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1.
J Vasc Access ; : 11297298241254564, 2024 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-38800968

RESUMEN

A peripherally inserted central catheter (PICC) is commonly used for fluid infusion in patients. However, rupture is one of the most serious complications associated with PICC placement. We investigated an 81-year-old patient who experienced a catheter break nearly 11 months after the placement of PICC, followed by a catheter break during catheter capture that was removed after accessing the superior vena cava with a catcher. This case suggests that silicone-based PICCs are fragile and have a high risk of spontaneous dislocation. Therefore, they should be replaced with polyurethane-based PICCs.

2.
Front Microbiol ; 14: 1188722, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37266020

RESUMEN

Pitaya canker, caused by Neoscytalidium dimidiatum, is one of the most important fungal diseases that cause significant losses in production. To replace chemical pesticides, the use of biocontrol strains to manage plant diseases has been the focus of research. In this study, the bacterial strain AF01, identified as Paenibacillus polymyxa, exhibited significant antifungal effects against N. dimidiatum and four other pitaya fungal pathogens. The strain P. polymyxa AF01 produces 13 fusaricidins, which directly inhibit mycelial growth, spore germination and germ tube elongation by causing the membrane integrity and cell ultrastructure to incur irreversible damage. Pot experiment and yield test confirmed that AF01 provided preservative effects by reducing the disease index. In comparison to the untreated control groups, RNA-seq data showed that P. polymyxa AF01 selectively blocked some transcription and translation processes and inhibited RNA and DNA structural dynamics, energy production and conversion, and signal transduction, particularly cell wall biosynthesis, changes in membrane permeability, and impairment of protein biosynthesis. Thus, P. polymyxa AF01 could be potentially useful as a suitable biocontrol agent for pitaya canker.

3.
J Orthop Surg Res ; 17(1): 168, 2022 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-35303885

RESUMEN

BACKGROUND: Mesenchymal stem cells (MSCs) have emerged as the attractive candidates for cell therapy for cartilage repair in clinical therapy of osteoarthritis (OA). MiR-539-3p was reported to differentially express during chondrogenic differentiation of adipose stem cells (ASCs) by miRNA microarrays. The aim of the study was to investigate the effects and underlying mechanisms of miR-539-3p on chondrogenic differentiation of ASCs. METHODS: Human ASCs (hASCs) were obtained from liposuction and transfected with miR-539-3p mimic or inhibitor. Then, the cells were cultured in chondrogenic differentiation medium including transforming growth factor-ß1 (TGF-ß1). RESULTS: Our results found that miR-539-3p was gradually down-regulated during chondrogenic differentiation of hASCs. MiR-539-3p overexpression inhibited TGF-ß1-induced chondrogenic differentiation of hASCs, as supported by reducing the gene and protein expression of chondrogenic differentiation markers type II collagen alpha 1 (COL2A1), aggrecan (ACAN), and type II collagen. In contrast, miR-539-3p inhibitor significantly promoted the chondrogenic differentiation of hASCs. Dual luciferase reporter assay demonstrated that Sox9 was a direct target gene of miR-539-3p. The expression of SRY-box transcription factor 9 (Sox9) was up-regulated progressively over time during chondrogenic differentiation of hASCs. Additionally, Sox9 overexpression notably reversed chondrogenic differentiation of hASCs inhibited by miR-539-3p mimic, as demonstrated by the decreased expression of COL2A1, ACAN, and type II collagen. CONCLUSIONS: Altogether, miR-539-3p inhibited chondrogenic differentiation of hASCs by targeting Sox9. MiR-539-3p may have significant clinical applications for use as a targeted therapy of OA.


Asunto(s)
Condrogénesis/genética , MicroARNs/genética , Osteoartritis , Factor de Transcripción SOX9/metabolismo , Células Madre , Adulto , Agrecanos/genética , Condrogénesis/efectos de los fármacos , Colágeno Tipo II/genética , Regulación hacia Abajo , Femenino , Voluntarios Sanos , Humanos , MicroARNs/metabolismo , Factor de Transcripción SOX9/genética , Células Madre/metabolismo , Factor de Crecimiento Transformador beta1/farmacología
4.
Minerva Anestesiol ; 88(4): 223-229, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35072431

