RESUMEN
OBJECTIVES: The effect of breastfeeding on periodontal disease in women remains unclear. This cross-sectional study used data from the Korean National Health and Nutrition Examination Survey to explore the association between breastfeeding and periodontitis in Korean women using data from the Korean National Health and Nutrition Examination Survey (KNHANES VII). MATERIALS AND METHODS: Cross-sectional data was analyzed from the KNHANES 2016-2018. The study population included 5,587 parous women aged ≥ 30 years. The outcome variable was the presence or absence of periodontitis. The explanatory variable, period of breastfeeding, was defined as "none", "1-11 months", and "more than 12 months". Confounder variables (socio-educational, personal healthcare practice, and systemic medical characteristics) were adjusted for in the logistic regression analysis. RESULTS: Approximately 60% of the participants breastfed for ≥ 12 months. In all statistical models, the prevalence of periodontitis was approximately 60% greater in women that did not breastfeed compared to women that had breastfed for 12 months or longer. When adjusted for age, statistical significance was only present in the 50-59 years age group (adjusted odds ratio [aOR], 1.678; 95% confidence interval [CIs], 1.046-2.691). CONCLUSION: Our study shows that women that breastfed for a relatively long duration had a lower risk of periodontitis. Therefore, breastfeeding may be beneficial for women's periodontal health. These results are expected to be helpful in oral health education for pregnant women.
Asunto(s)
Lactancia Materna , Periodontitis , Embarazo , Humanos , Femenino , Persona de Mediana Edad , Masculino , Estudios Transversales , Encuestas Nutricionales , Periodontitis/epidemiología , República de Corea/epidemiologíaRESUMEN
Inducing strong metal-support interaction (SMSI) has been a useful way to control the structure of surface active sites. The SMSI often causes the encapsulation of metal particles with an oxide layer. Herein, an amorphous ceria shell was formed on Cu nanoparticles under a mild gas condition with high activity and durability for surface reaction. Cu-Ce solid solution promoted the transfer of surface oxygen species, which induced the ceria shell formation on Cu nanoparticles. This catalyst was used for CO2 hydrogenation, selectively producing CO with high low-temperature activity and good durability for operation at high temperature. CO2 activation and H2 spillover could occur at low temperatures, enhancing the activity. The shell prevented the sintering, assuring durability. This catalyst was applied to a bench-scale reactor without loss in performance, resulting in high CO productivity in all temperature ranges.
RESUMEN
PURPOSE: This study evaluates the oncogenic role of PIBF1 in triple-negative breast cancer (TNBC). TNBC is considered to have a poorer prognosis than other types of breast cancer and is associated with high risk of recurrence and distant metastasis. Currently, there are no effective therapies for the TNBC patients with distant metastasis due to the lack of targeted therapeutic options. METHODS: The effects of PIBF1 knockdown on the cell viability and motility of TNBC cell lines were investigated. Effects of PIBF1 overexpression on tumorigenicity and cell motility were confirmed using Ba/F3 cell line and xenograft study on BALB/c nude mice. RESULTS: In TNBC cell lines that highly express PIBF1, knockdown of PIBF1 induces apoptosis and suppresses cell viability and motility with activation of the ATR/CHK1 signaling pathway. Moreover, the oncogenic function of PIBF1 was confirmed using the Ba/F3 cell line. CONCLUSION: For the first time, these findings clarify the role of PIBF1 in regulating ATR/CHK1 signaling pathway and inhibiting the proliferation and migration of TNBC cell lines. These results demonstrate the oncogenic roles of PIBF1 and provide new insights into the function and the molecular mechanism of PIBF1 in malignant TNBC.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Proteínas Gestacionales/metabolismo , Factores Supresores Inmunológicos/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Animales , Apoptosis/fisiología , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Femenino , Técnicas de Silenciamiento del Gen , Xenoinjertos , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas Gestacionales/biosíntesis , Proteínas Gestacionales/genética , Transducción de Señal , Factores Supresores Inmunológicos/biosíntesis , Factores Supresores Inmunológicos/genética , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Células Tumorales CultivadasRESUMEN
