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BACKGROUND AND AIMS: The increased serum uric acid (SUA) level is associated with the prevalence of cardiovascular disease (CVD) risks. Aortic arch calcification (AAC) reflects subclinical coronary atherosclerosis and is linked to subsequent cardiovascular morbidity and mortality risks closely. To better understand the role of SUA on arteriosclerosis and CVD, we aim to determine the association between SUA and the presence of AAC. METHODS AND RESULTS: A total of 5920 individuals aged >45 years old without prior CVD disease were included. The prevalence rate of AAC was 14.4% in all participants and a significantly increasing trend for AAC prevalence rate was found across the SUA tertiles (p < 0.001 for trend). Subsequent subgroup analyses revealed that this positive association trend was only significant in female subjects. After adjusting for confounders, SUA is an independent predictor for the presence of AAC in overall participants and in women. CONCLUSION: SUA is independently associated with AAC in middle-aged and elderly population, especially in the women. More research needs to determine whether lower thresholds for CVD risk screening for those middle-aged and elderly women with higher SUA tertile even without hyperuricemia are warranted.
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Aorta Torácica , Enfermedades de la Aorta/epidemiología , Hiperuricemia/epidemiología , Ácido Úrico/sangre , Calcificación Vascular/epidemiología , Factores de Edad , Anciano , Aorta Torácica/diagnóstico por imagen , Enfermedades de la Aorta/diagnóstico por imagen , Biomarcadores/sangre , China/epidemiología , Estudios Transversales , Femenino , Humanos , Hiperuricemia/sangre , Hiperuricemia/diagnóstico , Persona de Mediana Edad , Prevalencia , Medición de Riesgo , Factores de Riesgo , Factores Sexuales , Regulación hacia Arriba , Calcificación Vascular/diagnóstico por imagenRESUMEN
This study aims to investigate the expression and significance of KPNA2 in human gastric adenocarcinoma progression and prognosis. Using immunohistochemistry and real-time reverse transcriptase polymerase chain reaction assay, we identified abnormally elevated expression of KPNA2 in gastric adenocarcinoma tissues compared to paired normal stomach mucosa tissues in 30 patients (p < 0.05). In order to investigate the correlations between KPNA2 and the clinicopathological features of gastric adenocarcinoma, the expression of KPNA2 in 142 patients with gastric adenocarcinoma was detected by immunohistochemistry, and the results showed that overexpression of KPNA2 was associated with the size of tumor (p < 0.001), histological grade (p < 0.001), lymph node involvement (p = 0.001), and tumor node metastasis stage (p < 0.001). Kaplan-Meier survival analysis showed that patients with high KPNA2 expression showed a significantly shorter overall survival time compared with patients with low KPNA2 expression. Multivariate analysis suggested that KPNA2 expression might be an independent prognostic indicator (p < 0.001) for the survival of patients with gastric adenocarcinoma. In conclusion, overexpression of KPNA2 is closely related to progression of gastric adenocarcinoma and might be regarded as an independent predictor of poor prognosis for gastric adenocarcinoma.
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Adenocarcinoma Mucinoso/mortalidad , Adenocarcinoma/mortalidad , Carcinoma Papilar/mortalidad , Carcinoma de Células en Anillo de Sello/mortalidad , Neoplasias Gástricas/mortalidad , alfa Carioferinas/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patología , Adulto , Anciano , Carcinoma Papilar/metabolismo , Carcinoma Papilar/patología , Carcinoma de Células en Anillo de Sello/metabolismo , Carcinoma de Células en Anillo de Sello/patología , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Ganglios Linfáticos/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Tasa de Supervivencia , Adulto Joven , alfa Carioferinas/genéticaRESUMEN
Pulmonary fibrosis is a major cause of morbidity and mortality in systemic sclerosis (SSc) with no effective medication. Polyporus polysaccharide (PPS), extracted from Chinese herbs, has immune regulation, anticancer, antioxidant and antiinflammatory activities. This study aims to investigate antifibrotic effects of PPS. We show that PPS markedly ameliorates bleomycin-induced lung fibrosis in mice. Myofibroblasts are the effector cells responsible for excessive deposition of extracellular matrix (ECM) proteins in fibrotic diseases. In vitro evidence reveals that PPS exerts potent antifibrotic effects by inhibiting fibroblast-to-myofibroblast transition, suppressing ECM deposition, and repressing lung fibroblast proliferation and migration. We also find that PPS inhibits TGF-ß1-induced Smad2/3 activating. This study is the first to demonstrate an antifibrotic role of PPS in lungs, thus warranting further therapeutic evaluation.