RESUMEN

BACKGROUND: Propofol-sufentanil is often used in clinical anesthesia for patients undergoing sedative gastroscopy, but there are still adverse events such as longer recovery time, respiratory depression and higher doses of propofol etc. This study was to evaluate the sedative effect of remimazolam-propofol-sufentanil in sedative gastroscopy. METHODS: Patients who were going to have gastroscopy examination were randomly divided into two groups: group RM (remimazolam-propofol-sufentanil group) and group PR (propofol-sufentanil group). Patients of each group were anesthetized according to the corresponding anesthesia procedure, and all observation indices were recorded. RESULTS: In the RM group, there were only small and unsignificant changes in the values of SBP, HR, RR and SpO2 after anesthesia (P>0.05), while the values of SBP, HR, RR and SpO2 in the PR group at each time point after anesthesia were significantly lower than those at T0, and the values of SBP and RR at T2, T3 and T4 were also significantly lower than those at T1 (P<0.05). The dosage of propofol (38±9 mg) in the RM group was significantly less than that (115±15 mg) in the PR group, meanwhile the anesthesia time (8.4±1.6 min), awakening time (2.9±0.8 min), discharge time (6.7±3.1 min) of the RM group were also significantly shorter than those of the PR group (14.5±3.3, 8.7±1.9, 12.4±3.6 min) (P<0.05), but there was no statistical significance between the two groups in other indices (P>0.05). CONCLUSIONS: In clinical practice, remimazolam-propofol-sufentanil sedative scheme has more advantages than propofol-sufentanil sedative scheme.


Asunto(s)
Anestesia , Propofol , Benzodiazepinas , Gastroscopía , Humanos , Hipnóticos y Sedantes/farmacología , Sufentanilo/farmacología
5.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 33(1): 84-88, 2021 Jan.
Artículo en Chino | MEDLINE | ID: mdl-33565407

RESUMEN

OBJECTIVE: To study the optimal pain control goal for preventing delirium in critical patients. METHODS: A prospective cohort study were conducted. The patients admitted to general departments and transferred to the intensive care unit (ICU) due to critical illness in the First People's Hospital of Changde from January 2017 to November 2019 were enrolled. The General data of the patients were collected within 48 hours after admission. All patients admitted to the ICU were evaluated for pain level using the critical care pain observation tool (CPOT) every 8 hours by nurses, and confusion assessment method of ICU (CAM-ICU) was used to screen delirium patient every 8 hours by the leader of nursing team without knowing the pain level of the patients, until the subjects were transferred out of ICU. The receiver operating characteristic (ROC) curve was drawn, the area under ROC curve (AUC) and the optimal threshold were analyzed with delirium as the reference standard; according to the optimal threshold, multivariate Logistic regression analysis was used to evaluate the correlation between CPOT score and delirium. RESULTS: During the study period, 575 patients were admitted to the participating departments and passed the preliminary screening according to the inclusion and exclusion criteria. During the study period, 34 patients were excluded due to incomplete data. Finally, a total of 541 patients were enrolled in the analysis, including 149 patients in delirium group and 392 patients in non-delirium group. There was no significant difference in gender, age, source of patients, education level, smoking history, drinking history, family mental history, acute physiology and chronic health evaluation II (APACHE II) score or other general information between the two groups. There were 10.1% (15/149) of patients in the delirium group used opioids, which was significantly higher than 4.3% (17/392) in the non-delirium group, and the difference was statistically significant (P < 0.05). The CPOT score in the delirium group was significantly higher than that in the non-delirium group (4.24±1.78 vs. 2.75±1.95, P < 0.01). The patients were subdivided into young group (< 40 years old), middle-aged group (40-65 years old) and old group (> 65 years old) according to age. The analysis results were consistent with the overall analysis results. ROC curve analysis showed that the AUC of CPOT score predicting delirium was 0.719; when the best threshold value of CPOT score was 2.5, the sensitivity was 91.3%, the specificity was 49.0%, the positive predictive value was 40.5% and the negative predictive value was 93.7%. Multivariate Logistic regression analysis showed that the risk of delirium in ICU patients with CPOT score ≥ 3 was 10.043 times higher than that in patients with CPOT score < 3 [odds ratio (OR) = 10.043, 95% confidence interval (95%CI) was 5.498-18.345, P < 0.001]. When the gender, age, APACHE II score, smoking history, drinking history, opioids usage were adjusted, the risk of delirium in patients with CPOT score ≥ 3 was 10.719 times higher than that in patients with CPOT score < 3 (OR = 10.719, 95%CI was 5.689-20.196, P < 0.001). CONCLUSIONS: The best pain control goal for preventing the occurrence of delirium in ICU patients is a CPOT score of 3 or less.


