RESUMEN
OBJECTIVE: We evaluated the efficacy of endovascular thrombectomy (EVT) on the functional outcome of patients with acute basilar artery occlusion and low posterior circulation acute stroke prognosis early computed tomography score (PC-ASPECTS). METHODS: We identified patients with acute ischemic stroke due to basilar artery occlusion and PC-ASPECTS of 6 or less, presenting within 24 h between August 2008 and April 2022. The primary outcome was a favorable functional outcome, defined as a modified Rankin Scale (mRS) score of 0-3 at 90 days. The secondary outcomes included an mRS score of 0-2, a favorable shift in the ordinal mRS scale, the occurrence of symptomatic intracranial hemorrhage (sICH), and mortality at 90 days. We compared the outcome of patients treated with EVT and those without EVT, using the inverse probability of treatment weighting methods. RESULTS: Out of 566 patients, 55.5% received EVT. In the EVT group, 106 (33.8%) achieved favorable outcomes, compared to 56 patients (22.2%) in the conservative group. EVT significantly increased the likelihood of achieving a favorable outcome compared to conservative treatment (relative risk [RR] 1.39, 95% confidence interval [CI], 1.11-1.74, p = 0.004). EVT was associated with a favorable shift in the mRS (RR 1.85, 95% CI, 1.49-2.29, p < 0.001) and reduced mortality without an increase in the risk of sICH. It did not have an impact on achieving an mRS score of 0-2. INTERPRETATION: Patients with acute basilar artery occlusion and a PC-ASPECTS of 6 or less might benefit from EVT without an increasing sICH. ANN NEUROL 2024;95:788-799.
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Procedimientos Endovasculares , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Arteria Basilar , Resultado del Tratamiento , Accidente Cerebrovascular Isquémico/etiología , Accidente Cerebrovascular/etiología , Trombectomía/efectos adversos , Hemorragias Intracraneales/etiología , Sistema de Registros , Procedimientos Endovasculares/efectos adversosRESUMEN
BACKGROUND: There is limited information on the delivery of acute stroke therapies and secondary preventive measures and clinical outcomes over time in young adults with acute ischemic stroke. This study investigated whether advances in these treatments improved outcomes in this population. METHODS: Using a prospective multicenter stroke registry in Korea, young adults (aged 18-50 years) with acute ischemic stroke hospitalized between 2008 and 2019 were identified. The observation period was divided into 4 epochs: 2008 to 2010, 2011 to 2013, 2014 to 2016, and 2017 to 2019. Secular trends for patient characteristics, treatments, and outcomes were analyzed. RESULTS: A total of 7050 eligible patients (mean age, 43.1; men, 71.9%) were registered. The mean age decreased from 43.6 to 42.9 years (Ptrend=0.01). Current smoking decreased, whereas obesity increased. Other risk factors remained unchanged. Intravenous thrombolysis and mechanical thrombectomy rates increased over time from 2008 to 2010 to 2017 to 2019 (9.5%-13.8% and 3.2%-9.2%, respectively; Ptrend<0.01). Door-to-needle time improved (Ptrend <.001), but onset-to-door and door-to-puncture times remained constant. Secondary prevention, including dual antiplatelets for noncardioembolic minor stroke (26.7%-47.0%), direct oral anticoagulants for atrial fibrillation (0.0%-56.2%), and statins for large artery atherosclerosis (76.1%-95.3%) increased (Ptrend<0.01). Outcome data were available from 2011. One-year mortality (2.5% in 2011-2013 and 2.3% in 2017-2019) and 3-month modified Rankin Scale scores 0 to 1 (68.3%-69.1%) and 0 to 2 (87.6%-86.2%) remained unchanged. The 1-year stroke recurrence rate increased (4.1%-5.5%; Ptrend=0.04), although the difference was not significant after adjusting for sex and age. CONCLUSIONS: Improvements in the delivery of acute stroke treatments did not necessarily lead to better outcomes in young adults with acute ischemic stroke over the past decade, indicating a need for further progress.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Masculino , Humanos , Adulto Joven , Adulto , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Isquemia Encefálica/epidemiología , Isquemia Encefálica/terapia , Isquemia Encefálica/complicaciones , Estudios Prospectivos , Anticoagulantes/uso terapéutico , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/terapia , Accidente Cerebrovascular/complicaciones , Resultado del TratamientoRESUMEN
