RESUMEN
Background: The aim of this study was to assess whether the anteroposterior coverage of the acromion reflecting acromial morphology affects the rotator cuff tear (RCT) and tear size, in addition to the lateral coverage. Methods: Medical records of 356 patients with RCTs, concentric osteoarthritis, and calcific tendinitis identified using three-dimensional computed tomography between January 2016 and December 2017 were retrospectively analyzed. The patients were divided into group A (those with RCTs) and group B (those with concentric osteoarthritis or calcific tendinitis). Subsequently, group A was subdivided into three categories according to the size of RCTs: small-to-medium, large, and massive. The lateral coverage was measured through the lateral acromial angle (LAA) and critical shoulder angle (CSA), whereas the anteroposterior coverage was measured via the acromial tilt (AT), acromiohumeral interval (AHI) in the sagittal view, and anteroposterior coverage index (APCI) as a new radiologic parameter. Results: Between groups A and B, CSA (34.5° ± 3.4° and 30.8° ± 3.4°, respectively), APCI (0.83 ± 0.10 and 0.75 ± 0.08, respectively), and AHI (6.3 ± 2.0 mm and 7.8 ± 1.8 mm, respectively) were significantly different (all p < 0.001), whereas LAA and AT did not show a significant difference between the groups (p = 0.089 and p = 0.665, respectively). The independent predictive radiologic parameters of the RCT were the CSA, APCI, and AHI (p < 0.001, p < 0.001, and p = 0.043, respectively); among these, the APCI showed the highest regression coefficient (odds ratio = 2.82). The parameters associated with the size of RCTs were CSA (p = 0.022) and AHI, of which AHI, in particular, had the most significant effect on both small-to-medium and large tears (all p < 0.001). Conclusions: Large CSA, high APCI, and low AHI were predictors of RCTs, with the APCI showing the strongest correlation. In addition to the large CSA, low AHI also correlated with the size of RCTs and affected the entire size groups. We suggest that both the lateral coverage and anteroposterior coverage of the acromion should be considered essential factors for predicting the presence of RCTs and tear size.
Asunto(s)
Osteoartritis , Lesiones del Manguito de los Rotadores , Articulación del Hombro , Tendinopatía , Humanos , Lesiones del Manguito de los Rotadores/diagnóstico por imagen , Acromion/diagnóstico por imagen , Acromion/anatomía & histología , Articulación del Hombro/anatomía & histología , RoturaRESUMEN
BACKGROUND: The tumor necrosis factor receptor superfamily, which includes CD40, LIGHT, and OX40, plays important roles in atherosclerosis. CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, has been reported to be expressed in human atherosclerotic lesions. However, limited information is available on the precise role of CD137 in atherosclerosis and the effects of blocking CD137/CD137 ligand signaling on lesion formation. METHODS AND RESULTS: We generated CD137-deficient apolipoprotein E-knockout mice (ApoE(-/-) CD137(-/-)) and LDL-receptor-knockout mice (Ldlr(-/-)CD137(-/-)) to investigate the role of CD137 in atherogenesis. The deficiency of CD137 induced a reduction in atherosclerotic plaque lesions in both atherosclerosis mouse models, which was attributed to the downregulation of cytokines such as interferon-gamma, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha. CD137 signaling promoted the production of inflammatory molecules, including monocyte chemoattractant protein-1, interleukin-6, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1, in endothelial cells. Stimulation of CD137 ligand signaling activated monocytes/macrophages and augmented the production of proinflammatory cytokines in atherosclerotic vessels. CONCLUSIONS: CD137/CD137 ligand signaling plays multiple roles in the progression of atherosclerosis, and thus, blockade of this pathway is a promising therapeutic target for the disease.