Asunto(s)
Delirio , Objetivos , APACHE , Adulto , Anciano , Delirio/prevención & control , Humanos , Unidades de Cuidados Intensivos , Persona de Mediana Edad , Dolor , Pronóstico , Estudios Prospectivos , Curva ROC
6.
Diabetes ; 67(12): 2494-2506, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30213825

RESUMEN

In clinical trials, inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels but does not robustly improve cardiovascular outcomes. Approximately two-thirds of trial participants are obese. Lower plasma CETP activity is associated with increased cardiovascular risk in human studies, and protective aspects of CETP have been observed in mice fed a high-fat diet (HFD) with regard to metabolic outcomes. To define whether CETP inhibition has different effects depending on the presence of obesity, we performed short-term anacetrapib treatment in chow- and HFD-fed CETP transgenic mice. Anacetrapib raised HDL cholesterol and improved aspects of HDL functionality, including reverse cholesterol transport, and HDL's antioxidative capacity in HFD-fed mice was better than in chow-fed mice. Anacetrapib worsened the anti-inflammatory capacity of HDL in HFD-fed mice. The HDL proteome was markedly different with anacetrapib treatment in HFD- versus chow-fed mice. Despite benefits on HDL, anacetrapib led to liver triglyceride accumulation and insulin resistance in HFD-fed mice. Overall, our results support a physiologic importance of CETP in protecting from fatty liver and demonstrate context selectivity of CETP inhibition that might be important in obese subjects.


Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Proteínas de Transferencia de Ésteres de Colesterol/genética , HDL-Colesterol/sangre , Dieta Alta en Grasa , Hígado Graso/genética , Resistencia a la Insulina/fisiología , Animales , Anticolesterolemiantes/farmacología , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Hígado Graso/metabolismo , Ratones , Ratones Transgénicos , Oxazolidinonas/farmacología
7.
Am J Physiol Endocrinol Metab ; 315(4): E583-E593, 2018 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-29944391

RESUMEN

ErbB4, a member of the EGF receptor family, plays a variety of roles in physiological and pathological states. Genetic studies have indicated a link between ErbB4 and type 2 diabetes and obesity, but its role in metabolic syndrome (MetS) has not been reported. In the current study we found that mice with ErbB4 deletion developed MetS after 24 wk on a medium-fat diet (MFD), as indicated by development of obesity, dyslipidemia, hepatic steatosis, hyperglycemia, hyperinsulinemia, and insulin resistance, compared with wild-type mice. ErbB4 deletion mice also exhibited increased amounts of subcutaneous and visceral fat, with increased serum leptin levels, compared with wild-type mice, whereas levels of adiponectin were not significantly different. Histologically, severe inflammation, indicated by F4/80 immunostaining and M1 macrophage polarization, was detected in inguinal and epididymal white adipose tissue in ErbB4 deletion mice. ErbB4 expression decreased during 3T3-L1 preadipocyte differentiation. Administration of neuroregulin 4, a specific ligand for ErbB4, to 3T3-L1 adipocytes had no effect on adipogenesis and lipolysis but significantly inhibited lipogenesis, promoted browning, induced GLUT4 redistribution to the cell membrane, and increased glucose uptake. Neuroregulin 4 also significantly increased glucose uptake in adipocytes isolated from wild-type mice, while these effects were significantly decreased in adipocytes isolated from ErbB4 deletion mice. In conclusion, our results indicate that ErbB4 may play an important role in glucose homeostasis and lipogenesis. ErbB4 deficiency-related obesity and adipose tissue inflammation may contribute to the development of MetS.


Asunto(s)
Grasas de la Dieta , Dislipidemias/genética , Hígado Graso/genética , Hiperglucemia/genética , Resistencia a la Insulina/genética , Síndrome Metabólico/genética , Obesidad/genética , Receptor ErbB-4/genética , Células 3T3-L1 , Adipogénesis/efectos de los fármacos , Adiponectina/metabolismo , Tejido Adiposo Blanco/inmunología , Animales , Eliminación de Gen , Predisposición Genética a la Enfermedad , Transportador de Glucosa de Tipo 4/efectos de los fármacos , Transportador de Glucosa de Tipo 4/metabolismo , Hiperinsulinismo/genética , Inflamación , Grasa Intraabdominal , Leptina/metabolismo , Lipogénesis/efectos de los fármacos , Macrófagos , Masculino , Ratones , Neurregulinas/farmacología , Grasa Subcutánea
8.
Kidney Int ; 94(2): 292-302, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29779708