Ischemia-reperfusion (IR) injury, a leading cause of acute kidney injury (AKI), is still without effective therapies. Succinate accumulation during ischemia followed by its oxidation during reperfusion leads to excessive reactive oxygen species (ROS) and severe kidney damage. Consequently, the targeting of succinate accumulation may represent a rational approach to the prevention of IR-induced kidney injury. Since ROS are generated primarily in mitochondria, which are abundant in the proximal tubule of the kidney, we explored the role of pyruvate dehydrogenase kinase 4 (PDK4), a mitochondrial enzyme, in IR-induced kidney injury using proximal tubule cell-specific Pdk4 knockout (Pdk4ptKO) mice. Knockout or pharmacological inhibition of PDK4 ameliorated IR-induced kidney damage. Succinate accumulation during ischemia, which is responsible for mitochondrial ROS production during reperfusion, was reduced by PDK4 inhibition. PDK4 deficiency established conditions prior to ischemia resulting in less succinate accumulation, possibly because of a reduction in electron flow reversal in complex II, which provides electrons for the reduction of fumarate to succinate by succinate dehydrogenase during ischemia. The administration of dimethyl succinate, a cell-permeable form of succinate, attenuated the beneficial effects of PDK4 deficiency, suggesting that the kidney-protective effect is succinate-dependent. Finally, genetic or pharmacological inhibition of PDK4 prevented IR-induced mitochondrial damage in mice and normalized mitochondrial function in an in vitro model of IR injury. Thus, inhibition of PDK4 represents a novel means of preventing IR-induced kidney injury, and involves the inhibition of ROS-induced kidney toxicity through reduction in succinate accumulation and mitochondrial dysfunction.
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Daño por Reperfusión , Ácido Succínico , Ratones , Animales , Ácido Succínico/farmacología , Especies Reactivas de Oxígeno , Ratones Noqueados , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & control , Isquemia/tratamiento farmacológico , Riñón , Mitocondrias , ReperfusiónRESUMEN
BACKGROUND: The use of intensive lipid-lowering therapy by means of statin medications is recommended after transient ischemic attack (TIA) and ischemic stroke of atherosclerotic origin. The target level for low-density lipoprotein (LDL) cholesterol to reduce cardiovascular events after stroke has not been well studied. METHODS: In this parallel-group trial conducted in France and South Korea, we randomly assigned patients with ischemic stroke in the previous 3 months or a TIA within the previous 15 days to a target LDL cholesterol level of less than 70 mg per deciliter (1.8 mmol per liter) (lower-target group) or to a target range of 90 mg to 110 mg per deciliter (2.3 to 2.8 mmol per liter) (higher-target group). All the patients had evidence of cerebrovascular or coronary-artery atherosclerosis and received a statin, ezetimibe, or both. The composite primary end point of major cardiovascular events included ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or death from cardiovascular causes. RESULTS: A total of 2860 patients were enrolled and followed for a median of 3.5 years; 1430 were assigned to each LDL cholesterol target group. The mean LDL cholesterol level at baseline was 135 mg per deciliter (3.5 mmol per liter), and the mean achieved LDL cholesterol level was 65 mg per deciliter (1.7 mmol per liter) in the lower-target group and 96 mg per deciliter (2.5 mmol per liter) in the higher-target group. The trial was stopped for administrative reasons after 277 of an anticipated 385 end-point events had occurred. The composite primary end point occurred in 121 patients (8.5%) in the lower-target group and in 156 (10.9%) in the higher-target group (adjusted hazard ratio, 0.78; 95% confidence interval, 0.61 to 0.98; P = 0.04). The incidence of intracranial hemorrhage and newly diagnosed diabetes did not differ significantly between the two groups. CONCLUSIONS: After an ischemic stroke or TIA with evidence of atherosclerosis, patients who had a target LDL cholesterol level of less than 70 mg per deciliter had a lower risk of subsequent cardiovascular events than those who had a target range of 90 mg to 110 mg per deciliter. (Funded by the French Ministry of Health and others; Treat Stroke to Target ClinicalTrials.gov number, NCT01252875.).
