RESUMEN
Recent studies have confirmed that ß-adrenergic receptors (ß-ARs) are expressed on the surface of osteoblasts and osteoclasts, and that the sympathetic nervous system can regulate bone metabolism by activating them. ß-AR blockers (BBs) are commonly used in the treatment of cardiovascular diseases in the elderly. It is important to investigate whether BBs have a beneficial effect on bone metabolism in the treatment of cardiovascular diseases, so as to expand their clinical application. This article reviews the effects of BB on bone metabolism and the progress of clinical research.
RESUMEN
Amyloid precursor protein (APP) is ubiquitously expressed in various types of cells including bone cells. Mutations in App gene result in early-onset Alzheimer's disease (AD). However, little is known about its physiological function in bone homeostasis. Here, we provide evidence for APP's role in promoting bone formation. Mice that knocked out App gene (APP-/-) exhibit osteoporotic-like deficit, including reduced trabecular and cortical bone mass. Such a deficit is likely due in large to a decrease in osteoblast (OB)-mediated bone formation, as little change in bone resorption was detected in the mutant mice. Further mechanical studies of APP-/- OBs showed an impairment in mitochondrial function, accompanied with increased reactive oxygen species (ROS) and apoptosis. Intriguingly, these deficits, resemble to those in Tg2576 animal model of AD that expresses Swedish mutant APP (APPswe), were diminished by treatment with an anti-oxidant NAC (n-acetyl-l-cysteine), uncovering ROS as a critical underlying mechanism. Taken together, these results identify an unrecognized physiological function of APP in promoting OB survival and bone formation, implicate APPswe acting as a dominant negative factor, and reveal a potential clinical value of NAC in treatment of AD-associated osteoporotic deficits.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Mitocondrias/metabolismo , Mitocondrias/fisiología , Osteoblastos/metabolismo , Osteoblastos/fisiología , Osteogénesis/fisiología , Estrés Oxidativo/fisiología , Acetilcisteína/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Antioxidantes/metabolismo , Apoptosis/fisiología , Resorción Ósea/metabolismo , Resorción Ósea/fisiopatología , Huesos/metabolismo , Huesos/fisiopatología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Células Cultivadas , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
YAP (yes-associated protein) is a transcriptional factor that is negatively regulated by Hippo pathway, a conserved pathway for the development and size control of multiple organs. The exact function of YAP in bone homeostasis remains controversial. Here we provide evidence for YAP's function in promoting osteogenesis, suppressing adipogenesis, and thus maintaining bone homeostasis. YAP is selectively expressed in osteoblast (OB)-lineage cells. Conditionally knocking out Yap in the OB lineage in mice reduces cell proliferation and OB differentiation and increases adipocyte formation, resulting in a trabecular bone loss. Mechanistically, YAP interacts with ß-catenin and is necessary for maintenance of nuclear ß-catenin level and Wnt/ß-catenin signaling. Expression of ß-catenin in YAP-deficient BMSCs (bone marrow stromal cells) diminishes the osteogenesis deficit. These results thus identify YAP-ß-catenin as an important pathway for osteogenesis during adult bone remodeling and uncover a mechanism underlying YAP regulation of bone homeostasis.
RESUMEN
Ghrelin has exhibited potent anti-inflammatory effects on various inflammatory diseases. The aim of this study was to investigate the potential effects of ghrelin on a model of ventilator-induced lung injury (VILI) established in rats. Male Sprague-Dawley rats were randomly divided into three groups: low volume ventilation (LV, Vt=8ml/kg) group, a VILI group (Vt=30ml/kg), and a VILI group pretreated with ghrelin (GH+VILI). For the LV group, for the VILI and GH+VILI groups, the same parameters were applied except the tidal volume was increased to 40ml/kg. After 4h of MV, blood gas, lung elastance, and levels of inflammatory mediators, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1ß, and (MIP)-2 and total protein in bronchoalveolar lavage fluid (BALF) were analyzed. Myeloperoxidase (MPO), (TLR)-4, and NF-κB, were detected in lung tissues. Water content (wet-to-dry ratio) and lung morphology were also evaluated. The VILI group had a higher acute lung injury (ALI) score, wet weight to dry ratio, MPO activity, and concentrations of inflammatory mediators (TNF-α, IL-6, IL-1ß, and MIP-2) in BALF, as well as higher levels of TLR4 and NF-κB expression than the LV group (P<0.05). All histopathologic ALI, the inflammatory profile, and pulmonary dynamics have been improved by ghrelin pretreatment (P<0.05). Ghrelin pretreatment also decreased TLR4 expression and NF-κB activity compared with the VILI group (P<0.05). Ghrelin pretreatment attenuated VILI in rats by reducing MV-induced pulmonary inflammation and might represent a novel therapeutic candidate for protection against VILI.
