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OBJECTIVE: To seek optimal keV settings for imaging carpal tunnel in adults by dual-energy computed tomography (DECT) monoenergetic technique; to describe anatomic characteristics of carpal tunnel and to observe correlation between carpal bony and soft tissue structures. METHODS: DECT images of 20 wrists (11 left and 9 right wrists; 14 men, mean age 26.93±1.38 years, range 23 to 28, and 6 women, mean age 24.17 ± 0.98 years, range 23 to 26) were evaluated. Monoenergetic images were reconstructed at 42, 62, 82, 102, 122, and 142 keV. Image quality was assessed along a 5-point Likert scale, and the highest-quality images were chosen for quantitative analysis. Two musculoskeletal radiologists performed both analyses independently. RESULTS: The optimal energy spectrum with the best contrast-to-noise ratio (CNR) for monoenergetic images were at 62 keV (19 wrists, 95%) and 61 keV (1 wrist, 5%). There was substantial interobserver agreement between the readers in the 5-point Likert scale analysis of image quality (k= 0.793). Bland-Altman plots also indicated good agreement between observers in quantitative analysis. Intra-category 1 and 2 correlation was mostly discovered at hamate hook level and middle level of pisiform (P < 0.05), while bony and soft tissue structures partly reached correlation (P < 0.05). CONCLUSIONS: The optimal energy spectrum for monoenergetic DECT imaging of carpal tunnel structures was 62 keV. DECT monoenergetic imaging could predict changes in soft tissue structures and demonstrate carpal tunnel anatomic structures.
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Imagen Radiográfica por Emisión de Doble Fotón , Muñeca , Adulto , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Radiólogos , Estudios Retrospectivos , Relación Señal-Ruido , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
The all-inorganic nature of CsPbI3 perovskites allows to enhance stability in perovskite devices. Research efforts have led to improved stability of the black phase in CsPbI3 films; however, these strategies-including strain and doping-are based on organic-ligand-capped perovskites, which prevent perovskites from forming the close-packed quantum dot (QD) solids necessary to achieve high charge and thermal transport. We developed an inorganic ligand exchange that leads to CsPbI3 QD films with superior phase stability and increased thermal transport. The atomic-ligand-exchanged QD films, once mechanically coupled, exhibit improved phase stability, and we link this to distributing strain across the film. Operando measurements of the temperature of the LEDs indicate that KI-exchanged QD films exhibit increased thermal transport compared to controls that rely on organic ligands. The LEDs exhibit a maximum EQE of 23 % with an electroluminescence emission centered at 640â nm (FWHM: ≈31â nm). These red LEDs provide an operating half-lifetime of 10â h (luminance of 200â cd m-2 ) and an operating stability that is 6× higher than that of control devices.
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BACKGROUND: Zinc-α2-glycoprotein (ZAG) is a recently novel lipolytic adipokine implicated in regulation of glucose and lipid metabolism in many metabolic disorders. In vitro and animal studies suggest that thyroid hormones (TH) up-regulates ZAG production in hepatocytes. However, there is no data evaluating the possible relationship between ZAG and TH in a human model of hyperthyroidism. The objective of the present study is to assess the association of serum ZAG levels with TH and lipid profile in patients with hyperthyroidism before and after methimazole treatment. METHODS: A total of 120 newly diagnosed overt hyperthyroidism and 122 healthy control subjects were recruited. Of them, 39 hyperthyroidism patients were assigned to receive methimazole treatment as follow-up study for 2 months. RESULTS: The clinical consequence showed that serum ZAG levels were elevated in patients with hyperthyroidism (P < 0.01). Adjust for age, gender and BMI, serum ZAG levels were positively related with serum free T3 (FT3), free T4 (FT4) levels and negatively correlated with serum total cholesterol (TC), low density lipoprotein cholesterol (LDLC) levels in hyperthyroidism subjects (all P < 0.01). After methimazole treatment, serum ZAG levels were decreased and the decline was associated with decreased FT3, FT4 and increased TC levels (all P < 0.001). CONCLUSION: We conclude that ZAG may be involved in the pathogenesis of lipid metabolism disorder in patients with hyperthyroidism. TRIAL REGISTRATION: ChiCTR-ROC-17012943 . Registered 11 October 2017, retrospectively registered.
