RESUMEN
Chronic oral inflammation and biofilm-mediated infections drive diseases such as dental caries and periodontitis. This study investigated the anti-inflammatory and antibacterial potential of an ethanol extract from Astilbe chinensis inflorescence (GA-13-6) as a prominent candidate for natural complex substances (NCS) with therapeutic potential. In LPS-stimulated RAW 264.7 macrophages, GA-13-6 significantly suppressed proinflammatory mediators, including interleukin-6 (IL-6), tumor necrosis factor (TNF), and nitric oxide (NO), surpassing purified astilbin, a known bioactive compound found in A. chinensis. Furthermore, GA-13-6 downregulated the expression of cyclooxygenase-2 (COX2) and inducible nitric oxide synthase (iNOS), indicating an inhibitory effect on the inflammatory cascade. Remarkably, GA-13-6 exhibited selective antibacterial activity against Streptococcus mutans, Streptococcus sanguinis, and Porphyromonas gingivalis, key players in dental caries and periodontitis, respectively. These findings suggest that complex GA-13-6 holds the potential for the treatment or prevention of periodontal and dental diseases, as well as various other inflammation-related conditions, while averting the induction of antibiotic resistance.
Asunto(s)
Macrófagos , Extractos Vegetales , Animales , Ratones , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/química , Células RAW 264.7 , Antibacterianos/farmacología , Inflamación/tratamiento farmacológico , Etanol/química , Óxido Nítrico Sintasa de Tipo II/metabolismo , Antiinflamatorios/farmacología , Inflorescencia/química , Ciclooxigenasa 2/metabolismo , Ciclooxigenasa 2/genética , Óxido Nítrico/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
PURPOSE: Factor Xa Inhibitors have emerged as a first-line agent in the management of non-valvular atrial fibrillation (NVAF), but there is a need for additional data surrounding their use in the morbidly obese population. The purpose of this study was to evaluate whether Factor Xa Inhibitors are as safe and effective as warfarin for the treatment of NVAF in individuals with a BMI ≥ 40 kg/m2 and/or weight ≥ 120 kg. METHODS: This was a multi-center retrospective cohort study comparing the use of Factor Xa Inhibitors (apixaban and rivaroxaban) to warfarin for the management of NVAF in adult patients with a BMI ≥ 40 kg/m2 and/or weight ≥ 120 kg. The primary outcomes were stroke or systemic embolism and major bleeding within 12 months. RESULTS: A total of 3,156 patients were included in the final analysis; 1,396 in the warfarin group and 1760 in the Factor Xa Inhibitor group. The mean weight and BMI of the overall cohort was 134.1 kg and 44.7 kg/m2, respectively. There was no difference in stroke or systemic embolism (OR 1.21, 95% CI 0.78-1.85) or major bleeding (OR 0.99, 95% CI 0.65 - 1.53) with Factor Xa Inhibitors compared to warfarin after controlling for covariates. CONCLUSION: This analysis of real-world data suggests no difference in bleeding or thrombotic outcomes for severely obese patients with NVAF taking Factor Xa Inhibitors compared to warfarin. Overall, our study adds further data to support the use of Factor Xa Inhibitors as an alternative to warfarin in severely obese patients with NVAF.
