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Methylene blue (MB) has recently completed a Phase-3 clinical trial as leuco-methylthioninium (LMT) bis(hydromethanesulfonate) for treating Alzheimer's disease. Herein, we investigated the mechanism underlying the MB inhibition of tubulin-associated unit (tau) aggregation by focusing on tau monomers. We found that MB causes disulfide bond formation, resulting in strong nuclear magnetic resonance chemical shift perturbations in a large area of tau proteins. The oxidized form of MB, namely methylthioninium (MT+), specifically catalyzed the oxidation of cysteine residues in tau proteins to form disulfide bonds directly using O2. This process is independent of the MT+-to-LMT redox cycle. Moreover, MT+ preferentially oxidized C291 and C322 in the lysine-rich R2 and R3 domains. Under in vivo brain physoxia conditions, LMT may convert to MT+, possibly interfering with tau fibrillation via disulfide bond formation.
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Although carboxylate-based frameworks are commonly used architectures in metal-organic frameworks (MOFs), liquid/glass MOFs have thus far mainly been obtained from azole- or weakly coordinating ligand-based frameworks. This is because strong coordination bonds of carboxylate ligands to metals block the thermal vitrification pathways of carboxylate-based MOFs. In this study, we present the example of carboxylate-based melt-quenched MOF glasses comprising Mg2+ or Mn2+ with an aliphatic carboxylate ligand, adipate. These MOFs have a low melting temperature (Tm) of 284 °C and 238 °C, respectively, compared to zeolitic-imidazolate framework (ZIF) glasses, and superior mechanical properties in terms of hardness and elastic modulus. The low Tm may be attributed to the flexibility and low symmetry of the aliphatic carboxylate ligand, which raises the entropy of fusion (ΔSfus), and the lack of crystal field stabilization energy on metal ions, reducing enthalpy of fusion (ΔHfus). This research will serve as a cornerstone for the integration of numerous carboxylate-based MOFs into MOF glasses.
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Reconfigurable optical devices hold great promise for advancing high-density optical interconnects, photonic switching, and memory applications. While many optical modulators based on active materials have been demonstrated, it is challenging to achieve a high modulation depth with a low operation voltage in the near-infrared (NIR) range, which is a highly sought-after wavelength window for free-space communication and imaging applications. Here, electrically switchable Tamm plasmon coupled with poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) is introduced. The device allows for a high modulation depth across the entire NIR range by fully absorbing incident light even under epsilon near zero conditions. Optical modulation exceeding 88% is achieved using a CMOS-compatible voltage of ±1 V. This modulation is facilitated by precise electrical control of the charge carrier density through an electrochemical doping/dedoping process. Additionally, the potential applications of the device are extended for a non-volatile multi-memory state optical device, capable of rewritable optical memory storage and exhibiting long-term potentiation/depression properties with neuromorphic behavior.
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There has been significant research focused on the development of stretchable materials that can provide a large area with minimal material usage for use in solar cells and displays. However, most materials exhibit perpendicular shrinkage when stretched, which is particularly problematic for polymer-based substrates commonly used in stretchable devices. To address this issue, biaxial strain-controlled substrates have been proposed as a solution to increase device efficiency and conserve material resources. In this study, we present the design and fabrication of a biaxial strain-controlled substrate with a re-entrant honeycomb structure and a negative Poisson's ratio. Using a precisely machined mold with a shape error of less than 0.15%, we successfully fabricated polydimethylsiloxane substrates with a 500 µm thick re-entrant honeycomb structure, resulting in a 19.1% reduction in perpendicular shrinkage. This improvement translates to a potential increase in device efficiency by 9.44% and an 8.60% reduction in material usage for substrate fabrication. We demonstrate that this design and manufacturing method can be applied to the fabrication of efficient stretchable devices, such as solar cells and displays.