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Biomarcadores/sangre , Hipertiroidismo/sangre , Metimazol/uso terapéutico , Proteínas de Plasma Seminal/sangre , Hormonas Tiroideas/sangre , Adulto , Antitiroideos/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Hipertiroidismo/diagnóstico , Hipertiroidismo/tratamiento farmacológico , Masculino , Pronóstico , Estudios Prospectivos , Zn-alfa-2-GlicoproteínaRESUMEN
OBJECTIVE: To study the level of circulating Alarin in obese children and its association with various metabolic parameters. METHODS: A total of 86 obese children with a body mass index (BMI) above the 95th percentile were enrolled as the obesity group, and 82 healthy children, matched for age and sex, with a BMI below the 85th percentile were enrolled as the healthy control group. According to the presence or absence of insulin resistance (IR), the obesity group was further divided into an IR group with 27 children and a non-IR group with 59 children. Related anthropometric parameters, including body height, body weight, systolic blood pressure (SBP), and diastolic blood pressure (DBP), were measured, and BMI was calculated. Total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), uric acid (UA), fasting insulin (FINS), and fasting blood glucose (FBG) were measured. The area under the receiver operating characteristic curve (AUC) for glucose and insulin, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), and whole-body insulin sensitivity index (WBISI) were calculated. ELISA was used to measure the level of circulating Alarin. RESULTS: The obesity group had a significantly higher level of circulating Alarin than the healthy control group (P<0.01). The IR group had a significantly higher level of circulating Alarin than the non-IR group (P<0.01). Circulating Alarin was positively correlated with BMI, TG, FBG, AUC-glucose, AUC-FINS, and HOMA-IR (P<0.05) and was negatively correlated with WBISI (P<0.05). The circulating Alarin level had a linear regression relationship with BMI, FBG, and HOMA-IR, among which HOMA-IR had the greatest influence on the circulating Alarin level (P<0.05). CONCLUSIONS: There is a significant increase in the circulating Alarin level in obese children, which may be associated with the development of obesity and IR.
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Resistencia a la Insulina , Obesidad , Glucemia , Índice de Masa Corporal , Niño , Péptido Similar a Galanina , Humanos , InsulinaRESUMEN
BACKGROUND/AIM: Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity, and chronic low-grade inflammation. Our previous studies indicated that zinc alpha2 glycoprotein (ZAG) alleviates palmitate (PA)-induced intracellular lipid accumulation in hepatocytes. This study is to further characterize the roles of ZAG on the development of hepatic steatosis, insulin resistance (IR), and inflammation. METHODS: ZAG protein levels in the livers of NAFLD patients, high-fat diet (HFD)-induced or genetically (ob/ob) induced obese mice, and in PA-treated hepatocytes were determined by western blotting. C57BL/6J mice injected with an adenovirus expressing ZAG were fed HFD for indicated time to induce hepatic steatosis, IR, and inflammation, and then biomedical, histological, and metabolic analyses were conducted to identify pathologic alterations in these mice. The molecular mechanisms underlying ZAG-regulated hepatic steatosis were further explored and verified in mice and hepatocytes. RESULTS: ZAG expression was decreased in NAFLD patient liver biopsy samples, obese mice livers, and PA-treated hepatocytes. Simultaneously, ZAG overexpression alleviated intracellular lipid accumulation via upregulating adiponectin and lipolytic genes (FXR, PPARα, etc.) while downregulating lipogenic genes (SREBP-1c, LXR, etc.) in obese mice as well as in cultured hepatocytes. ZAG improved insulin sensitivity and glucose tolerance via activation of IRS/AKT signaling. Moreover, ZAG significantly inhibited NF-ĸB/JNK signaling and thus resulting in suppression of obesity-associated inflammatory response in hepatocytes. CONCLUSIONS: Our results revealed that ZAG could protect against NAFLD by ameliorating hepatic steatosis, IR, and inflammation.