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Ligando 4-1BB/fisiología , Aterosclerosis/prevención & control , Hipercolesterolemia/complicaciones , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/fisiología , Animales , Animales Congénicos , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/etiología , Aterosclerosis/inmunología , Cruzamientos Genéticos , Citocinas/biosíntesis , Citocinas/genética , Dieta Aterogénica , Modelos Animales de Enfermedad , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Retroalimentación Fisiológica , Femenino , Hipercolesterolemia/genética , Mediadores de Inflamación/metabolismo , Interferón gamma/inmunología , Activación de Linfocitos , Activación de Macrófagos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de LDL/deficiencia , Receptores de LDL/genética , Transducción de Señal , Linfocitos T/inmunología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/deficiencia , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genéticaRESUMEN
Ceramide has been suggested to function as a mediator of exocytosis in response to the addition of a calcium ionophore from PC12 cells. Here, we show that although cell-permeable C(6)-ceramide or a calcium ionophore alone did not increase either the degranulation of serotonin or the release of arachidonic acid (AA) from RBL-2H3 cells, their combined effect significantly stimulated these processes in a time- and dose-dependent manner. This effect was inhibited by the presence of an exogenous calcium chelator and significantly suppressed by the CERK inhibitor (K1) and phospholipase A(2) (PLA(2)) inhibitors. Moreover, cytosolic PLA(2) GIVA (cPLA(2) GIVA) siRNA-transfected RBL-2H3 cells showed a lower level of serotonin release than scramble siRNA-transfected cells. Little is known about the regulation of degranulation proximal to the activation of cytosolic phospholipase A(2) GIVA, the initial rate-limiting step in RBL-2H3 cells. In this study, we suggest that CERK, ceramide-1-phosphate, and PLA(2) are involved in degranulation in a calcium-dependent manner. Inhibition of p44/p42 mitogen-activated protein kinase partially decreased the AA release, but did not affect degranulation. Furthermore, treatment of the cells with AA (ω-6, C20:4), not linoleic acid (ω-6, C18:2) or α-linolenic acid (ω-6, C18:3), induced degranulation. Taken together, these results suggest that ceramide is involved in mast cell degranulation via the calcium-mediated activation of PLA(2).
Asunto(s)
Ceramidas/metabolismo , Mastocitos/enzimología , Fosfolipasas A2/metabolismo , Serotonina/metabolismo , Animales , Calcio/metabolismo , Calcio/farmacología , Degranulación de la Célula/fisiología , Línea Celular , Ceramidas/farmacología , Ionóforos/metabolismo , Ionóforos/farmacología , Mastocitos/efectos de los fármacos , Fosfolipasas A2/genética , ARN Interferente Pequeño/genética , Ratas , Serotonina/fisiología , Transducción de Señal/genética , Transducción de Señal/fisiologíaRESUMEN
Ceramide is produced by sphingomyelinase (SMase) and it plays a key role in cellular responses such as apoptosis. In this study, we report the purification and characterization of neutral SMase2 (nSMase2) from bovine brain tissue. Triton X-100 extracts of bovine brain membranes were purified in nine steps, including sequential chromatography. The specific activity of purified nSMase increased 8183-fold over the brain membrane fraction. Purified nSMase showed similarities to nSMase2, which had been purified and cloned previously. Interestingly, purified nSMase2 was Ca2+-dependent and could be activated by micromolar concentrations of Ca2+ under Mg2+-free conditions. Ceramide generation was dependent upon the calcium ionophore A23187 and was observed in nSMase2-over-expressing COS-7 cells. This generation was suppressed by GW4869, an nSMase2 inhibitor, but not to fumonisin B(1), an inhibitor of the de novo ceramide synthesis pathway. The present study demonstrates the Ca2+-dependent activation of nSMase2.
Asunto(s)
Química Encefálica , Encéfalo/metabolismo , Calcio/metabolismo , Esfingomielina Fosfodiesterasa/aislamiento & purificación , Esfingomielina Fosfodiesterasa/metabolismo , Compuestos de Anilina/farmacología , Animales , Compuestos de Bencilideno/farmacología , Encéfalo/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Células COS , Calcimicina/farmacología , Bovinos , Ceramidas/metabolismo , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Líquido Intracelular/efectos de los fármacos , Líquido Intracelular/metabolismo , Ionóforos/farmacología , Octoxinol/farmacología , Ácido Palmítico/metabolismo , Tensoactivos/farmacología , Transfección/métodos , Tritio/metabolismo , Fosfolipasas de Tipo C/metabolismoRESUMEN
Neurotransmitter release is mediated by ceramide, which is generated by sphingomyelin hydrolysis. In the present study, we examined whether synaptosomal-associated protein 25 (SNAP-25) is involved in ceramide production and exocytosis. Neutral sphingomyelinase 2 (nSMase2) was partially purified from bovine brain and we found that SNAP-25 was enriched in the nSMase2-containing fractions. In rat synaptosomes and PC12 cells, the immunoprecipitation pellet of anti-SNAP-25 antibody showed higher nSMase activity than the immunoprecipitation pellet of anti-nSMase2 antibody. In PC12 cells, SNAP-25 was colocalized with nSMase2. Transfection of SNAP-25 small interfering RNA (siRNA) significantly inhibited nSMase2 translocation to the plasma membrane. A23187-induced ceramide production was concomitantly reduced in SNAP-25 siRNA-transfected PC12 cells compared with that in scrambled siRNA-transfected cells. Moreover, transfection of SNAP-25 siRNA inhibited dopamine release, whereas addition of C6-ceramide to the siRNA-treated cells moderately reversed this inhibition. Additionally, nSMase2 inhibition reduced dopamine release. Collectively, our results indicate that SNAP-25 interacts with nSMase2 during ceramide production, which mediates exocytosis and neurotransmitter release.
