
4.
Biochem Biophys Res Commun ; 457(1): 23-30, 2015 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-25529449

RESUMO

The peroxisome proliferator-activated receptor-γ (PPARγ) is an important regulator of lipid and glucose metabolism, and its activation is reported to suppress the progression of atherosclerosis. We have reported that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) activate PPARγ in macrophages. However, it is not yet known whether statins activate PPARγ in other vascular cells. In the present study, we investigated whether statins activate PPARγ in smooth muscle cells (SMCs) and endothelial cells (ECs) and thus mediate anti-atherosclerotic effects. Human aortic SMCs (HASMCs) and human umbilical vein ECs (HUVECs) were used in this study. Fluvastatin and pitavastatin activated PPARγ in HASMCs, but not in HUVECs. Statins induced cyclooxygenase-2 (COX-2) expression in HASMCs, but not in HUVECs. Moreover, treatment with COX-2-siRNA abrogated statin-mediated PPARγ activation in HASMCs. Statins suppressed migration and proliferation of HASMCs, and inhibited lipopolysaccharide-induced expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) in HASMCs. These effects of statins were abrogated by treatment with PPARγ-siRNA. Treatment with statins suppressed atherosclerotic lesion formation in Apoe(-/-) mice. In addition, transcriptional activity of PPARγ and CD36 expression were increased, and the expression of MCP-1 and TNF-α was decreased, in the aorta of statin-treated Apoe(-/-) mice. In conclusion, statins mediate anti-atherogenic effects through PPARγ activation in SMCs. These effects of statins on SMCs may be beneficial for the prevention of atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , PPAR gama/metabolismo , Animais , Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Aterosclerose/enzimologia , Aterosclerose/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocina CCL2/metabolismo , Ciclo-Oxigenase 2/metabolismo , Progressão da Doença , Ácidos Graxos Monoinsaturados/farmacologia , Fluvastatina , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Indóis/farmacologia , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
5.
Biochem Biophys Res Commun ; 430(4): 1189-94, 2013 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-23274494

RESUMO

Tumor necrosis factor α (TNFα) is a pro-inflammatory cytokine and one of the major mediators of obesity-induced insulin resistance. TNFα is generated through TNFα converting enzyme (TACE)-mediated cleavage of the transmembrane precursor pro-TNFα. Inhibition of TACE resulted in the improvement in glucose and insulin levels in diabetic animals, suggesting a crucial role of TACE activity in glucose metabolism. However, the regulation of TACE activity in insulin-sensitive tissues has not been fully determined. This study aimed to investigate the impact of TACE in insulin-sensitive tissues in the early stage of the development of obesity. C57BL6 mice were fed standard chow (B6-SC) or high-fat/high-sucrose diet (B6-HF/HS). KK-Ay mice were fed SC ad libitum (Ay-AL) or fed reduced amounts of SC (caloric restriction (CR); Ay-CR). As control for Ay-AL, KK mice fed SC ad libitum (KK-AL) were used. TACE activity in visceral adipose tissue (VAT), but not in liver or skeletal muscle, was significantly elevated in B6-HF/HS and Ay-AL compared with B6-SC and KK-AL, respectively. Phosphorylation of JNK and p38MAPK, but not ERK, in VATs from B6-HF/HS and Ay-AL was also significantly elevated. Ay-CR showed significantly lower TACE, JNK and p38MAPK activities in VAT and serum TNFα level compared with those of Ay-AL. In contrast, intraperitoneal injection of TNFα activated TACE, JNK and p38MAPK activities in VAT in KK mice. In conclusion, during the development of obesity, TACE activity is elevated only in VAT, and CR effectively reduced TACE activity and TACE-mediated pro-TNFα shedding in VAT.