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Carcinoma Papilar , Neoplasias de la Tiroides , Humanos , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/patología , Metástasis Linfática , Carcinoma Papilar/genética , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/secundarioRESUMEN
Owing to its exceptional physicochemical properties, graphene has demonstrated unprecedented potential in a wide array of scientific and industrial applications. By exploiting its chemically inert surface endowed with unique barrier functionalities, we herein demonstrate antiadhesive monolayer graphene films for realizing a peel-and-pick transfer process of target materials from the donor substrate. When the graphene antiadhesion layer (AAL) is inserted at the interface between the metal and the arbitrary donor substrate, the interfacial interactions can be effectively weakened by the weak interplanar van der Waals forces of graphene, enabling the effective release of the metallic electrode from the donor substrate. The flexible embedded metallic electrode with graphene AAL exhibited excellent electrical conductivity, mechanical durability, and chemical resistance, as well as excellent performance in flexible heater applications. This study afforded an effective strategy for fabricating high-performance and ultraflexible embedded metallic electrodes for applications in the field of highly functional flexible electronics.
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INTRODUCTION: Low- and middle-income countries (LMICs) have a large percentage of global mortality and morbidity rates from non-communicable diseases, including trauma. The establishment and development of emergency care systems is crucial for addressing this problem. Defining gaps in the resources and capacity to provide emergency healthcare in LMICs is essential for proper design and operation of ECS (emergency care services) reinforcement programs. Myanmar has particular challenges with road access for providing timely emergency medical care, and a shortage of trained health workers. To examine the ECS capacity in Myanmar, we used the Emergency Care Assessment Tool (ECAT), which features newly developed tools for assessing sentinel conditions and signal functions (key interventions to address morbidity and mortality) in emergency care facilities. METHODS: ECAT is composed of six emergent sentinel conditions and corresponding signal functions. We surveyed a total of nine hospitals in five states in Myanmar. A constructed survey sheet was delivered by e-mail, and follow-up interviews were conducted via messenger to clarify ambiguous answers. RESULTS: We categorized the nine participating institutions according to predefined criteria: four basic-level hospitals; four intermediate-level; and one advanced-level hospital. All basic hospitals were weak in trauma care, and two of 12 signal functions were unavailable. Half of the intermediate hospitals showed weakness in trauma care, as well as critical care such as shock management. Only half had a separate triage area for patients. In contrast, all signal functions and resources listed in ECAT were available in the advanced-level hospital. CONCLUSION: Basic-level facilities in Myanmar were shown to be suboptimal in trauma management, with critical care also inadequate in intermediate facilities. To reinforce signal functions in Myanmar health facilities, stakeholders should consider expanding critical functions in selected lower-level health facilities. A larger scale survey would provide more comprehensive data to improve emergency care in Myanmar.
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Atención a la Salud/estadística & datos numéricos , Servicios Médicos de Urgencia/normas , Servicio de Urgencia en Hospital , Hospitales/normas , Estudios Transversales , Servicios Médicos de Urgencia/estadística & datos numéricos , Servicio de Urgencia en Hospital/normas , Necesidades y Demandas de Servicios de Salud , Hospitales/estadística & datos numéricos , Humanos , Mianmar , Indicadores de Calidad de la Atención de SaludRESUMEN
Obesity is generally caused by quantitative changes in adipocyte differentiation and fat metabolism. Only a few studies have been determined the effect of red beans extract on obesity and plasma cholesterol concentration. We have been studied the functional activities of red-bean extracts including anti-oxidative effect against DNA and cell damages. Histological study including micro CT analysis showed that the accumulation of fat in hepatocytes and intestines was significantly decreased in red bean extract treated group. In addition, plasma cholesterol and triglyceride levels were decreased in blood samples. In addition, it was confirmed that the red bean extract inhibited the expression of PPARγ, Fabp4 and RETN genes, which regulate total adipocyte differentiation and lipid metabolism. Red bean extract inhibits the expressions of transcription factors associated with adipocyte differentiation in a dose-dependent manner, thereby inhibiting fat accumulation and decreasing blood lipid levels in obese mice induced by high fat diet.