Asunto(s)
Esfingomielina Fosfodiesterasa/metabolismo , Esfingomielinas/metabolismo , Proteína 25 Asociada a Sinaptosomas/metabolismo , Animales , Transporte Biológico , Bovinos , Membrana Celular/metabolismo , Ceramidas/biosíntesis , Dopamina/metabolismo , Células PC12 , Ratas , Esfingomielina Fosfodiesterasa/química , SinaptosomasRESUMEN
Melanotic neuroectodermal tumor of infancy (MNTI) is a rare pigmented tumor generally occurring in the head and neck region in children 12 months of age or younger. Approximately 380 instances of this tumor are reported in the medical literature. We presented a case of MNTI that occurred in the left temporal bone of a 2-month old female infant. And, the clinical assessment, histologic diagnosis, and management is reviewed.
Asunto(s)
Tumor Neuroectodérmico Melanótico/cirugía , Neoplasias Craneales/cirugía , Hueso Temporal , Antígenos de Neoplasias/análisis , Femenino , Humanos , Inmunohistoquímica , Lactante , Queratinas/análisis , Antígenos Específicos del Melanoma , Proteínas de Neoplasias/análisis , Tumor Neuroectodérmico Melanótico/diagnóstico , Tumor Neuroectodérmico Melanótico/metabolismo , Neoplasias Craneales/diagnóstico , Neoplasias Craneales/metabolismo , Sinaptofisina/análisisRESUMEN
Methanol extracts of domestic plants of Korea were evaluated as a potential inhibitor of neutral pH optimum and membrane-associated 60 kDa sphingomyelinase (N-SMase) activity. In this study, we partially purified N-SMase from bovine brain membranes using ammonium sulfate. It was purified approximately 163-fold by the sequential use of DE52, Butyl-Toyopearl, DEAE-Cellulose, and Phenyl-5PW column chromatographies. The purified N-SMase activity was assayed in the presence of the plant extracts of three hundreds species. Based on the in vitro assay, three plant extracts significantly inhibited the N-SMase activity in a time- and concentration-dependent manner. To further examine the inhibitory pattern, a Dixon plot was constructed for each of the plant extracts. The extracts of Abies nephrolepis, Acer tegmentosum, and Ginkgo biloba revealed a competitive inhibition with the inhibition constant (Ki) of 11.9 microg/ mL, 9.4 microg/mL, and 12.9 microg/mL, respectively. These extracts also inhibited in a dose-dependent manner the production of ceramide induced by serum deprivation in human neuroblastoma cell line SH-SY5Y.
Asunto(s)
Abies , Acer , Encéfalo/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Ginkgo biloba , Proteínas de la Membrana/antagonistas & inhibidores , Extractos Vegetales/farmacología , Esfingomielina Fosfodiesterasa/antagonistas & inhibidores , Animales , Unión Competitiva , Encéfalo/enzimología , Bovinos , Línea Celular Tumoral , Ceramidas/biosíntesis , Medio de Cultivo Libre de Suero/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Corea (Geográfico) , Magnesio , Proteínas de la Membrana/aislamiento & purificación , Proteínas de la Membrana/metabolismo , Corteza de la Planta , Esfingomielina Fosfodiesterasa/aislamiento & purificación , Esfingomielina Fosfodiesterasa/metabolismo , Esfingomielinas/metabolismo , Factores de TiempoRESUMEN
The purpose of this study was to observe the effects of autonomic nerve pharmacopuncture (ANP) treatment on cancer-related fatigue (CRF) in patients with advanced cancer. This observational case study was conducted at the East West Cancer Center of Daejeon University's Dunsan Korean Medical Hospital. Two patients were observed. One patient was diagnosed with left thymic cancer metastatic to the left pleura. The other patient had terminal-stage cervical cancer with iliac bone and lumbar 5 metastases. We injected mountain ginseng pharmacopuncture (MGP) into acupoints alongside the spine (Hua-Tuo-Jia-Ji-Xue, EX B2). We examined the patients for CRF using the Korean version of the Revised Piper Fatigue Scale (RPFS-K), which is a self-assessment tool. The scores on the RPFS-K for both patients tended to decrease during the treatment. Laboratory findings, including hematological changes, were also checked. Liver and renal function tests showed that the treatment was safe. Although further large-population studies are necessary, this case study suggests that ANP has a favorable effect on CRF in patients with advanced cancer.
