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Rhenium sulfide (ReS2) has emerged as a promising two-dimensional material, demonstrating broad-spectrum visible absorption properties that make it highly relevant for diverse optoelectronic applications. Manipulating and optimizing the pathway of photogenerated carriers play a pivotal role in enhancing the efficiency of charge separation and transfer in novel semiconductor composites. This study focuses on the strategic construction of a semiconductor heterostructure by synthesizing ZnO on vacancy-containing ReS2 (VRe-ReS2) through chemical bonding processes. The ingeniously engineered built-in electric field within the heterostructure effectively suppresses the recombination of photogenerated electron-hole pairs. A direct and well-established interfacial connection between VRe-ReS2 and ZnO is achieved through a robust Zn-S bond. This distinctive bond configuration leads to enhanced nonlinear optical conversion efficiency, attributed to shortened carrier migration distances and accelerated charge transfer rates. Furthermore, theoretical calculations unveil the superior chemical interactions between Re vacancies and sulfide moieties, facilitating the formation of Zn-S bonds. The photoluminescence (PL) intensity is increased by the formation of VRe-ReS2 and ZnO heterostructure and the PL quantum yield of VRe-ReS2 is improved. The intricate impact of the Zn-S bond on the nonlinear absorption behavior of the VRe-ReS2@ZnO heterostructure is systematically investigated using femtosecond Z-scan techniques. The charge transfer from ZnO to ReS2 defect levels induces a transition from saturable absorption to reverse saturable absorption in the VRe-ReS2@ZnO heterostructure. Transient absorption measurements further confirm the presence of the Zn-S bond between the interfaces, as evidenced by the prolonged relaxation time (τ3) in the VRe-ReS2@ZnO heterostructure. This study offers valuable insights into the rational construction of heterojunctions through tailored interfacial bonding and surface/interface charge transfer pathways. These endeavors facilitate the modulation of electron transfer dynamics, ultimately yielding superior nonlinear optical conversion efficiency and effective charge regulation in optoelectronic functional materials.
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In the past decades, remarkable efforts have been made to unravel the regulation of adipose tissue metabolism, given the increasing prevalence of obesity and its huge impact on human health. Wnt signaling pathway is closely involved in this entity. As extracellular inhibitors to Wnt signaling, secreted protein Dickkopfs (Dkks) may be potential targets to combat obesity and related metabolic disorders. In this study, we showed that Dkk2 was a beige fat-enriched adipokine to regulate adipogenesis. Dkk2 was strikingly expressed in beige fat depot compared to classic white, brown, and subcutaneous fat. Dkk2 treatment inhibited adipogenesis in 3T3-L1 pre-adipocytes, C3H10T1/2 mesenchymal stem cells, and primary bone marrow mesenchymal stromal cells. Activation of the master adipogenic factor PPARγ by the synthetic Thiazolidinedione ligand rosiglitazone largely rescued the inhibition of adipogenesis by Dkk2. Furthermore, adenoviral overexpression of Dkk2 in the liver to mimic its gain-of-function showed minimal effect on whole-body metabolism. These results collectively suggest that Dkk2 is a first-in-class beige fat adipokine and functions mainly through a paracrine manner to inhibit adipogenesis rather than as an endocrine factor. Our findings aid a better understanding of beige fat function and regulation and further, provide a potential therapeutic target for treating obesity.
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Adipogénesis , Adipoquinas/metabolismo , Tejido Adiposo Beige/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Células 3T3-L1 , Adenoviridae/metabolismo , Adipocitos Beige/efectos de los fármacos , Adipocitos Beige/metabolismo , Adipogénesis/efectos de los fármacos , Adipogénesis/genética , Animales , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Endogámicos C57BL , PPAR gamma/metabolismo , Rosiglitazona/farmacologíaRESUMEN
BACKGROUND: Recently, the relationship between thyroid hormones (THs) across the euthyroid ranges and metabolic syndrome (MetS) has been widely discussed. This study aimed to present specific cutoff values of THs to assess the association between THs and MetS in a euthyroid cohort. METHODS: Data of 2694 subjects, aged 18-80 years, who attended health examination in Xi'an Electric Power Central Hospital from April 2011 to December 2015 were collected and analyzed. The first cohort enrolled 929 participants (followed up by 2221 person-years totally) to assess correlations between serum thyrotropin (TSH), triiodothyronine (T3), thyroxine (T4) levels and MetS. The second cohort included 698 participants (followed up by 1709 person-years totally) to evaluate relationships between serum free triiodothyronine (FT3), free thyroxine (FT4) levels and MetS. MetS was defined according to the criteria of the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) scientific statements of 2009. Euthyroidism was defined as serum TSH, FT3 and FT4 levels within the reference ranges without taking any thyroid medication. RESULTS: The cutoff values for TSH, T3, T4, FT3 and FT4 were 2.0mIU/L, 1.9 nmol/L, 117 nmol/L, 4.3 pmol/L and 16 pmol/L, respectively. Participants were categorized into two groups according to cutoff values: the lower-THs group and the higher-THs group. There was no significant difference in the risk of MetS between two groups in TSH, T3, T4 and FT3. The incidence of MetS was significantly higher in lower-FT4 group than higher-FT4 group (1.00 vs 0.622 (0.458, 0.846), P = 0.002). The lower-FT4/higher-TSH group had the highest hazard ratios of MetS. (2.131vs 1.0 (1.380,3.291), P = 0.006). CONCLUSIONS: Lower normal FT4 (FT4 ≤ 16.0 pmol/L) is an independent risk factor for MetS, and lower normal thyroid function (TSH > 2.0 mIU/L and FT4 ≤ 16.0 pmol/L) is associated with a higher risk of developing MetS.