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OBJECTIVE: We investigated the characteristics of pediatric emergency department (ED) patients in Korea and determined factors associated with hospital admission after ED treatment. METHODS: Korea Health Panel data from 2008 through 2013 were analyzed retrospectively; we included patients under 18 years old who visited the ED at least once. We collected patient and household epidemiologic data such as sex, age group, region of residence, disability, chronic disease, household income quintile, national health insurance type, use of private insurance, and annual frequency of ED visits. We also examined data related to each ED visit, such as reason for visit, medical service provided, and hospital size/ownership. We then investigated which factors were correlated with case disposition (discharge home or hospital admission) after ED treatment. RESULTS: In total, 3,160 pediatric ED visits occurred during the six-year period. Males (57.5%) and children aged 0-5 years (47.7%) made more visits than females and older children, respectively. The proportion of ED visits for disease (67.7%) was much higher than for injury or poisoning (32.2%), and 452 cases (14.3%) required hospital admission. For hospital admission, the odds ratio (OR) of females was 0.73 compared to males, and the OR of children aged 6-11 was 0.68 compared to children aged 0-5. The OR of capital residents was 0.69 compared to province residents, and the OR of the highest income quintile was 0.51 compared to the lowest quintile. The OR of children with private insurance coverage was 0.49 compared to those lacking private insurance, and the OR of ED visits due to disease was 1.82 compared to visits due to injury/poisoning. CONCLUSION: This analysis of clinical and demographic characteristics of pediatric ED visits and hospital admissions can serve as the foundation of future prospective studies required for establishing appropriate policies for the Korean pediatric emergency medical system.
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Servicio de Urgencia en Hospital/estadística & datos numéricos , Admisión del Paciente/estadística & datos numéricos , Alta del Paciente/estadística & datos numéricos , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Oportunidad Relativa , República de Corea , Estudios Retrospectivos , Factores SocioeconómicosRESUMEN
BACKGROUND: Minimally invasive direct coronary artery bypass grafting (MIDCAB) has the advantage of allowing arterial grafting on the left anterior descending artery without a sternotomy incision. We present our single-center clinical experience of 66 consecutive patients. METHODS: All patients underwent MIDCAB through a left anterior small thoracotomy between August 2007 and July 2015. Preoperative, intraoperative, postoperative and follow-up data-including major adverse cardiovascular and cerebrovascular events (MACCE), graft patency, and the need for re-intervention-were collected. RESULTS: The mean age of the patients was 69.4±11.1 years and 73% were male. There was no conversion to an on-pump procedure or a sternotomy incision. The 30-day mortality rate was 1.5%. There were no cases of stroke, although 2 patients had to be re-explored for bleeding, and 81.8% were extubated in the operating room or on the day of surgery. The median stay in the intensive care unit and in the hospital were 1.5 and 9.6 days, respectively. The median follow-up period was 11 months, with a 5-year overall survival rate of 85.3%±0.09% and a 5-year MACCE-free survival rate of 72.8%±0.1%. Of the 66 patients, 32 patients with 36 grafts underwent a postoperative graft patency study with computed tomography angiography or coronary angiography, and 88.9% of the grafts were patent at 9.7±10.8 months postoperatively. CONCLUSION: MIDCAB is a safe procedure with low postoperative morbidity and mortality and favorable mid-term MACCE-free survival.
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Excessive bone resorption caused by increased osteoclast number or activity leads to a variety of bone diseases including osteoporosis, rheumatoid arthritis and periodontitis. Thus, the therapeutic strategy for these diseases has been focused primarily on the inhibition of osteoclast formation and function. This study shows that euphorbia factor L1 (EFL1), a diterpenoid isolated from Euphorbia lathyris, inhibited osteoclastogenesis and induced osteoclast apoptosis. EFL1 suppressed osteoclast formation and bone resorption at both initial and terminal differentiation stages. EFL1 inhibited receptor activator of NF-κB ligand (RANKL)-induced NFATc1 induction with attenuated NF-κB activation and c-Fos expression. EFL1 decreased the level of reactive oxygen species by scavenging them or activating Nrf2, and inhibited PGC-1ß that regulates mitochondria biogenesis. In addition, EFL1 induced apoptosis in differentiated osteoclasts by increasing Fas ligand expression followed by caspase activation. Moreover, EFL1 inhibited inflammation-induced bone erosion and ovariectomy-induced bone loss in mice. These findings suggest that EFL1 inhibits osteoclast differentiation by regulating cellular redox status and induces Fas-mediated apoptosis in osteoclast, and may provide therapeutic potential for preventing or treating bone-related diseases caused by excessive osteoclast.