Asunto(s)
Antiinflamatorios/uso terapéutico , Líquido del Lavado Bronquioalveolar/inmunología , Ghrelina/uso terapéutico , Neumonía/tratamiento farmacológico , Lesión Pulmonar Inducida por Ventilación Mecánica/tratamiento farmacológico , Animales , Células Cultivadas , Citocinas/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Masculino , Peroxidasa/metabolismo , Ratas , Ratas Sprague-Dawley , Respiración ArtificialRESUMEN
Vertical sleeve gastrectomy (VSG) is becoming more and more popular among the world. Despite its dramatic efficacy, however, the mechanism of VSG remains largely undetermined. This study aimed to test interferon (IFN)-γ secretion n of mesenteric lymph nodes in obese mice (ob/ob mice), a model of VSG, and its relationship with farnesoid X receptor (FXR) expression in the liver and small intestine, and to investigate the weight loss mechanism of VSG. The wild type (WT) mice and ob/ob mice were divided into four groups: A (WT+Sham), B (WT+VSG), C (ob/ob+Sham), and D (ob/ob+VSG). Body weight values were monitored. The IFN-γ expression in mesenteric lymph nodes of ob/ob mice pre- and post-operation was detected by flow cytometry (FCM). The FXR expression in the liver and small intestine was detected by Western blotting. The mouse AML-12 liver cells were stimulated with IFN-γ at different concentrations in vitro. The changes of FXR expression were also examined. The results showed that the body weight of ob/ob mice was significantly declined from (40.6±2.7) g to (27.5±3.8) g on the 30th day after VSG (P<0.05). At the same time, VSG induced a higher level secretion of IFN-γ in mesenteric lymph nodes of ob/ob mice than that pre-operation (P<0.05). The FXR expression levels in the liver and small intestine after VSG were respectively 0.97±0.07 and 0.84±0.07 fold of GAPDH, which were significantly higher than pre-operative levels of 0.50±0.06 and 0.48±0.06 respectively (P<0.05). After the stimulation of AML-12 liver cells in vitro by different concentrations of IFN-γ (0, 10, 25, 50, 100, and 200 ng/mL), the relative FXR expression levels were 0.22±0.04, 0.31±0.04, 0.39±0.05, 0.38±0.05, 0.56±0.06, and 0.35±0.05, respectively, suggesting IFN-γ could distinctly promote the FXR expression in a dose-dependent manner in comparison to those cells without IFN-γ stimulation (P<0.05). It was concluded that VSG induces a weight loss in ob/ob mice by increasing IFN-γ secretion of mesenteric lymph nodes, which then increases the FXR expression of the liver and small intestine.
Asunto(s)
Interferón gamma/biosíntesis , Intestino Delgado/efectos de los fármacos , Hígado/efectos de los fármacos , Ganglios Linfáticos/efectos de los fármacos , Obesidad/cirugía , Receptores Citoplasmáticos y Nucleares/agonistas , Animales , Peso Corporal , Línea Celular , Gastrectomía/métodos , Expresión Génica , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Interferón gamma/metabolismo , Interferón gamma/farmacología , Intestino Delgado/metabolismo , Hígado/metabolismo , Ganglios Linfáticos/metabolismo , Mesenterio/efectos de los fármacos , Mesenterio/metabolismo , Ratones , Ratones Obesos , Obesidad/metabolismo , Obesidad/patología , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Pérdida de PesoRESUMEN
Our objective was to evaluate thyroid nodule malignancy prediction using thyroid function tests, autoantibodies, ultrasonographic imaging, and clinical data. We conducted a retrospective cohort study in 1400 patients with nodular thyroid disease (NTD). The thyroid stimulating hormone (TSH) concentration was significantly higher in patients with differentiated thyroid cancer (DTC) versus benign thyroid nodular disease (BTND) (p = 0.004). The receiver operating characteristic curve of TSH showed an AUC of 0.58 (95% CI 0.53-0.62, p = 0.001), sensitivity of 74%, and specificity of 57% at a cut-off of 1.59 mIU/L. There was an incremental increase in TSH concentration along with the increasing tumor size (p < 0.001). Thyroglobulin antibody (TgAb) concentration was associated with an increased risk of malignancy (p = 0.029), but this association was lost when the effect of TSH was taken into account (p = 0.11). Thyroid ultrasonographic characteristics, including fewer than three nodules, hypoechoic appearance, solid component, poorly defined margin, intranodular or peripheral-intranodular flow, and punctate calcification, can be used to predict the risk of thyroid cancer. In conclusion, our study suggests that preoperative serum TSH concentration, age, and ultrasonographic features can be used to predict the risk of malignancy in patients with NTD.
