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BACKGROUND: Disruptions in vascular formation attributable to chemical insults is a pivotal risk factor or potential etiology of developmental defects and various disease settings. Among the thousands of chemicals threatening human health, the highly concerning groups prevalent in the environment and detected in biological monitoring in the general population ought to be prioritized because of their high exposure risks. However, the impacts of a large number of environmental chemicals on vasculature are far from understood. The angioarchitecture complexity and technical limitations make it challenging to analyze the entire vasculature efficiently and identify subtle changes through a high-throughput in vivo assay. OBJECTIVES: We aimed to develop an automated morphometric approach for the vascular profile and assess the vascular morphology of health-concerning environmental chemicals. METHODS: High-resolution images of the entire vasculature in Tg(fli1a:eGFP) zebrafish were collected using a high-content imaging platform. We established a deep learning-based quantitative framework, ECA-ResXUnet, combined with MATLAB to segment the vascular networks and extract features. Vessel scores based on the rates of morphological changes were calculated to rank vascular toxicity. Potential biomarkers were identified by vessel-endothelium-gene-disease integrative analysis. RESULTS: Whole-trunk blood vessels and the cerebral vasculature in larvae exposed to 150 representative chemicals were automatically segmented as comparable to human-level accuracy, with sensitivity and specificity of 95.56% and 95.81%, respectively. Chemical treatments led to heterogeneous vascular patterns manifested by 31 architecture indexes, and the common cardinal vein (CCV) was the most affected vessel. The antipsychotic medicine haloperidol, flame retardant 2,2-bis(chloromethyl)trimethylenebis[bis(2-chloroethyl) phosphate], and tert-butylphenyl diphenyl phosphate ranked as the top three in vessel scores. Pesticides accounted for the largest group, with a vessel score of ≥1, characterized by a remarkable inhibition of subintestinal venous plexus and delayed development of CCV. Multiple-concentration evaluation of nine per- and polyfluoroalkyl substances (PFAS) indicated a low-concentration effect on vascular impairment and a positive association between carbon chain length and benchmark concentration. Target vessel-directed single-cell RNA sequencing of fli1a+ cells from larvae treated with λ-cyhalothrin, perfluorohexanesulfonic acid, or benzylbutyl phthalate, along with vessel-endothelium-gene-disease integrative analysis, uncovered potential associations with vascular disorders and identified biomarker candidates. DISCUSSION: This study provides a novel paradigm for phenotype-driven screenings of vascular-disrupting chemicals by converging morphological and transcriptomic profiles at a high-resolution level, serving as a powerful tool for large-scale toxicity tests. Our approach and the high-quality morphometric data facilitate the precise evaluation of vascular effects caused by environmental chemicals. https://doi.org/10.1289/EHP13214.
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Peixe-Zebra , Animais , Poluentes Ambientais/toxicidade , Vasos Sanguíneos/efeitos dos fármacosRESUMO
Tetrabromobisphenol A (TBBPA), the most extensively utilized brominated flame retardant, has raised growing concerns regarding its environmental and health risks. Neurovascular formation is essential for metabolically supporting neuronal networks. However, previous studies primarily concerned the neuronal injuries of TBBPA, its impact on the neurovascularture, and molecular mechanism, which are yet to be elucidated. In this study, 5, 30, 100, 300 µg/L of TBBPA were administered to Tg (fli1a: eGFP) zebrafish larvae at 2-72 h postfertilization (hpf). The findings revealed that TBBPA impaired cerebral and ocular angiogenesis in zebrafish. Metabolomics analysis showed that TBBPA-treated neuroendothelial cells exhibited disruption of the TCA cycle and the Warburg effect pathway. TBBPA induced a significant reduction in glycolysis and mitochondrial ATP production rates, accompanied by mitochondrial fragmentation and an increase in mitochondrial reactive oxygen species (mitoROS) production in neuroendothelial cells. The supplementation of alpha-ketoglutaric acid, a key metabolite of the TCA cycle, mitigated TBBPA-induced mitochondrial damage, reduced mitoROS production, and restored angiogenesis in zebrafish larvae. Our results suggested that TBBPA exposure impeded neurovascular injury via mitochondrial metabolic perturbation mediated by mitoROS signaling, providing novel insight into the neurovascular toxicity and mode of action of TBBPA.