RESUMEN

Albumin degradation in the renal tubules is impaired in diabetic nephropathy such that levels of the resulting albumin fragments increase with the degree of renal injury. However, the mechanism of albumin degradation is unknown. In particular, fragmentation of the endogenous native albumin has not been demonstrated in the kidney and the enzymes that may contribute to fragmentation have not been identified. To explore this we utilized matrix-assisted laser desorption/ionization imaging mass spectrometry for molecular profiling of specific renal regions without disturbing distinct tissue morphology. Changes in protein expression were measured in kidney sections of eNOS-/-db/db mice, a model of diabetic nephropathy, by high spatial resolution imaging allowing molecular localizations at the level of single glomeruli and tubules. Significant increases were found in the relative abundances of several albumin fragments in the kidney of the mice with diabetic nephropathy compared with control nondiabetic mice. The relative abundance of fragments detected correlated positively with the degree of nephropathy. Furthermore, specific albumin fragments accumulating in the lumen of diabetic renal tubules were identified and predicted the enzymatic action of cathepsin D based on cleavage specificity and in vitro digestions. Importantly, this was demonstrated directly in the renal tissue with the endogenous nonlabeled murine albumin. Thus, our results provide molecular insights into the mechanism of albumin degradation in diabetic nephropathy.


Asunto(s)
Albúminas/metabolismo , Nefropatías Diabéticas/patología , Glomérulos Renales/patología , Túbulos Renales/patología , Imagen Molecular/métodos , Albuminuria/diagnóstico por imagen , Albuminuria/patología , Albuminuria/orina , Animales , Catepsina D/metabolismo , Nefropatías Diabéticas/diagnóstico por imagen , Nefropatías Diabéticas/orina , Modelos Animales de Enfermedad , Secciones por Congelación , Humanos , Glomérulos Renales/diagnóstico por imagen , Túbulos Renales/diagnóstico por imagen , Túbulos Renales/metabolismo , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo III/genética , Proteolisis , Eliminación Renal , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción
9.
Am J Physiol Renal Physiol ; 314(5): F773-F787, 2018 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-28724608

RESUMEN

Tubulointerstitial fibrosis (TIF) is a prominent factor in the progression of chronic kidney disease regardless of etiology. Avian erythroblastic leukemia viral oncogene homolog 4 (ErbB4) expression levels were inversely correlated to renal fibrosis in human fibrotic kidneys. In both unilateral ureteral obstruction (UUO) and ischemia-reperfusion injury followed by uninephrectomy (IRI/UNx) mouse models, expression levels of ErbB4 were elevated in the early stage of renal injury. Using mice with global ErbB4 deletion except for transgenic rescue in cardiac tissue ( ErbB4-/-ht+), we determined that UUO induced similar injury in proximal tubules compared with wild-type mice but more severe injury in distal nephrons. TIF was apparent earlier and was more pronounced following UUO in ErbB4-/-ht+ mice. With ErbB4 deletion, UUO injury inhibited protein kinase B phosphorylation and increased the percentage of cells in G2/M arrest. There was also increased nuclear immunostaining of yes-associated protein and increased expression of phospho-Mothers against decapentaplegic homolog 3, snail1, and vimentin. These results indicate that ErbB4 deletion accelerates the development and progression of renal fibrosis in obstructive nephropathy. Similar results were found in a mouse IRI/UNx model. In conclusion, increased expression of ErbB4 in the early stages of renal injury may reflect a compensatory effect to lessen tubulointerstitial injury.


Asunto(s)
Lesión Renal Aguda/etiología , Eliminación de Gen , Riñón/metabolismo , Receptor ErbB-4/deficiencia , Insuficiencia Renal Crónica/etiología , Daño por Reperfusión/etiología , Lesión Renal Aguda/genética , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Estudios de Casos y Controles , Proteínas de Ciclo Celular , Desdiferenciación Celular , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Fibrosis , Puntos de Control de la Fase G2 del Ciclo Celular , Predisposición Genética a la Enfermedad , Riñón/patología , Ratones Noqueados , Nefrectomía , Fenotipo , Fosfoproteínas/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor ErbB-4/genética , Receptor ErbB-4/metabolismo , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Daño por Reperfusión/genética , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Índice de Severidad de la Enfermedad , Transducción de Señal , Proteína smad3/metabolismo , Factores de Transcripción de la Familia Snail/metabolismo , Factores de Tiempo , Obstrucción Ureteral/complicaciones , Vimentina/metabolismo , Proteínas Señalizadoras YAP
10.
Tumour Biol ; 39(3): 1010428317695944, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28351330

