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The growing use of plastic materials has resulted in a constant increase in the risk associated with microplastics (MPs). Ultra-violet (UV) light and wind break down modify MPs in the environment into smaller particles known as weathered MPs (WMPs) and these processes increase the risk of MP toxicity. The neurotoxicity of weathered polystyrene-MPs remains unclear. Therefore, it is important to understand the risks posed by WMPs. We evaluated the chemical changes of WMPs generated under laboratory-synchronized environmentally mimetic conditions and compared them with virgin MPs (VMPs). We found that WMP had a rough surface, slight yellow color, reduced molecular weight, and structural alteration compared with those of VMP. Next, 2 µg of â¼100 µm in size of WMP and VMP were orally administered once a day for one week to C57BL/6 male mice. Proteomic analysis revealed that the WMP group had significantly increased activation of immune and neurodegeneration-related pathways compared with that of the VMP group. Consistently, in in vitro experiments, the human brain-derived microglial cell line (HMC-3) also exhibited a more severe inflammatory response to WMP than to VMP. These results show that WMP is a more profound inflammatory factor than VMP. In summary, our findings demonstrate the toxicity of WMPs and provide theoretical insights into their potential risks to biological systems and even humans in the ecosystem.
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Microplásticos , Contaminantes Químicos del Agua , Animales , Humanos , Ratones , Masculino , Microplásticos/toxicidad , Plásticos , Poliestirenos/toxicidad , Poliestirenos/análisis , Proteoma , Ecosistema , Proteómica , Ratones Endogámicos C57BL , Contaminantes Químicos del Agua/toxicidad , Contaminantes Químicos del Agua/análisis , EncéfaloRESUMEN
Mouse embryonic stem cells (mESCs) are characterized by self-renewal and pluripotency and can undergo differentiation into the three germ layers (ectoderm, mesoderm, and endoderm). Melanoma-associated antigen D1 (Maged1), which is expressed in all developing and adult tissues, modulates tissue regeneration and development. In the present study, we examined the expression and function of Maged1 in mESCs. Maged1 protein and mRNA expression increased during mESC differentiation. The pluripotency of mESCs was significantly reduced through extracellular signal-regulated kinase 1/2 phosphorylation upon knockdown of Maged1, and through G1 cell cycle arrest during cell division, resulting in significantly reduced mESC proliferation. Moreover, the diameter of the embryoid bodies was significantly reduced, accompanied by increased levels of ectodermal differentiation markers and decreased levels of mesodermal and endodermal differentiation markers. Maged1-knockdown mESC lines showed significantly reduced teratoma volumes and inhibition of teratoma formation in nude mice. Additionally, we observed increased ectodermal markers but decreased mesodermal and endodermal markers in teratoma tissues. These findings show that Maged1 affects mESC pluripotency, proliferation, cell cycle, and differentiation, thereby contributing to our understanding of the basic molecular biological mechanisms and potential roles of Maged1 as a regulator of various mESC properties.
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Células Madre Embrionarias de Ratones , Animales , Antígenos de Diferenciación/metabolismo , Ciclo Celular/genética , Muerte Celular , Diferenciación Celular/genética , División Celular , Ratones , Ratones Desnudos , Células Madre Embrionarias de Ratones/citología , Células Madre Embrionarias de Ratones/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Teratoma/genética , Teratoma/metabolismo , Teratoma/patologíaRESUMEN
Waste plastics are degraded into microplastics (MPs), which are easily accumulated in the human body through digestive tracts, via the food chain. Alcohol is a widely consumed chemical throughout the world with the ability to alter the intestinal barrier. For this reason, this study was aimed to investigate exact relevance between alcohol consumption and organ distributions of MPs in an ethanol feeding animal model characterized by disrupted intestinal mucosal barriers. In this study, C57BL/6 mice were separated into control, control + MP, ethanol (EtOH), and EtOH + MP groups. Mice in the EtOH group ingested a Lieber-DeCarli diet containing EtOH. Mice in the MP groups ingested 0.1 mg/kg fluorophore polymerized polystyrene microplastics via oral gavage polystyrene MPs via oral gavage. The EtOH + MP group showed higher MP accumulation in the liver than the control + MP group. The same pattern was observed in the intestines, spleen, and brain. This pattern was more prominent in the intestines, with the EtOH + MP group showing the most severe damage due to EtOH ingestion. This result suggests that the intestinal mucosa disruption caused by EtOH ingestion exacerbates MP accumulation in the organs. Moreover, hepatic steatosis was more severe in the EtOH + MP group than in the EtOH group, suggesting the secondary manifestation mediated by MP accumulation. This study reports a novel MP accumulation pattern in the body by providing novel insights into alcohol-induced gut permeability and microplastics toxicity from the perspective of gut-liver axis.