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Retardadores de Chama , Bifenil Polibromatos , Animais , Humanos , Peixe-Zebra , Células Endoteliais/metabolismo , Bifenil Polibromatos/toxicidade , Larva/metabolismo , Retardadores de Chama/toxicidadeRESUMO
Background: This study aims to investigate the changes in circulating dipeptidyl peptidase-4 (DPP-4) activity following short-term intensive insulin therapy (SIIT) in newly diagnosed type 2 diabetes (T2D) patients and to assess its potential in predicting long-term remission. Methods: Ninety-five patients underwent SIIT for 2-3 weeks to attain and sustain near-normal glycemia. Insulin was then discontinued, and patients were followed for a year to evaluate glycemic outcomes. Biochemical tests, serum DPP-4 activity, and mixed meal tolerance tests were conducted at baseline, post-SIIT, and the 3-month follow-up. Results: DPP-4 activity decreased from 44.08 ± 9.58 to 40.53 ± 8.83 nmol/min/mL after SIIT (P<0.001). After three months post-SIIT, DPP-4 activity remained stable in the remission group (39.63 ± 8.53 nmol/L) but increased in the non-remission group (42.34 ± 6.64 nmol/L). This resulted in a more pronounced decrease in DPP-4 activity from baseline in the remission group (-3.39 ± 8.90 vs. -1.10 ± 8.95, P = 0.035). Logistic regression analyses showed that patients with greater DPP-4 activity reduction had a higher likelihood of 1-year remission (70% vs. 51.1%, OR: 7.939 [1.829, 34.467], P = 0.006 in the fully adjusted model). A non-linear relationship between â³DPP-4 and 1-year remission rate was observed, with a clear threshold and saturation effect. Conclusion: Circulating DPP-4 activity significantly decreases after SIIT. The change in circulating DPP-4 activity during the 3-month post-treatment phase has the potential to predict long-term remission.
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Diabetes Mellitus Tipo 2 , Insulina , Humanos , Insulina/uso terapêutico , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glicemia , Dipeptidil Peptidases e Tripeptidil Peptidases/uso terapêuticoRESUMO
Background: While evidence supports glycemic control benefits for individuals with type 1 diabetes mellitus (T1DM) using hybrid closed-loop (HCL) systems, HCL automated insulin delivery therapy in China has not been assessed. This study evaluated safety events and effectiveness during HCL system use by Chinese adolescents and adults with T1DM. Methods: Sixty-two participants (n = 12 adolescents with a mean ± standard deviation [SD] of 15.5 ± 1.1 years and n = 50 adults [mean ± SD of 37.6 ± 11.1 years]) with T1DM and baseline A1C of 7.1% ± 1.0% underwent a run-in period (â¼2 weeks) using open-loop Manual Mode (sensor-augmented pump) insulin delivery with the MiniMed™ 770G system with the Guardian™ Sensor (3) glucose sensor, followed by a study period (4 weeks) with HCL Auto Mode enabled. Analyses compared continuous glucose monitoring data and insulin delivered during the run-in versus study period (Wilcoxon signed-rank test or t-test). Safety events included rates of severe hypoglycemia and diabetic ketoacidosis (DKA). Results: Compared to baseline run-in, overall Auto Mode use increased time in range (TIR, 70-180 mg/dL) from 75.3% to 80.9% (P < 0.001) and reduced time below range (TBR, <70 mg/dL) from 4.7% to 2.2% (P < 0.001). Subgroup analysis demonstrated that participants (n = 29) with baseline A1C <7.0% had TBR that reduced from 5.6% to 2.0%, while participants (n = 21) with baseline A1C ≥7.5% had time above range (TAR, >180 mg/dL) that reduced from 31.6% to 20.8%. Auto Mode use also increased the percentage achieving combined recommendations for time at sensor glucose ranges (i.e., TIR of >70%, TBR of <4% and TAR of <25%) from 24.2% at baseline to 77.4% at study end. Total daily insulin dose reduced from 42.8 ± 19.8 to 40.7 ± 18.9 U (P = 0.013). There were no severe hypoglycemic, DKA, or serious adverse events. Conclusions: Chinese adolescents and adults, some of whom met target A1C at baseline, safely achieved significantly improved glycemia with 1 month of MiniMed 770G system use when compared to open-loop insulin delivery. ClinicalTrials.gov ID: NCT04663295.