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Síndrome Metabólico/sangre , Síndrome Metabólico/epidemiología , Vigilancia de la Población , Tiroxina/sangre , Adulto , Anciano , China/epidemiología , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Masculino , Síndrome Metabólico/diagnóstico , Persona de Mediana Edad , Vigilancia de la Población/métodos , Estudios Retrospectivos , Factores de Riesgo , Hormonas Tiroideas/sangreRESUMEN
The association between subclinical hypothyroidism (SCH) and metabolic syndrome (MetS) has been widely discussed. This study aimed to conduct an update and comprehensive meta-analysis to reveal the risk of MetS and its components in SCH. PubMed, Embase and ISI Web of Knowledge were searched to identify relevant studies through February 20th, 2020. Review Manager 5.3 and Stata 14.0 were used to conduct the meta-analysis. Both fixed-effects and random-effects models were used. In total, 18 articles (19 studies) incorporating 79,727 participants were included. The pooled OR for MetS comparing subjects with SCH with euthyroid subjects was 1.28 (95% CI: 1.19 to 1.39, p = 0.04, I2 = 40%). Subgroup analysis results showed significant associations of SCH and MetS in the adult subgroup (OR = 1.28, 95% CI: 1.18-1.40), Asian population subgroup (OR = 1.30, 95% CI: 1.19-1.42) and cross-sectional study design subgroup (OR = 1.31, 95% CI: 1.16-1.47). Significant associations of SCH and MetS also existed in all MetS definition criteria subgroups except the Chinese Diabetes Society (CDS) subgroup. SCH was correlated with MetS and was not affected by the subgroup analysis stratified by the proportion of females in the total population, the TSH cutoff value in SCH diagnostic criteria, or the adjustment for confounding factors. SCH was identified to be associated with an increased risk of obesity, hypertension, high triglyceride (TG) levels and low high-density lipoprotein cholesterol (HDL-C) levels. In conclusion, SCH is significantly associated with an increased risk of MetS and four out of five components of MetS.
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Hipotiroidismo/epidemiología , Síndrome Metabólico/epidemiología , Adolescente , Adulto , Femenino , Humanos , Hipertensión/epidemiología , Hipertrigliceridemia/epidemiología , Hipotiroidismo/sangre , Masculino , Obesidad/epidemiología , Estudios Observacionales como Asunto , Oportunidad Relativa , Factores de Riesgo , Tirotropina/sangreRESUMEN
Objective Graves' disease is the most common autoimmune thyroid disease and its prevalence and clinical manifestations are disparate between females and males. Costimulatory molecules play an essential role in regulating autoimmune responses. The objective of this study was to determine if expression of inhibitory molecules was correlated with treatment by dihydrotestosterone (DHT) in an in vivo BALB/c mouse model of experimental autoimmune Graves' disease.Methods Female BALB/c mice were immunized three times with thyroid stimulating hormone receptor A-subunit encoded by adenovirus to establish a Graves' disease model. Three different doses of DHT or a matching placebo were administered by implantation of slow-release pellets a week before the first immunization. Four weeks after the third immunization, the mice were euthanatized, and then the spleen and thymus were removed. Total thyroxine and free thyroxine levels in serum of mice were detected using a radioimmunoassay kit. Real-time polymerase chain reaction was performed to estimate the expression of costimulatory molecules in lymphocytes from the spleen and thymus. Flow cytometry was used to analyze the percentage of CD4+ T cells in splenic lymphocytes. Quantitative data were compared with unpaired t-tests. Correlation between two variables was analyzed using Analysis of Variance.Results Treatment with DHT can dramatically reduce total thyroxine and free thyroxine levels. Higher expression of programmed death-1 was found in the spleen of Graves' disease mice receiving 5 mg of DHT treatment (0.635±0.296 vs. 0.327±0.212; t=2.714, P=0.014), similarly, T-cell immunoglobulin domain and mucin domain 3 (TIM-3) in both the spleen (1.004±0.338 vs. 0.646±0.314; t=2.205, P=0.022) and the thymus (0.263±0.127 vs. 0.120±0.076; t=3.221, P=0.004) also increased after 5 mg of DHT treatment compared with the parallel placebo model mice. Moreover, the percentage of CD4+ T cells declined in the splenic lymphocytes of Graves' disease mice treated with 5 mg of DHT (19.90%±3.985% vs. 24.05%±2.587%; t=2.804, P=0.012). A significant negative association was observed between expression of TIM-3 in the spleen and serum levels of total thyroxine (r=-0.7106, P=0.014) as well as free thyroxine (r=-0.6542, P=0.029).Conclusion This study demonstrates that DHT can ameliorate experimental autoimmune Graves' disease, which may occur by up-regulating expression of programmed death-1 and TIM-3 and inhibiting development of CD4+ T cells.