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Enfermedad del Hígado Graso no Alcohólico/metabolismo , Obesidad/metabolismo , Proteínas de Plasma Seminal/metabolismo , Animales , Humanos , Hígado/química , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Proteínas de Plasma Seminal/análisis , Proteínas de Plasma Seminal/genética , Transducción de Señal/genética , Regulación hacia Arriba/genética , Zn-alfa-2-GlicoproteínaRESUMEN
Diabetic nephropathy (DN) is one of the most important diabetic microangiopathies. The epithelial-to-mesenchymal transition (EMT) plays an important role in DN. The physiological role of microRNA-21 (miR-21) was closely linked to EMT. However, it remained elusive whether tongxinluo (TXL) ameliorated renal structure and function by regulating miR-21-induced EMT in DN. This study aimed to determine the effect of TXL on miR-21-induced renal tubular EMT and to explore the relationship between miR-21 and TGF-ß1/smads signals. Real-time RT-PCR, cell transfection, in situ hybridization (ISH), and laser confocal microscopy were used, respectively. Here, we revealed that TXL dose dependently lowered miR-21 expression in tissue, serum, and cells. Overexpression of miR-21 can enhance α-smooth muscle actin (SMA) expression and decrease E-cadherin expression by upregulating smad3/p-smad3 expression and downregulating smad7 expression. Interestingly, TXL also increased E-cadherin expression and decreased α-SMA expression by regulating miR-21 expression. More importantly, TXL decreased collagen IV, fibronectin, glomerular basement membrane, glomerular area, and the albumin/creatinine ratio, whereas it increased the creatinine clearance ratio. The results demonstrated that TXL ameliorated renal structure and function by regulating miR-21-induced EMT, which was one of the mechanisms to protect against DN, and that miR-21 may be one of the therapeutic targets for TXL in DN.
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Nefropatías Diabéticas/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Transición Epitelial-Mesenquimal/efectos de los fármacos , MicroARNs/metabolismo , Cadherinas/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Línea Celular , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , HumanosRESUMEN
To discover novel biomarkers for early detection of human lung squamous cell cancer (LSCC) and explore possible mechanisms of LSCC carcinogenesis, iTRAQ-tagging combined with two dimensional liquid chromatography tandem MS analysis was used to identify differentially expressed proteins in human bronchial epithelial carcinogenic process using laser capture microdissection-purified normal bronchial epithelium (NBE), squamous metaplasia (SM), atypical hyperplasia (AH), carcinoma in situ (CIS) and invasive LSCC. As a result, 102 differentially expressed proteins were identified, and three differential proteins (GSTP1, HSPB1 and CKB) showing progressively expressional changes in the carcinogenic process were selectively validated by Western blotting. Immunohistochemistry was performed to detect the expression of the three proteins in an independent set of paraffin-embedded archival specimens including various stage tissues of bronchial epithelial carcinogenesis, and their ability for early detection of LSCC was evaluated by receiver operating characteristic analysis. The results showed that the combination of the three proteins could perfectly discriminate NBE from preneoplastic lesions (SM, AH and CIS) from invasive LSCC, achieving a sensitivity of 96% and a specificity of 92% in discriminating NBE from preneoplatic lesions, a sensitivity of 100% and a specificity of 98% in discriminating NBE from invasive LSCC, and a sensitivity of 92% and a specificity of 91% in discriminating preneoplastic lesions from invasive LSCC, respectively. Furthermore, we knocked down GSTP1 in immortalized human bronchial epithelial cell line 16HBE cells, and then measured their susceptibility to carcinogen benzo(a)pyrene-induced cell transformation. The results showed that GSTP1 knockdown significantly increased the efficiency of benzo(a)pyrene-induced 16HBE cell transformation. The present data first time show that GSTP1, HSPB1 and CKB are novel potential biomarkers for early detection of LSCC, and GSTP1 down-regulation is involved in human bronchial epithelial carcinogenesis.