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Anticolesterolemiantes/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , LDL-Colesterol/sangre , Ezetimiba/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Ataque Isquémico Transitorio/tratamiento farmacológico , Accidente Cerebrovascular/tratamiento farmacológico , Adulto , Anciano , Anticolesterolemiantes/efectos adversos , Aterosclerosis/complicaciones , Aterosclerosis/tratamiento farmacológico , Isquemia Encefálica/tratamiento farmacológico , Enfermedades Cardiovasculares/mortalidad , Quimioterapia Combinada , Femenino , Humanos , Análisis de Intención de Tratar , Ataque Isquémico Transitorio/complicaciones , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Accidente Cerebrovascular/sangreRESUMEN
Manipulation and control of cell chemotaxis remain an underexplored territory despite vast potential in various fields, such as cytotherapeutics, sensors, and even cell robots. Herein is achieved the chemical control over chemotactic movement and direction of Jurkat T cells, as a representative model, by the construction of cell-in-catalytic-coat structures in single-cell nanoencapsulation. Armed with the catalytic power of glucose oxidase (GOx) in the artificial coat, the nanobiohybrid cytostructures, denoted as Jurkat[Lipo_GOx] , exhibit controllable, redirected chemotactic movement in response to d-glucose gradients, in the opposite direction to the positive-chemotaxis direction of naïve, uncoated Jurkat cells in the same gradients. The chemically endowed, reaction-based fugetaxis of Jurkat[Lipo_GOx] operates orthogonally and complementarily to the endogenous, binding/recognition-based chemotaxis that remains intact after the formation of a GOx coat. For instance, the chemotactic velocity of Jurkat[Lipo_GOx] can be adjusted by varying the combination of d-glucose and natural chemokines (CXCL12 and CCL19) in the gradient. This work offers an innovative chemical tool for bioaugmenting living cells at the single-cell level through the use of catalytic cell-in-coat structures.
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Quimiotaxis , Glucosa , Humanos , Células Jurkat , Glucosa Oxidasa , CatálisisRESUMEN
Human induced pluripotent stem cells (hiPSCs) are reprogrammed from somatic cells and are regarded as promising sources for regenerative medicine and disease research. Recently, techniques for analyses of individual cells, such as single-cell RNA-Seq and mass cytometry, have been used to understand the stem cell reprogramming process in the mouse. However, the reprogramming process in hiPSCs remains poorly understood. Here we used mass cytometry to analyze the expression of pluripotency and cell cycle markers in the reprogramming of human stem cells. We confirmed that, during reprogramming, the main cell population was shifted to an intermediate population consisting of neither fibroblasts nor hiPSCs. Detailed population analyses using computational approaches, including dimensional reduction by spanning-tree progression analysis of density-normalized events, PhenoGraph, and diffusion mapping, revealed several distinct cell clusters representing the cells along the reprogramming route. Interestingly, correlation analysis of various markers in hiPSCs revealed that the pluripotency marker TRA-1-60 behaves in a pattern that is different from other pluripotency markers. Furthermore, we found that the expression pattern of another pluripotency marker, octamer-binding protein 4 (OCT4), was distinctive in the pHistone-H3high population (M phase) of the cell cycle. To the best of our knowledge, this is the first mass cytometry-based investigation of human reprogramming and pluripotency. Our analysis elucidates several aspects of hiPSC reprogramming, including several intermediate cell clusters active during the process of reprogramming and distinctive marker expression patterns in hiPSCs.
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Biomarcadores , Regulación de la Expresión Génica , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Fosfatasa Alcalina/metabolismo , Antígenos de Superficie/metabolismo , Biomarcadores/metabolismo , Ciclo Celular/genética , Ciclo Celular/fisiología , Línea Celular , Reprogramación Celular/genética , Reprogramación Celular/fisiología , Biología Computacional , Técnica del Anticuerpo Fluorescente , Humanos , Citometría de Imagen , Proteína Homeótica Nanog/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Fenotipo , Proteoglicanos/metabolismo , Factores de Transcripción SOXB1/metabolismo , Análisis de la Célula IndividualRESUMEN
The proviral integration moloney murine leukaemia virus (Pim) kinases, consisting of Pim-1, Pim-2 and Pim-3, are involved in the control of cell growth, metabolism and differentiation. Pim kinases are emerging as important mediators of adipocyte differentiation. AZD1208 is a pan-Pim kinase inhibitor and is known for its anti-cancer activity. In this study, we investigated the effect of AZD1208 on adipogenesis and lipolysis in 3T3-L1 cells, a murine preadipocyte cell line. AZD1208 markedly suppressed lipid accumulation and reduced triglyceride contents in differentiating 3T3-L1 cells, suggesting the drug's anti-adipogenic effect. On mechanistic levels, AZD1208 reduced not only the expressions of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC) and perilipin A but also the phosphorylation of signal transducer and activator of transcription-3 (STAT-3) in differentiating 3T3-L1 cells. Remarkably, AZD1208 increased cAMP-activated protein kinase (AMPK) and LKB-1 phosphorylation while decreased intracellular ATP contents in differentiating 3T3-L1 cells. Furthermore, in differentiated 3T3-L1 adipocytes, AZD1208 also partially promoted lipolysis and enhanced the phosphorylation of hormone-sensitive lipase (HSL), a key lipolytic enzyme, indicating the drug's HSL-dependent lipolysis. In summary, the findings show that AZD1208 has anti-adipogenic and lipolytic effects on 3T3-L1 adipocytes. These effects are mediated by the expression and/or phosphorylation levels of C/EBP-α, PPAR-γ, FAS, ACC, perilipin A, STAT-3, AMPK and HSL.