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Puntos de Acupuntura , Fatiga/etiología , Fatiga/terapia , Neoplasias/complicaciones , Fitoterapia , Extractos Vegetales/uso terapéutico , Adulto , Vías Autónomas/fisiología , Fatiga/fisiopatología , Femenino , Humanos , Inyecciones Subcutáneas , Persona de Mediana Edad , Panax , Extractos Vegetales/administración & dosificaciónRESUMEN
In the present study, silver-doped silica thin films were successfully prepared by sol-gel method to apply for antibacterial materials. The starting solution was prepared from 1:0.24:3.75:2.2 molar ratios of Si(OC2H5)4):AgNO3:H2O:C2H5OCH2CH2OH and then the pH value controlled at 3 with 0.5 N HNO3 solution. The formation of silver-doped glassy silica thin films at various temperatures was investigated through infrared spectroscopy, ultraviolet-visible, scanning electron microscopy and X-ray diffraction. From these analysis data, it was found that silver ions were completely trapped in the silica matrix and their reduction could be achieved at 600 degrees C annealing temperature. The antibacterial effects of silica thin films against Escherichia coli and Staphylococcus aureus were examined by film attachment method. The coating films had an excellent antibacterial performance.
Asunto(s)
Antibacterianos/farmacología , Materiales Biocompatibles Revestidos/síntesis química , Materiales Biocompatibles Revestidos/farmacocinética , Dióxido de Silicio/química , Plata/química , Plata/farmacología , Esterilización/métodos , Recuento de Colonia Microbiana , Contaminación de Equipos/prevención & control , Escherichia coli/citología , Escherichia coli/efectos de los fármacos , Ensayo de Materiales , Transición de Fase , Staphylococcus aureus/citología , Staphylococcus aureus/efectos de los fármacos , Propiedades de SuperficieRESUMEN
OBJECTIVES: To evaluate the efficacy of DA-8031 against premature ejaculation, we performed in vitro and in vivo pharmacologic studies. METHODS: We used a monoamine transporter binding affinity assay, receptor binding affinity assay, monoamine reuptake inhibition assay, and serotonin uptake inhibition assay in platelets and chemically induced ejaculation models in rats. RESULTS: The present study reports on the pharmacologic profile of the putative antipremature ejaculation drug, DA-8031. DA-8031 exhibits high affinity and selectivity to the serotonin transporter (Ki value 1.94 nM for 5-hydroxytryptamine transporter, 22 020 nM for norepinephrine transporter, and 77 679 nM for dopamine transporter) and potency to inhibit serotonin reuptake into the rat brain synaptosome in vitro (half maximal inhibitory concentration 6.52 nM for 5-hydroxytryptamine, 30.2 µM for norepinephrine, and 136.9 µM for dopamine). In the platelet serotonin uptake study, DA-8031 exhibited significant inhibition at oral doses of 10 and 30 mg/kg in a dose-dependent manner. In the sexual response studies, after oral and intravenous administration of DA-8031, ejaculation was significantly inhibited in both para-chloroamphetamine- and meta-chlorophenylpiperazine-mediated ejaculation models in rats. CONCLUSIONS: The pharmacologic profiles observed in the present study suggest the potential for DA-8031 as a therapeutic agent useful in the treatment of premature ejaculation.