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BACKGROUND: Tight glycemic control during short-term intensive insulin therapy (SIIT) is critical for inducing diabetes remission in patients with newly diagnosed type 2 diabetes (T2D). This work aimed to investigate the role of time in range (TIR) during SIIT as a novel glycemic target by predicting clinical outcomes. METHODS: SIIT was given to 116 patients with newly diagnosed T2D, with daily eight-point capillary glucose monitored. Glycemic targets (fasting/premeal glucose, 3.9-6.0 mmol/L; 2 h postprandial blood glucose, 3.9-7.8 mmol/L) were achieved and maintained for 2 weeks. TIRPIR was calculated as the percentage of glucose points within these glycemic targets during the maintenance period and was compared to TIR3.9-7.8mmol/L and TIR3.9-10.0mmol/L . Acute insulin response (AIR), HOMA-IR, HOMA-B, and disposition index (DI) were measured. Patients were followed up for 1 year to observe clinical outcomes. RESULTS: TIRPIR , TIR3.9-7.8mmol/L , and TIR3.9-10.0mmol/L were 67.2 ± 11.2%, 80.8 ± 9.2%, and 90.1 ± 6.2%, respectively. After SIIT, ß-cell function and insulin sensitivity improved remarkably, and the 1-year remission rate was 55.2%. â³AIR and â³DI were positively correlated with all the TIR values, whereas only TIRPIR was correlated with â³HOMA-IR (r = -0.22, p = 0.03). Higher TIRPIR but not TIR3.9-7.8mmol/L or TIR3.9-10.0mmol/L was robustly associated with diabetes remission; patients in the lower TIRPIR tertile had an elevated risk of hyperglycemia relapse (hazard ratio 3.4, 95% confidence interval 1.6-7.2ï¼ p = .001). Only those with TIRPIR ≥ 65% had a one-year remission rate of over 60%. CONCLUSIONS: These findings advocate TIRPIR ≥ 65% as a novel glycemic target during SIIT for clinical decision-making.
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Diabetes Mellitus Tipo 2 , Hiperglicemia , Humanos , Insulina/uso terapêutico , Hipoglicemiantes/uso terapêutico , Glicemia , Hiperglicemia/tratamento farmacológicoRESUMO
Triphenyl phosphate (TPhP) is a non-halogenated organophosphorus flame retardant, and there is a higher exposure risk in children. TPhP has been found to be neurotoxic upon developmental exposure, yet the specific mechanism remains unclear. To characterize the cellular responses underlying TPhP-induced developmental neurotoxicity, we administered TPhP (0.5, 5 or 50 mg/kg/day) to neonatal mice from postnatal day 10 (P10)-P70. A total of 17,229 cells and 26,338 genes were identified in cortical samples from control and low-dose (the internal doses of metabolite DPhP comparable to human exposure level) groups using single-cell RNA sequencing (scRNA-seq). TPhP exposure led to heterogeneous transcriptional alterations and intercellular crosstalk among neurons, neural stem/progenitor cells (NSPCs), endothelial cells, and immunocytes. Deprivation of NSPCs, loss of mature neurons, and concomitant neuroinflammation mediated by extrinsic and intrinsic immunocytes were found in TPhP-exposed cortices. In addition, we observed blood-brain barrier destruction prior to the anxiety/depression-like neurobehavioral changes. These results reveal the distinctive cellular processes in TPhP's neurodevelopmental toxicity and uncover that the impeded neurogenesis, disrupted vascular barrier, and concomitant neuroinflammation are the sensitive responses to TPhP exposure. Our study paves the way for the application of scRNA-seq in toxicity assessments for emerging neurotoxic pollutants.