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Dihidrotestosterona/uso terapéutico , Enfermedad de Graves/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Dihidrotestosterona/farmacología , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Enfermedad de Graves/sangre , Enfermedad de Graves/patología , Enfermedad de Graves/fisiopatología , Péptidos y Proteínas de Señalización Intercelular/genética , Modelos Lineales , Ratones Endogámicos BALB C , ARN Mensajero/genética , ARN Mensajero/metabolismo , Bazo/efectos de los fármacos , Bazo/metabolismo , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/patología , Glándula Tiroides/fisiopatología , Tirotropina/metabolismo , Tiroxina/sangreRESUMEN
OBJECTIVE: To assess the design and the Mainland China subgroup baseline characteristics of the study to evaluate the efficacy and safety of alogliptin versus placebo in subjects with type 2 diabetes (T2DM) as monotherapy, add-on to metformin or add-on to pioglitazone. METHODS: This was a multi-center, randomized, double-blind, placebo-controlled, 16-week study comparing alogliptin (ALO, 25 mg, 1/d) versus placebo (PLA) as monotherapy (A), add-on to metformin (B) or add-on to pioglitazone ± metformin (C). The T2DM subjects with glycosylated hemoglobin A1c(HbA1c) between 7% and 10% and aged between 18 years and 75 years were enrolled and randomized to the alogliptin group and the placebo group in 1: 1 ratio with 16 weeks treatment. All patients were followed up every 4 weeks. The safety endpoints consisted of the incidence of hypoglycemia and other adverse events. RESULTS: A total of 491 patients were enrolled in the Mainland China subgroup of the study (181 in group A, 186 in group B and 124 in group C). In each treatment group, the baseline characteristics including age, gender, body mass index, diabetes duration, HbA1c, fasting plasma glucose, body weight, daily dosage of metformin and daily dosage of pioglitazone were all well balanced. CONCLUSION: The demographic data, medical history, glycemic profile and treatment regimen at baseline in Mainland China subgroup are well balanced. The result of this study will provide the clinical evidence for the use of alogliptin in Chinese T2DM patients.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Piperidinas/efectos adversos , Piperidinas/uso terapéutico , Uracilo/análogos & derivados , Adulto , China , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proyectos de Investigación , Resultado del Tratamiento , Uracilo/efectos adversos , Uracilo/uso terapéuticoRESUMEN
OBJECTIVE: Epithelial-mesenchymal transition (EMT) has been implicated in the initiation and conversion of early stage tumors into invasive malignancies and is associated with the "stemness" of cancer cells. The present study was designed to identify whether EMT induces cancer stem cell generation and tumor progression in human thyroid cancer cells in vitro. METHODS: FTC133 cells, as EMT-negative cells, were used for EMT induction by hypoxia-inducible factor-1α (HIF-1α) transfection. And EMT features were then examined by Western blot, immunofluorescent staining, invasion and proliferation assays. Moreover, stem-like side population (SP) cells were sorted with flow cytometry from FTC133 cells before and after EMT. The proportion of SP was compared and stemness, self-renewal and tumorigenicity in vitro were identified in SP cells. RESULTS: Overexpression of HIF-1α induced FTC133 cells to undergo EMT. And it down-regulated epithelial marker E-cadherin, up-regulated mesenchymal marker vimentin and caused nucleus translocation of ß-catenin and highly invasive and metastatic properties. Most importantly, the induction of EMT promoted proportion of stem-like side population cells (0.70% vs 0.03%, P < 0.05) with higher sphere formation and clone forming capability in contrast to non-side population cells. CONCLUSIONS: EMT can induce cancer stem cell generation and tumor progression in thyroid cancers. Further understanding the role of EMT and cancer stem cells in cancer progression may reveal new preventive and therapeutic targets for thyroid cancers.