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Benzofuranos/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Disfunciones Sexuales Fisiológicas/tratamiento farmacológico , Animales , Benzofuranos/uso terapéutico , Modelos Animales de Enfermedad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Eyaculación , Masculino , Inhibidores de la Captación de Neurotransmisores/farmacología , Inhibidores de la Captación de Neurotransmisores/uso terapéutico , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Receptores Adrenérgicos/efectos de los fármacos , Receptores Dopaminérgicos/efectos de los fármacos , Receptores Muscarínicos/efectos de los fármacos , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Simportadores/metabolismoRESUMEN
A variety of benzylidenethiazole analogs have been demonstrated to inhibit 5-lipoxygenase (5-LOX). Here we report the anti-atherogenic potential of 5-(4-hydroxy- 2,3,5-trimethylbenzylidene) thiazolidin-2,4-dione (HMB-TZD), a benzylidenethiazole analog, and its potential mechanism of action in LDL receptor-deficient (Ldlr-/-) mice. HMB-TZD Treatment reduced leukotriene B4 (LTB4) production significantly in RAW264.7 macrophages and SVEC4-10 endothelial cells. Macrophages or endothelial cells pre-incubated with HMB-TZD for 2 h and then stimulated with lipopolysaccharide or tumor necrosis factor-alpha (TNF-α) displayed reduced cytokine production. Also, HMB-TZD reduced cell migration and adhesion in accordance with decreased proinflammatory molecule production in vitro and ex vivo. HMB-TZD treatment of 8-week-old male Ldlr-/- mice resulted in significantly reduced atherosclerotic lesions without a change to plasma lipid profiles. Moreover, aortic expression of pro-atherogenic molecules involved in the recruitment of monocytes to the aortic wall, including TNF-α , MCP-1, and VCAM-1, was downregulated. HMB-TZD also reduced macrophage infiltration into atherosclerotic lesions. In conclusion, HMB-TZD ameliorates atherosclerotic lesion formation possibly by reducing the expression of proinflammatory molecules and monocyte/macrophage recruitment to the lesion. These results suggest that HMB-TZD, and benzylidenethiazole analogs in general, may have therapeutic potential as treatments for atherosclerosis.
Asunto(s)
Aterosclerosis/tratamiento farmacológico , Monocitos/efectos de los fármacos , Tiazolidinedionas/uso terapéutico , Animales , Adhesión Celular/efectos de los fármacos , Línea Celular , Movimiento Celular/efectos de los fármacos , Quimiocina CCL2/metabolismo , Dinoprostona/metabolismo , Ensayo de Inmunoadsorción Enzimática , Humanos , Leucotrieno B4/metabolismo , Macrófagos/citología , Macrófagos/efectos de los fármacos , Masculino , Ratones , Monocitos/citología , Distribución Aleatoria , Receptores de LDL/deficiencia , Receptores de LDL/genética , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Ceramide serves as a second messenger produced from sphingomyelin by the activation of sphingomyelinase (SMase). Here, we suggest that neutral SMase 2 (nSMase2) may regulate dopamine (DA) uptake. nSMase2 siRNA-transfected PC12 cells showed lower levels of nSMase activity and ceramide than scramble siRNA-transfected and control cells. Interestingly, transfection of nSMase2 siRNA or pretreatment with the nSMase2-specific inhibitor GW4869 resulted in decreased DA uptake. Reciprocally, exposure of PC12 cells to cell-permeable C(6)-ceramide induced a concentration-dependent increase in DA uptake. Removal of extracellular calcium by EGTA increased DA uptake in scramble-transfected and control cells, but not in nSMase2 siRNA-transfected or GW4869-pretreated cells. Moreover, siRNA-transfected cells showed higher levels of intracellular calcium than scramble cells, while C(6)-ceramide treatment resulted in decreased intracellular calcium compared to vehicle treatment alone. Taken together, these data suggest that nSMase2 may increase DA uptake through inducing ceramide production and thereby decreasing intracellular calcium levels.