RESUMEN

The aspartate aminotransferase-to-platelet ratio index has been reported to predict prognosis of patients with hepatocellular carcinoma. This study examined the prognostic potential of stratified aspartate aminotransferase-to-platelet ratio index for hepatocellular carcinoma patients undergoing curative liver resection. A total of 661 hepatocellular carcinoma patients were retrieved and the associations between aspartate aminotransferase-to-platelet ratio index and clinicopathological variables and survivals (overall survival and disease-free survival) were analyzed. Higher aspartate aminotransferase-to-platelet ratio index quartiles were significantly associated with poorer overall survival (p = 0.002) and disease-free survival (p = 0.001). Multivariate analysis showed aspartate aminotransferase-to-platelet ratio index to be an independent risk factor for overall survival (p = 0.018) and disease-free survival (p = 0.01). Patients in the highest aspartate aminotransferase-to-platelet ratio index quartile were at 44% greater risk of death than patients in the first quartile (hazard ratio = 1.445, 95% confidence interval = 1.081 - 1.931, p = 0.013), as well as 49% greater risk of recurrence (hazard ratio = 1.49, 95% confidence interval = 1.112-1.998, p = 0.008). Subgroup analysis also showed aspartate aminotransferase-to-platelet ratio index to be an independent predictor of poor overall survival and disease-free survival in patients positive for hepatitis B surface antigen or with cirrhosis (both p < 0.05). Similar results were obtained when aspartate aminotransferase-to-platelet ratio index was analyzed as a dichotomous variable with cutoff values of 0.25 and 0.62. Elevated preoperative aspartate aminotransferase-to-platelet ratio index may be independently associated with poor overall survival and disease-free survival in hepatocellular carcinoma patients following curative resection.


Asunto(s)
Aspartato Aminotransferasas/sangre , Plaquetas/metabolismo , Carcinoma Hepatocelular/sangre , Neoplasias Hepáticas/sangre , Adulto , Anciano , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Periodo Preoperatorio , Pronóstico , Resultado del Tratamiento
11.
World J Gastroenterol ; 22(39): 8798-8805, 2016 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-27818595

RESUMEN

AIM: To determine whether cyclooxygenase-2 (COX-2) and prostaglandin E1 receptor (EP1) contribute to disease and whether they help predict prognosis. METHODS: We retrospectively reviewed the records of 116 patients with hepatocellular carcinoma (HCC) who underwent surgery between 2008 and 2011 at our hospital. Expression of COX-2 and EP1 receptor was examined by immunohistochemistry of formalin-fixed, paraffin-embedded tissues using polyclonal antibodies. Possible associations between immunohistochemical scores and survival were determined. RESULTS: Factors associated with poor overall survival (OS) were alpha-fetoprotein > 400 ng/mL, tumor size ≥ 5 cm, and high EP1 receptor expression, but not high COX-2 expression. Disease-free survival was not significantly different between patients with low or high levels of COX-2 or EP1. COX-2 immunoreactivity was significantly higher in well-differentiated HCC tissues (Edmondson grade I-II) than in poorly differentiated tissues (Edmondson grade III-IV) (P = 0.003). EP1 receptor immunoreactivity was significantly higher in poorly differentiated tissue than in well-differentiated tissue (P = 0.001). CONCLUSION: COX-2 expression appears to be linked to early HCC events (initiation), while EP1 receptor expression may participate in tumor progression and predict survival.


Asunto(s)
Carcinoma Hepatocelular/enzimología , Ciclooxigenasa 2/biosíntesis , Ciclooxigenasa 2/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/enzimología , Subtipo EP1 de Receptores de Prostaglandina E/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/mortalidad , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento
12.
Am J Physiol Renal Physiol ; 311(4): F695-F707, 2016 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-27226110

RESUMEN

Transactivation of EGF receptor (EGFR) by angiotensin II (Ang II) plays important roles in the initiation and progression of chronic kidney diseases. Studies suggest that heparin-binding EGF-like factor (HB-EGF) may be a critical mediator in this process, but its role in vivo has not been investigated. In the current study, we found that in response to Ang II infusion, kidneys from endothelial HB-EGF deletion mice had significantly reduced EGFR activation compared with controls. Meanwhile, deletion of endothelial HB-EGF expression decreased Ang II infusion related renal injury, as demonstrated by 1) less albuminuria; 2) less glomerulosclerosis; 3) preserved endothelial integrity and decreased podocyte injury, as shown by greater glomerular tuft area and WT1-positive cells, and fewer apoptotic cells measured by cleaved caspase 3 staining; 4) reduced inflammation in the perivascular area and interstitium measured by F4/80 and CD3 immunostaining; and 5) reduced renal fibrosis. In conclusion, our results suggest that shedding of HB-EGF from endothelium plays an important role in Ang II-induced renal injury by linking Ang II-AT1R with EGFR transactivation. Inhibition of HB-EGF shedding could be a potential therapeutic strategy for chronic kidney disease.