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Comparison of the bleeding risk for long-term oral anticoagulation (OAC) in patients with nonvalvular atrial fibrillation (AF) with and without cancers has been inconsistent. This study aimed to clarify the differences in the bleeding risk in patients with AF with cancers and those without cancers during the long-term OAC.The CODE-AF prospective registry enrolled 5,902 consecutive patients treated for AF at 10 tertiary referral centers in Korea. Of the enrolled patients, 464 (7.8%) were diagnosed with cancers and were followed for all stroke and bleeding events (net composite events).The age, CHA2DS2-VASC, and HAS-BLED scores were similar between AF patients with and without cancers. Male population greatly comprised patients with AF with cancers. They were equally prescribed with direct OAC compared to those without cancers. The incidence rate for clinically relevant nonmajor (CRNM) bleeding events was higher in the patients with AF with cancers than in those without cancers (4.4 per 100 person-years versus 2.8 per 100 person-years, P = 0.023), and net composite events were also more frequent in patients with AF with cancers than in those without cancers (6.4 per 100 person-years versus 4.0 per 100 person-years, P = 0.004). Patients with AF with cancers showed a significantly higher rate of CRNM bleeding (hazard ratio [HR] 1.54, confidence interval [CI] 1.05-2.25, P = 0.002) than those without cancers.Based on the AF cohort, AF with cancers could face a significantly higher risk for CRNM bleeding events in the long-term OAC than those without cancers.
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Apocrine cystomatosis, also called epitrichial sweat gland cystomatosis, is a non-neoplastic condition characterised by multiple dilated cysts of sweat gland origin. Histopathologically, these cysts comprise two layers of cells: an inner layer of glandular epithelial cells and an outer layer of myoepithelial cells. A case of apocrine cystomatosis was admitted to a local hospital. The microscopic investigation revealed that some enlarged cysts showed the transition of glandular epithelial cells into a spindle, mesenchymal cell-like morphology. The epithelial-to-mesenchymal transition (EMT) has long been studied as a pathway for embryogenesis, organ development, and carcinogenesis. While various molecular factors, including cytokines and growth factors, are known to induce EMT, mechanical forces have also been proposed to initiate EMT. The present case describes a possible relationship between EMT occurring in a cystic condition and further pathological inspection.
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Mouse embryonic stem cells (mESCs) are a widely used model for their diverse availability in studying early embryonic development and their application in regenerative treatment of various intractable diseases. Transient receptor potential melastatin 7 (Trpm7) regulates Ca2+ as a nonselective ion channel and is essential for early embryonic development; however, the precise role of Trpm7 in mESCs has not been clearly elucidated. In this study, we showed that the inhibition of Trpm7 affects the pluripotency and self-renewal of mESCs. We found that short hairpin RNA (shRNA)-mediated suppression of Trpm7 resulted in decreased expression of transcriptional regulators, Oct4 and Sox2, which maintain stemness in mESCs. In addition, Trpm7 knockdown led to alterations in the basic properties of mESCs, such as decreased proliferation, cell cycle arrest at the G0/G1 phase, and increased apoptosis. Furthermore, embryoid body (EB) formation and teratoma formation assays revealed abnormal regulation of differentiation due to Trpm7 knockdown, including the smaller size of EBs, elevated ectodermal differentiation, and diminished endodermal and mesodermal differentiation. We found that EB Day 7 samples displayed decreased intracellular Ca2+ levels compared to those of the scrambled group. Finally, we identified that these alterations induced by Trpm7 knockdown occurred due to decreased phosphorylation of mechanistic target of rapamycin (mTOR) and subsequent activation of extracellular signal-regulated kinase (ERK) in mESCs. Our findings suggest that Trpm7 could be a novel regulator for maintaining stemness and modulating the differentiation of mESCs.