Asunto(s)
Calcio/metabolismo , Dopamina/metabolismo , Espacio Intracelular/metabolismo , Esfingomielina Fosfodiesterasa/metabolismo , Compuestos de Anilina/farmacología , Animales , Compuestos de Bencilideno/farmacología , Diferenciación Celular/efectos de los fármacos , Permeabilidad de la Membrana Celular/efectos de los fármacos , Ceramidas/biosíntesis , Ácido Egtácico/farmacología , Espacio Intracelular/efectos de los fármacos , Factor de Crecimiento Nervioso/farmacología , Células PC12 , ARN Interferente Pequeño/metabolismo , Ratas , TransfecciónRESUMEN
Cellular hypoxia can lead to cell death or adaptation and has important effects on development, physiology, and pathology. Here, we investigated the role and regulation of ceramide in hypoxia-induced apoptosis of SH-SY5Y neuroblastoma cells. Hypoxia increased the ceramide concentration; subsequently, we observed biochemical changes indicative of apoptosis, such as DNA fragmentation, nuclear staining, and poly ADP-ribose polymerase (PARP) cleavage. The hypoxic cell death was potently inhibited by a caspase inhibitor, zVAD-fmk (benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone). l-Cycloserine, a serine palmitoyltransferase (SPT) inhibitor, and fumonisin B(1) (FB(1)), a ceramide synthase inhibitor, inhibited the hypoxia-induced increase in ceramide, indicating that the increase occurred via the de novo pathway. Hypoxia increased the activity and protein levels of SPT2, suggesting that the hypoxia-induced increase in ceramide is due to the transcriptional up-regulation of SPT2. Specific siRNA of SPT2 prevented hypoxia-induced cell death and ceramide production. However, hypoxia also increased the cellular level of glucosylceramide, which was inhibited by a glucosylceramide synthase (GCS) inhibitor and specific siRNA, but not a ceramidase inhibitor. The increase in glucosylceramide was accompanied by increases in both PARP cleavage and DNA fragmentation. Together, the current results suggest that both SPT and GCS may regulate the cellular level of ceramide, and thus may be critical enzymes for deciding the fate of the cells exposed to hypoxia.
Asunto(s)
Apoptosis , Hipoxia de la Célula , Ceramidas/metabolismo , Serina C-Palmitoiltransferasa/metabolismo , Línea Celular Tumoral , Endocannabinoides , Inhibidores Enzimáticos/farmacología , Etanolaminas/farmacología , Glucosilceramidas/metabolismo , Glucosiltransferasas/metabolismo , Humanos , Morfolinas/farmacología , Neuronas/citología , Neuronas/metabolismo , Ácidos Oléicos , Esfingosina/metabolismoRESUMEN
Cyclooxygenase (COX) and 5-lipoxygenase (5-LOX), which play pivotal roles in atherogenesis, have been reported to be involved in plaque stability. Licofelone, a dual COX and 5-LOX inhibitor, has been reported to possess anti-atherogenic effect in rabbit atherosclerosis model. We therefore investigated the anti-atherogenic effect of BHB-TZD [5-(3,5-di-tert-butyl-4-hydroxybenzylidene)thiazolidin-2,4-dione], a dual COX and 5-LOX inhibitor, in low density lipoprotein receptor null (LDLR-/-) mice. Fifteen LDLR-/- mice were fed a western diet (control group), whereas 15 were fed a western diet plus 0.1% (w/w) BHB-TZD (BHB-TZD group). After 8 weeks, the BHB-TZD group had markedly lower serum levels of leukotriene B(4) and prostaglandin E(2) than the control group. Interestingly, BHB-TZD treatment also reduced plasma triglyceride level without significant changes in total cholesterol and HDL levels. Compared with control mice, BHB-TZD fed mice had 52% fewer fatty streak lesions in the aortic sinus, as well as fewer initial lesions in the aortic arch. Macrophage infiltration into the lesions was 40% lower, and collagen and smooth muscle cells were increased by 102% and 96%, respectively, in the BHB-TZD group compared with the control group. In addition, aortic expression of proatherogenic molecules including TNF-alpha, IL-1beta, IL-6, MCP-1 and VCAM-1, was lower in the BHB-TZD group than the control group. BHB-TZD treatment also reduced MMP-2 and MMP-9 expressions in aorta. In conclusion, BHB-TZD effectively attenuated atherosclerosis in mouse model, suggesting its therapeutic potential for atherosclerosis.