Asunto(s)
Albuminuria/metabolismo , Endotelio Vascular/metabolismo , Receptores ErbB/metabolismo , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Factor de Crecimiento Similar a EGF de Unión a Heparina/genética , Riñón/metabolismo , Insuficiencia Renal Crónica/metabolismo , Albuminuria/inducido químicamente , Albuminuria/genética , Albuminuria/patología , Angiotensina II , Animales , Endotelio Vascular/patología , Glomeruloesclerosis Focal y Segmentaria/inducido químicamente , Glomeruloesclerosis Focal y Segmentaria/genética , Glomeruloesclerosis Focal y Segmentaria/patología , Factor de Crecimiento Similar a EGF de Unión a Heparina/metabolismo , Riñón/patología , Ratones , Ratones Noqueados , Fosforilación , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patología
13.
Physiol Rev ; 96(3): 1025-1069, 2016 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33003261

RESUMEN

The epidermal growth factor receptor (EGFR) is the prototypical member of a family of membrane-associated intrinsic tyrosine kinase receptors, the ErbB family. EGFR is activated by multiple ligands, including EGF, transforming growth factor (TGF)-α, HB-EGF, betacellulin, amphiregulin, epiregulin, and epigen. EGFR is expressed in multiple organs and plays important roles in proliferation, survival, and differentiation in both development and normal physiology, as well as in pathophysiological conditions. In addition, EGFR transactivation underlies some important biologic consequences in response to many G protein-coupled receptor (GPCR) agonists. Aberrant EGFR activation is a significant factor in development and progression of multiple cancers, which has led to development of mechanism-based therapies with specific receptor antibodies and tyrosine kinase inhibitors. This review highlights the current knowledge about mechanisms and roles of EGFR in physiology and disease.

14.
Kidney Int ; 86(3): 538-47, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24670412

RESUMEN

ErbB4 is highly expressed in the cystic kidneys with polycystic kidney diseases. To investigate its potential role in cystogenesis, cpk mice carrying a heart-rescued ErbB4 deletion were generated. Accelerated cyst progression and renal function deterioration were noted as early as 10 days postnatally in cpk mice with ErbB4 deletion compared to cpk mice, as indicated by increased cystic index, higher kidney weight to body weight ratios, and elevated BUN levels. No apparent defects in renal development were noted with ErbB4 deletion itself. Increased cell proliferation was predominately seen in the cortex of cystic kidneys with or without ErbB4 deletion. However, there was significantly more cell proliferation in the cyst-lining epithelial cells in cpk mice with ErbB4 deletion. TUNEL staining localized apoptotic cells mainly to the renal medulla. There were significantly more apoptotic cells in the cyst-lining epithelial cells in ErbB4-deleted cpk kidneys, with decreased levels of cyclin D1, increased levels of p21, p27, and cleaved caspase 3. Thus, lack of ErbB4 may contribute to elevated cell proliferation and unbalanced cell apoptosis, resulting in accelerated cyst formation and early renal function deterioration. These studies suggest that the high level of ErbB4 expression seen in cpk mice may exert relative cytoprotective effects in renal epithelia.


Asunto(s)
Células Epiteliales/metabolismo , Corteza Renal/patología , Médula Renal/patología , Enfermedades Renales Poliquísticas/genética , Enfermedades Renales Poliquísticas/patología , Receptor ErbB-4/genética , Animales , Apoptosis , Nitrógeno de la Urea Sanguínea , Caspasa 3/metabolismo , Proliferación Celular , Ciclina D/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Fibrosis , Eliminación de Gen , Ratones , Tamaño de los Órganos , Enfermedades Renales Poliquísticas/fisiopatología , Receptor ErbB-4/metabolismo
15.
Semin Cell Dev Biol ; 28: 2-11, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24513230

RESUMEN

In 1962, epidermal growth factor (EGF) was discovered by Dr. Stanley Cohen while studying nerve growth factor (NGF). It was soon recognized that EGF is the prototypical member of a family of peptide growth factors that activate the EGF receptors, and that the EGF/EGF receptor signaling pathway plays important roles in proliferation, differentiation and migration of a variety of cell types, especially in epithelial cells. After the basic characterization of EGF function in the first decade or so after its discovery, the studies related to EGF and its signaling pathway have extended to a broad range of investigations concerning its biological and pathophysiological roles in development and in human diseases. In this review, we briefly describe the gene organization and tissue distribution of EGF, with emphasis on its biological and pathological roles in human diseases.