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Biomarcadores de Tumor/metabolismo , Detección Precoz del Cáncer , Neoplasias Pulmonares/metabolismo , Neoplasias de Células Escamosas/metabolismo , Secuencia de Aminoácidos , Biomarcadores de Tumor/química , Biomarcadores de Tumor/genética , Bronquios/patología , Línea Celular , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/metabolismo , Análisis por Conglomerados , Forma BB de la Creatina-Quinasa/química , Forma BB de la Creatina-Quinasa/genética , Forma BB de la Creatina-Quinasa/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/patología , Expresión Génica , Gutatión-S-Transferasa pi/química , Gutatión-S-Transferasa pi/genética , Gutatión-S-Transferasa pi/metabolismo , Proteínas de Choque Térmico HSP27/química , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico , Humanos , Captura por Microdisección con Láser , Neoplasias Pulmonares/diagnóstico , Chaperonas Moleculares , Datos de Secuencia Molecular , Neoplasias de Células Escamosas/diagnóstico , Proteómica , Curva ROC , Estadísticas no Paramétricas , Espectrometría de Masas en TándemRESUMEN
Purpose: The increasing prevalence of obesity in children and its associated risk with cardiovascular diseases demand more discovery of the novel biomarkers for developing new treatment options for this complex disease. This study aimed to investigate the association of serum MOTS-C (a peptide encoded in the mitochondrial genome) levels and vascular endothelial function in obese children. Patients and Methods: A total of 225 obese children (aged 8.1 ± 2.6 years) and 218 healthy children (aged 7.9 ± 2.2 years) were enrolled. Related anthropometric assessment and biochemical evaluation were done in all subjects. Reactive hyperemia index (RHI), as assessed by the peripheral arterial tonometry, was used for evaluation of peripheral endothelial function. Enzyme-linked immunosorbent assay (ELISA) was used to measure the level of serum MOTS-C. Results: Levels of serum MOTS-C and RHI were lower in the obese children compared with the healthy children (P < 0.01). The RHI level was independently associated with body mass index, high-density lipoprotein cholesterol, and MOTS-C in linear regression analysis. Further analysis showed a significant mediating effect of MOTS-C on the correlation between body mass index and RHI in children, with the ratio of mediating effect value of 9.12%. Conclusion: These data identify that MOTS-C is a previously unknown regulator in the development process of obesity-induced vascular changes.
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BACKGROUND AND OBJECTIVES: MicroRNA-dependent regulation of hepatic lipid metabolism has been recognized recently as a key pathological mechanism contributing to the development of NAFLD. However, whether miR-32-5p (miR-32) plays a role in lipid metabolism or contributes to NAFLD remains unclear. METHODS AND RESULTS: A marked increase in miR-32 expression was observed in liver samples from patients and mice with NAFLD, as well as in palmitate-induced hepatocytes. Hepatocyte-specific miR-32 knockout (miR-32-HKO) dramatically ameliorated hepatic steatosis and metabolic disorders in high-fat diet-fed mice. Conversely, hepatic miR-32 overexpression markedly exacerbated the progression of these abnormalities. Further, combinational analysis of transcriptomics and lipidomics suggested that miR-32 was a key trigger for de novo lipogenesis in the liver. Mechanistically, RNA sequencing, luciferase assay and adenovirus-mediated downstream gene rescue assay demonstrated that miR-32 directly bound to insulin-induced gene 1 (INSIG1) and subsequently activated sterol regulatory element binding protein-mediated lipogenic gene programs, thereby promoting hepatic lipid accumulation and metabolic disorders. Notably, pharmacological administration of miR-32 antagonist significantly inhibited palmitate-induced triglyceride deposition in hepatocytes and markedly mitigated hepatic steatosis and metabolic abnormalities in obesity-associated NAFLD mice. CONCLUSION: miR-32 is an important checkpoint for lipogenesis in the liver, and targeting miR-32 could be a promising therapeutic approach for NAFLD treatment.
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Hiperlipidemias , MicroARNs , Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Humanos , Lipogénesis/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Hiperlipidemias/metabolismo , Células Hep G2 , Hígado/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Dieta Alta en Grasa/efectos adversos , Palmitatos , Ratones Endogámicos C57BLRESUMEN
Background: Breast cancer is a highly heterogeneous disease. Early-stage, non-metastatic breast cancer is considered curable after definitive treatment. Early detection of tumor recurrence and metastasis through sensitive biomarkers is helpful for guiding clinical decision-making and early intervention in second-line treatment, which could improve patient prognosis and survival. Methods: In this real-world study, we retrospectively analyzed 82 patients with stages I to III breast cancer who had been analyzed by molecular residual disease (MRD) assay. A total of 82 tumor tissues and 224 peripheral blood samples were collected and detected by next-generation sequencing (NGS) based on a 1,021-gene panel in this study. Results: MRD positivity was detected in 18 of 82 patients (22.0%). The hormone receptor-/human epidermal growth factor receptor 2+ (HR-/HER2+) subgroup had the highest postoperative MRD detection rate at 30.8% (4/13). The BRCA2 and SLX4 genes were significantly enriched in all patients in the MRD positive group and FGFR1 amplification was significantly enriched in the MRD negative group with HR+/HER2-. The number of single nucleotide variants (SNVs) in tissue samples of MRD-positive patients was higher than that of MRD-negative patients (11.94 vs. 8.50 SNVs/sample). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that there was a similar biological function of the tumor-mutated genes in the 2 MRD status groups. Conclusions: This real-world study confirmed that patient samples of primary tumor tissue with different MRD status and molecular subtypes had differential genetic features, which may be used to predict patients at high risk for recurrence.