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Adipocitos/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Compuestos de Bifenilo/farmacología , Lipólisis/efectos de los fármacos , Tiazolidinas/farmacología , Células 3T3-L1 , Animales , Proteínas Potenciadoras de Unión a CCAAT/genética , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Proliferación Celular/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Ratones , PPAR gamma/genética , Perilipina-1/genética , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Receptor fas/genéticaRESUMEN
Meridianin C is a marine natural product known for its anti-cancer activity. At present, the anti-tumour effects of meridianin C on oral squamous cell carcinoma are unknown. Here, we investigated the effect of meridianin C on the proliferation of four different human tongue cancer cells, YD-8, YD-10B, YD-38 and HSC-3. Among the cells tested, meridianin C most strongly reduced the growth of YD-10B cells; the most aggressive and tumorigenic of the cell lines tested. Strikingly, meridianin C induced a significant accumulation of macropinosomes in the YD-10B cells; confirmed by the microscopic and TEM analysis as well as the entry of FITC-dextran, which was sensitive to the macropinocytosis inhibitor amiloride. SEM data also revealed abundant long and thin membrane extensions that resemble lamellipodia on the surface of YD-10B cells treated with meridianin C, pointing out that meridianin C-induced macropinosomes was the result of macropinocytosis. In addition, meridianin C reduced cellular levels of Dickkopf-related protein-3 (DKK-3), a known negative regulator of macropinocytosis. A role for DKK-3 in regulating macropinocytosis in the YD-10B cells was confirmed by siRNA knockdown of endogenous DKK-3, which led to a partial accumulation of vacuoles and a reduction in cell proliferation, and by exogenous DKK-3 overexpression, which resulted in a considerable inhibition of the meridianin C-induced vacuole formation and decrease in cell survival. In summary, this is the first study reporting meridianin C has novel anti-proliferative effects via macropinocytosis in the highly tumorigenic YD-10B cell line and the effects are mediated in part through down-regulation of DKK-3.
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Regulación hacia Abajo/efectos de los fármacos , Alcaloides Indólicos/farmacología , Indoles/farmacología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Pinocitosis/efectos de los fármacos , Pirimidinas/farmacología , Neoplasias de la Lengua/metabolismo , Neoplasias de la Lengua/patología , Proteínas Adaptadoras Transductoras de Señales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Quimiocinas , Humanos , Alcaloides Indólicos/química , Indoles/química , Pirimidinas/química , Neoplasias de la Lengua/ultraestructura , Vacuolas/efectos de los fármacos , Vacuolas/metabolismoRESUMEN
Two-photon endoscopy based on a gradient-index lens has been widely utilized for studying cellular behaviors in deep-lying tissues with minimal invasiveness in vivo. Although the efficient collection of emitted light is critical to attain high-contrast spatiotemporal information, the intrinsic low numerical aperture of the endoscopic probe poses a physical limitation. We report a simple solution to overcome this limit by incorporating a reflective waveguide ensheathing the endoscopic probe, which improves the collection efficiency by approximately two-fold. We describe its principle, fabrication procedure, optical characterization, and utilities in biological tissues.