Asunto(s)
Anticoagulantes , Fibrilación Atrial , Inhibidores del Factor Xa , Hemorragia , Obesidad Mórbida , Pirazoles , Rivaroxabán , Accidente Cerebrovascular , Warfarina , Humanos , Fibrilación Atrial/tratamiento farmacológico , Inhibidores del Factor Xa/uso terapéutico , Inhibidores del Factor Xa/efectos adversos , Masculino , Femenino , Warfarina/uso terapéutico , Obesidad Mórbida/complicaciones , Obesidad Mórbida/tratamiento farmacológico , Estudios Retrospectivos , Anciano , Anticoagulantes/uso terapéutico , Anticoagulantes/efectos adversos , Anticoagulantes/administración & dosificación , Persona de Mediana Edad , Accidente Cerebrovascular/prevención & control , Hemorragia/inducido químicamente , Rivaroxabán/uso terapéutico , Rivaroxabán/efectos adversos , Pirazoles/uso terapéutico , Piridonas/uso terapéutico , Piridonas/efectos adversos , Piridonas/administración & dosificación , Índice de Masa CorporalRESUMEN
We investigated the virulence gene expression of carbapenem-resistant Acinetobacter baumanii (CRAB) isolated from the respiratory samples of patients with CRAB pneumonia and those with CRAB colonization to identify the virulence genes contributing to CRAB pneumonia's development and mortality. Patients with CRAB identified from respiratory specimens were screened at a tertiary university hospital between January 2018 and January 2019. Patients were classified into CRAB pneumonia or CRAB colonization groups according to predefined clinical criteria. A. baumannii isolated from respiratory specimens was examined for the expression levels of ompA, uspA, hfq, hisF, feoA, and bfnL by quantitative reverse-transcription polymerase chain reaction. Among 156 patients with CRAB from respiratory specimens, 17 and 24 met the criteria for inclusion in the pneumonia and colonization groups, respectively. The expression level of ompA was significantly higher in the pneumonia group than in the colonization group (1.45 vs. 0.63, P=0.03). The expression levels of ompA (1.97 vs. 0.86, P=0.02), hisF (1.06 vs. 0.10, P < 0.01), uspA (1.62 vs. 1.01, P < 0.01), and bfnL (3.14 vs. 2.14, P=0.03) were significantly higher in patients with 30-day mortality than in the surviving patients. Elevated expression of hisF (adjusted odds ratio = 5.93, P=0.03) and uspA (adjusted odds ratio = 7.36, P=0.02) were associated with 30-day mortality after adjusting for age and the Charlson score. uspA and hisF may serve as putative targets for novel therapeutic strategies.
RESUMEN
Rapid response teams have been adopted to prevent unexpected in-ward cardiac arrest. However, there is no convincing evidence of optimal operation with rapid response team. Our aim was to address the impact of focused rapid response team on the safety of patients in wards. Comparison of focused with extended rapid response teams was performed in single center. The extended team operated on adult patients in whole ward (both medical and nonmedical ward) 24âhours per day, 7 days per week during 2012. In 2015, the operational time of the focused team was office hours from Monday to Friday and study population were limited to adult patients in the nonmedical ward. Unexpected in-ward cardiac arrests were compared between the extended team and focused team periods. During the focused team period, there was significant reduction in cardiac arrest per 1000 admissions in whole ward compared to the before the rapid response team period (1.09 vs 1.67, Pâ<â.001). Compared to that of the extended team period (1.42), there was also a significant reduction in cardiac arrest rate (Pâ=â.04). The cardiac arrest rate of nonmedical ward patients was also significantly decreased in the focused team period compared to that before the rapid response team period (0.43 vs 0.95, Pâ<â.001). Compared to the extended team period (0.64), there was a marginally significant reduction in cardiac arrest of nonmedical ward patients (Pâ=â.05). The focused rapid response team was associated with a reduced incidence of unexpected in-ward cardiac arrest. Further research on the optimal composition and operational time is needed.