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Células Madre Embrionarias de Ratones , Canales Catiónicos TRPM , Animales , Diferenciación Celular , Proliferación Celular , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Ratones , Células Madre Embrionarias de Ratones/metabolismo , ARN Interferente Pequeño/metabolismo , Sirolimus , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Canales Catiónicos TRPM/genética , Canales Catiónicos TRPM/metabolismoRESUMEN
Although several studies have focused on cancer diagnosis and therapy, prostate cancer (PC) remains an intractable disease. Androgen deprivation therapy (ADT), which is used to treat early stage PC can lead to the development of castration-resistant prostate cancer (CRPC), which is highly associated with androgen receptor (AR) mutations. Nucleolar and coiled-body phosphoprotein 1 (NOLC1) is a chaperone that shuttles between the nucleus and the cytoplasm. Studies suggest that NOLC1 regulates PC progression; however, the underlying mechanisms remain unclear. Herein, we showed that NOLC1 knockdown suppresses PC cell proliferation by altering the signaling pathways and the expression of various proteins involved in DNA replication, amino acid metabolism, and RNA processing. Mechanistically, NOLC1 knockdown suppressed cell cycle progression by inhibiting AKT phosphorylation and ß-catenin accumulation. Finally, we showed that NOLC1 expression is higher in human PC than in human hyperplastic prostate tissues. Altogether, we demonstrated that NOLC1 knockdown suppresses the progression of both AR-positive and AR-negative PC cells by inducing changes in the expression of several genes leading to cell cycle arrest. Thus, NOLC1 might be a novel and promising therapeutic target for PC.
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Neoplasias de la Próstata Resistentes a la Castración , beta Catenina , Masculino , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Próstata/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Fosforilación , Antagonistas de Andrógenos , Línea Celular Tumoral , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismoRESUMEN
Despite the increasing clinical importance of nonalcoholic fatty liver disease (NAFLD), little is known about its underlying pathogenesis or specific treatment. The senescence marker protein 30 (SMP30), which regulates the biosynthesis of vitamin C (VC) in many mammals, except primates and humans, was recently recognized as a gluconolactonase. However, the precise relation between VC and lipid metabolism in NAFLD is not completely understood. Therefore, this study aimed to clearly reveal the role of VC in NAFLD progression. SMP30 knockout (KO) mice were used as a VC-deficient mouse model. To investigate the precise role of VC on lipid metabolism, 13- to 15-week-old SMP30 KO mice and wild-type mice fed a 60% high-fat diet were exposed to tap water or VC-containing water (1.5 g/L) ad libitum for 11 weeks. Primary mouse hepatocytes isolated from the SMP30 KO and wild-type mice were used to demonstrate the relation between VC and lipid metabolism in hepatocytes. Long-term VC deficiency significantly suppressed the progression of simple steatosis. The high-fat diet-fed VC-deficient SMP30 KO mice exhibited impaired sterol regulatory element-binding protein-1c activation because of excessive cholesterol accumulation in hepatocytes. Long-term VC deficiency inhibits de novo lipogenesis through impaired sterol regulatory element-binding protein-1c activation.