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Transición Epitelial-Mesenquimal , Células Madre Neoplásicas/citología , Neoplasias de la Tiroides/patología , Línea Celular Tumoral , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , TransfecciónRESUMEN
The family of high mobility group box (HMGB) proteins participates in various biological processes including immunity, inflammation, as well as cancer formation and progression. However, its role in thyroid cancer remains to be clarified. We performed quantitative RT-PCR (qRT-PCR), western blot, enzyme-linked immunosorbent, immunohistochemistry, and immunofluorescence assays to evaluate the expression level and subcellular location of HMGB3. The effects of HMGB3 knockdown on malignant biological behaviors of thyroid cancer were determined by cell proliferation assays, cell cycle and apoptosis assays, and transwell chamber migration and invasion assays. Differential expression genes (DEGs) altered by HMGB3 were analyzed using the Ingenuity Pathway Analysis (IPA) and TRRUST v2 database. HMGB3 correlated pathways predicted by bioinformatic analysis were then confirmed using western blot, co-immunoprecipitation, dual-luciferase reporter assay, and flow cytometry. We found that HMGB3 is overexpressed and its downregulation inhibits cell viability, promotes cell apoptosis and cell cycle arrest, and suppresses cell migration and invasion in thyroid cancer. In PTC, both tissue and serum levels of HMGB3 are elevated and are correlated with lymph node metastasis and advanced tumor stage. Mechanistically, we observed the translocation of HMGB3 in PTC, induced at least partially by hypoxia. Cytoplasmic HMGB3 activates nucleic-acid-mediated TLR3/NF-κB signaling and extracellular HMGB3 interacts with the transmembrane TREM1 receptor in PTC. This study demonstrates the oncogenic role of HMGB3 cytoplasmic and extracellular translocation in papillary thyroid cancers; we recommend its future use as a potential circulating biomarker and therapeutic target for PTC.
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Proteína HMGB3 , MicroARNs , Neoplasias de la Tiroides , Humanos , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/patología , Receptor Toll-Like 3/genética , Receptor Toll-Like 3/metabolismo , Línea Celular Tumoral , Receptor Activador Expresado en Células Mieloides 1/genética , Receptor Activador Expresado en Células Mieloides 1/metabolismo , Neoplasias de la Tiroides/genética , Proteína HMGB3/genética , Proteína HMGB3/metabolismo , Proliferación Celular/genética , MicroARNs/genética , Movimiento Celular/genética , Regulación Neoplásica de la Expresión GénicaRESUMEN
CD4+ cytotoxic T lymphocytes (CTLs) were recently implicated in immune-mediated inflammation and fibrosis progression of Graves' orbitopathy (GO). However, little is known about therapeutic targeting of CD4+ CTLs. Herein, we studied the effect of rapamycin, an approved mTOR complex 1 (mTORC1) inhibitor, in a GO mouse model, in vitro, and in patients with refractory GO. In the adenovirus-induced model, rapamycin significantly decreased the incidence of GO. This was accompanied by the reduction of both CD4+ CTLs and the reduction of orbital inflammation, adipogenesis, and fibrosis. CD4+ CTLs from patients with active GO showed upregulation of the mTOR pathway, while rapamycin decreased their proportions and cytotoxic function. Low-dose rapamycin treatment substantially improved diplopia and the clinical activity score in steroid-refractory patients with GO. Single-cell RNA-Seq revealed that eye motility improvement was closely related to suppression of inflammation and chemotaxis in CD4+ CTLs. In conclusion, rapamycin is a promising treatment for CD4+ CTL-mediated inflammation and fibrosis in GO.