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Apoptosis/efectos de los fármacos , Diterpenos/farmacología , Osteoclastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Fenilpropionatos/farmacología , Ligando RANK/antagonistas & inhibidores , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Animales , Apoptosis/genética , Resorción Ósea , Caspasas/genética , Caspasas/metabolismo , Diferenciación Celular , Proteína Ligando Fas/genética , Proteína Ligando Fas/metabolismo , Femenino , Regulación de la Expresión Génica , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/metabolismo , Osteoclastos/citología , Osteoclastos/metabolismo , Osteogénesis/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Cultivo Primario de Células , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ligando RANK/farmacología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Receptor fas/genética , Receptor fas/metabolismoRESUMEN
The actual incidence of multiple thymoma is unknown and rarely reported because it remains controversial whether the cases represent a disease of multicentric origin or a disease resulting from intrathymic metastasis. In this case, a patient underwent total thymectomy for multiple thymoma with myasthenia gravis via bilateral video-assisted thoracic surgery. A well-encapsulated multinodular cystic mass, measuring 57 mm×50 mm×22 mm in the right lobe of the thymus, and a well-encapsulated mass, measuring 32 mm×15 mm×14 mm in the left lobe, were found. Both tumors were type B2 thymoma. Few cases of multiple thymoma with myasthenia gravis have ever been reported in the literature. We report a case of synchronous multiple thymoma associated with myasthenia gravis.
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The N-terminal 34-amino-acid peptide fragment of human parathyroid hormone PTH (1-34), is used clinically to treat osteoporosis; however, it is currently administered by a once-daily subcutaneous injection, resulting in poor patient compliance. We have developed enteric microcapsules containing an ionic nanocomplex between PTH (1-34) and lysine-linked deoxycholic acid (LysDOCA) for the oral delivery of PTH (1-34). We measured the particle size of the PTH/LysDOCA complex and assessed its biological activity by determining the cAMP content in MC3T3-E1 cells. We also assessed its permeability across a Caco-2 cell monolayer and the bioavailability of the intrajejunally administered PTH/LysDOCA complex compared with PTH (1-34) in rats. In addition, the antiosteoporotic activity of the PTH/LysDOCA complex, encapsulated in an enteric carrier by coaxial ultrasonic atomization, was evaluated after it was orally administered to ovariectomized (OVX) rats. The formation of an ionic complex between PTH (1-34) and LysDOCA produced nanoparticles of diameter 33.0±3.36 nm, and the bioactivity of the complex was comparable with that of PTH (1-34). The Caco-2 cell permeability and AUClast value of the PTH/LysDOCA (1:10) nanocomplex increased by 2.87- and 16.3-fold, respectively, compared with PTH (1-34) alone. Furthermore, the OVX rats treated with oral PTH/LysDOCA-loaded enteric microcapsules showed an increase in bone mineral density (159%), bone volume fraction (175%), and trabecular number (174%) compared with those in the OVX control group. Therefore, the PTH/LysDOCA nanocomplex oral delivery system is a promising treatment modality for osteoporosis because it improves osteogenesis and trabecular connectivity.
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Ácido Desoxicólico/química , Sistemas de Liberación de Medicamentos/métodos , Nanocompuestos/administración & dosificación , Hormona Paratiroidea/administración & dosificación , Administración Oral , Animales , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea/administración & dosificación , Células CACO-2/efectos de los fármacos , Ácido Desoxicólico/administración & dosificación , Composición de Medicamentos/métodos , Femenino , Humanos , Lisina/química , Ratones , Nanocompuestos/química , Osteogénesis/efectos de los fármacos , Osteoporosis/tratamiento farmacológico , Hormona Paratiroidea/química , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/química , Ratas , Ratas Sprague-Dawley , Teriparatido/administración & dosificaciónRESUMEN
SCOPE: Yuja (Citrus junos Tanaka) possesses various health benefits, but its effects on bone health are unknown. In this study, the preventative effects of yuja peel ethanol extract (YPEE) on osteopenia were determined in ovariectomized (OVX) rats, and the mechanisms by which YPEE and its flavanones regulate osteoblastogenesis were examined in vitro. METHODS AND RESULTS: The effects of YPEE on osteoblastogenesis were investigated in MC3T3-E1 cells. YPEE promoted alkaline phosphatase (ALP) activity, mineralization, and the expression of osteoblast differentiation marker genes, such as ALP, runt-related transcription factor 2 (Runx2), and osteocalcin. YPEE and its flavanones promoted osteoblast differentiation via BMP-2-mediated p38 and the Smad1/5/8 signaling pathway. YPEE supplementation significantly decreased body weight and increased uterine weight and bone mineral density in OVX rats. Based on a micro-CT analysis of femurs, YPEE significantly attenuated osteopenia and increased trabecular volume fraction, trabecular separation, and trabecular number (p < 0.05). CONCLUSION: Dietary YPEE has a protective effect on OVX-induced osteopenia. YPEE and its flavanones promote osteoblastogenesis via the activation of the BMP/p38/Smad/Runx2 pathways. These results extend our knowledge of the beneficial effects of YPEE and provide a basis for the development of novel therapies for osteoporosis.