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Parathyroid hormone (PTH) plays critical, but distinct, roles in bone remodeling, including bone formation (anabolic response) and resorption (catabolic response). Although its signaling and function have been extensively investigated, it just began to be understood how distinct functions are induced by PTH activating a common receptor, the PTH type 1 receptor (PTH1R), and how PTH1R signaling is terminated. Here, we provide evidence for vacuolar protein sorting 35 (VPS35), a major component of retromer, in regulating PTH1R trafficking, turning off PTH signaling, and promoting its catabolic function. VPS35 is expressed in osteoblast (OB)-lineage cells. VPS35-deficiency in OBs impaired PTH(1-34)-promoted PTH1R translocation to the trans-Golgi network, enhanced PTH(1-34)-driven signaling, and reduced PTH(1-34)'s catabolic response in culture and in mice. Further mechanical studies revealed that VPS35 interacts with not only PTH1R, but also protein phosphatase 1 regulatory subunit 14C (PPP1R14C), an inhibitory subunit of PP1 phosphatase. PPP1R14C also interacts with PTH1R, which is necessary for the increased endosomal PTH1R signaling and decreased PTH(1-34)'s catabolic response in VPS35-deficient OB-lineage cells. Taken together, these results suggest that VPS35 deregulates PTH1R-signaling likely by its interaction with PTH1R and PPP1R14C. This event is critical for the control of PTH(1-34)-signaling dynamics, which may underlie PTH-induced catabolic response and adequate bone remodeling.
Asunto(s)
Osteoblastos/metabolismo , Proteína Fosfatasa 1/metabolismo , Receptor de Hormona Paratiroídea Tipo 1/metabolismo , Transducción de Señal , Proteínas de Transporte Vesicular/metabolismo , Animales , Biomarcadores , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Remodelación Ósea/genética , Huesos/metabolismo , Línea Celular , Técnicas de Cocultivo , Endosomas/metabolismo , Aparato de Golgi/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular , Ratones , Ratones Noqueados , Modelos Biológicos , Hormona Paratiroidea/farmacología , Unión Proteica , Transporte de Proteínas , Transducción de Señal/efectos de los fármacos , Proteínas de Transporte Vesicular/genéticaRESUMEN
Patients of Alzheimer's disease (AD) frequently have lower bone mineral density and higher rate of hip fracture. Tg2576, a well characterized AD animal model that ubiquitously express Swedish mutant amyloid precursor protein (APPswe), displays not only AD-relevant neuropathology, but also age-dependent bone deficits. However, the underlying mechanisms remain poorly understood. As APP is implicated as a regulator of iron export, and the metal chelation is considered as a potential therapeutic strategy for AD, we examined iron chelation's effect on the osteoporotic deficit in Tg2576 mice. Remarkably, in vivo treatment with iron chelator, clinoquinol (CQ), increased both trabecular and cortical bone-mass, selectively in Tg2576, but not wild type (WT) mice. Further in vitro studies showed that low concentrations of CQ as well as deferoxamine (DFO), another iron chelator, selectively inhibited osteoclast (OC) differentiation, without an obvious effect on osteoblast (OB) differentiation. Intriguingly, both CQ and DFO's inhibitory effect on OC was more potent in bone marrow macrophages (BMMs) from Tg2576 mice than that of wild type controls. The reduction of intracellular iron levels in BMMs by CQ was also more dramatic in APPswe-expressing BMMs. Taken together, these results demonstrate a potent inhibition on OC formation and activation in APPswe-expressing BMMs by iron chelation, and reveal a potential therapeutic value of CQ in treating AD-associated osteoporotic deficits.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Diferenciación Celular/efectos de los fármacos , Clioquinol/uso terapéutico , Quelantes del Hierro/uso terapéutico , Osteoclastos/fisiología , Enfermedad de Alzheimer/patología , Animales , Resorción Ósea , Proteínas de Transporte de Catión/metabolismo , Células Cultivadas , Clioquinol/farmacología , Evaluación Preclínica de Medicamentos , Quelantes del Hierro/farmacología , Factor Estimulante de Colonias de Macrófagos/fisiología , Macrófagos/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Osteoblastos/efectos de los fármacos , Osteoclastos/efectos de los fármacos , Ligando RANK/fisiologíaRESUMEN
The objective of this study was to reveal the exact role of Kupffer cells in the diet-induced insulin resistance, inflammation and liver autophagy. C57BL/6j male mice were fed with either chow diet or high-fat diet (HFD) for 12 weeks. Meanwhile, HFD feeding mice received an intraperitoneal injection of either 0.2% GdCl3 solution (20mg/kg) twice a week to deplete Kupffer cells or natural saline (5mL/kg) as control. The mRNA expressions of Kupffer cells markers (CD68 and F4/80), insulin sensitivity, TNF-α concentration and NF-κB activation and parameters of autophagy were assessed. Results demonstrated that CD68 and F4/80 mRNA expressions in the liver were up-regulated in HFD fed animals, while significantly reduced after GdCl3 administration. HFD feeding led to insulin resistance and TNF-α level and activation of NF-κB in insulin-sensitive tissues (liver, adipose tissue and skeletal muscle) were significantly elevated. Interestingly, alterations above were reversed by varying degrees but significantly after Kupffer cells depletion. Furthermore, western blot showed hepatic LC3-II as well as phosphorylation of AMPK in liver and skeletal muscle were significantly lower in mice fed HFD, and these changes dramatically ameliorated by GdCl3 treating. In conclusion, selective depletion of Kupffer cells significantly attenuated diet-induced insulin resistance, inflammation and promoted liver autophagy. Strategies targeting Kupffer cells function or autophagic processes could be a promising approach to counteract diet induced obesity and related metabolic disorders.