Ginkgolic acid C 17:1 (GAC 17:1) extracted from Ginkgo biloba leaves, has been previously reported to exhibit diverse antitumor effect(s) through modulation of several molecular targets in tumor cells, however the detailed mechanism(s) of its actions still remains to be elucidated. Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor that regulates various critical functions involved in progression of diverse hematological malignancies, including multiple myeloma, therefore attenuating STAT3 activation may have a potential in cancer therapy. We determined the anti-tumor mechanism of GAC 17:1 with respect to its effect on STAT3 signaling pathway in multiple myeloma cell lines. We found that GAC 17:1 can inhibit constitutive activation of STAT3 through the abrogation of upstream JAK2, Src but not of JAK1 kinases in U266 cells and also found that GAC can suppress IL-6-induced STAT3 phosphorylation in MM.1S cells. Treatment of protein tyrosine phosphatase (PTP) inhibitor blocked suppression of STAT3 phosphorylation by GAC 17:1, thereby indicating a critical role for a PTP. We also demonstrate that GAC 17:1 can induce the substantial expression of PTEN and SHP-1 at both protein and mRNA level. Further, deletion of PTEN and SHP-1 genes by siRNA can repress the induction of PTEN and SHP-1, as well as abolished the inhibitory effect of drug on STAT3 phosphorylation. GAC 17:1 down-regulated the expression of STAT3 regulated gene products and induced apoptosis of tumor cells. Overall, GAC 17:1 was found to abrogate STAT3 signaling pathway and thus exert its anticancer effects against multiple myeloma cells.
Asunto(s)
Ginkgo biloba/química , Fosfohidrolasa PTEN/metabolismo , Extractos Vegetales/farmacología , Hojas de la Planta/química , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , Factor de Transcripción STAT3/agonistas , Salicilatos/farmacología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Interleucina-6/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Fosforilación/efectos de los fármacos , Extractos Vegetales/química , Unión Proteica , Salicilatos/químicaRESUMEN
This study was conducted to evaluate the effects of foam dressing with human recombinant human epidermal growth factor (rhEGF) on the healing process in head and neck cancer patients who experience radiation-induced dermatitis (RID). Seven patients, including three with oropharyngeal, two with nasopharyngeal and one each with hypopharyngeal and laryngeal carcinoma, who underwent radiotherapy (RT) for head and neck cancer at the Asan Medical Center from March to December 2008 were prospectively included in this study. Patients who showed severe RID (more than wet desquamation) on the supraclavicular fossa or neck areas were treated by wound cleaning and debridement of granulation tissue, followed by daily rhEGF spray and foam dressing. Median time to stop exudates and reepithelialisation was 4 days. Within 14 days (median 8 days), all patients showed complete healing of RID and no longer required dressings. This new method of treatment with dressing containing rhEGF may have the potential to accelerate the healing process in patients with RID. A case-control study is needed to confirm this finding.
Asunto(s)
Radiodermatitis , Vendajes , Estudios de Casos y Controles , Factor de Crecimiento Epidérmico , Neoplasias de Cabeza y Cuello , HumanosRESUMEN
OBJECTIVES: The aim of this study was to estimate the association between household income and dental flossing. METHODS: This cross-sectional study investigated the impact of household income on flossing among 9,391 adults aged 30+ with ≥20 natural teeth, utilizing data from the seventh Korea National Health and Nutrition Examination Survey (2016-2018). Outcome measures included flossing (yes/no), with income categorized into 4 levels: lowest, medium to low, medium to high, and highest. Logistic regression, adjusted for age, gender, brushing frequency, recent dental exams, periodontitis, smoking, and alcohol use, was employed to evaluate the influence of socioeconomic status on oral hygiene practices. RESULTS: In the highest income group, flossing was 62.6% more prevalent than in the lowest income group (adjusted odds ratio [aOR], 1.63; 95% CI, 1.27 to 2.08). The strongest association between income levels and flossing was observed in individuals aged ≥70 years (aOR, 3.64; 95% CI, 1.86 to 7.11), with a decreasing strength of association in the 60s (aOR, 1.72; 95% CI, 1.05 to 2.84) and 50s age groups (aOR, 1.69; 95% CI, 1.07 to 2.68). Higher-income women demonstrated a higher frequency of flossing than their lower-income counterparts (aOR, 1.67; 95% CI, 1.24 to 2.23). Higher-income individuals without periodontitis were more likely to floss (aOR, 1.64; 95% CI, 1.23 to 2.18), and among those with periodontitis, flossing was significantly associated only with the highest income category (aOR, 1.64; 95% CI, 1.10 to 2.44). CONCLUSIONS: The findings of this study indicate a significant correlation between higher household income levels and an increased prevalence of flossing.