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Endoscopía/métodos , Óptica y Fotónica , Fotones , Animales , Encéfalo/anatomía & histología , Encéfalo/irrigación sanguínea , Fluorescencia , Masculino , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
The posttranslational modification of neural cell-adhesion molecule (NCAM) with polysialic acid (PSA) and the spatiotemporal distribution of PSA-NCAM play an important role in the neuronal development. In this work, we developed a tissue-based strategy for metabolically incorporating an unnatural monosaccharide, peracetylated N-azidoacetyl-D-mannosamine, in the sialic acid biochemical pathway to present N-azidoacetyl sialic acid to PSA-NCAM. Although significant neurotoxicity was observed in the conventional metabolic labeling that used the dissociated neuron cells, neurotoxicity disappeared in this modified strategy, allowing for investigation of the temporal and spatial distributions of PSA in the primary hippocampal neurons. PSA-NCAM was synthesized and recycled continuously during neuronal development, and the two-color labeling showed that newly synthesized PSA-NCAMs were transported and inserted mainly to the growing neurites and not significantly to the cell body. This report suggests a reliable and cytocompatible method for in vitro analysis of glycans complementary to the conventional cell-based metabolic labeling for chemical glycobiology.
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Hipocampo/metabolismo , Neuronas/metabolismo , Ácidos Siálicos/metabolismo , Animales , Hipocampo/citología , Proteínas del Tejido Nervioso/metabolismo , Proteómica , Ratas , Ratas Sprague-DawleyRESUMEN
Diabetes mellitus is a complex and heterogeneous disease, which has ß-cell dysfunction at its core. Glucotoxicity affects pancreatic islets, causing ß-cell apoptosis. However, the role of JNK/ß-catenin signaling in glucotoxic ß-cell apoptosis is not well understood. Recently, we identified tetraspanin-2 (TSPAN2) protein as a proapoptotic ß-cell factor induced by glucose, suggesting that TSPAN2 might contribute to pancreatic ß-cell glucotoxicity. To investigate the effects of glucose concentration on TSPAN2 expression and apoptosis, we used reverted immortalized RNAKT-15 human pancreatic ß cells. High TSPAN2 levels up-regulated phosphorylated (p) JNK and induced apoptosis. p-JNK enhanced the phosphorylation of ß-catenin and Dickkopf-1 (Dkk1). Dkk1 knockdown by small interfering (si)RNA up-regulated nuclear ß-catenin, suggesting that it is a JNK/ß-catenin-dependent pathway. siRNA-mediated TSPAN2 depletion in RNAKT-15 cells increased nuclear ß-catenin. This decreased BCL2-associated X protein (Bax) activation, leading to marked protection against high glucose-induced apoptosis. Bax subfamily proteins induced apoptosis through caspase-3. Thus, TSPAN2 might have induced Bax translocation and caspase-3 activation in pancreatic ß cells, thereby promoting the apoptosis of RNAKT-15 cells by regulating the JNK/ß-catenin pathway in response to high glucose concentrations. Targeting TSPAN2 could be a potential therapeutic strategy to treat glucose toxicity-induced ß-cell failure.-Hwang, I.-H., Park, J., Kim, J. M., Kim, S. I., Choi, J.-S., Lee, K.-B., Yun, S. H., Lee, M.-G., Park, S. J., Jang, I.-S. Tetraspanin-2 promotes glucotoxic apoptosis by regulating the JNK/ß-catenin signaling pathway in human pancreatic ß cells.
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Apoptosis/efectos de los fármacos , Glucosa/toxicidad , Células Secretoras de Insulina/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Tetraspaninas/metabolismo , beta Catenina/metabolismo , Línea Celular , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/administración & dosificación , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Proteínas del Tejido Nervioso/genética , Transducción de Señal/fisiología , Tetraspaninas/genética , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo , beta Catenina/genéticaRESUMEN
BACKGROUND: Transient receptor potential melastatin 7 (TRPM7) regulates breast cancer cell proliferation, migration, invasion and metastasis in its ion channel- and kinase domain-dependent manner. The pharmacological effects of TRPM7 ion channel inhibitors on breast cancer cells have been studied, but little is known about the effects of TRPM7 kinase domain inhibitors due to lack of potent TRPM7 kinase inhibitors. METHODS: Screening was performed by using TRPM7 kinase assay. Effects of TG100-115 on breast cancer cell proliferation, migration, invasion, myosin IIA phosphorylation, and TRPM7 ion channel activity were assessed by using MTT, wound healing, transwell assay, Western blotting, and patch clamping, respectively. RESULTS: We found that CREB peptide is a potent substrate for the TR-FRET based TRPM7 kinase assay. Using this method, we discovered a new and potent TRPM7 kinase inhibitor, TG100-115. TG100-115 inhibited TRPM7 kinase activity in an ATP competitive fashion with over 70-fold stronger activity than that of rottlerin, known as a TRPM7 kinase inhibitor. TG100-115 has little effect on proliferation of MDA-MB-231 cells, but significantly decreases cell migration and invasion. Moreover, TG100-115 inhibits TRPM7 kinase regulated phosphorylation of the myosin IIA heavy chain and phosphorylation of focal adhesion kinase. TG100-115 also suppressed TRPM7 ion channel activity. CONCLUSIONS: TG100-115 can be used as a potent TRPM7 kinase inhibitor and a potent inhibitor of breast cancer cell migration. GENERAL SIGNIFICANCE: TG100-115 could be a useful tool for studying the pharmacological effects of TRPM7 kinase activity aimed at providing insight into new therapeutic approaches to the treatment of breast cancer.