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Oftalmopatía de Graves , Ratones , Animales , Oftalmopatía de Graves/metabolismo , Linfocitos T Citotóxicos/metabolismo , Sirolimus , Inflamación , Linfocitos T CD4-Positivos/metabolismo , Serina-Treonina Quinasas TOR , FibrosisRESUMEN
OBJECTIVE: To compare the efficacy of Graves disease animal models induced by thyroid stimulating hormone receptor (TSHR) plasmid DNA (pcDNA3.1-TSHR) and by TSHR A subunit recombinant adenovirus (Ad-TSHR289), and to investigate the influence of duration for preparing animal model induced by Ad-TSHR289 on Graves hyperthyroidism and its related indices. METHODS: The plasmid group and the adenovirus group were set up respectively. The plasmid group: 21 female BALB/c mice were randomly divided into model group (n = 12) and control group (n = 9). The model group were injected intradermally with pcDNA3.1-TSHR 50 µg, once every 3 weeks, totally 3 times. Then 4 weeks after the last immunization, the mice were euthanized to obtain blood for testing TSHR antibody (TRAb), total T(4), and thyroid tissue for histological examination. The controls were injected with the same dose of pcDNA3.1 in the same way. The adenovirus group: 52 female BALB/c mice were divided into 10-week model group (n = 8), 14-week model group (n = 10) and 18-week model group (n = 8), and the respective controls (n = 8, n = 10, n = 8) were set up. All model groups were injected intramuscularly with Ad-TSHR289, three times at three weekly intervals. Then the mice were euthanized at 4, 8 and 12 weeks to test TRAb, total T(4) level and to observe the change of thyroid histology. The controls were treated with the same dose of Ad-lacz in the same way. Another 8 mice were scheduled to test the dynamic variation of TRAb before and after the 3 times immunization. RESULTS: In the plasmid model group, only two of 12 mice developed weak antibody responses against TSHR, and no elevated total T(4) level and no hyperplasia changes of thyroid were observed. In the 10-week model group, all mice had high level TRAb [(807.65 ± 136.33) U/L], Six-eighths mice had hyperthyroidism exhibited hyperplasia changes. In the 14-week model group, the TRAb level [(650.12 ± 192.88) U/L] and the incidence of hyperthyroidism (3/10) were lower than those in 10-week group. Histologically, the degree of thyroid hyperplasia lightened to a small extent, but its positive rate did not decline. In the 18-week model group, only 2 of 8 mice displayed slightly elevated TRAb level, and no mice showed increased total T(4) level. Additionally, thyroid tissues of 2 mice were mildly abnormal. Compared with the model groups at different time, the change of antibody levels of the mice for TRAb dynamic observation exhibited the similar trend. CONCLUSIONS: Being good at repeatability and high incidence of hyperthyroidism, the animal model of Graves disease induced by Ad-TSHR289 is still an ideal research tool presently. The duration of model can be maintained 18 weeks, and 10 weeks is the best period to sustain characteristic of Graves disease.
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Modelos Animales de Enfermedad , Enfermedad de Graves , Animales , Femenino , Ratones , Ratones Endogámicos BALB CRESUMEN
OBJECTIVE: To explore the presence of a characteristic stem cell population (side population, SP) in human thyroid gland and perform sphere culture method for the isolation and proliferation of thyroid stem cell. METHODS: Flow cytometry and cell sorting were performed to identify and isolate the ABCG2-positive SP cells from primary thyroid cells. The comparison of gene profiles and morphology between SP and main population (MP) were performed. Primary thyroid cells were also cultured in neurosphere-like growth condition for sphere formation. Gene profile of developed spheres was determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and thyroid lineage commitment was then induced in a differentiating condition. In stem cell-derived thyrocytes, embedded in collagen to form follicles, TSH-dependent (125)iodide uptake was measured. RESULTS: The SP was identified as a population enriched in stem cells with typical morphology, and characteristics of self-renewal and differentiation. Nonadherent clonal spheres developed in thyroid cell cultures, displaying an expression pattern resembling that of SP cells and in response to TSH and serum these sphere cells differentiated into thyrocytes expressing PAX8, thyroglobulin, sodium iodide symporter, thyroid-stimulating hormone receptor and thyroperoxidase mRNA. And there was TSH-dependent (125)iodide uptake. CONCLUSION: It is shown first time that human thyroid contains an undescribed population of cells with SP phenotype and clonal expansion capacity. Moreover sphere culture method is developed for the isolation and proliferation of thyroid stem cell.
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Diferenciación Celular , Proliferación Celular , Células Madre/citología , Glándula Tiroides/citología , Técnicas de Cultivo de Célula , Separación Celular , Células Cultivadas , HumanosRESUMEN
In this paper, plasma silver (Ag) modified zinc oxide (ZnO) (AZO) was used to form AZO nanomaterials (including AZO nanofilms (NFm), AZO nanowires (NWs) and AZO nanoflowers (NFw)) in a two-step-controlled manner to investigate the effect of compounding different contents of Ag on the linear optical aspects of ZnO materials. The growth mechanism of the AZO nanomaterials with different strategies is discussed. If Ag nanoparticles (NPs) grow on the ZnO NFm surface, they first grow with ZnO as the core and then self-core into islands, which are undoubtedly influenced by factors such as the growth mechanism of ZnO as well as Ag. If Ag is grown on the surface of the ZnO NWs and ZnO NFw, it is more likely to self-core owing to factors such as the roughness of the ZnO NWs and ZnO NFw surfaces. The AZO nanomaterials have excellent optical properties based on the surface plasmon resonance, local electromagnetic field and charge transfer mechanism between Ag and ZnO. With the increase in Ag content, the absorption edges of AZO NFm are red-shifted, and the absorption edges of AZO NWs and AZO NFw are first blue-shifted and then red-shifted. The results show that AZO nanomaterials prepared using different methods not only have different growth morphologies, but also have different optical properties with potential for the preparation of optical devices.