Asunto(s)
Dispositivos para el Autocuidado Bucal , Renta , Encuestas Nutricionales , Humanos , República de Corea/epidemiología , Femenino , Masculino , Dispositivos para el Autocuidado Bucal/estadística & datos numéricos , Estudios Transversales , Renta/estadística & datos numéricos , Persona de Mediana Edad , Adulto , Anciano , Higiene Bucal/estadística & datos numéricosRESUMEN
Introduction: Humanized mouse models to recapitulate human biological systems still have limitations, such as the onset of lethal graft-versus-host disease (GvHD), a variable success rate, and the low accessibility of total body irradiation (TBI). Recently, mice modified with the CD47-SIRPA axis have been studied to improve humanized mouse models. However, such trials have been rarely applied in NOD mice. In this study, we created a novel mouse strain, NOD-CD47nullRag2nullIL-2rγnull (RTKO) mice, and applied it to generate humanized mice. Methods: Four-week-old female NOD-Rag2nullIL-2rγnull (RID) and RTKO mice pre-conditioned with TBI or busulfan (BSF) injection were used for generating human CD34+ hematopoietic stem cell (HSC) engrafted humanized mice. Clinical signs were observed twice a week, and body weight was measured once a week. Flow cytometry for human leukocyte antigens was performed at intervals of four weeks or two weeks, and mice were sacrificed at 48 weeks after HSC injection. Results: For a long period from 16 to 40 weeks post transplantation, the percentage of hCD45 was mostly maintained above 25% in all groups, and it was sustained the longest and highest in the RTKO BSF group. Reconstruction of human leukocytes, including hCD3, was also most prominent in the RTKO BSF group. Only two mice died before 40 weeks post transplantation in all groups, and there were no life-threatening GvHD lesions except in the dead mice. The occurrence of GvHD has been identified as mainly due to human T cells infiltrating tissues and their related cytokines. Discussion: Humanized mouse models under all conditions applied in this study are considered suitable models for long-term experiments based on the improvement of human leukocytes reconstruction and the stable animal health. Especially, RTKO mice pretreated with BSF are expected to be a valuable platform not only for generating humanized mice but also for various immune research fields.
Asunto(s)
Busulfano , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas , Ratones Endogámicos NOD , Ratones Noqueados , Acondicionamiento Pretrasplante , Animales , Busulfano/farmacología , Humanos , Ratones , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Células Madre Hematopoyéticas/metabolismo , Femenino , Subunidad gamma Común de Receptores de Interleucina/genética , Subunidad gamma Común de Receptores de Interleucina/deficiencia , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/inmunología , Modelos Animales de Enfermedad , Irradiación Corporal TotalRESUMEN
OBJECTIVES: Numerous studies have investigated the efficacy of whole grains; however, research on multigrain remains limited. Grains exhibit combined positive effects against various diseases. The purpose of this study was to examine the impact of multigrain and white rice consumption on periodontitis. METHODS: We analyzed data from the Korea National Health and Nutrition Examination Survey V-3 and VI, collected between 2012 and 2015, which included 12,450 patients (4,859 male and 7,591 female) aged 19-64 years. The World Health Organization's Community Periodontal Index (CPI) was utilized to assess the presence of periodontitis, with periodontitis defined as a CPI index score of ≥3. Multivariable logistic regression analysis was performed after adjusting for potential confounding variables. RESULTS: The group that consumed only multigrain rice was less likely to have periodontitis than the group that consumed only white rice (odds ratio [OR], 0.80; 95% confidence interval [CI], 0.69 to 0.93). When stratified by sex, the risk of periodontitis demonstrated a 24% decrease in female who consumed only multigrain rice (OR, 0.76; 95% CI, 0.62 to 0.93). A similar result was observed in the age group of 40-64 years (OR, 0.84; 95% CI, 0.71 to 0.99). In the diabetes stratification model, the normal group that consumed only multigrain rice exhibited a 25% decrease in the odds of periodontitis (OR, 0.75; 95% CI, 0.62 to 0.91). CONCLUSIONS: Our findings suggest that the prevalence of periodontitis may vary depending on the type of rice consumed.