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Neoplasias de la Mama/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Invasividad Neoplásica/patología , Fenoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pteridinas/farmacología , Canales Catiónicos TRPM/antagonistas & inhibidores , Adenosina Trifosfato/metabolismo , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Femenino , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Humanos , Miosina Tipo IIA no Muscular/metabolismo , Fosforilación/efectos de los fármacosRESUMEN
Tanshinone IIA is a diterpene quinone isolated from the roots of Salviamiltiorrhiza bunge that has traditionally been used in China for the treatment of cardiovascular and cerebrovascular disorders. Although there is recent evidence showing that tanshinone IIA has an anti-obesity effect, its underlying mechanism of anti-obesity effect is poorly understood. Here, we investigated the effect of tanshinone IIA on lipid accumulation in 3T3-L1 preadipocytes and zebrafish. Notably, tanshinone IIA at 10 µM concentration greatly reduced lipid accumulation and triglyceride (TG) contents during 3T3-L1 preadipocyte differentiation, suggesting its anti-adipogenic effect. On mechanistic levels, tanshinone IIA reduced the expression levels of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FAS), and perilipin A but also the phosphorylation levels of signal transducer and activator of transcription-3/5 (STAT-3/5) in differentiating 3T3-L1 cells. In addition, tanshinone IIA strongly inhibited leptin and resistin mRNA expression in differentiating 3T3-L1 cells. Importantly, the tanshinone IIA's lipid-reducing effect was also seen in zebrafish. In sum, these findings demonstrate that tanshinone IIA has anti-adipogenic effects on 3T3-L1 cells and zebrafish, and its anti-adipogenic effect on 3T3-L1 cells is largely attributable to the reduced expression and/or phosphorylation levels of C/EBP-α, PPAR-γ, FAS, perilipin A, and STAT-3/5.
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Abietanos/farmacología , Adipogénesis/efectos de los fármacos , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipogénesis/genética , Animales , Biomarcadores , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Células Cultivadas , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Lipólisis , Ratones , PPAR gamma/genética , PPAR gamma/metabolismo , Fosforilación , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT5/metabolismo , Pez CebraRESUMEN
Mesothelial cells are composed of monolayer of the entire surface of serosal cavities including pleural, pericardial, and peritoneal cavity. Although mesothelial cells are known to express multiple Toll-like receptors (TLRs) which contribute to trigger innate immune responses against infections, the precise molecular mechanism remains still unclear. In the present study, we investigated the role of Toll/IL-1 domain-containing adaptor inducing IFN-ß (TRIF), one of the two major TLRs-adaptor molecules, on innate immune response induced by TLR3 and TLR4 stimulation in murine peritoneal mesothelial cells (PMCs). TRIF was strongly expressed in PMCs and its deficiency led to impaired production of cytokines and chemokines by poly I:C and LPS in the cells. Activation of NF-κB or MAPKs through poly I:C and LPS stimulation was reduced in TRIF-deficient PMCs as compared to the WT cells. TRIF was also necessary for optimal nitric oxide synthesis and gene expression of inducible nitric oxide synthase (iNOS) and IFN-ß in PMCs in response to poly I:C and LPS. Furthermore, both Escherichia coli and Pseudomonas aeruginosa induced high level of IL-6, CXCL1, and CCL2 production in PMCs, which was significantly impaired by TRIF deficiency. These results demonstrated that TRIF is required for optimal activation of innate immune responses in mesothelial cells against microbial infections.