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Objectives: To determine the relationship between bone marrow edema (BME), synovitis, and bone erosion longitudinally using a collagen induced arthritis mice (CIA) model and to explore the potential pathogenic role of BME in bone erosion. Methods: CIA was induced in DBA/1J mice. BME and corresponding clinical symptoms of arthritis and synovitis during the different time points of CIA development were assayed by magnetic resonance imaging (MRI), arthritis sore, and histologic analyses. The expression of osteoclasts (OCs), OCs-related cytokines, and immune cells in bone marrow were determined by flow cytometry, immunohistochemistry, immunofluorescence staining, and real-time PCR. The OCs formation was estimated using in vitro assays. Results: MRI detected BME could emerge at day 25 in 70% mice after the first immunization (n = 10), when there were not any arthritic symptoms, histological or MRI synovitis. At day 28, BME occurred in 90% mice whereas the arthritic symptom and histological synovitis were only presented in 30 and 20% CIA mice at that time (n = 10). The emergence of BME was associated with an increased bone marrow OCs number and an altered distribution of OCs adherent to subchondral bone surface, which resulted in increased subchondral erosion and decreased trabecular bone number during the CIA process. Obvious marrow environment changes were identified after BME emergence, consisting of multiple OCs related signals, including highly expressed RANKL, increased proinflammatory cytokines and chemokines, and highly activated T cells and monocytes. Conclusions: BME reflects a unique marrow "osteoclastic environment," preceding the arthritic symptoms and synovitis during the development of CIA.
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Médula Ósea/patología , Microambiente Celular , Osteoclastos/metabolismo , Sinovitis/etiología , Sinovitis/metabolismo , Animales , Artritis Experimental , Biopsia , Colágeno/efectos adversos , Colágeno/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inmunohistoquímica , Inmunofenotipificación , Imagen por Resonancia Magnética , Ratones , Sinovitis/diagnóstico por imagen , Sinovitis/patologíaRESUMEN
INTRODUCTION: Iguratimod (T-614) has been confirmed as a highly efficacious and safe novel disease-modifying anti-rheumatic drug (DMARD) for rheumatoid arthritis therapy in China and Japan due to its potent anti-inflammation effect. Here, we investigate the effects of Iguratimod on osteoclast differentiation, migration and function. METHODS: The effect of Iguratimod on osteoclastogenesis, migration and bone resorption were assessed by TRAP staining, transwell migration assay and osteologic discs, respectively. Relative expressions of osteoclastic related genes, chemokines and transcription factors were assessed by reverse transcription polymerase chain reaction (RT-PCR) and signaling pathways were analyzed by western blotting. RESULTS: Iguratimod significantly inhibits osteoclast differentiation, migration and bone resorption in RANKL-induced RAW264.7 cell in a dose-dependent manner. The expressions of osteoclastic related genes including TRAP, CTSK and CTR were increased in RAW264.7 cell upon RANKL stimulation but were obviously suppressed in the presence of Iguratimod. RANKL induced the expression of chemokines including CCL7, CCL4 and CCL12 and osteoclastic related transcription factors of c-Fos, c-Jun and NFATc1 could be significantly inhibited by Iguratimod in a dose dependent manner. Western blotting indicated Iguratimod could suppress the activation of MAPKs and NF-κB pathway in RANKL induced osteoclastogenesis in RAW264.7. CONCLUSIONS: These findings revealed a directly inhibitory role of Iguratimod on osteoclast formation and function, which is distinct from previous report, suggesting Iguratimod provide a unique therapeutic strategy for RA and especially in light of preventing bone destruction.