Asunto(s)
Oryza , Periodontitis , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Encuestas Nutricionales , Periodontitis/epidemiología , Prevalencia , República de Corea/epidemiologíaRESUMEN
BACKGROUND: We aimed to compare the clinical outcomes of patients with positive Xpert Carba-R assay results for carbapenemase-producing Enterobacterales (CPE) according to CPE culture positivity. METHODS: We retrospectively collected data for patients with positive CPE (positive Xpert Carba-R or culture) who underwent both tests from August 2018 to March 2021 in a 2700-bed tertiary referral hospital in Seoul, South Korea. We compared the clinical outcomes of patients positive for Xpert Carba-R according to whether they were positive (XPCP) or negative (XPCN) for CPE culture. RESULTS: Of 322 patients with CPE who underwent both Xpert Carba-R and culture, 313 (97%) were positive for Xpert Carba-R for CPE. Of these, 87 (28%) were XPCN, and 226 (72%) were XPCP. XPCN patients were less likely to have a history of previous antibiotic use (75.9% vs 90.3%; Pâ =â .001) and to have Klebsiella pneumoniae carbapenemase (21.8% vs 48.9%; Pâ <â .001). None of the XPCN patients developed infection from colonization within 6 months, whereas 13.4% (29/216) of the XPCP patients did (Pâ <â .001). XPCN patients had lower transmission rates than XPCP patients (3.0% [9/305] vs 6.3% [37/592]; Pâ =â .03). There was no significant difference in CPE clearance from positive culture results between XPCN and XPCP patients (40.0% [8/20] vs 26.7% [55/206]; Pâ =â .21). CONCLUSIONS: Our study suggests that XPCN patients had lower rates of both infection and transmission than XPCP patients. The Xpert Carba-R assay is clinically useful not only for rapid identification of CPE but also for predicting risks of infection and transmission when performed along with culture.
RESUMEN
Mucus secretion is an important protective mechanism for the luminal lining of open tubular organs, but mucin overproduction in the respiratory tract can exacerbate the inflammatory process and cause airway obstruction. Production of MUC5AC, a predominant gel-forming mucin secreted by airway epithelia, can be induced by various inflammatory mediators such as prostaglandins. The two major prostaglandins involved in inflammation are PGE(2) and PGF(2alpha). PGE(2)-induced mucin production has been well studied, but the effect of PGF(2alpha) on mucin production remains poorly understood. To elucidate the effect and underlying mechanism of PGF(2alpha) on MUC5AC production, we investigated the signal transduction of PGF(2alpha) associated with this effect using normal human tracheobronchial epithelial cells. Our results demonstrated that PGF(2alpha) induces MUC5AC overproduction via a signaling cascade involving protein kinase C, ERK, p90 ribosomal S6 protein kinase, and CREB. The regulation of PGF(2alpha)-induced MUC5AC expression by CREB was further confirmed by cAMP response element-dependent MUC5AC promoter activity and by interaction between CREB and MUC5AC promoter. The abrogation of all downstream signaling activities via suppression of each signaling molecule along the pathway indicates that a single pathway from PGF(2alpha) receptor to CREB is responsible for inducing MUC5AC overproduction. As CREB also mediates mucin overproduction induced by PGE(2) and other inflammatory mediators, our findings have important clinical implications for the management of airway mucus hypersecretion.
Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Dinoprost/metabolismo , Células Epiteliales/metabolismo , Mucina 5AC/biosíntesis , Mucosa Respiratoria/metabolismo , Transducción de Señal/fisiología , Western Blotting , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/inmunología , Dinoprost/inmunología , Células Epiteliales/inmunología , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Mucina 5AC/inmunología , Análisis de Secuencia por Matrices de Oligonucleótidos , Interferencia de ARN , Mucosa Respiratoria/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , TransfecciónRESUMEN
Vitamin A and its metabolite retinoic acid (RA) are essential elements for normal lung development and the differentiation of lung epithelial cells. We previously showed that RA rapidly activated cyclic AMP response element-binding protein (CREB) in a nonclassical manner in normal human tracheobronchial epithelial (NHTBE) cells. In the present study, we further demonstrated that this nonclassical signaling of RA on the activation of CREB plays a critical role in regulating the expression of airway epithelial cell differentiation markers, the MUC2, MUC5AC, and MUC5B genes. We found that RA rapidly activates the protein kinase Calpha isozyme and transmits the activation signal to CREB via the Raf/MEK/extracellular signal-regulated kinase/p90 ribosomal S6 kinase (RSK) pathway. Activated RSK translocated from the cytoplasm to the nucleus, where it phosphorylates CREB. Activated CREB then binds to a cis-acting replication element motif on the promoter (at nucleotides [nt] -878 to -871) of the MUC5AC gene. The depletion of CREB using small interfering RNA abolished not only the RA-induced MUC5AC but also RA-induced MUC2 and MUC5B. Taken together, our findings demonstrate that CREB activation via this nonclassical RA signaling pathway may play an important role in regulating the expression of mucin genes and mediating the early biological effects of RA during normal mucous differentiation in NHTBE cells.
Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Regulación de la Expresión Génica , Mucinas , Transducción de Señal/fisiología , Tretinoina/metabolismo , Células Cultivadas , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Activación Enzimática , Células Epiteliales/citología , Células Epiteliales/fisiología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Isoenzimas/metabolismo , Quinasas Quinasa Quinasa PAM/metabolismo , Mucina 5AC , Mucina 2 , Mucina 5B , Mucinas/genética , Mucinas/metabolismo , Proteína Quinasa C-alfa/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Receptores de Ácido Retinoico/metabolismo , Mucosa Respiratoria/citología , Receptores X Retinoide/metabolismo , Proteínas Quinasas S6 Ribosómicas/metabolismo , Quinasas raf/metabolismoRESUMEN
Background: Invasive aspergillosis (IA) is an opportunistic fungal infection that mostly occurs in immunocompromised patients, such as those having hematologic malignancy or receiving hematopoietic stem cell transplantation. Inhalation of Aspergillus spores is the main transmission route of IA in immunocompromised patients. Construction work in hospitals is a risk factor for environmental fungal contamination. We measured airborne fungal contamination and the incidence of IA among immunocompromised patients, and evaluated their correlation with different types of construction works. Methods: Our tertiary hospital in Seoul, Korea underwent facility construction from September 2017 to February 2018. We divided the entire construction period into period 1 (heavier works: demolition and excavation) and period 2 (lighter works: framing, interior designing, plumbing, and finishing). We conducted monthly air sampling for environmental spore surveillance in three hematologic wards. We evaluated the incidence of IA among all immunocompromised patients hospitalized in the three hematologic wards (2 adult wards and 1 pediatric ward) during this period. IA was categorized into proven, probable, and possible aspergillosis based on the revised European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) criteria. Results: A total of 15 patients was diagnosed with proven (1 case), probable (8 cases), or possible (6 cases) hospital-acquired IA during period 1. In period 2, 14 patients were diagnosed with either proven (1 case), probable (10 cases), or possible (3 cases) hospital-acquired IA. Total mold and Aspergillus spp. spore levels in the air tended to be higher in period 1 (p = 0.06 and 0.48, respectively). The incidence rate of all IA by the EORTC/MSG criteria was significantly higher in period 1 than in period 2 (1.891 vs. 0.930 per 1000 person-days, p = 0.05). Conclusions: Airborne fungal spore levels tended to be higher during the period with heavier construction works involving demolition and excavation, during which the incidence of IA was significantly higher as well. We recommend monitoring airborne fungal spore levels during construction periods in hospitals with immunocompromised patients. Subsequently, the effect of airborne fungal spore level monitoring in reducing hospital-acquired IA should be evaluated.