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Instability in mixed-halide perovskites (MHPs) is a key issue limiting perovskite solar cells and light-emitting diodes (LEDs). One form of instability arises during the processing of MHP quantum dots using an antisolvent to precipitate and purify the dots forming surface traps that lead to decreased luminescence, compromised colloidal stability, and emission broadening. Here, the introduction of inorganic ligands in the antisolvents used in dot purification is reported in order to overcome this problem. MHPs that are colloidally stable for over 1 year at 25 °C and 40% humidity are demonstrated and films that are stable under 100 W cm-2 photoirradiation, 4× longer than the best previously reported MHPs, are reported. In LEDs, the materials enable an EQE of 24.4% (average 22.5 ± 1.3%) and narrow emission (full-width at half maximum of 30 nm). Sixfold-enhanced operating stability relative to the most stable prior red perovskite LEDs having external quantum efficiency >20% is reported.
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OBJECTIVE: Asprosin, a new adipocytokine, has reportedly been associated with glucose release, dyslipidemia, and insulin resistance (IR). However, the relationship of asprosin with metabolic syndrome (MetS) remains unknown. This study aimed to investigate serum asprosin levels in MetS as well as their association with various metabolic parameters in humans. METHODS: A total of 131 consecutive patients with MetS, and 162 age-matched, healthy subjects were recruited for this study. Serum asprosin concentrations were determined using the enzyme-linked immunosorbent assay. Lipid profile, glucose, insulin, and inflammatory markers were also measured. RESULTS: Serum asprosin levels were higher in subjects with MetS (23.52 [16.70, 32.05] ng/mL) than in controls (16.70 [12.87, 22.38] ng/mL; P < 0.01), and they showed an increasing trend with increasing numbers of metabolic components (P for trend < 0.01). In all studied subjects, serum asprosin levels were positively correlated with body mass index, waist circumference, triglycerides, fasting plasma glucose, 2-hour plasma glucose, fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR) index, interleukin-6, and monocyte chemoattractant protein-1 and negatively correlated with high-density lipoprotein cholesterol (P < 0.05). In multiple linear regression, asprosin was independently and positively correlated with triglyceride and HOMA-IR (P < 0.05). Binary logistic regression revealed that asprosin was independently and positively correlated with the occurrence of MetS and IR, even after controlling for anthropometric variables, lipid profiles, and inflammatory markers. CONCLUSION: Asprosin is a potential metabolic-related adipokine and may be related to IR and MetS. This trial was registered with ChiCTR, ChiCTR1800018347.
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Fatty acids induced hepatic inflammation plays an important role in nonalcoholic fatty liver disease (NAFLD) pathogenesis. Hydrogen sulfide (H2S), an endogenous gasotransmitter, has been established to possess potent anti-inflammation in various human organs. However, the anti-inflammation property of H2S in the fatty liver is still needed to further elucidate. Hence, this study aimed to investigate whether exogenous H2S can protect hepatocytes against inï¬ammation induced by palmitic acid (PA). HepG2 hepatocytes were exposed to PA for 24 h to induce free fatty acids-induced inflammation. The cells were pretreated with NaHS (a donor of H2S) before exposure to PA. Cell viability, inflammatory cytokines (TNF-α, IL-6 and IL-1ß), NLRP3 inflammasome and NF-κB were measured by a combination of MTT assay, ELISA, Western blot and Immunofluorescence. Here, we found that exogenous H2S dose-dependently inhibited the expression of pro-inflammatory cytokines, NLRP3 inflammasome and activation of NF-κB signaling in PA-induced HepG2 cells. Thus, H2S might be a candidate therapeutic agent against NAFLD.