Asunto(s)
Paro Cardíaco/prevención & control , Equipo Hospitalario de Respuesta Rápida/normas , Evaluación de Resultado en la Atención de Salud , Adulto , China , Femenino , Paro Cardíaco/mortalidad , Mortalidad Hospitalaria , Hospitalización , Humanos , Incidencia , Unidades de Cuidados Intensivos , Masculino , Habitaciones de Pacientes , Estudios Prospectivos , Mejoramiento de la CalidadRESUMEN
PURPOSE: Modulated electro-hyperthermia (mEHT) has been shown to be effective against various types of human tumours, including hepatocellular carcinoma (HCC). Here we aimed to investigate the molecular mechanism underlying the cytotoxic effects of mEHT to HCC cells. MATERIALS AND METHODS: Human liver cancer cell lines, Huh7 and HepG2, were treated with mEHT (42 °C/60 min) three times at 2-day intervals. Growth inhibition and apoptotic induction were evaluated using MTS, microscopic analysis, a clonogenic assay, annexin V/PI staining and a ccK18 ELISA. Global changes in gene expression were examined using RNA sequencing to obtain insights into molecular changes in response to mEHT. For in vivo evaluation of mEHT we used HepG2 HCC xenografts grown in nude mice. RESULTS: mEHT suppressed HCC cell proliferation and long-term colony formation through induction of apoptosis. The growth inhibitory effects are induced through a subset of molecular changes. Notably the expression level of septin 4 (SEPT4) (involved in pro-apoptotic activity and growth suppression) was up-regulated, whereas a key regulator of invasiveness G-Protein coupled receptor 64 (GPR64) was repressed. Subsequent Western blotting confirmed that the common increase in tumour suppressor SEPT4 in both Huh7 and HepG2 cells is accompanied by the restoration of cyclin-dependent kinase (CDK) inhibitor p21 and decrease in pro-caspase 7 and pro-caspase 3, thereby accelerating apoptotic signalling in HCC cells. Additionally, mEHT significantly inhibited the growth of human HCC xenografts in nude mice. CONCLUSIONS: These findings suggest that apoptotic cell death induced by mEHT is mediated by the up-regulation of tumour suppressor SEPT4 in human HCC cells.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/terapia , Hipertermia Inducida , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/terapia , Septinas/metabolismo , Animales , Apoptosis , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular , Humanos , Neoplasias Hepáticas/patología , Ratones Desnudos , Carga Tumoral , Regulación hacia ArribaRESUMEN
PURPOSE: Modulated electro-hyperthermia (mEHT), also known as oncothermia, shows remarkable treatment efficacies for various types of tumours, including glioma. The aim of the present study was to investigate the molecular mechanism underlying phenotypic changes in oncothermic cancer cells. MATERIALS AND METHODS: U87-MG and A172 human glioma cells were exposed to mEHT (42 °C/60 min) three times with a 2-day interval and subsequently tested for growth inhibition using MTS, FACS and microscopic analysis. To obtain insights into the molecular changes in response to mEHT, global changes in gene expression were examined using RNA sequencing. For in vivo evaluation of mEHT, we used U87-MG glioma xenografts grown in nude mice. RESULTS: mEHT inhibited glioma cell growth through the strong induction of apoptosis. The transcriptomic analysis of differential gene expression under mEHT showed that the anti-proliferative effects were induced through a subset of molecular alterations, including the up-regulation of E2F1 and CPSF2 and the down-regulation of ADAR and PSAT1. Subsequent Western blotting revealed that mEHT increased the levels of E2F1 and p53 and decreased the level of PARP-1, accelerating apoptotic signalling in glioma cells. mEHT significantly suppressed the growth of human glioma xenografts in nude mice. We also observed that mEHT dramatically reduced the portion of CD133(+) glioma stem cell population and suppressed cancer cell migration and sphere formation. CONCLUSIONS: These findings suggest that mEHT suppresses glioma cell proliferation and mobility through the induction of E2F1-mediated apoptosis and might be an effective treatment for eradicating brain tumours.
Asunto(s)
Apoptosis/fisiología , Neoplasias Encefálicas/terapia , Factor de Transcripción E2F1/fisiología , Terapia por Estimulación Eléctrica , Glioma/terapia , Hipertermia Inducida/métodos , Animales , Neoplasias Encefálicas/patología , Citometría de Flujo , Glioma/patología , Humanos , Ratones , Ratones DesnudosRESUMEN
BACKGROUND: Low survival rate of transplanted cells compromises the efficacy of cell therapy. Hexokinase II (HKII) is known to have anti-apoptotic activity through its interaction with mitochondria. The objective was to identify miRNAs targeting HKII and investigate whether miRNA-mediated modulation of HKII could improve the survival of mesenchymal stem cells (MSCs) exposed to H2O2. The expression of HKII in MSCs exposed to H2O2 was evaluated, and HKII-targeting miRNA was screened based on miRNA-target prediction databases. The effect of H2O2 on the expression of the selected HKII-targeting miRNA was examined and the effect of modulation of the selected HKII-targeting miRNA using anti-miRNA on H2O2-induced apoptosis of MSC was evaluated. RESULTS: H2O2 (600 µM) induced cell death of MSCs and decreased mitochondrial HKII expression. We have identified miR-181a as a HKII-targeting miRNA and H2O2 increased the expression of miR-181a in MSCs. Delivery of anti-miR-181a, which neutralizes endogenous miR-181a, significantly attenuated H2O2-induced decrease of HKII expression and disruption of mitochondrial membrane potential, improving the survival of MSCs exposed to H2O2. CONCLUSIONS: These findings suggest that H2O2-induced up-regulation of miR-181a contributes to the cell death of MSCs by down-regulating HKII. Neutralizing miR-181a can be an effective way to prime MSCs for transplantation into ischemic tissues.