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Enfermedades Óseas Metabólicas/tratamiento farmacológico , Diferenciación Celular/efectos de los fármacos , Flavanonas/farmacología , Osteoblastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Extractos Vegetales/farmacología , Células 3T3 , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Animales , Densidad Ósea/efectos de los fármacos , Proteína Morfogenética Ósea 2/genética , Proteína Morfogenética Ósea 2/metabolismo , Citrus/química , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Dislipidemias/tratamiento farmacológico , Dislipidemias/etiología , Femenino , Ratones , Osteoblastos/citología , Osteocalcina/genética , Osteocalcina/metabolismo , Ovariectomía , Células RAW 264.7 , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Proteínas Smad Reguladas por Receptores/genética , Proteínas Smad Reguladas por Receptores/metabolismoRESUMEN
Global deletion of the gene encoding a nuclear histone deacetylase sirtuin 6 (Sirt6) in mice leads to osteopenia with a low bone turnover due to impaired bone formation. But whether Sirt6 regulates osteoclast differentiation is less clear. Here we show that Sirt6 functions as a transcriptional regulator to directly repress anti-osteoclastogenic gene expression. Targeted ablation of Sirt6 in hematopoietic cells including osteoclast precursors resulted in increased bone volume caused by a decreased number of osteoclasts. Overexpression of Sirt6 led to an increase in osteoclast formation, and Sirt6-deficient osteoclast precursor cells did not undergo osteoclast differentiation efficiently. Moreover, we showed that Sirt6, induced by RANKL-dependent NFATc1 expression, forms a complex with B lymphocyte-induced maturation protein-1 (Blimp1) to negatively regulate expression of anti-osteoclastogenic gene such as Mafb. These findings identify Sirt6 as a novel regulator of osteoclastogenesis by acting as a transcriptional repressor.
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Diferenciación Celular , Osteoclastos/fisiología , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Sirtuinas/metabolismo , Animales , Células Cultivadas , Regulación de la Expresión Génica , Ratones Endogámicos C57BL , Ratones Noqueados , Unión Proteica , Mapeo de Interacción de ProteínasRESUMEN
Small molecule-inhibition targeting protein-protein interaction (PPI) is now recognized as an emerging and challenging area in drug design. We developed a novel interactive drug discovery methodology known as Protein Chip technology (ProteoChip) as a cutting-edge PPI assay system applicable for unique PPI-targeting therapeutics integrated with computer-aided drug design (CADD). Here, we describe a novel small molecular PPI inhibitor, IPS-02001, which the blocks integrin αvß3-osteopontin interface a novel PPI inhibitor identified by the interactive methodology of both ProteoChip- and CADD-based PPI assay. IPS-02001 (6,7-Dichloro-2,3,5,8-tetrahydroxy-1,4-naphthoquinone) was screened from different compound libraries (InterBioScreen, Commercial libraries) using an in silico structure-based molecular docking simulation method and a protein chip-based protein-protein interaction assay system. Additionally, integrin αvß3, an adhesion receptor expressed in osteoclasts (OCs), was implicated in the regulation of OC function via regulation of the cytoskeletal organization of OCs. IPS-02001 blocked OC maturation from murine bone marrow-derived macrophages, as well as the resorptive function of OCs. Moreover, treatment with IPS-02001 impaired downstream signaling of integrin αvß3 linked to Pyk2, c-Src, PLCγ2, and Vav3 and disrupted the actin cytoskeleton in mature OCs. Furthermore, IPS-02001 blocked RANKL-induced bone destruction by reducing the number of OCs and protected against ovariectomy-induced bone loss in mice. Thus, IPS-02001 may represent a promising new class of anti-resorptive drugs for treatment of bone diseases associated with increased OC function.