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Deficiencia de Ácido Ascórbico/metabolismo , Hepatocitos/metabolismo , Lipogénesis/fisiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Animales , Progresión de la Enfermedad , Metabolismo de los Lípidos/fisiología , Masculino , Ratones , Ratones NoqueadosRESUMEN
BACKGROUND: The extent to which cognitive function differs between patients who receive implantable cardioverter-defibrillator (ICD) therapy and patients with heart failure (HF) who do not receive ICD therapy remains to be elucidated. OBJECTIVES: The aim of this study was to compare the cognitive function between patients with primary or secondary ICDs and patients with HF without an ICD. METHODS: This descriptive, comparative study included 116 patients who received ICDs and 74 patients with HF who did not receive ICDs. Patients underwent neuropsychological assessment for general cognition, memory, and executive function. RESULTS: Immediate recall memory loss (18.9%) occurred more often in patients with HF without an ICD than in patients with primary (3.1%) and secondary (7.1%) ICDs (P = .018). After adjusting for age and education, delayed recall memory of patients with HF without ICDs was significantly worse than that of patients with primary ICDs (4.0 vs 6.5; P < .001), whereas delayed recall memory of patients with primary ICDs was better than that of patients with secondary ICDs (6.0 vs 6.5; P = .006). Executive function of patients with HF without ICDs was significantly worse than that of patients with primary (35 vs 58 seconds; P < .001) and secondary (28 vs 58 seconds; P = .0012) ICDs. CONCLUSIONS: Patients with ICDs, regardless of primary or secondary indication, had less impairment of memory and executive function than patients with HF without ICDs, implying that ICD therapy did not interfere with cognitive performance. Cognitive screening as a part of routine care could be helpful for identifying impairment and implementing early cognitive training, especially in patients with HF.
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Trastornos del Conocimiento , Desfibriladores Implantables , Insuficiencia Cardíaca Sistólica , Insuficiencia Cardíaca , Cognición , Trastornos del Conocimiento/complicaciones , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/prevención & control , Desfibriladores Implantables/efectos adversos , Función Ejecutiva , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/terapia , Insuficiencia Cardíaca Sistólica/complicaciones , Insuficiencia Cardíaca Sistólica/terapia , HumanosRESUMEN
Chaga mushroom (Inonotus obliquus) comprises polyphenolic compounds, triterpenoids, polysaccharides, and sterols. Among the triterpenoid components, inotodiol has been broadly examined because of its various biological activities. The purpose of this study is to examine inotodiol from a safety point of view and to present the potential possibilities of inotodiol for medical usage. From chaga mushroom extract, crude inotodiol (INO20) and pure inotodiol (INO95) were produced. Mice were treated with either INO20 or INO95 once daily using oral administration for repeated dose toxicity evaluation. Serum biochemistry parameters were analyzed, and the level of pro-inflammatory cytokines in the serum was quantified. In parallel, the effect of inotodiol on food allergic symptoms was investigated. Repeated administration of inotodiol did not show any mortality or abnormalities in organs. In food allergy studies, the symptoms of diarrhea were ameliorated by administration with INO95 and INO20. Furthermore, the level of MCPT-1 decreased by treatment with inotodiol. In this study, we demonstrated for the first time that inotodiol does not cause any detrimental effect by showing anti-allergic activities in vivo by inhibiting mast cell function. Our data highlight the potential to use inotodiol as an immune modulator for diseases related to inflammation.
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Lanosterol , Triterpenos , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Modelos Animales de Enfermedad , Inonotus , Lanosterol/análogos & derivados , Lanosterol/farmacología , RatonesRESUMEN
The oxidation of diaryl sulfides and aryl alkyl sulfides to the corresponding sulfoxides and sulfones under electrochemical conditions is reported. Sulfoxides are selectively obtained in good yield under a constant current of 5 mA for 10 h in DMF, while sulfones are formed as the major product under a constant current of 10 or 20 mA for 10 h in MeOH. The oxygen of both the sulfoxide and sulfone function is derived from water.
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AIMS: The aim of this study is to determine the relationship between alcohol consumption and atrial fibrillation (AF)-related adverse events in the AF population. METHODS AND RESULTS: A total of 9411 patients with nonvalvular AF in a prospective observational registry were categorized into four groups according to the amount of alcohol consumption-abstainer-rare, light (<100 g/week), moderate (100-200 g/week), and heavy (≥200 g/week). Data on adverse events (ischaemic stroke, transient ischaemic attack, systemic embolic event, or AF hospitalization including for AF rate or rhythm control and heart failure management) were collected for 17.4 ± 7.3 months. A Cox proportional hazard models was performed to calculate hazard ratios (HRs), and propensity score matching was conducted to validate the results. The heavy alcohol consumption group showed an increased risk of composite adverse outcomes [adjusted hazard ratio (aHR) 1.32, 95% confidence interval (CI) 1.06-1.66] compared with the reference group (abstainer-rare group). However, no significant increased risk for adverse outcomes was observed in the light (aHR 0.88, 95% CI 0.68-1.13) and moderate (aHR 0.91, 95% CI 0.63-1.33) groups. In subgroup analyses, adverse effect of heavy alcohol consumption was significant, especially among patients with low CHA2DS2-VASc score, without hypertension, and in whom ß-blocker were not prescribed. CONCLUSION: Our findings suggest that heavy alcohol consumption increases the risk of adverse events in patients with AF, whereas light or moderate alcohol consumption does not.