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Células Hep G2/metabolismo , Hepatocitos/metabolismo , Sulfuro de Hidrógeno/metabolismo , Inflamación/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Citocinas/metabolismo , Humanos , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ácido Palmítico/metabolismoRESUMEN
Remodeling of energy-storing white fat into energy-consuming beige fat has led to a promising new approach to alleviate adiposity. Several studies have shown adipokines can induce white adipose tissue (WAT) beiging through autocrine or paracrine actions. Betatrophin, a novel adipokine, has been linked to energy expenditure and lipolysis but not clearly clarified. Here, we using high-fat diet-induced obesity to determine how betatrophin modulate beiging and adiposity. We found that betatrophin-knockdown mice displayed less white fat mass and decreased plasma TG and NEFA levels. Consistently, inhibition of betatrophin leads to the phenotype change of adipocytes characterized by increased mitochondria contents, beige adipocytes and mitochondria biogenesis-specific markers both in vivo and in vitro. Of note, blocking AMP-activated protein kinase (AMPK) signaling pathway is able to abolish enhanced beige-like characteristics in betatrophin-knockdown adipocytes. Collectively, downregulation of betatrophin induces beiging in white adipocytes through activation of AMPK signaling pathway. These processes suggest betatrophin as a latent therapeutic target for obesity.
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Adipocitos Beige/metabolismo , Adipocitos Blancos/metabolismo , Tejido Adiposo Blanco/metabolismo , Proteínas Similares a la Angiopoyetina/metabolismo , Mitocondrias/metabolismo , Células 3T3-L1 , Proteínas Quinasas Activadas por AMP/metabolismo , Adipocitos Beige/citología , Adipocitos Blancos/citología , Tejido Adiposo Blanco/citología , Adiposidad/genética , Proteína 8 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina/genética , Animales , Dieta Alta en Grasa/efectos adversos , Metabolismo Energético/genética , Ácidos Grasos no Esterificados/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/etiología , Obesidad/genética , Obesidad/metabolismo , Interferencia de ARN , Transducción de Señal , Triglicéridos/sangreRESUMEN
Overexpression of ANXA1 and EphA2 has been linked to various cancers and both proteins have attracted considerable attention for the development of new anticancer drugs. Here we report that ANXA1 competes with Cbl for binding EphA2 and increases its stability by inhibiting Cbl-mediated EphA2 ubiquitination and degradation in nasopharyngeal carcinoma (NPC). Binding of ANXA1 to EphA2 promoted NPC cell growth and metastasis in vitro and in vivo by elevating EphA2 levels and increasing activity of EphA2 oncogenic signaling (pS897-EphA2). Expression of ANXA1 and EphA2 was positively correlated and both were significantly higher in NPC tissues than in the normal nasopharyngeal epithelial tissues. Patients with high expression of both proteins presented poorer disease-free survival and overall survival relative to patients with high expression of one protein alone. Furthermore, amino acid residues 20-30aa and 28-30aa of the ANXA1 N-terminus bound EphA2. An 11 amino acid-long ANXA1-derived peptide (EYVQTVKSSKG) was developed on the basis of this N-terminal region, which disrupted the connection of ANXA1 with EphA2, successfully downregulating EphA2 expression and dramatically suppressing NPC cell oncogenicity in vitro and in mice. These findings suggest that ANXA1 promotes NPC growth and metastasis via binding and stabilization of EphA2 and present a strategy for targeting EphA2 degradation and treating NPC with a peptide. This therapeutic strategy may also be extended to other cancers with high expression of both proteins. SIGNIFICANCE: These findings show that EphA2 is a potential target for NPC therapeutics and an ANXA1-derived peptide suppresses NPC growth and metastasis. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4386/F1.large.jpg.