Asunto(s)
Enfermedades de la Aorta/prevención & control , Araquidonato 5-Lipooxigenasa/metabolismo , Aterosclerosis/prevención & control , Inhibidores de la Ciclooxigenasa/farmacología , Hiperlipidemias/tratamiento farmacológico , Inhibidores de la Lipooxigenasa/farmacología , Prostaglandina-Endoperóxido Sintasas/metabolismo , Tiazolidinedionas/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/enzimología , Aorta Torácica/patología , Enfermedades de la Aorta/enzimología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Aterosclerosis/enzimología , Aterosclerosis/genética , Colesterol/sangre , Dinoprostona/sangre , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Hiperlipidemias/enzimología , Hiperlipidemias/genética , Mediadores de Inflamación/metabolismo , Leucotrieno B4/sangre , Lipoproteínas HDL/sangre , Macrófagos/efectos de los fármacos , Macrófagos/enzimología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/enzimología , ARN Mensajero/metabolismo , Receptores de LDL/deficiencia , Receptores de LDL/genética , Factores de Tiempo , Triglicéridos/sangreRESUMEN
This study was designed to assess whether DA-6034 (7-carboxymethyloxy-3',4',5-trimethoxy flavone monohydrate), a new synthetic derivative of eupatilin, increases secretion of mucin-like glycoprotein and some mucins species in conjunctiva and cornea, and contributes to the preservation of ocular surface integrity. Human conjunctival and corneal epithelial cells were incubated with DA-6034 (1-250 microM). To investigate mucin secreting activity more directly, isolated rat conjunctival goblet cells were also used. Corneal protection was investigated using a desiccation-induced rabbit model of dry eye syndrome. It was found that DA-6034 increased mucin-like glycoprotein levels of both conjunctival and corneal epithelial cells at concentrations above 100 microM. Using human conjunctival epithelial cells, it was demonstrated that treatment with DA-6034 (200 microM) significantly increased production of some mucins species including MUC1, MUC2, MUC4, MUC5AC, MUC5B, and MUC16. DA-6034 also significantly increased MUC5AC production from conjunctival goblet cells isolated from rats. In the rabbit desiccation model, an ophthalmic suspension containing 3% DA-6034 significantly reduced corneal damage induced by desiccation. These results suggest that DA-6034 is a good candidate for treatment of dry eye through maintaining ocular surface integrity, which might be related to mucin secretion.
Asunto(s)
Conjuntiva/efectos de los fármacos , Córnea/efectos de los fármacos , Flavonoides/farmacología , Glicoproteínas/metabolismo , Mucinas/metabolismo , Animales , Línea Celular , Conjuntiva/patología , Córnea/metabolismo , Córnea/patología , Deshidratación/patología , Ojo/efectos de los fármacos , Ojo/metabolismo , Humanos , Masculino , Conejos , RatasRESUMEN
INTRODUCTION: The use of radiotherapy plus temozolomide administered concomitantly with and after radiotherapy for glioblastoma was recently shown to improve median and 2-year survival in a large international multicenter study. To compare this result in routine clinical practice, an audit of the management and outcome of patients with glioblastoma at our institute was performed. METHODS: A total of 79 patients with pathologically confirmed glioblastoma were treated with radiotherapy (daily fractions of 2 Gy for a total of 60 Gy) combined with temozolomide at a dose of 75 mg/m(2) per day, followed by 6 cycles of adjuvant temozolomide (150-200 mg/m(2), 5 consecutive days per month). The primary end point was overall survival (OS). Secondary endpoints included progression-free survival (PFS) and toxicity. We evaluated the clinical outcome of concomitant chemoradiotherapy for newly diagnosed glioblastomas at a single institute in Korea. RESULTS: The median age was 52 years (15-76 years), 47 patients were male and 32 patients were female. 92.4% of the patients had undergone debulking surgery. The median overall survival (OS) was 18.3 months (95% CI, 16.3-20.1 months), and the time to progression was 6.7 months (95% CI, 5.2-8.3 months). The 1-year and 2-year survival rates were 70.1% and 37.1%, respectively. In the retrospective analysis, the patients with a post-operative KPS over 80 showed more prolonged survival than those who had a KPS less 80 (23.1 months vs. 13.4 months; p<0.001). Age and extent of surgery did not emerge as significant factors. Twenty-four patients (30%) were treated with low-dose continuous temozolomide therapy after the tumor had recurred. Hematologic toxicity was the main adverse effect, occurring in seven patients (8.8%). Patients with lymphopenia were not reported. CONCLUSIONS: This study is the largest study of radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma in Korean patients, who share a common genetic feature. The median and 2-year survival outcomes in this study are comparable to the previous reports. However, for the recurrent glioblastomas refractory to temozolomide, further clinical trials using other agents should be studied continuously in the future.
Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Neoplasias Encefálicas/terapia , Dacarbazina/análogos & derivados , Glioblastoma/terapia , Adolescente , Adulto , Anciano , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/etnología , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/radioterapia , Quimioterapia Adyuvante , Estudios de Cohortes , Terapia Combinada , Dacarbazina/administración & dosificación , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/etnología , Glioblastoma/mortalidad , Glioblastoma/radioterapia , Humanos , Corea (Geográfico) , Masculino , Persona de Mediana Edad , Dosis de Radiación , Radioterapia Adyuvante/métodos , Tasa de Supervivencia , Temozolomida , Resultado del Tratamiento , Adulto JovenRESUMEN
Methylmercury (MeHg) is a ubiquitous environmental toxicant to which humans can be exposed by ingestion of contaminated food. MeHg has been suggested to exert its toxicity through its high reactivity to thiols, generation of arachidonic acid and reactive oxygen species (ROS), and elevation of free intracellular Ca(2+) levels ([Ca(2+)](i)). However, the precise mechanism has not been fully defined. Here we show that phosphatidylcholine-specific phospholipase C (PC-PLC) is a critical pathway for MeHg-induced toxicity in MDCK cells. D609, an inhibitor of PC-PLC, significantly reversed the toxicity in a time- and dose-dependent manner with concomitant inhibition of the diacylglycerol (DAG) generation and the phosphatidylcholine (PC)-breakdown. MeHg activated the group IV cytosolic phospholipase A(2) (cPLA(2)) and acidic form of sphingomyelinase (A-SMase) downstream of PC-PLC, but these enzymes as well as protein kinase C (PKC) were not linked to the toxicity by MeHg. Furthermore, MeHg produced ROS, which did not affect the toxicity. Addition of EGTA to culture media resulted in partial decrease of [Ca(2+)](i) and partially blocked the toxicity. In contrast, when the cells were treated with MeHg in the presence of Ca(2+) in the culture media, D609 completely prevented cell death with parallel decrease in [Ca(2+)](i). Our results demonstrated that MeHg-induced toxicity was linked to elevation of [Ca(2+)](i) through activation of PC-PLC, but not attributable to the signaling pathways such as cPLA(2), A-SMase, and PKC, or to the generation of ROS.
Asunto(s)
Calcio/metabolismo , Contaminantes Ambientales/toxicidad , Riñón/metabolismo , Compuestos de Metilmercurio/toxicidad , Neuroblastoma/metabolismo , Fosfolipasas de Tipo C/metabolismo , Animales , Hidrocarburos Aromáticos con Puentes/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Quelantes/farmacología , Diglicéridos/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Ácido Egtácico/farmacología , Activación Enzimática/efectos de los fármacos , Humanos , Riñón/efectos de los fármacos , Riñón/patología , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/patología , Norbornanos , Fosfatidilcolinas/metabolismo , Inhibidores de Fosfodiesterasa/farmacología , Fosfolipasas A/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Esfingomielina Fosfodiesterasa/metabolismo , Tiocarbamatos , Tionas/farmacología , Fosfolipasas de Tipo C/antagonistas & inhibidoresRESUMEN
A presynaptic membrane disturbance is an essential process for the release of various neurotransmitters. Ceramide, which is a tumor suppressive lipid, has been shown to act as a channel-forming molecule and serve as a precursor of ceramide-1-phosphate, which can disturb the cellular membrane. This study found that while permeable ceramide increases the rate of dopamine release in the presence of a Ca(2+)-ionophore, A23187, permeable ceramide-1-phosphate provoked its release even without the ionophore. The treatment of PC12 cells with the ionophore at concentrations < 2 microM produced ceramide via the sphingomyelin (SM) pathway with a concomitant release of dopamine, and no cell damage was observed. The addition of a Ca(2+) chelator, EGTA, to the medium inhibited the increase in the release of both the ceramide and dopamine. This suggests that ceramide might be produced by Ca(2+) and is implicated in the membrane disturbance associated with the release of dopamine as a result of its conversion to ceramide-1-phosphate. Consistent with these results, this study detected a membrane-associated and neutral pH optimum sphingomyelinase (SMase) whose activity was increased by Ca(2+). Together, these results demonstrate that ceramide can be produced via the activation of a neutral form of SMase through Ca(2+), and is involved in the dopamine release in concert with Ca(2+).