Asunto(s)
Factor de Crecimiento Epidérmico/genética , Factor de Crecimiento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Transducción de Señal/fisiología , Animales , Diferenciación Celular/fisiología , Células Epiteliales/metabolismo , Expresión Génica/fisiología , Humanos
16.
Kidney Int ; 84(6): 1176-88, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23760291

RESUMEN

Decreased nitric oxide bioavailability has an important role in the initiation and progression of diabetic nephropathy, but the underlying mechanisms remain unclear. Here, we found that heparin-binding epidermal growth factor-like growth factor (HB-EGF) expression levels increased in the kidneys of both endothelial nitric oxide synthase (eNOS)-knockout and eNOS-knockout diabetic (Lepr(db/db)) mice as early as at 8 weeks of age. Further increases in expression were only seen in eNOS-knockout diabetic mice and paralleled the progression of glomerulopathy. HB-EGF expression increased in endothelium, podocytes, and tubular epithelial cells. In cultured glomerular endothelial cells, the nitric oxide synthase inhibitors NG-nitro-L-arginine methyl ester (L-NAME) or L-N5-(1-iminoethyl) ornithine increased HB-EGF protein expression. Administration of L-NAME dramatically increased renal HB-EGF expression and urinary HB-EGF excretion in diabetic mice. On the other hand, replenishing nitric oxide with sodium nitrate in eNOS-knockout diabetic mice reduced urinary HB-EGF excretion and inhibited the progression of diabetic nephropathy. Furthermore, specific deletion of HB-EGF expression in the endothelium attenuated renal injury in diabetic eNOS-knockout mice. Thus, our results suggest that decreased nitric oxide bioavailability leads to increased HB-EGF expression, which may be an important mediator of the resulting progressive diabetic nephropathy in eNOS-knockout diabetic mice.


Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Nefropatías Diabéticas/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Riñón/metabolismo , Óxido Nítrico/metabolismo , Albuminuria/etiología , Albuminuria/metabolismo , Animales , Células Cultivadas , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/prevención & control , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Células Endoteliales/metabolismo , Inhibidores Enzimáticos/farmacología , Factor de Crecimiento Similar a EGF de Unión a Heparina , Péptidos y Proteínas de Señalización Intercelular/deficiencia , Péptidos y Proteínas de Señalización Intercelular/genética , Riñón/irrigación sanguínea , Riñón/efectos de los fármacos , Glomérulos Renales/metabolismo , Túbulos Renales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos del Músculo Liso/metabolismo , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/deficiencia , Óxido Nítrico Sintasa de Tipo III/genética , Factores de Tiempo , Regulación hacia Arriba
17.
FASEB J ; 23(6): 1935-45, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19193720

RESUMEN

ErbB4, a type I transmembrane receptor tyrosine kinase, is a member of the epidermal growth factor receptor family. Its cleavage releases an intracellular C-terminal domain (ICD), which can be either degraded following ubiqitination or translocated to the nucleus and regulate gene expression. There are 2 ErbB4 ICD isoforms: CYT-1 and CYT-2. We and others have previously reported that following cleavage, CYT-2 selectively translocates to the nucleus. In the current study we found that following cleavage, the intracellular levels of CYT-1 ICD decreased rapidly, while levels of CYT-2 ICD remained relatively stable. CYT-1 ICD degradation could be prevented by administration of either the proteasome inhibitor lactacystin or the lysosome inhibitor chloroquine, indicating both proteasomal and lysosomal degradation. Further studies implicated Nedd4, an E3 ubiquitin ligase, as a mediator of CYT-1 ubiquitination and degradation. The interaction of Nedd4 with CYT-1 was shown by coimmnunoprecipitation, an in vitro direct binding assay, and an in vitro ubiquitination assay. Three PPxY or PY motifs present in the CYT-1 C terminus are necessary for binding by Nedd4 WW domains, because impaired interactions are seen in mutation of any of the PY motifs. Nedd4-CYT-1 binding was associated with increased CYT-1 ubiquitination following proteasome inhibitor treatment. Impaired Nedd4 binding to CYT-1 by PY motif mutations led to increased CYT-1 ICD stability, whereas only one of the PY motif mutations (Y1056A), which disrupts the binding sites for both a WW domain and an SH2 domain of PI3 kinase, demonstrated enhanced nuclear translocation following HB-EGF treatment. These studies indicate that Nedd4 mediates ErbB4 CYT-1 ICD ubiquitination and degradation, and the prevention of both WW binding and PI3 kinase activity are required for ErbB4 nuclear translocation.