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Antirreumáticos/farmacología , Artritis Reumatoide/tratamiento farmacológico , Resorción Ósea/prevención & control , Cromonas/farmacología , Osteoclastos/efectos de los fármacos , Sulfonamidas/farmacología , Animales , Artritis Reumatoide/complicaciones , Resorción Ósea/etiología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Movimiento Celular/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Ratones , FN-kappa B/metabolismo , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/metabolismo , Osteoclastos/fisiología , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ligando RANK/metabolismo , Células RAW 264.7 , Transducción de Señal/efectos de los fármacosRESUMEN
Recently, the traditional Chinese medicine Tripterygium wilfordii Hook f (TwHF) of the Celastraceae family has attracted increasing attention for its potential therapeutic application in patients with rheumatoid arthritis (RA). It is well accepted that TwHF exerts the antirheumatic activity and mainly depends on its potent anti-inflammatory property. To further explore the therapeutic potential of the well-defined TwHF-derived single compound - celastrol in RA, we study the therapeutic efficacy of celastrol on bone erosion in collagen-induced arthritis (CIA) mice and delineate its effects on osteoclast differentiation and functions in RANKL-induced osteoclast precursors RAW264.7 cell line. In CIA mice, daily injection of celastrol (beginning on day 28 after arthritis induction) markedly suppressed arthritis, and reduced bone damage in the joints as demonstrated by histology and bone micro-computed tomography (CT). The effects were accompanied by reductions of osteoclast cells in joints, serum tartrate-resistant acid phosphatase (TRAP) 5b, and expression of osteoclastic genes (Trap, Ctsk, Ctr, Mmp-9) and transcriptional factors (c-Fos, c-Jun and NFATc1). When RAW264.7 cells were treated with RANKL, celastrol inhibited the formation of TRAP+ multinucleated cells and the bone-resorbing activity in dose-dependent manners. Furthermore, celastrol reduced the RANKL-induced expression of osteoclastic genes and transcriptional factors, as well as phosphorylation of NF-kB and mitogen-activated protein kinases (MAPK). These findings show that celastrol could directly inhibit osteoclast formation and function, suggesting a novel therapeutic strategy of celastrol for managing RA, especially in preventing bone destruction.
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Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Resorción Ósea/tratamiento farmacológico , Articulaciones/efectos de los fármacos , Medicina Tradicional China , Osteoclastos/efectos de los fármacos , Triterpenos/administración & dosificación , Fosfatasa Ácida/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Línea Celular , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Isoenzimas/metabolismo , Articulaciones/patología , Ratones , Ratones Endogámicos , Triterpenos Pentacíclicos , Ligando RANK/metabolismo , Fosfatasa Ácida Tartratorresistente , Activación Transcripcional/efectos de los fármacos , Tripterygium/inmunologíaRESUMEN
The colorectal cancer is the leading contributor of cancer-related mortality. Mammalian target of rapamycin (mTOR), existing in 2 complexes (mTORC1/2), is frequently dysregulated and constitutively activated in colorectal cancers. It represents an important drug target. Here we found that INK-128, the novel ATP-competitive kinase inhibitor of mTOR, blocked both mTORC1 and mTORC2 activation in colorectal cancer cells (both primary and transformed cells). The immunoprecipitation results showed that the assembly of mTORC1 (mTOR-Raptor association) and mTORC2 (mTOR-Rictor-Sin1 association) was also disrupted by INK-128. INK-128 inhibited colorectal cancer cell growth and survival, and induced both apoptotic and non-apoptotic cancer cell death. Further, INK-128 showed no effect on Erk/MAPK activation, while MEK/Erk inhibition by MEK-162 enhanced INK-128-induced cytotoxicity in colorectal cancer cells. Meanwhile, INK-128 downregulated Fascin1 (FSCN1)/E-Cadherin expressions and inhibited HT-29 cell in vitro migration. In vivo, daily INK-128 oral administration inhibited HT-29 xenograft growth in mice, which was further enhanced by MEK-162 administration. Finally, we found that INK-128 sensitized 5-fluorouracil-(5-FU)-mediated anti-HT-29 activity in vivo and in vitro. Thus, our preclinical studies strongly suggest that INK-128 might be investigated for colorectal cancer treatment in clinical trials.