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Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Células Epiteliales/metabolismo , Inmunidad Innata/inmunología , Receptor Toll-Like 3/metabolismo , Receptor Toll-Like 4/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/genética , Animales , Western Blotting , Células Cultivadas , Quimiocina CCL2/metabolismo , Quimiocina CXCL1/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/microbiología , Escherichia coli/fisiología , Expresión Génica/efectos de los fármacos , Inmunidad Innata/genética , Interferón beta/genética , Interferón beta/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Peritoneo/citología , Peritoneo/metabolismo , Poli I-C/farmacología , Pseudomonas aeruginosa/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptor Toll-Like 3/genética , Receptor Toll-Like 4/genéticaRESUMEN
Uremic encephalopathy with bilateral basal ganglia lesions has been reported as an acute neurometabolic disease which shows reversible clinical course and brain imaging features. The exact nature and pathophysiology have not been well established. We encountered two patients who showed a relapsing and aggravating course and an atypical phenotype including parkinsonism with paroxysmal dystonic head tremor and acute onset monoparesis of the lower extremity. They also showed unusual radiological findings which revealed combined lesions in the basal ganglia and cortex, persistent hemorrhagic transformation, and focal ischemic lesion in the internal capsule. Herein, we present the unusual phenomenology with atypical radiologic findings and suggest the possible multifactorial pathogenesis of uremic encephalopathy.
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Encefalopatías Metabólicas/diagnóstico por imagen , Encéfalo/patología , Imagen por Resonancia Magnética , Trastornos Parkinsonianos/diagnóstico por imagen , Adulto , Encefalopatías Metabólicas/patología , Humanos , Masculino , Trastornos Parkinsonianos/patología , RecurrenciaRESUMEN
The purpose of this study was to examine the antidepressant-like effects of clary sage oil on human beings by comparing the neurotransmitter level change in plasma. The voluntary participants were 22 menopausal women in 50's. Subjects were classified into normal and depression tendency groups using each of Korean version of Beck Depression Inventory-I (KBDI-I), KBDI-II, and Korean version of Self-rating Depression Scale. Then, the changes in neurotransmitter concentrations were compared between two groups. After inhalation of clary sage oil, cortisol levels were significantly decreased while 5-hydroxytryptamine (5-HT) concentration was significantly increased. Thyroid stimulating hormone was also reduced in all groups but not statistically significantly. The different change rate of 5-HT concentration between normal and depression tendency groups was variable according to the depression measurement inventory. When using KBDI-I and KBDI-II, 5-HT increased by 341% and 828% for the normal group and 484% and 257% for the depression tendency group, respectively. The change rate of cortisol was greater in depression tendency groups compared with normal groups, and this difference was statistically significant when using KBDI-II (31% vs. 16% reduction) and Self-rating Depression Scale inventory (36% vs. 8.3% reduction). Among three inventories, only KBDI-II differentiated normal and depression tendency groups with significantly different cortisol level. Finally, clary sage oil has antidepressant-like effect, and KBDI-II inventory may be the most sensitive and valid tool in screening for depression status or severity.
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Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Hidrocortisona/sangre , Aceites Volátiles/uso terapéutico , Serotonina/sangre , Administración por Inhalación , Femenino , Humanos , Menopausia , Persona de Mediana Edad , Aceites Volátiles/química , Aceites de Plantas/química , Aceites de Plantas/uso terapéutico , Escalas de Valoración Psiquiátrica , Salvia/química , Tirotropina/sangreRESUMEN
BACKGROUND: Intracranial arterial calcification (IAC) is an evidence of advanced atherosclerosis. This study was aimed to investigate whether IAC predicts early vascular events (EVEs) during acute period of ischemic stroke. METHODS: We prospectively enrolled consecutive patients with acute ischemic stroke and transient ischemic attack within 48 hours from January 2005 to October 2012. Three IAC categories were defined according to the total IAC score as follows: no IAC (0 point), mild IAC (1-2 points), and severe IAC (≥3 points). EVEs included early progression/recurrence of stroke, coronary events, and vascular deaths within 2 weeks from stroke onset. We used multivariable Cox regression analyses to determine the effect of IAC on EVE. RESULTS: In the trend analysis of 1017 total patients, there were significant trends of increased IAC toward higher total EVEs (10.5% versus 13.8% versus 21.2%, P < .001). Severe IAC was related to increased rate of early progression/recurrence (hazard ratio [HR] 2.00; 95% confidence interval [CI] 1.07-3.71, P = .029) and coronary events (HR 3.51; 95% CI 1.00-12.31, P = .050) but did not show an association for mortality (HR .54; 95% CI .19-1.53, P = .224). Increased IAC was also related to a poor functional outcome after 3 months (odds ratio 2.23; 95% CI 1.38-3.59). CONCLUSIONS: IAC was significantly associated with increased early progression/recurrence of stroke and coronary events during acute period of ischemic stroke. IAC on the initial brain computed tomography would be used as a predictor for recurrent vascular events after acute ischemic stroke before further angiographic evaluation.