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Fibrilación Atrial , Isquemia Encefálica , Preparaciones Farmacéuticas , Accidente Cerebrovascular , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/epidemiología , Anticoagulantes , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/epidemiología , Humanos , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/prevención & controlRESUMEN
PURPOSE: Despite a beneficial role of iodine and seaweed consumption against metabolic syndrome (MetS), which is high in postmenopausal women, few studies investigated such associations in a prospective study. This study aimed to investigate the association of dietary iodine and seaweed consumption with the incidence of MetS and its components in postmenopausal women. METHODS: A total of 2588 postmenopausal women aged ≥ 40 years were recruited between 2005 and 2011 in the Multi-Rural Communities Cohort (MRCohort). A validated semiquantitative food frequency questionnaire was used to collect dietary intake data. MetS was defined as three of five components [abdominal obesity, elevated blood pressure, glucose, triglyceride, and low-high density lipoprotein cholesterol (HDL-C)] and the incidence of MetS was checked every 2-4 years. The incidence rate ratio (IRR) was estimated using a modified Poisson regression model with a robust error estimator. RESULTS: During the mean follow-up period (3.4 ± 2.1 years), MetS occurred in 481 participants. The median cumulative average iodine intake was 108.9 µg/day (interquartile range, 60.8-190.2 µg/day). In multivariable analyses, average iodine and seaweed consumption were inversely associated with MetS (IRR = 0.61, 95% CI 0.47-0.78 in the highest quartile of iodine intake, P for trend = 0.0018; IRR = 0.52, 95% CI 0.39-0.69 in the highest quartile of seaweed consumption, P for trend = 0.0004). Among MetS components, blood glucose (> 100 mg/dL), blood pressure (≥ 130/85 mmHg), and lipid profiles (triglyceride, ≥ 150 mg/dL and HDL-C, < 50 mg/dL) were significantly inversely associated with dietary iodine and seaweed consumption, but there was no clear association for waist circumference (≥ 85 cm). CONCLUSION: Dietary iodine and seaweed consumption may be inversely associated with MetS incidence and its individual abnormalities in postmenopausal women.
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Yodo , Síndrome Metabólico , Algas Marinas , Estudios de Cohortes , Femenino , Humanos , Incidencia , Síndrome Metabólico/epidemiología , Posmenopausia , Estudios Prospectivos , República de Corea , Factores de Riesgo , Población RuralRESUMEN
Mouse embryonic stem cells (mESCs) are pluripotent cells that possess the ability to self-renew and differentiate into three germ layers. Owing to these characteristics, mESCs act as important models for stem cell research and are being used in many clinical applications. Among the many cathepsins, cathepsin A (Ctsa), a serine protease, affects the function and properties of stem cells. However, studies on the role of Ctsa in stem cells are limited. Here, we observed a significant increase in Ctsa expression during mESC differentiation at protein levels. Furthermore, we established Ctsa knockdown mESCs. Ctsa knockdown led to Erk1/2 phosphorylation, which in turn inhibited the pluripotency of mESCs and induced G2/M cell cycle arrest to inhibit mESC proliferation. The knockdown also induced abnormal differentiation in mESCs and aberrant expression of differentiation markers. Furthermore, we identified inhibition of teratoma formation in nude mice. Our results suggested that Ctsa affects mESC pluripotency, proliferation, cell cycle and differentiation, and highlighted the potential of Ctsa to act as a core factor that can regulate various mESC properties. SIGNIFICANCE OF THE STUDY: Our results indicate that cathepsin A (Ctsa) affects the properties of mESCs. Inhibition of Ctsa resulted in a decrease in the pluripotency of mouse embryonic stem cells (mESCs). Further, Ctsa suppression resulted in decreased proliferation via cell cycle arrest. Moreover, Ctsa inhibition reduced differentiation abilities and formation of teratoma in mESCs. Our results demonstrated that Ctsa is an important factor controlling mESC abilities.