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Background: Graves' orbitopathy (GO) is the most common and serious manifestation of Graves' disease (GD). It is characterized by orbital inflammation and tissue remodeling. Although several GO models have been reported, most lack a full assessment or mechanistic evaluation. Here, we established a promising mouse model mimicking many aspects of human GO with a frequency of 70% and characterized the key role of T cells in the progression of GO. Methods: An adenovirus expressing the human thyrotropin (TSH) receptor A subunit (Ad-TSHRA) was injected in the muscles of female BALB/C mice nine times to induce GO. At predetermined time points, histological examinations of retrobulbar tissues and thyroid glands were performed to dynamically monitor changes; serum autoantibodies and total thyroxine levels were examined to evaluate thyroid function. Flow cytometry of CD4+ T cell subgroups and RNA sequencing (RNA-Seq) of splenocytes were also performed to explore the underlying mechanism. Results: After nine injections, 7 of 10 mice challenged with Ad-TSHRA developed the orbital changes associated with GO. Seven mice manifested retrobulbar fibrosis, and four mice showed adipogenesis. Exophthalmia, conjunctival redness, and orbital lymphocyte infiltration were also observed in a subset of mice. The orbitopathy was first detected after seven injections and followed the hyperplastic change observed in thyroids after four injections. Flow cytometry revealed increased proportions of Th1 cells and decreased proportions of Th2 cells and regulatory T (Treg) cells in the splenocytes of GO mice. This change in CD4+ T cell subgroups was confirmed by orbital immunohistochemical staining. Genes involved in T cell receptor signaling, proliferation, adhesion, inflammation, and cytotoxicity were upregulated in GO mice according to the RNA-Seq; a trend of upregulation of these GO-specific genes was observed in mice with hyperthyroidism without orbitopathy after four injections. Conclusions: A GO mouse model was successfully established by administering nine injections of Ad-TSHRA. The model was achieved with a frequency of 70% and revealed the importance of T cell immunity. A potential time window from Graves' hyperthyroidism to GO was presented for the first time. Therefore, this model could be used to study the pathogenesis and novel treatments for GO.
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Adenoviridae/genética , Oftalmopatía de Graves/genética , Receptores de Tirotropina/genética , Transducción Genética , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Vectores Genéticos , Oftalmopatía de Graves/inmunología , Oftalmopatía de Graves/metabolismo , Oftalmopatía de Graves/patología , Inyecciones Intramusculares , Ratones Endogámicos BALB C , Fenotipo , Receptores de Tirotropina/metabolismo , Glándula Tiroides/inmunología , Glándula Tiroides/metabolismo , Glándula Tiroides/patología , Factores de TiempoRESUMEN
Persistent acinar to ductal metaplasia (ADM) is a recently recognized precursor of pancreatic ductal adenocarcinoma (PDAC). Here we show that the ADM area of human pancreas tissue adjacent to PDAC expresses significantly higher levels of regenerating protein 3A (REG3A). Exogenous REG3A and its mouse homolog REG3B induce ADM in the 3D culture of primary human and murine acinar cells, respectively. Both Reg3b transgenic mice and REG3B-treated mice with caerulein-induced pancreatitis develop and sustain ADM. Two out of five Reg3b transgenic mice with caerulein-induced pancreatitis show progression from ADM to pancreatic intraepithelial neoplasia (PanIN). Both in vitro and in vivo ADM models demonstrate activation of the RAS-RAF-MEK-ERK signaling pathway. Exostosin-like glycosyltransferase 3 (EXTL3) functions as the receptor for REG3B and mediates the activation of downstream signaling proteins. Our data indicates that REG3A/REG3B promotes persistent ADM through binding to EXTL3 and activating the RAS-RAF-MEK-ERK signaling pathway. Targeting REG3A/REG3B, its receptor EXTL3, or other downstream molecules could interrupt the ADM process and prevent early PDAC carcinogenesis.