Asunto(s)
Receptores ErbB/metabolismo , Isoformas de Proteínas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina/metabolismo , Secuencias de Aminoácidos , Animales , Células Cultivadas , Perros , Complejos de Clasificación Endosomal Requeridos para el Transporte , Inhibidores Enzimáticos/metabolismo , Receptores ErbB/genética , Humanos , Lisosomas/metabolismo , Mutagénesis Sitio-Dirigida , Ubiquitina-Proteína Ligasas Nedd4 , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma , Isoformas de Proteínas/genética , Estructura Terciaria de Proteína , Receptor ErbB-4 , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Acetato de Tetradecanoilforbol/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitinación
18.
Exp Cell Res ; 315(4): 602-10, 2009 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-18761338

RESUMEN

Mammalian kidney expresses all of the members of the ErbB family of receptors and their respective ligands. Studies support a role for ErbB family receptor activation in kidney development and differentiation. Under physiologic conditions, EGFR activation appears to play an important role in the regulation of renal hemodynamics and electrolyte handling by the kidney, while in different pathophysiologic states, EGFR activation may mediate either beneficial or detrimental effects to the kidney. This article provides an overview of the expression profile of the ErbB family of ligands and receptors in the mammalian kidney and summarizes known physiological and pathophysiological roles of EGFR activation in the organ.


Asunto(s)
Receptores ErbB/metabolismo , Riñón/crecimiento & desarrollo , Riñón/fisiopatología , Animales , Humanos , Riñón/lesiones , Ligandos , Proteínas Oncogénicas v-erbB/clasificación , Proteínas Oncogénicas v-erbB/metabolismo
19.
J Cell Biochem ; 104(5): 1843-52, 2008 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-18393358

RESUMEN

The myotubularin (MTM) enzymes are phosphatidylinositol 3-phosphate (PI3P) and phosphatidylinositol 3,5-bisphosphate phosphatases. Mutation of MTM1, the founder member of this family, is responsible for X-linked myotubular myopathy in humans. Here, we have isolated and characterized a Caenorhabditis elegans homology of the enzymes designated ceMTM3. ceMTM3 preferably dephosphorylates PI3P and contains a FYVE lipid-binding domain at its C-terminus which binds PI3P. Immunoblotting analyses revealed that the enzyme is expressed during the early development and adulthood of the animal. Immunofluorescent staining revealed predominant expression of the enzyme in eggs and muscles. Knockdown of the enzyme by using feeding-based RNA interference resulted in an increased level of PI3P and caused severe impairment of body movement of the worms at their post-reproductive ages and significantly shortened their lifespan. This study thus reveals an important role of the MTM phosphatases in maintaining muscle function, which may have clinical implications in prevention and treatment of sarcopenia.


Asunto(s)
Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/enzimología , Proteínas Tirosina Fosfatasas no Receptoras/química , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Animales , Clonación Molecular , Locomoción , Fosfatos de Fosfatidilinositol/metabolismo , Estructura Terciaria de Proteína , Transporte de Proteínas , Interferencia de ARN , Especificidad por Sustrato , Análisis de Supervivencia
20.
Mol Biol Cell ; 18(11): 4446-56, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17761534

RESUMEN

ErbB4, a member of the epidermal growth factor (EGF) receptor family that can be activated by heregulin beta1 and heparin binding (HB)-EGF, is expressed as alternatively spliced isoforms characterized by variant extracellular juxtamembrane (JM) and intracellular cytoplasmic (CYT) domains. ErbB4 plays a critical role in cardiac and neural development. We demonstrated that ErbB4 is expressed in the ureteric buds and developing tubules of embryonic rat kidney and in collecting ducts in adult. The predominant isoforms expressed in kidney are JM-a and CYT-2. In ErbB4-transfected MDCK II cells, basal cell proliferation and hepatocyte growth factor (HGF)-induced tubule formation were decreased by all four isoforms. Only JM-a/CYT-2 cells formed tubules upon HB-EGF stimulation. ErbB4 was activated by both HRG-beta1 and HB-EGF stimulation; however, compared with HRG-beta1, HB-EGF induced phosphorylation of the 80-kDa cytoplasmic cleavage fragment of the JM-a/CYT-2 isoform. HB-EGF also induced early activation of ERK1/2 in JM-a/CYT-2 cells and promoted nuclear translocation of the JM-a/CYT-2 cytoplasmic tail. In summary, our data indicate that JM-a/CYT-2, the ErbB4 isoform that is proteinase cleavable but does not contain a PI3K-binding domain in its cytoplasmic tail, mediates important functions in renal epithelial cells in response to HB-EGF.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Receptores ErbB/metabolismo , Péptidos y Proteínas de Señalización Intercelular/farmacología , Neurregulina-1/farmacología , Transporte Activo de Núcleo Celular , Envejecimiento/fisiología , Secuencia de Aminoácidos , Animales , Adhesión Celular , Línea Celular , Proliferación Celular , Colágeno Tipo I , Perros , Receptores ErbB/química , Receptores ErbB/genética , Regulación de la Expresión Génica , Factor de Crecimiento Similar a EGF de Unión a Heparina , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Riñón/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Datos de Secuencia Molecular , Fosforilación , Ratas , Receptor ErbB-4
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