Assuntos
Proteínas ADAM/metabolismo , Tecido Adiposo/enzimologia , Obesidade/enzimologia , Proteína ADAM17 , Animais , Restrição Calórica , MAP Quinase Quinase 4/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Fosforilação , Regulação para Cima , Vísceras/enzimologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Biochem Biophys Res Commun ; 431(2): 124-30, 2013 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-23318172

RESUMO

Production of reactive oxygen species (ROS) and other proinflammatory substances by macrophages plays an important role in atherogenesis. Apocynin (4-hydroxy-3-methoxy-acetophenone), which is well known as a NADPH oxidase inhibitor, has anti-inflammatory effects including suppression of the generation of ROS. However, the suppressive effects of apocynin on the progression of atherosclerosis are not clearly understood. Thus, we investigated anti-atherosclerotic effects of apocynin using apolipoprotein E-deficient (apoE(-/-)) mice in vivo and in mouse peritoneal macrophages in vitro. In atherosclerosis-prone apoE(-/-) mice, apocynin suppressed the progression of atherosclerosis, decreased 4-hydroxynonenal-positive area in atherosclerotic lesions, and mRNA expression of monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) in aorta. In mouse peritoneal macrophages, apocynin suppressed the Ox-LDL-induced ROS generation, mRNA expression of MCP-1, IL-6 and granulocyte/macrophage colony-stimulating factor, and cell proliferation. Moreover, immunohistochemical studies revealed that apocynin decreased the number of proliferating cell nuclear antigen-positive macrophages in atherosclerotic lesions of apoE(-/-) mice. These results suggested that apocynin suppressed the formation of atherosclerotic lesions, at least in part, by inactivation of macrophages. Therefore, apocynin may be a potential therapeutic material to prevent the progression of atherosclerosis.


Assuntos
Acetofenonas/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Aterosclerose/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Animais , Apolipoproteínas E/genética , Aterosclerose/patologia , Quimiocina CCL2/biossíntese , Fator Estimulador de Colônias de Granulócitos/biossíntese , Interleucina-6/biossíntese , Lipoproteínas LDL/metabolismo , Camundongos , Camundongos Mutantes , RNA Mensageiro/biossíntese , Espécies Reativas de Oxigênio/antagonistas & inibidores
7.
Cardiovasc Diabetol ; 12: 177, 2013 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-24373412

RESUMO

BACKGROUND: An increased leukocyte count is an independent risk factor for cardiovascular events, but the association between leukocyte subtype counts and carotid atherosclerosis in patients with diabetes has not been determined. We therefore investigated the correlation between leukocyte subtype counts and intima-media thickness of the common carotid artery (CCA-IMT) in subjects with type 2 diabetes. METHODS: This cross-sectional study involved 484 in-patients with type 2 diabetes (282 males and 202 females), who were hospitalized for glycemic control and underwent carotid ultrasonography at Kumamoto University Hospital between 2005 and 2011. Mean and maximum CCA-IMT was measured by high-resolution B-mode ultrasonography. RESULTS: Univariate analyses revealed that mean CCA-IMT was positively correlated with age, systolic blood pressure, brachial-ankle pulse wave velocity (PWV), urinary albumin excretion and duration of diabetes, but was negatively correlated with diastolic blood pressure and fasting plasma glucose. Maximum CCA-IMT was positively and negatively correlated with the same factors as mean CCA-IMT except for fasting plasma glucose. Mean CCA-IMT was positively correlated with total leukocyte (r = 0.124, p = 0.007), monocyte (r = 0.373, p < 0.001), neutrophil (r = 0.139, p = 0.002) and eosinophil (r = 0.107, p = 0.019) counts. Maximum CCA-IMT was positively correlated with total leukocyte (r = 0.154, p < 0.001), monocyte (r = 0.398, p < 0.001), neutrophil (r = 0.152, p < 0.001) and basophil counts (r = 0.102, p = 0.027). Multiple regression analyses showed that monocyte count, age and PWV were significant and independent factors associated with mean CCA-IMT (adjusted R2 = 0.239, p < 0.001), and that monocyte count, age and urinary albumin excretion were significant and independent factors associated with maximum CCA-IMT (adjusted R2 = 0.277, p < 0.001). CONCLUSIONS: Monocyte counts were positively correlated with both mean CCA-IMT and maximum CCA-IMT in patients with type 2 diabetes. Monocyte count may be a useful predictor of macrovascular complications in patients with type 2 diabetes. TRIAL REGISTRATION: Trial registry no: UMIN000003526.