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Antineoplásicos/farmacología , Benzoxazoles/farmacología , Neoplasias Colorrectales/metabolismo , Complejos Multiproteicos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Benzoxazoles/administración & dosificación , Cadherinas/metabolismo , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Activación Enzimática/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Fluorouracilo/farmacología , Células HT29 , Humanos , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Diana Mecanicista del Complejo 2 de la Rapamicina , Ratones , Proteínas de Microfilamentos/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
AIM: To determine whether Chinese herbs (CHs) relieve xerostomia (dry mouth) by increasing salivary secretion. METHODS: The submandibular glands of Wistar rats were surgically isolated and perfused arterially with buffered salt solution. After control perfusion, recording started 5 min prior to the start of stimulation. After fluid secretion was induced by 0.2 mumol/L carbamylcholine (CCh) in the perfusate for 10 min, Chinese herb (CH) was added in the perfusion for 5 min. CCh was then overloaded at 0.2 mumol/L in the perfusion for 20 min. The volume of salivary fluid secretion was recorded by a computer-controlled balance system. RESULTS: Saliva secretion formed an initial ephemeral peak at 30 s followed by a gradual increase to a sustained level. CH alone induced no or little saliva in all types of CH selected. During perfusion with CH, overloading of CCh promoted fluid secretion in 15 of 20 CHs. This promotion was classified into four patterns, which were eventually related to the categories of CH: Overall sustained phase was continuously raised (Yin-nourishing, fluid production-promoting and heat-clearing agents); The sustained secretion rose to reach a maximum then decreased (Qi-enhancing agent); Sustained secretion rose to reach the highest maximum and was then sustained with a slight decline (swelling-reducing, phlegm-resolving and pus-expelling agents); Stimulation of salivary secretion without any added stimulants. Addition of CCh raised the fluid secretion to reach the highest maximum then sharply decreased to a lower sustained level (blood activating agent). CONCLUSION: The present findings lead to the conclusion that various CHs have different promotional effects directly on the salivary gland.
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Medicamentos Herbarios Chinos/farmacología , Saliva/metabolismo , Glándula Submandibular , Animales , Carbacol/farmacología , Agonistas Colinérgicos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Medicina Tradicional China , Ratas , Ratas Wistar , Glándula Submandibular/efectos de los fármacos , Glándula Submandibular/metabolismo , Xerostomía/tratamiento farmacológicoRESUMEN
OBJECTIVES: The major objectives of this article are first to measure the levels of expression of adiponectin and its 2 receptors (adipoR1 and adipoR2) in the peripheral blood mononuclear cells and in the synovial compartment of rheumatoid arthritis (RA) patients, and second, to assess their pro-inflammatory potential. Osteoarthritis patients and healthy subjects served as controls. METHODS: Expression of adiponectin, adipoR1, and adipoR2 were assayed by real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistology. The potential pro-inflammatory activity of adiponectin was studied by adding recombinant adiponectin to cultures of synovial fibroblasts. RESULTS: Immunohistology showed that numerous cells in the synovial biopsies of RA expressed adiponectin, adipoR1, and adipoR2. The synovial fibroblasts were distinctly rich in adiponectin. As expected, high adiponectin levels were present in the synovial fluids. In contrast to the synovial compartment, in peripheral blood mononuclear cells, only adipoR1 exceeded those of osteoarthritis and healthy subjects. When recombinant adiponectin was added to cultures of synovial fibroblasts, it induced up to 8.1- and 11.4-fold increase in the release of monocyte chemoattractant protein-1 and interleukin-6. CONCLUSIONS: The adiponectin adipokine axis might play a role in RA.