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Carcinoma Ductal Pancreático/metabolismo , N-Acetilglucosaminiltransferasas/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Asociadas a Pancreatitis/metabolismo , Animales , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Humanos , Sistema de Señalización de MAP Quinasas , Masculino , Metaplasia/metabolismo , Metaplasia/patología , Ratones Endogámicos C57BL , N-Acetilglucosaminiltransferasas/análisis , Conductos Pancreáticos/metabolismo , Conductos Pancreáticos/patología , Neoplasias Pancreáticas/patología , Proteínas Asociadas a Pancreatitis/análisis , Transducción de Señal , Células Tumorales Cultivadas , Quinasas raf/metabolismo , Proteínas ras/metabolismo , Neoplasias PancreáticasRESUMEN
OBJECTIVE: To investigate the anti metastatic potential of retinoic acid as an important determinant of metastatic behavior in thyroid carcinoma and understand the role of invasion associated proteins. METHODS: Differentiated thyroid carcinoma cell lines FTC-133 and XTC.UC1, anaplastic thyroid cancer cell lines C643 and HTH74 were studied. All cell lines were cultured with all-trans-RA (ATRA) or solvent ethanol. The in vitro invasion and adhesion potency were studied by transwell experiment and short-term adhesion assay. The functions of invasion associated proteins, urokinase type plasminogen activator (uPA), uPA receptor (uPAR), MMP2 and E-cadherin were investigated by semi-quantitative RT-PCR and Western blot. RESULTS: In vitro invasion assay revealed that ATRA treatment could reduce the invasive potency in all the thyroid cancer cell lines. On Day 5 of ATRA treatment, the numbers of cells that migrated through extracellular matrix were as follows, in contrast to control group, FTC-133: 91±9 vs 118±10, C643: 92±17 vs 164±21, HTH74: 87±18 vs 169±15, and XTC.UC1: 95±23 vs 136±15, respectively (all P<0.05). Short term adhesion assay suggested that ATRA increases cancer cell adhesion to extracellular matrix (ECM) in C643, HTH74 and XTC.UC1. RT-PCR and Western blot both revealed diminished expression of uPAR in all four carcinoma cell lines. In C643 and HTH74 cell lines, the expression of uPA was reduced and the expression of E-Cadherin was increased; whereas the MMP2 expression was not significantly down-regulated in ATRA treated group. In ATRA treated FTC-133 and XTC.UC1 cell lines, MMP2 expression was decreased, but no significant changes in uPA and E-Cadherin expression were observed. CONCLUSION: The present study demonstrates the influence of ATRA on two important determinants of metastatic behavior ("de adhesion" and proteolysis) in thyroid carcinoma cell lines.
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Neoplasias de la Tiroides/patología , Tretinoina/farmacología , Cadherinas/metabolismo , Adhesión Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Invasividad Neoplásica , Metástasis de la Neoplasia , Receptores de Ácido Retinoico/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/metabolismoRESUMEN
BACKGROUND: To date, there is only scare evidence characterizing the temporal features and progression of metabolic dysfunction in high-fat diet (HFD)-fed obese mice. Hence, its specific pathogenesis remains unclear. METHODS: Sixty 6-week-old male C57BL/6J mice were randomly divided into HFD and control diet (CD) groups and sacrificed at 1, 5, 9, 13, 17, and 21 weeks, respectively. At weekly intervals, intraperitoneal glucose tolerance testing (IPGTT) and intraperitoneal insulin tolerance testing (IPITT) were performed in both groups. A detailed time course in HFD-fed mice was investigated by evaluating the initiation of glucose homeostasis impairment, dyslipidemia, systemic insulin sensitivity, monocyte chemoattractant protein-1 (MCP-1) levels, epididymal white adipose tissue (eWAT) expansion, macrophage content changes, pro-inflammatory (M1)/anti-inflammatory (M2) macrophage imbalance, lipid accumulation in the liver, and ß-cell morphometry in the pancreas. RESULTS: In the HFD group, progressive weight gain and impairments in glucose metabolism (elevated fasting blood glucose and area under the curve (AUC) of IPGTT) were observed from the 3rd week, and a significantly elevated AUC of IPITT was first detected after week 7 of HFD feeding. As for dyslipidemia, after 9 weeks of feeding, the low-density lipoprotein cholesterol level and total cholesterol level in HFD group were significantly higher than those in the CD group (all P < 0.05), whereas no significant differences were shown in triglyceride level. Adipocyte size increased significantly in the HFD group in the 1st week, a phenotypic switch in eWAT from anti-inflammatory (M2) to pro-inflammatory (M1) macrophages was observed in the 5th week, and the metabolic inflammation was distinct in eWAT in the 9th week. Additionally, liver steatosis was considerably obvious at the 17th week and pancreatic ß-cell morphometry did not change during 21 weeks of HFD feeding. CONCLUSION: The eWAT expansion was detected early in HFD-induced obese mice, which occurred prior to obvious insulin resistance.