Asunto(s)
Apoptosis , Glioma/patología , Hexoquinasa/metabolismo , Peróxido de Hidrógeno/toxicidad , Células Madre Mesenquimatosas/patología , MicroARNs/metabolismo , Diferenciación Celular , Movimiento Celular , Supervivencia Celular , Glioma/metabolismo , Humanos , Peróxido de Hidrógeno/administración & dosificación , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/enzimología , MicroARNs/antagonistas & inhibidores , Mitocondrias/enzimología , Invasividad Neoplásica , Especies Reactivas de Oxígeno , Reacción en Cadena en Tiempo Real de la Polimerasa , Semaforinas/genética , Semaforinas/metabolismoRESUMEN
Under distinct pathological heart conditions, the expression of a single miRNA can display completely opposite patterns. However, the mechanism underlying the bidirectional regulation of a single miRNA and the clinical implications of this regulation remain largely unknown. To address this issue, we examined the regulation of miR-1, one of the most abundant miRNAs in the heart, during cardiac hypertrophy and ischemia/reperfusion (I/R). Our data indicated that different magnitudes and chronicities of ROS levels in cardiomyocytes resulted in differential expression of miR-1, subsequently altering the expression of myocardin. In animal models, the administration of a miR-1 mimic attenuated cardiac hypertrophy by suppressing the transverse aortic constriction-induced increase in myocardin expression, whereas the administration of anti-miR-1 ameliorated I/R-induced cardiac apoptosis and deterioration of heart function. Our findings indicated that a pathologic stimulus such as ROS can bidirectionally alter the expression of miRNA to contribute to the development of pathological conditions exhibiting distinct phenotypes and that the meticulous adjustment of the pathological miRNA levels is required to improve clinical outcomes.
Asunto(s)
Cardiomegalia/metabolismo , Insuficiencia Cardíaca/metabolismo , MicroARNs/metabolismo , Miocardio/metabolismo , Proteínas Nucleares/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transactivadores/metabolismo , Animales , Apoptosis , Cardiomegalia/genética , Células Cultivadas , Regulación de la Expresión Génica/genética , Insuficiencia Cardíaca/genética , MicroARNs/genética , Proteínas Nucleares/genética , Ratas , Ratas Sprague-Dawley , Transactivadores/genéticaRESUMEN
Dynamin-related protein-1 (Drp1) plays a critical role in mitochondrial fission which allows cell proliferation and Mdivi-1, a specific small molecule Drp1 inhibitor, is revealed to attenuate proliferation. However, few molecular mechanisms-related to Drp1 under stimulus for restenosis or atherosclerosis have been investigated in vascular smooth muscle cells (vSMCs). Therefore, we hypothesized that Drp1 inhibition can prevent vascular restenosis and investigated its regulatory mechanism. Angiotensin II (Ang II) or hydrogen peroxide (H2 O2 )-induced proliferation and migration in SMCs were attenuated by down-regulation of Drp1 Ser 616 phosphorylation, which was demonstrated by in vitro assays for migration and proliferation. Excessive amounts of ROS production and changes in mitochondrial membrane potential were prevented by Drp1 inhibition under Ang II and H2 O2 . Under the Ang II stimulation, activated Drp1 interacted with PKCδ and then activated MEK1/2-ERK1/2 signaling cascade and MMP2, but not MMP9. Furthermore, in ex vivo aortic ring assay, inhibition of the Drp1 had significant anti-proliferative and -migration effects for vSMCs. A formation of vascular neointima in response to a rat carotid artery balloon injury was prevented by Drp1 inhibition, which shows a beneficial effect of Drp1 regulation in the pathologic vascular condition. Drp1-mediated SMC proliferation and migration can be prevented by mitochondrial division inhibitor (Mdivi-1) in in vitro, ex vivo and in vivo, and these results suggest the possibility that Drp1 can be a new therapeutic target for restenosis or atherosclerosis.
Asunto(s)
Reestenosis Coronaria/metabolismo , Dinaminas/metabolismo , Mitocondrias/metabolismo , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/metabolismo , Proteína Quinasa C-delta/metabolismo , Angiotensina II/farmacología , Animales , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Peróxido de Hidrógeno/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Neointima/metabolismo , Fosforilación , RatasRESUMEN
BACKGROUND: Low survival rate of transplanted cells compromises the efficacy of cell therapy. Hexokinase II (HKII) is known to have anti-apoptotic activity through its interaction with mitochondria. The objective was to identify miRNAs targeting HKII and investigate whether miRNA-mediated modulation of HKII could improve the survival of mesenchymal stem cells (MSCs) exposed to H2O2. The expression of HKII in MSCs exposed to H2O2 was evaluated, and HKII-targeting miRNA was screened based on miRNA-target prediction databases. The effect of H2O2 on the expression of the selected HKII-targeting miRNA was examined and the effect of modulation of the selected HKII-targeting miRNA using anti-miRNA on H2O2-induced apoptosis of MSC was evaluated. RESULTS: H2O2 (600 µM) induced cell death of MSCs and decreased mitochondrial HKII expression. We have identified miR-181a as a HKII-targeting miRNA and H2O2 increased the expression of miR-181a in MSCs. Delivery of anti-miR-181a, which neutralizes endogenous miR-181a, significantly attenuated H2O2-induced decrease of HKII expression and disruption of mitochondrial membrane potential, improving the survival of MSCs exposed to H2O2. CONCLUSIONS: These findings suggest that H2O2-induced up-regulation of miR-181a contributes to the cell death of MSCs by down-regulating HKII. Neutralizing miR-181a can be an effective way to prime MSCs for transplantation into ischemic tissues.
Asunto(s)
Humanos , Apoptosis , MicroARNs/metabolismo , Células Madre Mesenquimatosas/patología , Glioma/patología , Hexoquinasa/metabolismo , Peróxido de Hidrógeno/toxicidad , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Diferenciación Celular , Movimiento Celular , Supervivencia Celular , Especies Reactivas de Oxígeno , Semaforinas/genética , Semaforinas/metabolismo , MicroARNs/antagonistas & inhibidores , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/enzimología , Reacción en Cadena en Tiempo Real de la Polimerasa , Glioma/metabolismo , Peróxido de Hidrógeno/administración & dosificación , Mitocondrias/enzimología , Invasividad NeoplásicaRESUMEN
The rapid response system (RRS) is an innovative system designed for in-hospital, at-risk patients but underutilization of the RRS generally results in unexpected cardiopulmonary arrests. We implemented an extended RRS (E-RRS) that was triggered by actively screening at-risk patients prior to calls from primary medical attendants. These patients were identified from laboratory data, emergency consults, and step-down units. A four-member rapid response team was assembled that included an ICU staff, and the team visited the patients more than twice per day for evaluation, triage, and treatment of the patients with evidence of acute physiological decline. The goal was to provide this treatment before the team received a call from the patient's primary physician. We sought to describe the effectiveness of the E-RRS at preventing sudden and unexpected arrests and in-hospital mortality. Over the 1-yr intervention period, 2,722 patients were screened by the E-RRS program from 28,661 admissions. There were a total of 1,996 E-RRS activations of simple consultations for invasive procedures. After E-RRS implementation, the mean hospital code rate decreased by 31.1% and the mean in-hospital mortality rate was reduced by 15.3%. In conclusion, the implementation of E-RRS is associated with a reduction in the in-hospital code and mortality rates.