Asunto(s)
Microbiología del Aire , Aspergillus/aislamiento & purificación , Arquitectura y Construcción de Hospitales , Infecciones Fúngicas Invasoras/transmisión , Esporas Fúngicas/aislamiento & purificación , Adolescente , Adulto , Monitoreo del Ambiente , Femenino , Hematología , Unidades Hospitalarias/estadística & datos numéricos , Humanos , Infecciones Fúngicas Invasoras/epidemiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , República de Corea/epidemiología , Factores de Riesgo , Centros de Atención Terciaria/estadística & datos numéricos , Adulto JovenRESUMEN
In the event of a mass casualty radiation scenario, biodosimetry has the potential to quantify individual exposures for triaging and providing dose-appropriate medical intervention. Structural maintenance of chromosomes 1 (SMC1) is phosphorylated in response to ionizing radiation. The goal of this study was to develop a new biodosimetry method using SMC1 phosphorylation as a measure of exposure to radiation. In the initial experiments, two normal human cell lines (WI-38VA-13 and HaCaT) and four lymphoblastoid cell lines were irradiated, and the levels of SMC1 phosphorylation at Ser-360 and Ser-957 were assessed using Western blotting. Subsequently, similar experiments were performed using peripheral blood mononuclear cells (PBMCs) obtained from 20 healthy adults. Phosphorylation of SMC1 at Ser-957 and Ser-360 was increased by exposure in a dose-dependent manner, peaked at 1-3 h postirradiation and then decreased gradually. Ser-360 was identified as a new phosphorylation site and was more sensitive to radiation than Ser-957, especially at doses below 1 Gy. Our results demonstrate a robust ex vivo response of phospho-SMC1-(Ser-360) to ionizing radiation in human PBMCs. Detection of phosphorylation at Ser-360 in SMC1 could be used as a marker of radiation exposure. Our findings suggest that it is feasible to measure blood cell-based changes in the phosphorylation level of a protein as an ex vivo radiation exposure detection method, even after low-dose exposure.
Asunto(s)
Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromosómicas no Histona/química , Proteínas Cromosómicas no Histona/metabolismo , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/efectos de la radiación , Serina/metabolismo , Línea Celular , Cromatina/metabolismo , Relación Dosis-Respuesta en la Radiación , Humanos , Fosforilación/efectos de la radiación , Factores de TiempoRESUMEN
PURPOSE: To determine whether systemically administered recombinant human epidermal growth factor (rhEGF) accelerates the recovery of mouse small intestinal mucosa after irradiation. METHODS AND MATERIALS: A mouse mucosal damage model was established by administering radiation to male BALB/c mice with a single dose of 15 Gy applied to the abdomen. After irradiation, rhEGF was administered subcutaneously at various doses (0.04, 0.2, 1.0, and 5.0 mg/kg/day) eight times at 2- to 3-day intervals. The evaluation methods included histologic changes of small intestinal mucosa, change in body weight, frequency of diarrhea, and survival rate. RESULTS: The recovery of small intestinal mucosa after irradiation was significantly improved in the mice treated with a high dose of rhEGF. In the mice that underwent irradiation without rhEGF treatment, intestinal mucosal ulceration, mucosal layer damage, and severe inflammation occurred. The regeneration of villi was noticeable in mice treated with more than 0.2 mg/kg rhEGF, and the villi recovered fully in mice given more than 1 mg/kg rhEGF. The frequency of diarrhea persisting for more than 3 days was significantly greater in the radiation control group than in the rhEGF-treated groups. CONCLUSIONS: Systemic administration of rhEGF accelerates recovery from mucosal damage induced by irradiation. We suggest that rhEGF treatment shows promise for the reduction of small intestinal damage after irradiation.