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Dieta Alta en Grasa , Inflamación/metabolismo , Resistencia a la Insulina/fisiología , Macrófagos del Hígado/citología , Hígado/metabolismo , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Autofagia , Macrófagos del Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Bone mass is maintained by balanced activity of osteoblasts and osteoclasts. Lrp4 (low-density lipoprotein receptor related protein 4) is a member of the LDL receptor family, whose mutations have been identified in patients with high-bone-mass disorders, such as sclerosteosis and van Buchem diseases. However, it remains unknown whether and how Lrp4 regulates bone-mass homeostasis in vivo. Here we provide evidence that Lrp4-null mutation or specific mutation in osteoblast-lineage cells increased cortical and trabecular bone mass, which was associated with elevated bone formation and impaired bone resorption. This phenotype was not observed in osteoclast-selective Lrp4 knockout mice. Mechanistic studies indicate that loss of Lrp4 function in osteoblast-lineage cells increased serum levels of sclerostin, a key factor for bone-mass homeostasis that interacts with Lrp4, but abolished the inhibition of Wnt/ß-catenin signaling and osteoblastic differentiation by sclerostin. Concomitantly, sclerostin induction of RANKL (receptor activator of nuclear kappa B ligand) was impaired, leading to a lower ratio of RANKL over OPG (osteoprotegerin) (a key factor for osteoclastogenesis). Taken together, these results support the view for Lrp4 as a receptor of sclerostin to inhibit Wnt/ß-catenin signaling and bone formation and identify Lrp4 as a critical player in bone-mass homeostasis.
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Resorción Ósea/metabolismo , Resorción Ósea/patología , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogénesis , Receptores de LDL/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Aminoácidos/sangre , Animales , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Resorción Ósea/sangre , Diferenciación Celular , Linaje de la Célula , Fémur/diagnóstico por imagen , Fémur/patología , Glicoproteínas/sangre , Glicoproteínas/metabolismo , Péptidos y Proteínas de Señalización Intercelular , Proteínas Relacionadas con Receptor de LDL , Ratones Noqueados , Músculos/metabolismo , Especificidad de Órganos , Osteoblastos/patología , Osteocalcina/metabolismo , Osteoclastos/patología , Osteoprotegerina/metabolismo , Ligando RANK/metabolismo , Receptores de LDL/deficiencia , Células del Estroma/metabolismo , Células del Estroma/patología , Vía de Señalización Wnt , Microtomografía por Rayos X , beta Catenina/metabolismoRESUMEN
OBJECTIVE: To investigate the effect of temperature on hospital admission among patients with chronic systolic heart failure (CSHF). METHODS: Data regarding in-hospital patients with CSHF were gathered from 12 hospitals in Hubei province, between 2000 and 2010. Patients with a history of congenital heart disease and the history of cancer from this series, were excluded. Chi-square (χ(2)) tests and t tests were used for descriptive analysis. Univariate and multivariate logistic regression methods were performed to determinate the risk of hospital admission of every month to compare with the previous one. We used 2-tailed 95% confidence interval (CI), and tests with P < 0.01 to consider the significant levels, statistically. We also used the SPSS 13.0 for Windows, release 15, 2006 (SPSS Inc, Chicago, Ill) for data analyses. RESULTS: (1) 48 964 patients were enrolled in the present study. The numbers of admission increased 18.71%, 13.84%, -21.90%, -34.62%, -21.97%, -3.81%, -2.04%, 10.13%, -17.13%, -0.85%, 21.54% and 42.70% from January to December when compared to the average number of admission. (2) The odds ratios (ORs) (95% CI, P values) of hospital admission in January, February and December were 1.09 (0.96 - 1.23, 0.54), 0.98 (0.84 - 1.10, 0.46) and 0.96 (0.84 - 1.08, 0.59), respectively in females which did not show any significant differences when compared to the number in August. However the ratios were 0.61 (0.54 - 0.69, < 0.01), 0.80 (0.68 - 0.92, < 0.01) and 0.73 (0.64 - 0.83, < 0.01), respectively, in males that showed significant differences when, compared to the figures in August. (3) The OR of admission increased more when temperature got lower for patients with coronary artery disease, hypertension heart disease or rheumatic heart disease, but not with dilated cardiomyopathy. (4) The OR of admission showed a different impact on patients with different occupation, along with the change of temperature. Low or high temperature did not seem to have different effects on the OR of admission in patients who were free-lanced or unemployed. CONCLUSION: Temperature seemed to have significant effects on the risk of admission, which related to gender, etiology or occupation.