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Resorción Ósea/tratamiento farmacológico , Resorción Ósea/prevención & control , Integrina alfaVbeta3/metabolismo , Osteopontina/metabolismo , Mapas de Interacción de Proteínas/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Actinas/metabolismo , Animales , Resorción Ósea/metabolismo , Diferenciación Celular/efectos de los fármacos , Citoesqueleto/efectos de los fármacos , Citoesqueleto/metabolismo , Femenino , Ligandos , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Ovariectomía , Unión Proteica/efectos de los fármacos , Ligando RANK , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/uso terapéuticoRESUMEN
The mitochondrial sirtuin 3 (SIRT3) is involved in suppressing the onset of multiple pathologies, including cardiovascular disease, fatty liver, age-related hearing loss, and breast cancer. But a physiological role of SIRT3 in bone metabolism is not known. Here we show that SIRT3 is a key regulatory molecule to maintain bone homeostasis. Mice deficient in SIRT3 exhibited severe osteopenia owing to increased numbers of osteoclasts. Osteoclast precursors from Sirt3-/- mice underwent increased osteoclastogenesis in response to receptor activator of nuclear factor-κB ligand (RANKL), an essential cytokine for osteoclast differentiation. SIRT3 expression from RANKL induction depended on the transcription coactivator PGC-1ß (peroxisome proliferator-activated receptor-γ co-activator-1ß) and the nuclear receptor ERRα (estrogen receptor-related receptor α), and that SIRT3 inhibited the differentiation by interfering with the RANKL-induced expression of PGC-1ß. Thus an auto-regulatory feedback mechanism operates to induce its own inhibitor SIRT3 by PGC-1ß. Moreover, Sirt3-/- osteoclast precursors reduced AMP-activated protein kinase (AMPK) phosphorylation through down-regulating the expression of AMPK. Our results suggest that a mitochondrial SIRT3 is an intrinsic inhibitor for RANKL-mediated osteoclastogenesis.
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Proteínas Quinasas Activadas por AMP/metabolismo , Osteoclastos/citología , Osteogénesis/fisiología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Receptores de Estrógenos/metabolismo , Sirtuina 3/metabolismo , Animales , Enfermedades Óseas Metabólicas/genética , Remodelación Ósea/genética , Remodelación Ósea/fisiología , Células Cultivadas , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Osteogénesis/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Ligando RANK/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/genética , Sirtuina 3/genética , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
We assessed the possibility of changing the route of administration of zoledronic acid to an oral dosage form and its therapeutic efficacy in an estrogen-deficient osteoporosis rat model. To enhance oral bioavailability, we formed an ionic complex by electrostatic conjugation of zoledronic acid with lysine-linked deoxycholic acid (Lys-DOCA, an oral absorption enhancer). After forming the complex, the characteristic crystalline features of pure zoledronic acid disappeared completely in the powder X-ray diffractogram and differential scanning calorimetry thermogram, indicating that zoledronic acid existed in an amorphous form in the complex. In vitro permeabilities of zoledronic acid/Lys-DOCA (1:1) (ZD1) and zoledronic acid/Lys-DOCA (1:2) (ZD2) complex across Caco-2 cell monolayers were 2.47- and 4.74-fold higher than that of zoledronic acid, respectively. Upon intra-jejunal administration to rats, the intestinal absorption of zoledronic acid was increased significantly and the resulting oral bioavailability of the ZD2 complex was determined to be 6.76±2.59% (0.548±0.161% for zoledronic acid). Ovariectomized (OVX) rats showed 122% increased bone mineral density versus the OVX control at 12weeks after treatment with once weekly oral administration of ZD2 complex (16µg/kg of zoledronic acid). Furthermore, rats treated with ZD2 complex orally showed significant improvement in the parameters of trabecular microarchitecture and bone strength: 149% higher bone volume fraction (BV/TV), 115% higher trabecular number (Tb.N), and 56% higher mean maximum load (Fmax) than in the OVX group. The trabecular microstructure and bone mechanical properties in the oral zoledronic acid group were not significantly changed compared with the OVX control. Thus, the oral ZD2 complex inhibited osteoporosis progression effectively by promoting osteogenesis and trabecular connectivity. The oral ZD2 complex would be expected to improve patient compliance by replacing the conventional injectable form and expand the indications, to include prophylaxis for osteoporosis and bone metastases.