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Anexina A1/metabolismo , Efrina-A2/metabolismo , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/patología , Animales , Anexina A1/química , Anexina A1/genética , Sitios de Unión , Unión Competitiva , Línea Celular Tumoral , Efrina-A2/química , Efrina-A2/genética , Humanos , Masculino , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/mortalidad , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/mortalidad , Complejo de la Endopetidasa Proteasomal/metabolismo , Estabilidad Proteica , Proteínas Proto-Oncogénicas c-cbl/metabolismo , Receptor EphA2 , Ubiquitina/metabolismoRESUMEN
Our phosphoproteomics identified that phosphorylation of EphA2 at serine 897 (pS897-EphA2) was significantly upregulated in the high metastatic nasopharyngeal carcinoma (NPC) cells relative to non-metastatic NPC cells. However, the role and underlying mechanism of pS897-EphA2 in cancer metastasis and stem properties maintenance remain poorly understood. In this study, we established NPC cell lines with stable expression of exogenous EphA2 and EphA2-S897A using endogenous EphA2 knockdown cells, and observed that pS897-EphA2 maintained EphA2-dependent NPC cell in vitro migration and invasion, in vivo metastasis and cancer stem properties. Using phospho-kinase antibody array to identify signaling downstream of pS897-EphA2, we found that AKT/Stat3 signaling mediated pS897-EphA2-promoting NPC cell invasion, metastasis and stem properties, and Sox-2 and c-Myc were the effectors of pS897-EphA2. Immunohistochemistry showed that pS897-EphA2 was positively correlated with NPC metastasis and negatively correlated with patient overall survival. Moreover, ERK/RSK signaling controlled serum-induced pS897-EphA2 in NPC cells. Collectively, our results demonstrate that pS897-EphA2 is indispensable for EphA2-dependent NPC cell invasion, metastasis and stem properties by activating AKT/Stat3/Sox-2 and c-Myc signaling pathway, suggesting that pS897-EphA2 can serve as a therapeutic target in NPC and perhaps in other cancers.
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Biomarcadores de Tumor/metabolismo , Neoplasias Pulmonares/secundario , Neoplasias Nasofaríngeas/patología , Células Madre Neoplásicas/patología , Receptor EphA2/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Metástasis Linfática , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Invasividad Neoplásica , Células Madre Neoplásicas/metabolismo , Fosforilación , Pronóstico , Receptor EphA2/genética , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUD: CCN3 is a novel adipokine and has emerged as a potential metabolic regulator. However, information regarding the role of CCN3 in type 2 diabetes mellitus (T2DM) remains unclear. This study measured for the first time serum CCN3 levels in T2DM and explored the correlations between its serum levels and various metabolic parameters in humans. METHODS: A total of 219 newly diagnosed T2DM (nT2DM) patients and 205 healthy control subjects, matched for age and sex ratio, were enrolled. Circulating CCN3 and TNF-α, IL-6 and MCP-1 were measured by ELISA. The anthropometric assessment and biochemical evaluation were done in all subjects. OGTT were performed in 34 healthy individuals to investigate the association of CCN3 with glucose. RESULTS: Serum CCN3 levels were significantly higher in nT2DM patients compared to those of the healthy controls (6.71[4.88, 8.56] vs. 4.51[3.55, 5.99] ng/ml, Pâ¯<â¯0.01). Serum CCN3 positively correlated with BMI, WC, FAT%, TG, FPG, 2â¯h-PG, HbA1c, FIns, HOMA-IR, hs-CRP and TNF-α, IL-6 and MCP-1, but negatively with HOMA-ß in all individuals (Pâ¯<â¯0.05). Multiple linear regression analysis indicated that BMI, HOMA-IR, TNF-α and MCP-1 were independently associated with CCN3. Multivariate logistic regression analysis demonstrated that CCN3 was correlated with nT2DM. Finally, area under ROC curve of CCN3 (gender and age adjusted) for predicting the presence of nT2DM was 0.725(95% CI: 0.676-0.773). After an oral glucose challenge, there was no obvious change in the circulating levels of CCN3 as compared to 0â¯min (Pâ¯>â¯0.05). CONCLUSIONS: Elevation of CCN3 in nT2DM supports the hypothesis that CCN3 may serve as a risk factor associated with the pathogenesis of T2DM.
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Diabetes Mellitus Tipo 2/sangre , Inflamación/sangre , Resistencia a la Insulina , Proteína Hiperexpresada del Nefroblastoma/sangre , Obesidad/sangre , Adulto , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , Inflamación/complicaciones , Inflamación/metabolismo , Masculino , Proteína Hiperexpresada del Nefroblastoma/metabolismo , Obesidad/complicaciones , Obesidad/metabolismoRESUMEN
A hybrid drug delivery system was successfully fabricated by attaching a camptothecin (CPT)-based polymeric prodrug onto the surface of silver nanoparticles (AgNPs). PEG was employed as a macro-RAFT agent in RAFT polymerization to synthesize a branched star copolymer, to which CPT is linked through the photo-responsive o-nitrobenzyl linkage. In vitro tests indicate that the fluorescence of CPT in the polymeric prodrug is quenched by AgNPs based on the nanomaterial surface energy transfer (NSET) effect and the fluorescence recovers when the CPT molecules are released from hybrid nanoparticles. Thus, the variation of fluorescence intensity is bound up with the drug release behaviours, which may enable this AgNP-based drug delivery system to trace the intracellular drug release process and observe the distribution of released CPT in cells.