RESUMEN
OBJECTIVE: To investigate insulin secretion function and insulin resistance in Chinese newly diagnosed type 2 diabetes (obese and non-obese patients) in order to provide evidence for clinical treatment. METHODS: 408 newly diagnosed type 2 diabetes and 40 normal controls were recruited. Height, weight were measured, insulin and glucose of 0 min, 30 min, 60 min, 120 min during oral glucose tolerance test were examined. The patients with fasting glucose level greater than 8.3mmol/L were treatment with Gliclazide for 1 - 3 months. After normalization of the plasma glucose levels for more than 2 weeks, and withdraw this medication for 48 hours, then OGTT were repeated to assess IR and IS. RESULTS: The patients were divided into four groups based on fasting plasma glucose (DM1: FPG < 6.9mmol/L; DM2: 6.9 mmol/L < or = FPG < 8.3 mmol/L; DM3: 8.3 mmol/L < or = FPG < 9.7 mmol/L; DM4: FPG > or = 9.7 mmol/L). Every groups were further stratified to subgroups by cut point of BMI = 24 kg/m(2). Their insulin sensitivity and insulin secretion function compared between subgroups. (1) True insulin level in BMI > or = 24 (FPG < 6.9 mmol/L) subgroups were higher than control's (3.5 +/- 0.5 vs 3.2 +/- 0.6 natural logarithm) (P < 0.05). (2) In BMI > or = 24 subgroups, their insulin sensitivity were even worse than BMI < 24 groups', but their insulin secretion function were better at the same FPG level. (3) After intervention, the change of insulin sensitivity in BMI < 24 group was better than BMI > or = 24 group's (-4.7 +/- 0.9 vs -5.5 +/- 1.4 natural logarithm) (P < 0.05); but the change of insulin secretion function in BMI < 24 group was worse. CONCLUSION: (1) In newly diagnostic type 2 diabetes, insulin sensitivity and insulin secretion function were decreased with the increase of FPG, but they were different between obese and non-obese group. (2) Insulin secretion function was recovered better in obese group when eliminated glucose toxicity.
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Índice de Masa Corporal , Diabetes Mellitus Tipo 2/diagnóstico , Resistencia a la Insulina , Insulina/metabolismo , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Secreción de Insulina , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
We describe a case of a 33-year-old female patient with chronic hepatitis B who developed type 1 diabetes mellitus (DM) after a 13-mo period of treatment with recombinant human interferon-alpha (IFN-alpha) 2b. The patient presented with polydipsia, polyuria, hyperglycemia, diabetic ketoacidosis, combined with C-peptide secretion deficiency and positive islet cell autoantibody (ICAb). IFN-alpha 2b treatment was terminated and instead insulin treatment was initiated. Five months after cessation of the recombinant human IFN-alpha 2b therapy, the patient remained insulin-dependent. Her serum HBV DNA became negative and serum transaminase returned to the normal level after a 10-mo period of IFN therapy. Type 1 DM induced by IFN-alpha is relatively rare in patients with chronic hepatitis B. We should pay more attention to patients on IFN-alpha therapy to avoid destruction of pancreatic beta cells. This is the first case report from China.
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Diabetes Mellitus Tipo 1/inducido químicamente , Hepatitis B Crónica/tratamiento farmacológico , Interferón-alfa/efectos adversos , Proteínas Recombinantes/efectos adversos , Adulto , China , Diabetes Mellitus Tipo 1/diagnóstico , Femenino , Humanos , Interferón alfa-2 , Interferón-alfa/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Factores de RiesgoRESUMEN
OBJECTIVE: To evaluate the distribution and significance of IgG subclasses of antithyroglobulin antibody in sera from patients with Hashimoto thyroiditis. METHODS: Sera from 112 patients with Hashimoto thyroiditis were collected and patients were divided into 3 groups, i. e. hypothyroidism, subclinical hypothyroidism and euthyroidism. Antigen specific ELISA was used to detect the distribution of IgG subclasses of antithyroglobulin antibody. RESULTS: The positive rates of IgG subclasses of TgAb were IgG1 90.2%, IgG2 58.0%, IgG3 19.6% and IgG4 87.5% respectively. The mean geometric titers of IgG1 in sera from patients with hypothyroidism and subclinical hypothyroidism were 1: 450.8 and 1: 245.5 respectively, both being significantly higher than that with euthyroidism (1:8.7, P < 0.01). The mean geometric titers of IgG2 in sera from patients with hypothyroidism and subclinical hypothyroidism were 1: 37.3 and 1: 3.2 respectively, both being also significantly higher than that with euthyroidism (1: 0.2, P < 0.01 and P < 0.05 respectively) and that with hypothyroidism was significantly higher than that with subclinical hypothyroidism (P < 0.05). CONCLUSION: The distribution of IgG subclasses of antithyroglobulin antibody in sera from patients with Hashimoto thyroiditis was predominantly IgG1, IgG2 and IgG4. High titers of IgG1 and IgG2 implicated the possibility of development from subclinical hypothyroidism to overt hypothyroidism.