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Conservadores de la Densidad Ósea/administración & dosificación , Ácido Desoxicólico/administración & dosificación , Difosfonatos/administración & dosificación , Imidazoles/administración & dosificación , Lisina/administración & dosificación , Osteoporosis/tratamiento farmacológico , Administración Oral , Animales , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea/química , Conservadores de la Densidad Ósea/farmacocinética , Conservadores de la Densidad Ósea/uso terapéutico , Células CACO-2 , Ácido Desoxicólico/química , Ácido Desoxicólico/farmacocinética , Ácido Desoxicólico/uso terapéutico , Difosfonatos/química , Difosfonatos/farmacocinética , Difosfonatos/uso terapéutico , Femenino , Humanos , Imidazoles/química , Imidazoles/farmacocinética , Imidazoles/uso terapéutico , Absorción Intestinal/efectos de los fármacos , Lisina/química , Lisina/farmacocinética , Lisina/uso terapéutico , Osteoporosis/metabolismo , Ovariectomía , Permeabilidad/efectos de los fármacos , Ratas Sprague-Dawley , Tibia/efectos de los fármacos , Tibia/patología , Tibia/fisiología , Ácido ZoledrónicoRESUMEN
Skeletal muscle atrophy can be defined as a decrease of muscle volume caused by injury or lack of use. This condition is associated with reactive oxygen species (ROS), resulting in various muscular disorders. We acquired 2D and 3D images using micro-computed tomography in gastrocnemius and soleus muscles of sciatic-denervated mice. We confirmed that sciatic denervation-small animal model reduced muscle volume. However, the intraperitoneal injection of Oenothera odorata root extract (EVP) delayed muscle atrophy compared to a control group. We also investigated the mechanism of muscle atrophy's relationship with ROS. EVP suppressed expression of SOD1, and increased expression of HSP70, in both H2O2-treated C2C12 myoblasts and sciatic-denervated mice. Moreover, EVP regulated apoptotic signals, including caspase-3, Bax, Bcl-2, and ceramide. These results indicate that EVP has a positive effect on reducing the effect of ROS on muscle atrophy.
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Músculo Esquelético/efectos de los fármacos , Atrofia Muscular/tratamiento farmacológico , Oenothera/química , Extractos Vegetales/farmacología , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Caspasa 3/genética , Caspasa 3/metabolismo , Línea Celular , Ceramidas/metabolismo , Desnervación/efectos adversos , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Proteínas HSP70 de Choque Térmico/agonistas , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Inyecciones Intraperitoneales , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Atrofia Muscular/etiología , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Mioblastos/citología , Mioblastos/efectos de los fármacos , Mioblastos/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Nervio Ciático/cirugía , Superóxido Dismutasa/antagonistas & inhibidores , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1 , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Low-level laser therapy/treatment (LLLT) using a minimally invasive laser needle system (MILNS) might enhance bone formation and suppress bone resorption. In this study, the use of 405 nm LLLT led to decreases in bone volume and bone mineral density (BMD) of tibial trabecular bone in wild-type (WT) and Per2 knockout (KO) mice. Bone volume and bone mineral density of tibial trabecular bone was decreased by 405 nm LLLT in Per2 KO compared to WT mice at two and four weeks. To determine the reduction in tibial bone, mRNA expressions of alkaline phosphatase (ALP) and Per2 were investigated at four weeks after 405 nm laser stimulation using MILNS. ALP gene expression was significantly reduced in the LLLT-stimulated right tibial bone of WT and Per2 KO mice compared to the non-irradiated left tibia (p < 0.001). Per2 mRNA expression in WT mice was significantly reduced in the LLLT-stimulated right tibial bone compared to the non-irradiated left tibia (p < 0.001). To identify the decrease in tibial bone mediated by the Per2 gene, levels of runt-related transcription factor 2 (Runx2) and ALP mRNAs were determined in non-irradiated WT and Per2 KO mice. These results demonstrated significant downregulation of Runx2 and ALP mRNA levels in Per2 KO mice (p < 0.001). Therefore, the reduction in tibial trabecular bone resulting from 405 nm LLLT using MILNS might be associated with Per2 gene expression.