Asunto(s)
Factor de Crecimiento Epidérmico/administración & dosificación , Enfermedades Intestinales/tratamiento farmacológico , Enfermedades Intestinales/fisiopatología , Mucosa Intestinal/fisiopatología , Traumatismos por Radiación/tratamiento farmacológico , Traumatismos por Radiación/fisiopatología , Recuperación de la Función/efectos de los fármacos , Animales , Proliferación Celular/efectos de los fármacos , Factor de Crecimiento Epidérmico/genética , Enfermedades Intestinales/etiología , Mucosa Intestinal/efectos de los fármacos , Intestino Delgado , Masculino , Ratones , Ratones Endogámicos C57BL , Traumatismos por Radiación/etiología , Protectores contra Radiación/administración & dosificación , Proteínas Recombinantes/administración & dosificación , Resultado del TratamientoRESUMEN
Epidermal growth factor (EGF) signaling promotes cell proliferation and survival in several types of cancer. Here, however, we showed that EGF inhibits proliferation and promotes programmed cell death in non-small cell lung cancer (NSCLC) cells. In A549 cells, EGF increased redox factor-1 (Ref-1) expression and the association of Ref-1 with zinc finger-containing transcriptional regulator (EGR1) via activation of p22phox, RAC1, and an NADPH oxidase subunit. EGF increased p22phox and RAC1 expression through activation of purinergic receptors (P2Y). Elevated Ref-1/EGR1 levels increased phosphatase and tensin homolog (PTEN) levels, leading to inhibition of the Akt pathway. EGF-induced PTEN upregulation increased apoptosis and autophagy-induced damage in A549 cells, whereas Ref-1 knockdown blocked EGF-induced PTEN upregulation in an NADPH oxidase p22phox subunit-independent manner. In addition, p22phox knockdown restored EGF-induced effects, implying that changes in P2Y activity caused by EGF, which activates NADPH oxidase via RAC1, influenced Ref-1-mediated redox regulation. Finally, EGF similarly attenuated cell proliferation and promoted autophagy and apoptosis in vivo in a xenograft model using A549 cells. These findings reveal that EGF-induced redox signaling is linked to Ref-1-induced death in NSCLC cells.
Asunto(s)
ADN-(Sitio Apurínico o Apirimidínico) Liasa/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Factor de Crecimiento Epidérmico/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Fosfohidrolasa PTEN/metabolismo , Regulación hacia Arriba , Células A549 , Animales , Apoptosis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , ADN-(Sitio Apurínico o Apirimidínico) Liasa/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Factor de Crecimiento Epidérmico/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ratones , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Fosfohidrolasa PTEN/genética , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
AIM: We investigated the therapeutic effects of a mitogen-activated protein (MEK) inhibitor, selumetinib, in a hepatic melanoma metastasis model and studied its possible mechanism of action. MATERIALS AND METHODS: Melanoma cell lines were exposed to selumetinib under different experimental conditions. We established a mouse model of liver metastasis and treated mice orally with vehicle or selumetinib and then evaluated metastasis progress. RESULTS: Growth inhibition was observed in melanoma cells as a consequence of G1-phase cell-cycle arrest and the subsequent induction of apoptosis in a dose- and time-dependent manner. Mice with established liver metastases that were treated with selumetinib exhibited significantly less tumor progression than vehicle-treated mice. c-Myc expression in metastasized liver tissues were suppressed by selumetinib. Moreover, oral treatment with selumetinib modulated expression of epithelial-to-mesenchymal transition- and metastasis-related genes, including integrin alpha-5 (ITGA5), jagged 1 (JAG1), zinc finger E-box-binding homeobox 1 (ZEB1), NOTCH, and serpin peptidase inhibitor clade E (SERPINE1). CONCLUSION: We established a mouse model of hepatic metastasis using a human melanoma cell line, such models are essential in elucidating the therapeutic effects of anti-metastatic drugs. Our data suggest the possibility that selumetinib presents a new strategy to treat liver metastasis in patients with melanoma by suppressing epithelial-to-mesenchymal transition-related genes.
Asunto(s)
Bencimidazoles/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Hepáticas/prevención & control , Melanoma/tratamiento farmacológico , Administración Oral , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Bencimidazoles/administración & dosificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Transición Epitelial-Mesenquimal/genética , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Puntos de Control de la Fase G1 del Ciclo Celular/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Immunoblotting , Integrina alfa5/genética , Integrina alfa5/metabolismo , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Masculino , Melanoma/genética , Melanoma/patología , Ratones Endogámicos BALB C , Ratones Desnudos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Radiation-induced fibrosis (RIF) is one of the most common late complications of radiation therapy. We found that α-lipoic acid (α-LA) effectively prevents RIF. In RIF a mouse model, leg contracture assay was used to test the in vivo efficacy of α-LA. α-LA suppressed the expression of pro-fibrotic genes after irradiation, both in vivo and in vitro, and inhibited the up-regulation of TGF-ß1-mediated p300/CBP activity. Thus, α-LA prevents radiation-induced fibrosis (RIF) by inhibiting the transcriptional activity of NF-κB through inhibition of histone acetyltransferase activity. α-LA is a new therapeutic methods that can be used in the prevention-treatment of RIF.