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Catepsina A/metabolismo , Diferenciación Celular , Proliferación Celular , Sistema de Señalización de MAP Quinasas , Células Madre Embrionarias de Ratones/enzimología , Animales , Catepsina A/genética , Línea Celular , Puntos de Control de la Fase G2 del Ciclo Celular/genética , Técnicas de Silenciamiento del Gen , Puntos de Control de la Fase M del Ciclo Celular/genética , Ratones , Células Madre Embrionarias de Ratones/citologíaRESUMEN
Senescence marker protein 30 (SMP30) is a cell survival factor playing an important role in vitamin C synthesis and antiapoptosis. Moreover, its cytoprotective role suggests a possibility to be related to cancer cell survival. Mammary carcinoma is a common cancer in both humans and animals. Because of its histopathological diversity, especially in the early stage, histopathological diagnosis may be complicated; therefore, a diagnostic marker is helpful for confirmation. The present study analyzed the expression pattern of SMP30 in mammary carcinoma in humans, dogs, and cats. Immunohistochemistry, immunofluorescence, and western blot analysis were used to investigate SMP30 expression patterns. The expression was specifically observed in neoplastic glandular epithelial cells. The expression increased with the malignancy of glandular epithelial cells with a highly proliferative status. However, SMP30 expression was low in normal mammary gland tissues or well-differentiated adenoma tissues. The patterns were consistently reproduced in canine primary mammary carcinoma cells and MCF-7 and MDA-MB-231 human carcinoma cell lines. This study provides useful information to understand SMP30 expression in various stages of mammary carcinoma and to suggest its utility as a pan-species diagnostic marker, thereby helping to establish strategies for diagnosing mammary carcinoma in several species.
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Neoplasias de la Mama/patología , Proteínas de Unión al Calcio/análisis , Enfermedades de los Gatos/patología , Enfermedades de los Perros/patología , Péptidos y Proteínas de Señalización Intracelular/análisis , Neoplasias Mamarias Animales/patología , Animales , Biomarcadores de Tumor/análisis , Mama/patología , Neoplasias de la Mama/diagnóstico , Enfermedades de los Gatos/diagnóstico , Gatos , Línea Celular Tumoral , Enfermedades de los Perros/diagnóstico , Perros , Femenino , Humanos , Células MCF-7 , Neoplasias Mamarias Animales/diagnóstico , PronósticoRESUMEN
Mouse embryonic stem cells (mESCs) exhibit self-renewal and pluripotency, can differentiate into all three germ layers, and serve as an essential model in stem cell research and for potential clinical application in regenerative medicine. Melanoma-associated antigen A2 (MAGEA2) is not expressed in normal somatic cells but rather in different types of cancer, especially in undifferentiated cells, such as in the testis, differentiating cells, and ESCs. However, the role of MAGEA2 in mESCs remains to be clarified. Accordingly, in this study, we examined the expression and functions of MAGEA2 in mESCs. MAGEA2 messenger RNA (mRNA) expression was decreased during mESCs differentiation. MAGEA2 function was then evaluated in knockdown mESC. MAGEA2 knockdown resulted in decreased pluripotency marker gene expression in mESCs consequent to increased Erk1/2 phosphorylation. Decreased MAGEA2 expression inhibited mESC proliferation via S phase cell cycle arrest with a subsequent decrease in cell cycle-associated genes Cdk1, Cdk2, Cyclin A1, Cyclin D1, and Cdc25a. Apoptotic mESCs markedly increased along with cleaved forms of caspases 3, 6, and 7 and PARP expression, confirming caspase-dependent apoptosis. MAGEA2 knockdown significantly decreased embryoid body size in vitro when cells were differentiated naturally and teratoma size in vivo, concomitant with decreased ectoderm marker gene expression. These findings suggested that MAGEA2 regulates ESC pluripotency, proliferation, cell cycle, apoptosis, and differentiation. The enhanced understanding of the regulatory mechanisms underlying diverse mESC characteristics will facilitate the clinical application of mESCs.