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Insuficiencia Cardíaca , Pacientes Internos/estadística & datos numéricos , Temperatura , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Clima , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Reduced bone mineral density and hip fracture are frequently observed in patients with Alzheimer's disease (AD). However, mechanisms underlying their association remain poorly understood. Amyloid precursor protein (APP) is a transmembrane protein that is ubiquitously expressed in bone marrow stromal cells (BMSCs), osteoblasts (OBs), macrophages (BMMs), and osteoclasts (OCs). Mutations in the APP gene identified in early-onset AD patients are believed to cause AD. But little is known about APP's role in bone remodeling. Here, we present evidence for Swedish mutant APP (APPswe) in suppression of OB differentiation and function in culture and in mouse. APP expression in BMSCs increases during aging. Ubiquitous expression of APPswe in young adult Tg2576 transgenic mice (under the control of a prion promoter) recaptured skeletal "aging-like" deficits, including decreased OB genesis and bone formation, increased adipogenesis and bone marrow fat, and enhanced OC genesis and bone resorption. Remarkably, selective expression of APPswe in mature OB-lineage cells in TgAPPswe-Ocn mice (under the control of osteocalcin [Ocn] promoter-driven Cre) also decreased OB genesis and increased OC formation, resulting in a trabecular bone loss. These results thus suggest a cell-autonomous role for APPswe in suppressing OB formation and function, but a nonautonomous effect on OC genesis. Notably, increased adipogenesis and elevated bone marrow fat were detected in young adult Tg2576 mice, but not in TgAPPswe-Ocn mice, implying that APPswe in BMSCs and/or multicell types in bone marrow promotes bone marrow adipogenesis. Intriguingly, the skeletal aging-like deficits in young adult Tg2576 mice were prevented by treatment with N-acetyl-L-cysteine (NAC), an antioxidant, suggesting that reactive oxygen species (ROS) may underlie APPswe-induced osteoporotic deficits. Taken together, these results demonstrate a role for APPswe in suppressing OB differentiation and bone formation, implicate APPswe as a detrimental factor for AD-associated osteoporotic deficit, and reveal a potential clinical value of NAC in the treatment of osteoporotic deficits. © 2013 American Society for Bone and Mineral Research.
Asunto(s)
Acetilcisteína/uso terapéutico , Péptidos beta-Amiloides/metabolismo , Diferenciación Celular , Mutación/genética , Osteoblastos/patología , Osteoporosis/tratamiento farmacológico , Osteoporosis/patología , Acetilcisteína/farmacología , Fosfatasa Ácida/metabolismo , Adipogénesis/efectos de los fármacos , Envejecimiento/patología , Animales , Animales Recién Nacidos , Resorción Ósea/complicaciones , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/metabolismo , Resorción Ósea/patología , Huesos/efectos de los fármacos , Huesos/metabolismo , Huesos/patología , Diferenciación Celular/efectos de los fármacos , Linaje de la Célula/efectos de los fármacos , Células Cultivadas , Cricetinae , Humanos , Isoenzimas/metabolismo , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Tamaño de los Órganos/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteogénesis/efectos de los fármacos , Osteoporosis/complicaciones , Osteoporosis/metabolismo , Fosfatasa Ácida TartratorresistenteRESUMEN
Receptor activator of NF-κB (RANK) plays a critical role in osteoclastogenesis, an essential process for the initiation of bone remodeling to maintain healthy bone mass and structure. Although the signaling and function of RANK have been investigated extensively, much less is known about the negative regulatory mechanisms of its signaling. We demonstrate in this paper that RANK trafficking, signaling, and function are regulated by VPS35, a major component of the retromer essential for selective endosome to Golgi retrieval of membrane proteins. VPS35 loss of function altered RANK ligand (RANKL)-induced RANK distribution, enhanced RANKL sensitivity, sustained RANKL signaling, and increased hyperresorptive osteoclast (OC) formation. Hemizygous deletion of the Vps35 gene in mice promoted hyperresorptive osteoclastogenesis, decreased bone formation, and caused a subsequent osteoporotic deficit, including decreased trabecular bone volumes and reduced trabecular thickness and density in long bones. These results indicate that VPS35 critically deregulates RANK signaling, thus restraining increased formation of hyperresorptive OCs and preventing osteoporotic deficits.