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Isquemia Encefálica/etiología , Enfermedades Arteriales Cerebrales/complicaciones , Ataque Isquémico Transitorio/etiología , Accidente Cerebrovascular/etiología , Calcificación Vascular/complicaciones , Anciano , Anciano de 80 o más Años , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/mortalidad , Enfermedades Arteriales Cerebrales/diagnóstico , Enfermedades Arteriales Cerebrales/mortalidad , Distribución de Chi-Cuadrado , Progresión de la Enfermedad , Femenino , Humanos , Ataque Isquémico Transitorio/diagnóstico , Ataque Isquémico Transitorio/mortalidad , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/mortalidad , Calcificación Vascular/diagnóstico , Calcificación Vascular/mortalidadRESUMEN
OBJECTIVES: Although the systemic immune-inflammatory index (SII) has recently been correlated with stroke severity and functional outcome, the underlying pathogenesis remains largely unknown. The objective of this study was to explore whether SII could predict early neurologic deterioration (END) in different etiologies of acute ischemic stroke. MATERIALS AND METHODS: From January 2019 to December 2021, a total of 697 consecutive patients with acute ischemic stroke, admitted within 72â¯hours from stroke onset, were prospectively enrolled. The patients were categorized into 4 groups based on quartiles of SII, calculated as platelets multiplied by neutrophils divided by lymphocytes. END and stroke progression/recurrence were assessed during the first 7 days after stroke onset using predetermined definitions. Logistic regression analysis was conducted to evaluate the association between SII and END, while considering the variation in association across stroke etiologies. RESULTS: END occurred in 135 patients: 24 (3.4%) for Group I, 25 (3.6%) for Group II, 33 (4.7%) for Group III, and 53 (7.6%) for Group IV. Among the END subtypes, stroke progression/recurrence stroke was the most prevalent. In the logistic regression model, the adjusted odds ratios (ORs) of END and stroke progression/recurrence for group IV were 2.51 (95% CI, 1.27-4.95) and 1.98 (95% CI, 1.03-3.89), respectively. Among the stroke etiologies, group IV showed a significant increase in END (OR 4.24; 95% CI, 1.42-12.64) and stroke progression/recurrence (OR 4.13; 95% CI, 1.39-12.27) specifically in case of large artery atherosclerosis. CONCLUSIONS: SII independently predicts early stroke progression/recurrence in patients with acute atherosclerotic ischemic stroke.
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Aterosclerosis , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular Isquémico/complicaciones , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/etiología , Aterosclerosis/complicaciones , Inflamación/complicaciones , LinfocitosRESUMEN
BACKGROUND: Late hospital arrival keeps patients with stroke from receiving recanalization therapy and is associated with poor outcomes. This study used a nationwide acute stroke registry to investigate the trends and regional disparities in prehospital delay and analyze the significant factors associated with late arrivals. METHODS: Patients with acute ischemic stroke or transient ischemic attack between January 2012 and December 2021 were included. The prehospital delay was identified, and its regional disparity was evaluated using the Gini coefficient for nine administrative regions. Multivariate models were used to identify factors significantly associated with prehospital delays of >4.5 h. RESULTS: A total of 144,014 patients from 61 hospitals were included. The median prehospital delay was 460 min (interquartile range, 116-1912), and only 36.8% of patients arrived at hospitals within 4.5 h. Long prehospital delays and high regional inequality (Gini coefficient > 0.3) persisted throughout the observation period. After adjusting for confounders, age > 65 years old (adjusted odds ratio [aOR] = 1.23; 95% confidence interval [CI], 1.19-1.27), female sex (aOR = 1.09; 95% CI, 1.05-1.13), hypertension (aOR = 1.12; 95% CI, 1.08-1.16), diabetes mellitus (aOR = 1.38; 95% CI, 1.33-1.43), smoking (aOR = 1.15, 95% CI, 1.11-1.20), premorbid disability (aOR = 1.44; 95% CI, 1.37-1.52), and mild stroke severity (aOR = 1.55; 95% CI, 1.50-1.61) were found to independently predict prehospital delays of >4.5 h. CONCLUSION: Prehospital delays were lengthy and had not improved in Korea, and there was a high regional disparity. To overcome these inequalities, a deeper understanding of regional characteristics and further research is warranted to address the vulnerabilities identified.