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Apoptosis , Diferenciación Celular , Proliferación Celular , Antígenos Específicos del Melanoma/metabolismo , Células Madre Embrionarias de Ratones/citología , Células Madre Pluripotentes/citología , Teratoma/patología , Animales , Ciclo Celular , Células Cultivadas , Humanos , Masculino , Antígenos Específicos del Melanoma/genética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células Madre Embrionarias de Ratones/metabolismo , Células Madre Pluripotentes/metabolismo , Teratoma/metabolismoRESUMEN
Prostate cancer has the highest incidence among men in advanced countries, as well as a high mortality rate. Despite the efforts of numerous researchers to identify a gene-based therapeutic target as an effective treatment of prostate cancer, there is still a need for further research. The cathepsin gene family is known to have a close correlation with various cancer types and is highly expressed across these cancer types. This study aimed at investigating the correlation between the cathepsin A (CTSA) gene and prostate cancer. Our findings indicated a significantly elevated level of CTSA gene expression in the tissues of patients with prostate cancer when compared with normal prostate tissues. Furthermore, the knockdown of the CTSA gene in the representative prostate cancer cell lines PC3 and DU145 led to reduced proliferation and a marked reduction in anchorage-independent colony formation, which was shown to be caused by cell cycle arrest in the S phase. In addition, CTSA gene-knockdown prostate cancer cell lines showed a substantial decrease in migration and invasion, as well as a decrease in the marker genes that promote epithelial mesenchymal transition (EMT). Such phenotypic changes in prostate cancer cell lines through CTSA gene suppression were found to be mainly caused by reduced p38 MAPK protein phosphorylation; i.e. the inactivation of the p38 MAPK cell signaling pathway. Tumorigenesis was also found to be inhibited in CTSA gene-knockdown prostate cancer cell lines when a xenograft assay was carried out using Balb/c nude mice, and the p38 MAPK phosphorylation was inhibited in tumor tissues. Thus, the CTSA gene is presumed to play a key role in human prostate cancer tissues through high-level expression, and the suppression of the CTSA gene leads to the inhibition of prostate cancer cell proliferation, colony formation, and metastasis. The mechanism, by which these effects occur, was demonstrated to be the inactivation of the p38 MAPK signaling pathway.
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Catepsina A/metabolismo , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Neoplasias de la Próstata/metabolismo , Transducción de Señal/fisiología , Animales , Secuencia de Bases , Catepsina A/genética , Línea Celular Tumoral , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Ratones Endogámicos BALB C , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/fisiopatología , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Pre-mRNA processing factor 4 (PRPF4), a core protein in U4/U6 snRNP, maintains snRNP structures by interacting with PRPF3 and cyclophilin H. Expression of the PRPF4 gene affects cell survival as well as apoptosis and is responsible for retinitis pigmentosa (RP). Proteomics analysis shows that PRPF4 may be a therapeutic target in human cancers. Nevertheless, the exact function and role of the PRPF4 gene are unclear. In this study, we assessed the expression of PRPF4 gene in human breast cancer cells. First, we confirmed that the PRPF4 gene was overexpressed in various breast cancer cell lines. Next, using breast cancer cell lines MCF7 and MDA-MB-468, we established stable cell lines with PRPF4 gene knockdown. We also performed microarray analysis to investigate molecular mechanisms underlying PRPF4 activity. All cell lines with PRPF4 gene knockdown exhibited reduced cell proliferation, remarkable reduction in anchorage-independent colony formation capacity, and reduction of PCNA protein, which is a marker cell of proliferation. Reduced expression of the PRPF4 gene induced apoptosis and changes in the expression of associated apoptotic markers in breast cancer cell lines. Knockdown of the PRPF4 gene reduced cellular capacity for migration and invasion (the key hallmarks of human cancers) and decreased the expression of genes involved in epithelial-mesenchymal transition (EMT). Microarray results showed that the expression of PPIP5K1, PPIPK2, and YWHAE genes was reduced at the transcriptional level, leading to reduced phosphorylation of p38 MAPK. These findings suggest that knockdown of PRPF4 gene slows down breast cancer progression via suppression of p38 MAPK phosphorylation. In conclusion, the PRPF4 gene plays an important role in the growth of breast cancer cells and is therefore a potential therapeutic target.