Assuntos
Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/sangue , Diabetes Mellitus Tipo 2/sangue , Eosinófilos , Monócitos , Neutrófilos , Fatores Etários , Idoso , Albuminúria/complicações , Índice Tornozelo-Braço , Povo Asiático , Glicemia , Pressão Sanguínea , Doenças das Artérias Carótidas/complicações , Doenças das Artérias Carótidas/diagnóstico por imagem , Espessura Intima-Media Carotídea , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Contagem de Leucócitos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise de Onda de Pulso , Fatores de Risco
8.
Front Hum Neurosci ; 17: 1133279, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37457499

RESUMO

Interlimb coordination involving cyclical movements of hand and foot in the sagittal plane is more difficult when the limbs move in opposite directions compared with the same direction (directional constraint). Here we first investigated whether the directional constraint on hand-foot coordination exists in motor imagery (imagined motion). Participants performed 10 cyclic coordinated movements of right wrist flexion-extension and right ankle dorsiflexion-plantarflexion as quickly and precisely as possible, in the following three conditions; (1) actual movements of the two limbs, (2) imaginary movements of the two limbs, and (3) actual movement of one limb combined with imaginary movement of the other limb. Each condition was performed under two directions; the same and the opposite direction. Task execution duration was measured as the time between the first and second press of a button by the participants. The opposite directional movement took a significantly longer time than did the same directional movement, irrespective of the condition type. This suggests that directional constraint of hand-foot coordination occurs even in motor imagery without actual motor commands or kinesthetic signals. We secondarily examined whether the corticospinal excitability of wrist muscles is modulated in synchronization with an imaginary foot movement to estimate the neural basis of directional constraint on imaginary hand-foot coordination. The corticospinal excitability of the forearm extensor in resting position increased during dorsiflexion and decreased during plantarflexion similarly in both actual and imaginary foot movements. This corticospinal modulation depending on imaginary movement phase likely produces the directional constraint on the imaginary hand-foot coordination.

9.
Biomolecules ; 13(3)2023 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-36979403

RESUMO

Remnant lipoproteins (RLs), which are typically present at high concentrations in patients with type 2 diabetes mellitus (T2DM), are associated with cardiovascular disease (CVD). Although an RL cholesterol homogeneous assay (RemL-C) is available for the measurement of RL concentrations, there have been no studies of the relationship between RemL-C and clinical parameters in T2DM. Therefore, we evaluated the relationships between RemL-C and CVD-related parameters in patients with T2DM. We performed a cross-sectional study of 169 patients with T2DM who were hospitalized at Kumamoto University Hospital. Compared with those with low RemL-C, those with higher RemL-C had higher fasting plasma glucose, homeostasis model assessment for insulin resistance (HOMA-R), total cholesterol, triglyceride, small dense low-density lipoprotein cholesterol (sdLDL-C), and urinary albumin-creatinine ratio; and lower high-density lipoprotein cholesterol, adiponectin, and ankle brachial pressure index (ABI). Multivariate logistic regression analysis showed that sdLDL-C and ABI were significantly and independently associated with high RemL-C. Although LDL-C was lower in participants with CVD, there was no difference in RemL-C between participants with or without CVD. Thus, RemL-C may represent a useful index of lipid and glucose metabolism, and that may be a marker of peripheral atherosclerotic disease (PAD) in male patients with T2DM.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Humanos , Masculino , Estudos Transversais , Colesterol , Lipoproteínas , Triglicerídeos , LDL-Colesterol
10.
Cell Metab ; 35(7): 1242-1260.e9, 2023 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-37339634

RESUMO

Type 1 (T1D) or type 2 diabetes (T2D) are caused by a deficit of functional insulin-producing ß cells. Thus, the identification of ß cell trophic agents could allow the development of therapeutic strategies to counteract diabetes. The discovery of SerpinB1, an elastase inhibitor that promotes human ß cell growth, prompted us to hypothesize that pancreatic elastase (PE) regulates ß cell viability. Here, we report that PE is up-regulated in acinar cells and in islets from T2D patients, and negatively impacts ß cell viability. Using high-throughput screening assays, we identified telaprevir as a potent PE inhibitor that can increase human and rodent ß cell viability in vitro and in vivo and improve glucose tolerance in insulin-resistant mice. Phospho-antibody microarrays and single-cell RNA sequencing analysis identified PAR2 and mechano-signaling pathways as potential mediators of PE. Taken together, our work highlights PE as a potential regulator of acinar-ß cell crosstalk that acts to limit ß cell viability, leading to T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Humanos , Camundongos , Animais , Células Acinares/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Elastase Pancreática/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Comunicação Celular
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA