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AIM: To perform a meta-analysis comparing real-world medication adherence to sodium-glucose cotransporter-2 inhibitors (SGLT2is) versus glucagon-like peptide-1 receptor agonists (GLP-1RAs). MATERIALS AND METHODS: A systematic search of Medline and Embase was conducted through October 2023. To meet inclusion criteria, articles had to be published in full text form and directly compare medication adherence to SGLT2is versus GLP-1RAs in adults. Only studies evaluating real-world data and utilizing the proportion of days covered (PDC) to measure adherence were included. Non-adherence, defined as the proportion of patients with a PDC <80%, was the primary outcome. A subgroup analysis evaluating results among studies conducted in the United States was performed. RESULTS: We identified eight studies evaluating 205 103 patients for inclusion. The most common country from which the data was derived was the United States (n = 5 studies). Upon meta-analysis, we observed no difference in non-adherence (i.e. PDC <80%) to SGLT2is versus GLP-1RAs (relative risk = 0.86; 95% confidence interval = 0.72-1.02). In the analysis, including only US studies, SGLT2i use was associated with a 23% lower risk of non-adherence compared with GLP-1RA use (relative risk = 0.77; 95% confidence interval = 0.72-0.82). CONCLUSIONS: In this meta-analysis of eight studies that included approximately 200 000 patients, there was no difference in adherence to SGLT2is versus GLP-1RAs. However, SGLT2i use was associated with higher adherence when the analysis was limited to US studies.
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Family-centered care (FCC) includes collaboration between families and healthcare providers, the creation of flexible policies, and the family taking an active role in the delivery of care. Secondary school athletic trainers provide care for underage patients in school-based health systems, making them responsible for maintaining communication with parents, guardians, and/or caregivers. This cross-sectional survey investigated the extent to which athletic trainers (n = 205) include aspects of FCC in their daily secondary school clinical practice (current practices = CP) and whether they believe that aspect of care is necessary for FCC to be provided in athletic training (perceived necessary = PN) in their everyday practice using the Family-Centered Care Questionnaire-Revised tool. The total mean score for the CP scale (mean = 26.83 ± 4.36) was significantly lower (p ≤ 0.01) than the PN scale (mean = 35.33 ± 4.17). All FCC subscales compared between CP and PN were significantly different (p ≤ 0.01), with each being of higher importance than CP in athletic training. Data analysis revealed four themes related to enhancing FCC in secondary schools: limited education and resources, staffing and space concerns, non-technical skills, and social determinants of health. Attention should be placed on developing resources and interventions for secondary school athletic trainers to collaboratively work with children and their support systems.
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Deportes , Niño , Humanos , Estudios Transversales , Deportes/educación , Instituciones Académicas , Cuidadores , Encuestas y Cuestionarios , Atención Dirigida al PacienteRESUMEN
Selective estrogen receptor modulators (SERMs) are synthetic non-steroidal agents which have variable estrogen agonist and antagonist activities in different target tissues. Tamoxifen is an anti-estrogen in the breast used for treatment and prevention of breast cancer, with estrogen agonist activity in the uterus. Raloxifene prevents and treats osteoporosis and prevents breast cancer, and can be safely combined with vaginal but not systemic estrogen. The tissue selective estrogen complex combines conjugated equine estrogens (CEE) with the SERM bazedoxifene (BZA). The five Selective Estrogen Menopause and Response to Therapy studies, with up to 2 years of data, demonstrated that CEE/BZA 0.45 mg/BZA 20 mg improved vasomotor symptoms and vulvovaginal atrophy, prevented bone loss, and was neutral on breast tenderness, breast density, with breast cancer incidence similar to placebo. Protection against estrogen-induced endometrial hyperplasia and cancer was found, with similar amenorrhea rates to placebo. Ospemifene is approved to treat dyspareunia, with potential benefits on bone and the breast, while lasofoxifene is being developed to treat resistant estrogen receptor-positive breast cancer in women. Estetrol is an estrogen synthesized exclusively during pregnancy by the human fetal liver and initially considered a weak estrogen, but it appears to have dual weak estrogenic/anti-estrogenic features.
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Posmenopausia , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Adulto , Anciano , Atrofia/prevención & control , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/prevención & control , Estrógenos Conjugados (USP)/administración & dosificación , Estrógenos Conjugados (USP)/efectos adversos , Femenino , Enfermedades Urogenitales Femeninas/tratamiento farmacológico , Sofocos/tratamiento farmacológico , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Persona de Mediana Edad , Osteoporosis Posmenopáusica/tratamiento farmacológico , Clorhidrato de Raloxifeno/uso terapéutico , Moduladores Selectivos de los Receptores de Estrógeno/efectos adversos , Tamoxifeno/uso terapéutico , Vagina/efectos de los fármacos , Vagina/patologíaRESUMEN
BACKGROUND: Premature infants may require packed red blood cell transfusions, but current guidelines lack empirical evidence and vary among institutions and prescribers. OBJECTIVE: To compare the physiological changes in cardiovascular hemodynamics and oxygen delivery between premature infants with anemia who receive packed red blood cell transfusions and premature infants without anemia. METHODS: The study was a prospective observational cohort investigation of 75 premature infants. Comparisons among the data were made before, during, and after transfusion in infants with anemia and over time in infants in the control group. In infants with anemia, feedings were withheld 12 hours before and after transfusions. RESULTS: Electrical cardiometry and near-infrared spectroscopy measurements in premature infants with anemia revealed changes in hemodynamic parameters not detected by standard bedside monitoring. Statistically significant changes were seen before and after transfusions in cardiac output, fractional tissue oxygen extraction, heart rate variability, heart rate complexity, and splanchnic regional tissue oxygen saturation. CONCLUSION: Bedside monitoring of cardiovascular hemodynamics and oxygen delivery during packed red blood cell transfusion may inform individualized care for the premature infant with anemia and could be useful for the development of evidence-based practice guidelines.
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Anemia/terapia , Circulación Sanguínea/fisiología , Transfusión de Eritrocitos , Hemodinámica/fisiología , Enfermedades del Recién Nacido/terapia , Recien Nacido Prematuro , Estudios de Cohortes , Femenino , Humanos , Recién Nacido , Masculino , Estudios Prospectivos , Sudeste de Estados UnidosRESUMEN
Background: Acupuncture has a long history of relieving many forms of pain. However, many of acupuncture's mechanisms are still unknown and/or misunderstood. Objective: This review looks at past research on many different methods and targets of study related to acupuncture. The main focus is upon the importance of connective-tissue planes in and around acupuncture points. Method: Relevant articles from journals as well as books on the topic were searched manually for information related to the topic. Results: Various studies offered different (and sometimes interrelated) mechanisms for how acupuncture needling results in analgesia among other effects. Emerging evidence, however, has shown the increasing importance of extracellular matrix rearrangements that result in lower mechanical stress states of surrounding tissues. This leads to lower constant stimulation of regional mechanoreceptors, in turn, reducing chronic pain and discomfort. Conclusions: The extracellular matrix has emerged as an important area of study on the effects of acupuncture needling.
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OBJECTIVE: Investigate a role for calcitonin gene-related peptide (CGRP) in osteoarthritis (OA)-related pain. DESIGN: Neutralizing antibodies to CGRP were generated de novo. One of these antibodies, LY2951742, was characterized in vitro and tested in pre-clinical in vivo models of OA pain. RESULTS: LY2951742 exhibited high affinity to both human and rat CGRP (KD of 31 and 246 pM, respectively). The antibody neutralized CGRP-mediated induction of cAMP in SK-N-MC cells in vitro and capsaicin-induced dermal blood flow in the rat. Neutralization of CGRP significantly reduced pain behavior as measured by weight bearing differential in the rat monoiodoacetate model of OA pain in a dose-dependent manner. Moreover, pain reduction with neutralization of CGRP occurred independently of prostaglandins, since LY2951742 and NSAIDs worked additively in the NSAID-responsive version of the model and CGRP neutralization remained effective in the NSAID non-responsive version of the model. Neutralization of CGRP also provided dose-dependent and prolonged (>60 days) pain reduction in the rat meniscal tear model of OA after only a single injection of LY2951742. CONCLUSIONS: LY2951742 is a high affinity, neutralizing antibody to CGRP. Neutralization of CGRP is efficacious in several OA pain models and works independently of NSAID mechanisms of action. LY2951742 holds promise for the treatment of pain in OA patients.
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Anticuerpos Neutralizantes/farmacología , Péptido Relacionado con Gen de Calcitonina/efectos de los fármacos , Osteoartritis/tratamiento farmacológico , Dolor/prevención & control , Animales , Antiinflamatorios no Esteroideos/farmacología , Péptidos Catiónicos Antimicrobianos , Catelicidinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Masculino , Ratas , Ratas Endogámicas Lew , Flujo Sanguíneo Regional , Piel/irrigación sanguíneaRESUMEN
Development of targeted therapy for hepatocellular carcinoma (HCC) remains a major challenge. We have recently identified an elevated expression of the fifth subunit of COP9 signalosome (CSN5) in early HCC as compared with dysplastic stage. In the present study, we explored the possibility of CSN5 being a potential therapeutic target for HCC. Our results show that CSN5 knockdown by small-interfering (si) RNA caused a strong induction of apoptosis and inhibition of cell-cycle progression in HCC cells in vitro. The down-regulation of CSN5 was sufficient to interfere with CSN function as evidenced by the accumulation of neddylated Cullin 1 and changes in the protein levels of CSN-controlled substrates SKP2, p53, p27 and nuclear factor-κB, albeit to a different degree depending on the HCC cell line, which could account for the CSN5 knockdown phenotype. The transcriptomic analysis of CSN5 knockdown signature showed that the anti-proliferative effect was driven by a common subset of molecular alterations including down-regulation of cyclin-dependent kinase 6 (CDK6) and integrin ß1 (ITGB1), which were functionally interconnected with key oncogenic regulators MYC and TGFß1 involved in the control of proliferation, apoptotic cell death and HCC progression. Consistent with microarray analysis, western blotting revealed that CSN5 depletion increased phosphorylation of Smad 2/3, key mediators of TGFß1 signaling, decreased the protein levels of ITGB1, CDK6 and cyclin D1 and caused reduced expression of anti-apoptotic Bcl-2, while elevating the levels of pro-apoptotic Bak. A chemically modified variant of CSN5 siRNA was then selected for in vivo application based on the growth inhibitory effect and minimal induction of unwanted immune response. Systemic delivery of the CSN5 3/8 variant by stable-nucleic-acid-lipid particles significantly suppressed the tumor growth in Huh7-luc+ orthotopic xenograft model. Taken together, these results indicate that CSN5 has a pivotal role in HCC pathogenesis and maybe an attractive molecular target for systemic HCC therapy.
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Carcinoma Hepatocelular/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Péptido Hidrolasas/metabolismo , Complejo del Señalosoma COP9 , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , División Celular , Línea Celular Tumoral , Regulación hacia Abajo , Técnicas de Silenciamiento del Gen , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Péptido Hidrolasas/genética , ARN Interferente Pequeño/genéticaRESUMEN
OBJECTIVE: Vaginal deliveries have been associated with pelvic organ prolapse and incontinence. The objective was to show whether markers of ischemia/reperfusion injury are dependent upon the mode of delivery and length of labor. METHOD: Complete venipuncture sets were obtained on 62 subjects. All samples collected were analyzed for serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). Lipid peroxidation was analyzed, using thiobarbituric acid reactive substances (TBARS), on a subset of 37 patients. RESULTS: There was a significant increase in CPK from admission to 1 h postpartum and postpartum day 1 in vaginal delivery versus cesarean delivery. Longer second stages were associated with significant increases in CPK. There were no significant changes in either LDH or TBARS from admission to any other time point regardless of mode of delivery. CONCLUSION: Vaginal delivery and longer second stages were associated with a much greater increase in one of these injury markers.
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Complicaciones del Trabajo de Parto , Parto , Daño por Reperfusión/etiología , Adulto , Biomarcadores/sangre , Cesárea/efectos adversos , Creatina Quinasa/sangre , Femenino , Humanos , L-Lactato Deshidrogenasa/sangre , Segundo Periodo del Trabajo de Parto , Peroxidación de Lípido , Embarazo , Prolapso , Incontinencia Urinaria/etiologíaRESUMEN
Isatin is an endogenous indole that is increased in stress, inhibits monoamine oxidase (MAO) B and improves bradykinesia and striatal dopamine levels in rat models of Parkinson's disease. Consequently, it has been suggested that isatin might be a possible treatment for Parkinson's disease although little is known about its effects on neural cell growth and survival. The aim of this study was to investigate the survival of dopaminergic human neuroblastoma (SH-SY5Y) cells following treatment with increasing concentrations of isatin. SH-SY5Y cells were exposed to isatin for defined time points, after which cell survival was determined by MTT assay. A combination of Annexin V binding and propidium iodide (PI) exclusion was used to distinguish apoptosis from necrosis in flow cytometry experiments and FACS profiles of permeabilised PI-labelled cells were employed for the assessment of cell cycle distribution. Isatin treatment (1-400 microM) for 24h induced a significant dose-dependent increase in MTT metabolism by SH-SY5Y cells in culture, but this was not due to an increase in cell division. At the higher concentrations (200-400 microm) isatin triggered cell death, although MTT metabolism was still increased in the culture, suggesting that surviving cells were hypermetabolic. Following a longer (48 h) exposure, isatin was found to cause cell death in a dose-dependent manner; at lower concentrations (50 microM), the predominant mode of cell death was apoptosis while at the highest concentration (400 microm) increasing numbers of necrotic cells were also evident. Thus, in dopaminergic SH-SY5Y cells isatin induces cell death in dose- and time-dependent manner. This death occurred as a continuum of survival, apoptosis and necrosis. Our results re-emphasise that caution should be exercised when considering high doses of isatin as a putative anti-Parkinson's disease therapeutic.
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Apoptosis/efectos de los fármacos , Dopamina/biosíntesis , Isatina/toxicidad , Inhibidores de la Monoaminooxidasa/toxicidad , Neuronas/efectos de los fármacos , Anexina A5/metabolismo , Antiparkinsonianos/uso terapéutico , Antiparkinsonianos/toxicidad , Apoptosis/fisiología , Ciclo Celular/efectos de los fármacos , Ciclo Celular/fisiología , Línea Celular Tumoral , Permeabilidad de la Membrana Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/fisiología , Humanos , Isatina/uso terapéutico , Inhibidores de la Monoaminooxidasa/uso terapéutico , Necrosis/inducido químicamente , Necrosis/metabolismo , Neuroblastoma , Neuronas/metabolismo , Neurotoxinas/uso terapéutico , Neurotoxinas/toxicidad , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología , Propidio , Sales de Tetrazolio , Tiazoles , Factores de TiempoRESUMEN
Our objective was to assess the perinatal management and neonatal outcomes of premature, severely intrauterine growth-restricted (IUGR) neonates. A cohort of neonates <1000 grams, < or = first percentile for weight, and <37 weeks' gestation was identified and matched 2:1 to two control sets of premature, appropriate-for-gestational age (AGA) infants-one with similar gestational age (AGA-GA group) and the other with similar birth weight (AGA-BW group) to determine the effect of IUGR on the outcome of the premature infant. The IUGR group was then examined in detail for descriptive statistics. Data were analyzed by t-tests and Chi-square analyses where appropriate. The IUGR infants had worse outcomes than AGA-GA controls but had somewhat better results than the AGA-BW controls. In the IUGR group, a birth weight less than 550 grams was significantly associated with neonatal death (p < 0.001). However, increasing gestational age was not associated with neonatal survival (p = 0.661) if birthweight remained below 550 grams. Classical cesarean delivery was associated with neonatal death (p = 0.003). Neonatal variables associated with poor outcome included patent ductus arteriosus (p = 0.034), feeding intolerance (p = 0.046), and failure to thrive (p = 0.05). Overall, neonatal survival was 73%. Of the surviving neonates, 69% had evidence of neurodevelopmental delay when tested at 6 and 12 months. Premature, growth-restricted neonates with birth weights of <550 grams versus those of >550 grams have dismal outcomes despite a gestational age that is compatible with survival.
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Peso al Nacer/fisiología , Retardo del Crecimiento Fetal/mortalidad , Adulto , Estudios de Cohortes , Parto Obstétrico , Femenino , Edad Gestacional , Humanos , Recién Nacido , Atención Posnatal , Embarazo , Resultado del Embarazo , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
OBJECTIVE: The primary objective of this study was to test the hypothesis that the degree of systemic endothelial activation, as measured by the release of von Willebrand factor antigen into the circulation and pulmonary edema fluid, is an important determinant of outcome from acute lung injury and acute respiratory distress syndrome. DESIGN: Observational study. SETTING: Intensive care unit patients in a tertiary university hospital and a university-affiliated city hospital. PATIENTS: Fifty-one intubated, mechanically ventilated intensive care unit patients with acute lung injury or acute respiratory distress syndrome as defined by the North American European Consensus Conference definitions. INTERVENTIONS: Undiluted pulmonary edema fluid and plasma were collected within 1 hr of endotracheal intubation in all patients. MEASUREMENTS: von Willebrand factor antigen concentrations and protein concentration were measured in pulmonary edema fluid and in plasma. MAIN RESULTS: At the time of intubation, median plasma von Willebrand factor antigen was 251%, two-fold higher than the median pulmonary edema fluid von Willebrand factor antigen of 130%. Median edema fluid and plasma von Willebrand factor antigen concentrations were significantly higher in patients who did not survive hospitalization. Plasma von Willebrand factor antigen was also higher in those patients who had a longer duration of mechanical ventilation (as measured by ventilator-free days). Plasma von Willebrand factor antigen was also significantly higher in patients with sepsis and two or more organ system failures. According to stepwise logistic regression analysis, plasma von Willebrand factor antigen was independently associated with in hospital death. The positive predictive value for death if the plasma von Willebrand factor antigen concentration was >450% was 83%. A plasma von Willebrand factor antigen concentration of >450% previously has been shown to predict the development of acute respiratory distress syndrome. CONCLUSIONS: These findings suggest that the degree of systemic endothelial activation and injury at the onset of acute lung injury is an important determinant of the outcome from acute lung injury.
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Antígenos/metabolismo , Síndrome de Dificultad Respiratoria/diagnóstico , Factor de von Willebrand/inmunología , Biomarcadores , California/epidemiología , Femenino , Mortalidad Hospitalaria , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Pronóstico , Edema Pulmonar/metabolismo , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/mortalidad , Estadísticas no Paramétricas , Resultado del TratamientoRESUMEN
A specific and potent inhibitor of S-adenosyl-L-homocysteine (AdoHcy) hydrolase, 9-[(1'R,2'S,3'R)-2', 3'-dihydroxycyclopentanyl]adenine (DHCaA), was evaluated for its immunosuppressive efficacy on murine T-cell proliferation in vitro and in several animal models, including delayed type hypersensitivity ear swelling and peptidoglycan polysaccharide-induced arthritis. The concanavalin A-induced [(3)H]thymidine incorporation into T cells was strongly inhibited by DHCaA with a 50% inhibition concentration (IC(50)) of 0.3 microM. In vivo, a dose-dependent reduction (39, 62, and 73%) of ear swelling was observed when 2,4-dinitrofluorobenzene-treated mice were orally administered with DHCaA at 1, 5, and 10 mg/kg, respectively. This inhibition in ear swelling dose dependently corresponded to the inhibition of AdoHcy hydrolase activity in the spleen. The more potent the AdoHcy hydrolase inhibitor, the stronger the immunosuppressive efficacy observed. In rat peptidoglycan polysaccharide-induced arthritis, orally dosed DHCaA significantly suppressed inflamed paw volumes with minimal effective dose of 0.1 mg/kg. At a dose of 1 mg/kg, DHCaA almost completely inhibited paw swelling. This inhibition of paw swelling was associated with an inhibition of interleukin-1beta production in joint tissues. Histopathological evaluation of the joints in rats treated with 1 mg/kg showed a significant improvement in the reduction of the histopathological grading score from untreated scores of 10.44 to 4. 78. Results from this study indicate that inhibitors of AdoHcy hydrolase could be effective anti-inflammatory agents.
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Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/prevención & control , Edema/prevención & control , Inhibidores Enzimáticos/farmacología , Hidrolasas/antagonistas & inhibidores , Hipersensibilidad Tardía/prevención & control , Inmunosupresores/farmacología , Adenosina/análogos & derivados , Adenosina/farmacología , Adenosilhomocisteinasa , Animales , Artritis Experimental/patología , Dinitrofluorobenceno/farmacología , Oído/patología , Edema/inducido químicamente , Femenino , Hipersensibilidad Tardía/inducido químicamente , Hipersensibilidad Tardía/patología , Interleucina-1/metabolismo , Articulaciones/enzimología , Articulaciones/metabolismo , Articulaciones/patología , Ratones , Ratones Endogámicos BALB C , Peptidoglicano , Polisacáridos , Ratas , Ratas Endogámicas Lew , Bazo/enzimología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Timidina/metabolismoRESUMEN
Deregulation of E2F transcriptional control has been implicated in oncogenic transformation. Consistent with this idea, we recently demonstrated that during hepatocarcinogenesis in c-myc/TGFalpha double transgenic mice, there is increased expression of E2F-1 and E2F-2, as well as induction of putative E2F target genes. Therefore, we generated transgenic mice expressing E2F-1 under the control of the albumin enhancer/promoter to test the hypothesis that E2F family members may contribute to liver tumor development. Overexpression of E2F-1 resulted in mild but persistent increases in cell proliferation and death during postnatal liver growth, and no increases in hepatic regenerative growth in response to partial hepatectomy. Nevertheless, from 2 months postnatally E2F-1 transgenic mice exhibited prominent hepatic histological abnormalities including preneoplastic foci adjacent to portal tracts and pericentral large cell dysplasia. From 6 to 8 months onward, there was an abrupt increase in the number of neoplastic nodules ('adenomas') with 100% incidence by 10 months. Some adenomas showed evidence of malignant transformation, and two of six mice killed at 12 months showed trabecular hepatocellular carcinoma. Endogenous c-myc was up-regulated in the early stages of E2F-1 hepatocarcinogenesis, whereas p53 was overexpressed in the tumors, suggesting that both E2F-1-mediated proliferation and apoptosis are operative but at different stages of hepatocarcinogenesis. In conclusion, E2F-1 overexpression in the liver causes dysplasia and tumors and suggests a cooperation between E2F-1 and c-myc oncogenes during liver oncogenesis.
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Proteínas Portadoras , Proteínas de Ciclo Celular , Transformación Celular Neoplásica/genética , Proteínas de Unión al ADN , Neoplasias Hepáticas Experimentales/genética , Factores de Transcripción/fisiología , Albúminas/genética , Animales , Apoptosis/fisiología , División Celular/fisiología , Transformación Celular Neoplásica/metabolismo , Cruzamientos Genéticos , Factores de Transcripción E2F , Factor de Transcripción E2F1 , Factor de Transcripción E2F2 , Elementos de Facilitación Genéticos/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Genes myc/genética , Hepatocitos/citología , Hepatocitos/metabolismo , Hepatocitos/fisiología , Humanos , Hígado/metabolismo , Hígado/patología , Hígado/fisiología , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Regeneración Hepática/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Lesiones Precancerosas/genética , Lesiones Precancerosas/metabolismo , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-myc/biosíntesis , Proteínas Proto-Oncogénicas c-myc/genética , Proteína 1 de Unión a Retinoblastoma , Factor de Transcripción DP1 , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/biosíntesis , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/fisiologíaRESUMEN
The objectives of this study were to quantify colonic cytokine and endothelial cell adhesion molecule (ECAM) expression in the colons of severe combined immunodeficient (SCID) mice reconstituted with different subsets of CD4+ T lymphocytes. We found that animals injected with CD45RBhigh but not CD45RBlow T cells or phosphate-buffered saline (PBS) developed clinical evidence of colitis at 6-8 weeks following reconstitution, as assessed by loss of body weight, development of loose stools and/or diarrhea, and histopathology. Concurrent with the onset of distal bowel inflammation was enhanced expression of a variety of Th1 and macrophage-derived cytokines including interferon gamma, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-12, and IL-18 lymphotoxin-beta. In addition, message levels and vascular surface expression of ICAM-1, VCAM-1, and MAdCAM-1 were all significantly enhanced in the colitic SCID mice reconstituted with CD45RBhigh T cells compared with SCID mice reconstituted with PBS or CD45RBlow T cells that did not develop disease. Significant increases in some of these ECAMs were also noted in the cecum and stomach and to a lesser degree in the small bowel. Our data confirm that reconstitution of SCID mice with CD45RBhigh but not CD45RBlow T cells induces chronic colitis, and that the colonic inflammation is associated with enhanced expression of proinflammatory cytokines and different ECAMs in the colon. Furthermore, our studies demonstrate that reconstitution of SCID mice with CD45RBhigh T cells enhances ECAM expression in tissues distant from the site of active inflammation.
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Moléculas de Adhesión Celular/biosíntesis , Citocinas/biosíntesis , Enfermedades Inflamatorias del Intestino/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Moléculas de Adhesión Celular/análisis , Citocinas/análisis , Modelos Animales de Enfermedad , Humanos , Molécula 1 de Adhesión Intercelular/análisis , Molécula 1 de Adhesión Intercelular/inmunología , Ratones , Ratones SCIDRESUMEN
The objective of this study was to quantify the duration of the hemodynamic activity of N(G)-nitro-l-arginine methyl ester (l-NAME) in a variety of different tissues following a single bolus injection of this nitric oxide synthase inhibitor to healthy rats. l-NAME (15 micromol x kg(-1)) was injected (ip) into rats to produce maximal inhibition of endothelial cell NOS. Animals were subsequently anesthetized and blood flow was quantified using the radioactive microsphere/reference organ technique. At 1 h following a single bolus injection of l-NAME blood flow was reduced to the entire gastrointestinal tract, pancreas, and liver. Three hours following l-NAME administration, blood flow to the stomach and upper small intestine had returned to pretreatment levels; however, blood flow to the jejunum, ileal-jejunal junction, and colon remained significantly reduced. Splenic blood flow was significantly reduced and hepatic arterial blood flow was further reduced at this time as well. After 6 h following l-NAME administration, blood flow in all organs had completely recovered to control levels. Although cardiac index and total peripheral resistance had also returned to preinjection values at this time, mean arterial pressure remained elevated at 6 h posttreatment. Blood flow to the brain, lungs, and psoas muscle were unaffected by l-NAME administration at any time point. Taken together, these data demonstrate a differential regulation of vascular tone by NO in different vascular beds and, depending upon the organ system in question, the vasoactive activity of l-NAME may last from 3 to 6 h following a single bolus injection of this NOS inhibitor.
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Hemodinámica/efectos de los fármacos , NG-Nitroarginina Metil Éster/farmacología , Animales , Femenino , Semivida , Inyecciones Intraperitoneales , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III , Ratas , Ratas Endogámicas LewRESUMEN
The objective of this study was to quantify E-selectin surface expression in the colon as well as other tissues in a CD4(+) T-cell model of chronic colitis in mice using the newly developed dual radiolabel monoclonal antibody technique. Male SCID mice were reconstituted with either 5 x 10(5) CD4(+) CD45RB(low) or CD45RB(high) T-cells isolated from normal CB-17 donor mouse spleens and subsequently monitored for clinical signs of colitis. We found that animals injected with CD45RB(high) but not CD45RB(low) T-cells nor PBS developed colitis at 6-8 weeks following reconstitution as assessed by loss of body weight, development of loose stools and/or diarrhea, and histopathology. Concurrent with the onset of distal bowel inflammation was enhanced expression of E-selectin compared to SCID mice injected with PBS or reconstituted with CD45RB(low) T-cells, both of which did not develop colitis. We also observed significant increases in E-selectin expression in cecum, small intestine, mesentery, and liver of colitic mice. Our data confirm that reconstitution of SCID mice with CD45RB(high) but not CD45RB(low) T-cells induces chronic colitis and demonstrate that this chronic colitis is associated with enhanced expression of an endothelial cell-specific adhesion molecule. Furthermore, our studies demonstrate that reconstitution of SCID mice with CD45RB(high) T-cells enhances E-selectin expression in a variety of tissues distant from the site of active inflammation.
Asunto(s)
Colitis/metabolismo , Selectina E/biosíntesis , Animales , Moléculas de Adhesión Celular/metabolismo , Enfermedad Crónica , Colitis/patología , Modelos Animales de Enfermedad , Endotelio/metabolismo , Femenino , Masculino , Ratones , Ratones SCID , Radioinmunoensayo/métodosAsunto(s)
Molécula 1 de Adhesión Intercelular/análisis , Edema Pulmonar/metabolismo , Síndrome de Dificultad Respiratoria/metabolismo , Biomarcadores/análisis , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Edema Pulmonar/terapia , Respiración Artificial , Síndrome de Dificultad Respiratoria/terapia , Factor de von Willebrand/análisis , Factor de von Willebrand/metabolismoRESUMEN
Current studies have indicated both positive and negative roles for the hepatocyte growth factor (HGF)/c-met receptor signaling system in tumor development. Recently, we have shown that HGF has the capacity to induce both growth inhibition and programmed cell death in aflatoxin-transformed (AFLB8) rat liver epithelial cells. Using the same cell line, we have now investigated a potential mechanism for HGF-induced apoptosis. Immunoblot analysis of bcl-2 gene family member (bax, bcl-2, bclX-s/l) expression showed no correlation with HGF treatment, suggesting that HGF-mediated apoptosis is bax independent. Following HGF treatment retinoblastoma protein (pRB) was present in the hypophosphorylated state. HGF treatment increased cyclin A, cyclin G1 and nuclear transcriptional factor (NFkappaB) protein expression. However, electrophoretic mobility shift analysis showed that NFkappaB activity decreased with HGF treatment. Under these apoptotic conditions, c-Jun N-terminal kinase (JNK1) and extracellular signal-regulated kinase (ERK2) were activated with lower level activation of ERK2, while no involvement of phosphatidylinositol-3 kinase was observed. Epidermal growth factor (EGF) was not protective, and actually induced cells to undergo apoptosis to a level similar to that of HGF alone or EGF/HGF in combination. These results suggest the possibility of cross-talk between HGF/c-met and EGF/EGFR signaling pathways, and the involvement of JNK1 induction in HGF-mediated apoptotic cell death.
Asunto(s)
Apoptosis/fisiología , Proteínas Quinasas Dependientes de Calcio-Calmodulina/fisiología , Factor de Crecimiento de Hepatocito/farmacología , Hígado/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos , Proteínas Proto-Oncogénicas c-bcl-2 , Proteínas Proto-Oncogénicas/fisiología , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/fisiología , Aflatoxinas/toxicidad , Animales , Apoptosis/efectos de los fármacos , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Línea Celular Transformada/efectos de los fármacos , Ciclinas/biosíntesis , Ciclinas/genética , Activación Enzimática/efectos de los fármacos , Factor de Crecimiento Epidérmico/farmacología , Receptores ErbB/fisiología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes bcl-2 , Proteínas Quinasas JNK Activadas por Mitógenos , Hígado/citología , Proteína Quinasa 1 Activada por Mitógenos , FN-kappa B/biosíntesis , FN-kappa B/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Ratas , Proteínas Recombinantes/farmacología , Proteína de Retinoblastoma/metabolismo , Proteína X Asociada a bcl-2RESUMEN
It is becoming increasingly apparent that NF-kappa B plays a critical role in regulating the inflammatory response. Data obtained from studies in our laboratories demonstrate that the proteasome plays an important role in the inflammatory cascade by regulating the activation of NF-kappa B. Indeed, the availability of selective and orally active proteasome inhibitors should prove useful in delineating the roles of the proteasome and NF-kappa B in other pathophysiological conditions such as cancer and heart disease.
Asunto(s)
FN-kappa B/metabolismo , Péptido Hidrolasas/efectos de los fármacos , Inhibidores de Proteasas/farmacología , Complejo de la Endopetidasa Proteasomal , Acetilcisteína/análogos & derivados , Acetilcisteína/farmacología , Animales , Artritis/tratamiento farmacológico , Ácidos Borónicos/farmacología , Moléculas de Adhesión Celular/biosíntesis , Citocinas/biosíntesis , Dipéptidos/farmacología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Femenino , Células HeLa , Humanos , Hipersensibilidad Tardía/tratamiento farmacológico , Células Jurkat , Leupeptinas/farmacología , Ratas , Ratas Endogámicas Lew , Linfocitos T/efectos de los fármacosRESUMEN
Nuclear factor kappaB (NF-kappaB) is an ubiquitous transcription factor and pleiotropic regulator of numerous inflammatory and immune responses. Once activated, NF-kappaB translocates from the cytosol to the nucleus of the cell, where it binds to its consensus sequence on the promoter-enhancer region of different genes. By so doing, this activates the transcription of a variety of different pro-inflammatory cytokines, adhesion molecules and specific enzymes, such as the inducible forms of nitric oxide synthase and cyclooxygenase. A number of different cytokines, bacterial products and oxidants activate NF-kappaB via selective phosphorlyation, polyubiquitination and degradation of the inhibitor protein, IkappaB. Since the 26S proteasome complex degrades the post-translationally modified IkappaB, thereby liberating the transcriptionally active p50/p65 heterodimeric NF-kappaB, this proteolytic complex represents a critical step in the activation of NF-kappaB. This review discusses the basic biology of the ubiquitin-proteasome pathway as it relates to the inflammatory response, and highlights those studies demonstrating that selective proteasome inhibitors are effective anti-inflammatory agents in vivo.