Asunto(s)
Neoplasias de la Mama/metabolismo , Ribonucleoproteína Nuclear Pequeña U4-U6/genética , Ribonucleoproteína Nuclear Pequeña U4-U6/metabolismo , Regulación hacia Arriba , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Apoptosis , Neoplasias de la Mama/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Sistema de Señalización de MAP Quinasas , Células MCF-7 , FosforilaciónRESUMEN
Mouse embryonic stem cells (mESCs) are characterized by their self-renewal and pluripotency and are capable of differentiating into all three germ layers. For this reason, mESCs are considered a very important model for stem cell research and clinical applications in regenerative medicine. The pre-mRNA processing factor 4 (PRPF4) gene is known to have a major effect on pre-mRNA splicing and is also known to affect tissue differentiation during development. In this study, we investigated the effects of PRPF4 knockdown on mESCs. First, we allowed mESCs to differentiate naturally and observed a significant decrease in PRPF4 expression during the differentiation process. We then artificially induced the knockdown of PRPF4 in mESCs and observed the changes in the phenotype. When PRPF4 was knocked down, various genes involved in mESC pluripotency showed significantly decreased expression. In addition, mESC proliferation increased abnormally, accompanied by a significant increase in mESC colony size. The formation of mESC embryoid bodies and teratomas was delayed following PRPF4 knockdown. Based on these results, the reduced expression of PRPF4 affects mESC phenotypes and is a key factor in mESC. SIGNIFICANCE OF THE STUDY: Our results indicate that PRPF4 affects the properties of mESCs. Suppression of PRPF4 resulted in a decrease in pluripotency of mESC and promoted proliferation. In addition, suppression of PRPF4 also resulted in decreased apoptosis. Moreover, the inhibition of PRPF4 reduced the ability to differentiate and formation of teratoma in mESC. Our results demonstrated that PRPF4 is a key factor of controlling mESC abilities.
Asunto(s)
Diferenciación Celular , Proliferación Celular , Ribonucleoproteína Nuclear Pequeña U4-U6/metabolismo , Animales , Células Cultivadas , Ratones , Células Madre Embrionarias de Ratones/citología , Células Madre Embrionarias de Ratones/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Ribonucleoproteína Nuclear Pequeña U4-U6/antagonistas & inhibidores , Ribonucleoproteína Nuclear Pequeña U4-U6/genética , Teratoma/genética , Teratoma/patologíaRESUMEN
BACKGROUND: A majority of patients with heart failure (HF) experience HF symptoms. Some literature suggests sex differences in the status of and also factors associated with HF symptoms. However, information on common HF symptom status and factors associated with HF symptoms in male and female patients is scarce. OBJECTIVES: The aim of this study was to examine HF symptom status and factors associated with HF symptoms in male and female patients with HF. METHODS: Descriptive data on HF symptoms, psychological factors (depressive symptoms and perceived control), sociodemographic factors (age and sex), clinical factors (body mass index, comorbidities, medication, and left ventricular ejection fraction), and a behavioral factor (self-care) were collected in 70 male and 49 female patients with HF. Mann-Whitney U tests, χ tests, and stepwise regression models were used to address the objectives. RESULTS: Fatigue was the most common HF symptom in both sexes, but male patients had less severe HF symptoms, including frequency, severity, and/or distress. In male patients, 2 psychological and 2 clinical factors (comorbidities and use of diuretics) were significantly associated with HF symptoms (adjusted R = 0.669, P < .001), whereas in female patients, only depressive symptoms were significantly associated with HF symptoms (adjusted R = 0.679, P < .001). DISCUSSION: There were sex differences in HF symptoms and the factors associated with HF symptoms. Clinicians and researchers need to recognize and manage psychological factors in both sexes and clinical factors in male patients by using effective interventions to improve HF symptoms.