Asunto(s)
Osteoclastos/metabolismo , Osteoporosis/metabolismo , Ligando RANK/metabolismo , Transducción de Señal , Proteínas de Transporte Vesicular/metabolismo , Animales , Huesos/metabolismo , Huesos/patología , Aparato de Golgi/genética , Aparato de Golgi/metabolismo , Ratones , Ratones Mutantes , Tamaño de los Órganos , Osteoclastos/patología , Osteoporosis/genética , Osteoporosis/patología , Transporte de Proteínas/genética , Ligando RANK/genética , Receptor Activador del Factor Nuclear kappa-B/genética , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Proteínas de Transporte Vesicular/genéticaRESUMEN
The aim of this study was to investigate the effect of propofol and its relation to postoperation recovery in children undergoing cardiac surgery with cardiopulmonary bypass (CPB). Twenty ASA class I-II children with congenital heart disease undergoing cardiac surgery were randomly allocated to a propofol group (n = 10) or a control group (n = 10). Blood samples were collected at five time points: before operation (T (0)), before the start of CPB (T (1)), 25 min after the aorta was cross-clamped (T (2)), 30 min after release of the aortic cross-clamp (T (3)), and 2 h after the cessation of CPB (T (4)). The myocardial samples were collected at the time of incubation into the right atrium before CPB and at 30 min after reperfusion. After CPB, propofol significantly suppressed the increase of the serum lactate dehydrogenase (LDH), creatine phosphokinase (CK), and interleukin-6 (IL-6) levels and the decrease of the serum superoxide dismutase (SOD) level. In addition, propofol inhibited the increase of myocardial nuclear factor-κB (NF-κB) expression and inflammatory cells infiltration after CPB. Furthermore, propofol significantly shortened the tracheal extubation time. In conclusion, propofol exerts a protective effect and improves postoperation recovery through its antioxidant and anti-inflammatory actions in children undergoing cardiac surgery with CPB.
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Procedimientos Quirúrgicos Cardíacos/métodos , Puente Cardiopulmonar , Cardiopatías Congénitas/cirugía , Estrés Oxidativo/efectos de los fármacos , Cuidados Preoperatorios/métodos , Propofol/administración & dosificación , Recuperación de la Función/efectos de los fármacos , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Cardiopatías Congénitas/metabolismo , Humanos , Hipnóticos y Sedantes/administración & dosificación , Lactante , Inyecciones Intravenosas , Masculino , Miocardio/metabolismo , Periodo Posoperatorio , Resultado del TratamientoRESUMEN
Insulin therapy has been shown to contribute to extended glycemia remission in newly diagnosed patients with type 2 diabetes mellitus. This study investigated the effects of insulin treatment on pancreatic lipid content, and ß-cell apoptosis and proliferation in glucose-intolerant rats to explore the protective role of insulin on ß-cell function. A rat glucose-intolerant model was induced by streptozotocin and a high-fat diet. Plasma and pancreatic triglycerides, free fatty acids, and insulin were measured; and pancreatic ß-cell cell apoptosis and proliferation were detected by a propidium iodide cell death assay and immunofluorescence for proliferating cell nuclear antigen. Relative ß-cell area was determined by immunohistochemistry for insulin, whereas insulin production in pancreas was assessed by reverse transcriptase polymerase chain reaction. Islet ß-cell secreting function was assessed by the index ΔI30/ΔG30. Glucose-intolerant rats had higher pancreatic lipid content, more islet ß-cell apoptosis, lower ß-cell proliferation, and reduced ß-cell area in pancreas when compared with controls. Insulin therapy reduced blood glucose, inhibited pancreatic lipid accumulation and islet ß-cell apoptosis, and increased ß-cell proliferation and ß-cell area in glucose-intolerant rats. Furthermore, impaired insulin secretion and insulin production in glucose-intolerant rats were improved by insulin therapy. Insulin can preserve ß-cell function by protecting islets from glucotoxicity and lipotoxicity. It can also ameliorate ß-cell area by enhancing ß-cell proliferation and reducing ß-cell apoptosis.