Asunto(s)
Fibrosis/prevención & control , Traumatismos por Radiación/prevención & control , Protectores contra Radiación/farmacología , Ácido Tióctico/farmacología , Animales , Antioxidantes/farmacología , Fibrosis/etiología , Ratones , Ratones Endogámicos BALB CRESUMEN
Furanosesterterpenes, isolated from a marine sponge Psammocinia sp. have been reported to display significant cytotoxicity to some cancer cell lines. In this study, EZZ, an inseparable 1:1 mixture of (8E,3Z,20Z)-strobilinin and (7E,3Z,20Z)-felixinin, showed significant antiproliferative effect on human cervix carcinoma cell line (HeLa). Cell cycle analysis revealed that EZZ could arrest HeLa cells in S phase with a concomitant decrease in the cell population of G1 phase. By using simian virus (SV40) DNA in vitro replication system, we found that EZZ could inhibit DNA replication, which suggests that EZZ-induced S phase arrest might be the direct result of blocked DNA synthesis. Furthermore, low concentration of EZZ was found to be capable of significantly inhibiting the DNA cleavage by topoisomerase I (topo I) and reducing the polymerase alpha-primase (pol alpha-primase) activity, while the ssDNA binding activity of replication protein A (RPA) was less affected. Taken together, these results suggest that EZZ-induced cell cycle arrest in S phase correlate with the inhibition of DNA replication, and topo I and pol alpha-primase might be the two main target molecules.
Asunto(s)
Antineoplásicos/farmacología , Ciclo Celular/efectos de los fármacos , Terpenos/química , Terpenos/farmacología , Animales , Catálisis , Proliferación Celular/efectos de los fármacos , Supervivencia Celular , ADN/metabolismo , ADN Primasa/metabolismo , ADN-Topoisomerasas de Tipo I/metabolismo , ADN de Cadena Simple/metabolismo , Relación Dosis-Respuesta a Droga , Citometría de Flujo , Células HeLa , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Poríferos , Unión Proteica , Proteína de Replicación A/metabolismo , Fase S , Virus 40 de los Simios/genéticaRESUMEN
Here we demonstrated that SKI2162, a small-molecule inhibitor of the TGF-ß type I receptor (ALK5), prevented radiation-induced fibrosis (RIF) in mice. SKI2162 inhibited phosphorylation of Smad and induction of RIF-related genes in vitro. In RIF a mouse model, SKI2162 reduced late skin reactions and leg-contracture without jeopardizing the acute skin reaction. Irradiation of mouse tissue increased COL1A2 mRNA levels, and topical administration of SKI2162 significantly inhibited this effect. Thus, these findings support that SKI2162 has potential value as novel RIF-protective agent, and could be candidate for clinical trials.
Asunto(s)
Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Traumatismos Experimentales por Radiación/prevención & control , Protectores contra Radiación/farmacología , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Fibrosis/etiología , Fibrosis/prevención & control , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Neoplasias/radioterapia , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Traumatismos Experimentales por Radiación/enzimología , Distribución Aleatoria , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína Smad2/metabolismo , Proteína smad3/metabolismoRESUMEN
Lung adenocarcinoma, the most common subtype of lung cancer, is the leading cause of cancer death worldwide. Despite attempts for the treatment of lung cancer which have been accumulating, promising new therapies are still needed. Here, we found that cyclic-AMP response element-binding protein (CREB)-CREB binding protein (CBP) transcription factors complex inhibitor, Naphthol AS-TR phosphate (NASTRp), is a potential therapeutic agent for lung cancer. We show that NASTRp inhibited oncogenic cell properties through cell cycle arrest with concomitant suppression of tumor-promoting autophagy with down-regulations of Atg5-12 and Atg7, and accumulation of p62 in human lung cancer cell lines. In addition, NASTRp induced expression of endoplasmic reticulum stress markers such as DDIT3/CHOP, and led to apoptosis along with Bim induction. These findings suggest that transcription factor/co-activator complex, CREB-CBP, can be a potential therapeutic target and its inhibition could be a novel therapeutic strategy for lung cancer.