RESUMEN
Annexin A1 (ANXA1) is dysregulated in the various tumors. However, the role and mechanism of ANXA1 in the cancers are poorly understood. In this study, we first showed a clinically positive correlation between ANXA1 and autophagy-associated protein SQSTM1 expression in nasopharyngeal carcinoma (NPC) and ANXA1-regulating SQSTM1 expression through autophagy, and further demonstrated that ANXA1 inhibited BECN1 and ATG5-dependent autophagy in the NPC cells. Using phospho-kinase antibody array to identify signaling through which ANXA1 regulated NPC cell autophagy, we found that ANXA1-suppressed autophagy was associated with PI3K/AKT signaling activation. We also showed that ANXA1 expression was significantly increased in the NPCs with metastasis relative to NPCs without metastasis and positively correlated with lymphonode and distant metastasis; high ANXA1 expression in the NPC cells promoted in vitro tumor cell migration and invasion and in vivo metastasis. Lastly, we showed that inhibition of autophagy restored the ability of tumor cell migration and invasion, epithelial-mesenchymal transition (EMT)-like alterations and in vivo metastasis in the ANXA1 knockdown NPC cells with autophagy activation; ANXA1-suppresed autophagy induced EMT-like alterations possibly by inhibiting autophagy-mediated degradation of Snail. Our data suggest that ANXA1-suppressed autophagy promotes NPC cell migration, invasion and metastasis by activating PI3K/AKT signaling pathway, highlighting that the activation of autophagy may inhibit metastasis of NPC with high ANXA1 expression.
Asunto(s)
Anexina A1/genética , Autofagia/genética , Carcinoma Nasofaríngeo/genética , Proteína Sequestosoma-1/genética , Proteína 5 Relacionada con la Autofagia/genética , Beclina-1/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Humanos , Carcinoma Nasofaríngeo/patología , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Metástasis de la Neoplasia , Fosfatidilinositol 3-Quinasas/genética , Proteolisis , Proteínas Proto-Oncogénicas c-akt/genética , Factores de Transcripción de la Familia Snail/genéticaRESUMEN
MiR-125b is aberrantly expressed and has a role in the various types of tumors. However, the role and mechanism of miR-125b in nasopharyngeal carcinoma (NPC) are unclear. In this study, we investigated the role and mechanism of miR-125b in NPC. We observed that miR-125b was significantly upregulated in the NPC tissues relative to normal nasopharyngeal mucosa (NNM), and its increment was correlated with poor patient survival, and was an independent predictor for reduced patient survival; miR-125b promoted NPC cell proliferation and inhibited NPC cell apoptosis; in a mouse model, administration of miR-125b antagomir significantly reduced the growth of NPC xenograft tumors. Mechanistically, we confirmed that A20 was a direct target of miR-125b, and found that activation of nuclear factor κB (NF-κB) signaling pathway by A20 mediated miR-125b-promoting NPC cell proliferation and -inhibiting NPC cell apoptosis. With a combination of loss-of-function and gain-of-function approaches, we further showed that A20 inhibited NPC cell proliferation, induced NPC cell apoptosis, and reduced the growth of NPC xenograft tumors. Moreover, A20 was significantly downregulated, whereas p-p65(RelA) was significantly upregulated in the NPC tissues relative to normal nasopharyngeal mucosa, and miR-125b level was negatively associated with A20 level, whereas positively associated with p-p65 level. Our data demonstrate that miR-125b regulates NPC cell proliferation and apoptosis by targeting A20/NF-κB signaling pathway, and miR-125b acts as oncogene, whereas A20 functions as tumor suppressor in NPC, highlighting the therapeutic potential of miR-125b/A20/NF-κB signaling axis in the NPC.