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Intolerancia a la Glucosa/tratamiento farmacológico , Células Secretoras de Insulina/efectos de los fármacos , Insulina/uso terapéutico , Animales , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/fisiopatología , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Ingestión de Alimentos/fisiología , Ácidos Grasos no Esterificados/análisis , Ácidos Grasos no Esterificados/sangre , Ácidos Grasos no Esterificados/metabolismo , Intolerancia a la Glucosa/etiología , Intolerancia a la Glucosa/genética , Intolerancia a la Glucosa/fisiopatología , Insulina/análisis , Insulina/genética , Insulina/farmacología , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiología , Masculino , Páncreas/química , Páncreas/metabolismo , Ratas , Ratas Wistar , Estreptozocina , Triglicéridos/análisis , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
PURPOSE: To investigate and compare the effects of propofol and midazolam on inflammation and oxidase stress in children with congenital heart disease undergoing cardiac surgery. MATERIALS AND METHODS: Thirty-two ASA class I-II children with congenital heart disease undergoing cardiac surgery were randomly divided into two groups: propofol combined with low dose fentanyl (PF group, n = 16) and midazolam combined with low dose fentanyl (MF group, n = 16). Tracheal extubation time and length of Intensive Care Unit (ICU) stay were recorded. Blood samples were taken before operation (T0), at 2 h after release of the aorta cross-clamp (T3) and at 24 h after operation (T4) to measure interleukin 6 (IL-6), IL-8, superoxide dismutase (SOD) and malondialdehyde (MDA) levels. Myocardium samples were collected at 10-20 min after aorta cross-clamp (T1) and at 10-20 min after the release of the aorta cross-clamp (T2) to detect heme oxygenase-1 (HO-1) expression. RESULTS: Tracheal extubation time and length of ICU stay in PF group were significantly shorter than those of the MF group (p < 0.05, respectively). After cardiopulmonary bypass, IL-6, IL-8 and MDA levels were significantly increased, and the SOD level was significantly reduced in both two groups, but PF group exhibited lower IL-6, IL-8 and MDA levels and higher SOD levels than the MF group (p < 0.05, respectively). The HO-1 expression in the PF group was significantly higher than that in MF group at the corresponding time points (p < 0.05, respectively). CONCLUSION: Propofol is superior to midazolam in reducing inflammation and oxidase stress and in improving post-operation recovery in children with congenital heart disease undergoing cardiac surgery.
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Anestesia Intravenosa/efectos adversos , Anestésicos Intravenosos/efectos adversos , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Cardiopatías Congénitas/cirugía , Inflamación/inducido químicamente , Midazolam/efectos adversos , Estrés Oxidativo/efectos de los fármacos , Propofol/efectos adversos , Niño , Femenino , Hemo-Oxigenasa 1/sangre , Humanos , Interleucina-6/sangre , Interleucina-8/sangre , Masculino , Malondialdehído/sangre , Superóxido Dismutasa/sangreRESUMEN
Atrial fibrillation (AF) is the most commonly sustained arrhythmia in clinical practice. Despite the extensive studies, the pathophysiology of AF, however, remains incompletely understood. Studies have demonstrated that oxidative stress may be involved in cardiac structural and electrical remodeling. More recently, a growing body of evidence suggests that oxidative stress is associated with the development of AF. The evidence for the hypotheses included that: (1) histological studies have demonstrated oxidative damage in both AF patients and animal models of AF; (2) oxidative stress markers are increased in AF patients, and are associated with the presence of AF; (3) drugs that have antioxidant properties show beneficial effects on AF development. Although the studies suggest the association between oxidative stress and AF, the exact pathogenesis of oxidative stress in AF development remains elusive and requires further investigation. Specifically, the causality between oxidative stress and AF; the levels of the oxidative stress in various types of AFs and their role in the pathogenesis of AF; the effects of strategies to reduce oxidative stress on atrial structural and electrical remodeling, and their exact role in the development of AF. Oxidative stress may provide a scientific basis for further research on the underlying mechanisms of AF and may target for pharmacological interruption of AF.
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Fibrilación Atrial/etiología , Estrés Oxidativo , Fibrilación Atrial/metabolismo , Biomarcadores/metabolismo , Calcio/metabolismo , Homeostasis , HumanosRESUMEN
OBJECTIVE: To observe the cardioprotective effects of propofol and midazolam in children with congenital heart diseases undergoing open heart surgery. METHODS: Thirty-two children with cyanotic congenital heart diseases of ASA classes I - II were randomly divided into 2 equal groups: propofol combined with low dose fentanyl group (Group PF) and midazolam combined with low dose fentanyl group (Group MF). The changes of hemodynaics, ECG, SpO2, nasopharyngeal and rectal temperatures were monitored continuously. The time of tracheal extubation and ICU staying time were recorded. Venous blood samples were collected when the venous channel was opened (T(0)), 2 h after declamping of the aorta (T(4)), and 24 h after operation (T(5)) to detect the plasma cardiac troponin I (cTnI). Myocardium samples were collected 10 - 20 min after aorta cross-clamp (T(2)), and 10 - 20 min after declamping of the aorta (T(3)) to undergo immunohistochemistry to observe the expression of heme oxygenase-1 (HO-1). RESULTS: The tracheal time of Group GF was 14.17 h, significantly shorter than that of Group MF (23.65 h, P < 0.05), and the ICU staying time of Group GF was 30.17 h, significantly shorter than that of Group MF (49.47 h, P < 0.05). The plasma cTnI level at T(4) of Group GF was 97 ng/ml +/- 33 ng/ml, significantly higher than those at T(0) (0.17 ng/ml +/- 0.10 ng/ml, P < 0.01) and T(5) (23 ng/ml +/- 13 ng/ml, P < 0.01). The plasma cTnI level at T(4) of Group MF was138 ng/ml +/- 56 ng/ml, significantly higher than those at T(0) (0.62 ng/ml +/- 0.96 ng/ml, P < 0.01) and T(5) (24 ng/ml +/- 6 ng/ml, P < 0.01). And the plasma cTnI levels at T(5) of these 2 groups were both significantly higher than those at T(0) (both P < 0.01), however, there was no significant difference in the plasma cTnI level at any time point between these 2 groups. The grey values of HO-1 in cardiac muscle cells at T(2) of Groups GF and MF were 182.2 +/- 0.8 and 193.5 +/- 1.4, both significantly higher than those at T(3) (125.6 +/- 2.1 and 145.5 +/- 7.4 respectively, both P < 0.01), and the grey values of HO-1 in cardiac muscle cells at T(2) and T(3) of Group MF were both significantly higher than those of Group GF (both P < 0.05). CONCLUSION: Both propofol and midazolam have protective effects for the children with congenital heart diseases undergoing open heart surgery, and propofol is superior to midazolam in the cardioprotection.
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Procedimientos Quirúrgicos Cardíacos/métodos , Cardiotónicos/administración & dosificación , Cardiopatías Congénitas/cirugía , Midazolam/administración & dosificación , Propofol/administración & dosificación , Adolescente , Anestésicos Intravenosos/administración & dosificación , Temperatura Corporal/efectos de los fármacos , Niño , Preescolar , Electrocardiografía/efectos de los fármacos , Circulación Extracorporea , Hemo-Oxigenasa 1/metabolismo , Humanos , Troponina I/sangreRESUMEN
OBJECTIVE: To observe the effect of Chinese herbs for supplementing Shen and strengthening bone (HB) on myelogenic osteoclasts formation, and gene expression of interleukin-6 (IL-6), IL-6 receptor (IL-6R) and gp130 in bone marrow. METHODS: Seventy-two healthy female SD rats of 3 months, were randomly divided into three groups, 24 in the sham-operated group (A), 24 in the ovariectomized group (B) and 24 in the after ovariectomy HB treated group (C). Bone marrow cells of 6 rats from each group were respectively collected and cultured at four time points (2nd, 4th, 6th and 12th weeks after operation). After 6 days of culture, the bone marrow cells were differentiated by Wright-Giemsa stain and TRAP stain, and total RNA in them was extracted by TRIZOL. RESULTS: Beginning from the 2nd week, the osteoclasts formation in Group B was higher than that in Group A (P < 0.05), and IL-6, IL-6R gene expression significantly increased in Group B (P < 0.05 or P < 0.01). These changes reached the peak in the 4th to 6th week, with the level maintained to the 12th week. As for comparison of Group B and C, the above-mentioned changes were significantly weakened in the latter (P < 0.05 or P < 0.01). No significant change of gp130 gene expression revealed in the whole course in either group. CONCLUSION: HB could inhibit the myelogenic osteoclasts formation in ovariectomized rats, this effect may be correlated with, partially at least, its inhibitory effect on the over-expressed IL-6 and IL-6R gene expression in myelocytes after ovariectomy.