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Retardadores de Chama , Animais , Criança , Células Endoteliais/metabolismo , Retardadores de Chama/toxicidade , Humanos , Camundongos , Organofosfatos/toxicidade , Compostos OrganofosforadosRESUMO
With the spread of organophosphorus flame retardants (OPFRs), the environmental and health risks they induce are attracting attention. Triphenyl phosphate (TPHP) is a popular alternative to brominated flame retardant and halogenated OPFRs. Neurodevelopmental toxicity is TPHP's primary adverse effect, whereas the biomarkers and the modes of action have yet to be elucidated. In the present study, 0.5, 5, and 50 mg/kg of TPHP were orally administered to mice from postnatal day 10 (P10) to P70. The behavioral tests showed a compromised learning and memory capability. Proteomic analysis of the hippocampus exposed to 0.5 or 50 mg/kg of TPHP identified 531 differentially expressed proteins that were mainly involved in axon guidance, synaptic function, neurotransmitter transport, exocytosis, and energy metabolism. Immunoblot and immunofluorescence analysis showed that exposure to TPHP reduced the protein levels of TUBB3 and SYP in the synapses of hippocampal neurons. TPHP exposure also downregulated the gene expression of neurotransmitter receptors including Grins, Htr1α, and Adra1α in a dose-dependent fashion. Moreover, the calcium-dependent synaptic exocytosis governed by synaptic vesicle proteins STX1A and SYT1 was inhibited in the TPHP-treated hippocampus. Our results reveal that TPHP exposure causes abnormal learning and memory behaviors by disturbing synaptogenesis and neurotransmission.
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Retardadores de Chama , Animais , Retardadores de Chama/toxicidade , Hipocampo , Camundongos , Organofosfatos/toxicidade , Proteômica , Transmissão Sináptica , Sinaptotagmina I , Peixe-ZebraRESUMO
BACKGROUND: The relationship between betatrophin/ANGPTL8 and obesity has been investigated using body mass index (BMI); however, since BMI reflects overall adiposity rather than body fat distribution, it remains unclear whether fat deposition in different areas of the body affects betatrophin expression. Here, we investigated the correlation between circulating betatrophin levels and body fat distribution in patients with different glucose tolerance. METHODS: We performed a cross-sectional study in 128 participants with impaired glucose tolerance (IGT; n = 64) or normal glucose tolerance (NGT; n = 64). Circulating betatrophin levels were detected by enzyme-linked immunosorbent assay (ELISA). Body fat distribution (subcutaneous, visceral, and limb fat) was measured by magnetic resonance imaging (MRI) and a body fat meter. RESULTS: After controlling for age, sex, and BMI, betatrophin was correlated positively with visceral adipose tissue-to-subcutaneous adipose tissue ratio (VAT/SAT ratio; r = 0.339, p = 0.009) and negatively with body fat ratio (BFR; r = - 0.275, p = 0.035), left lower limb fat ratio (LLR; r = - 0.330, p = 0.011), and right lower limb fat ratio (RLR; r = - 0.288, p = 0.027) in the NGT group, with these correlations remaining after controlling for triglycerides. VAT/SAT ratio (standardized ß = 0.419, p = 0.001) was independently associated with serum betatrophin levels; however, betatrophin was not associated with body fat distribution variables in the IGT group. CONCLUSIONS: Circulating betatrophin levels correlated positively with VAT/SAT ratio and negatively with lower limb fat, but not with subcutaneous or upper limb fat, in individuals with normal glucose tolerance. Thus, betatrophin may be a potential biomarker for body fat distribution in individuals without glucose disorders.
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Proteínas Semelhantes a Angiopoietina/sangue , Distribuição da Gordura Corporal , Intolerância à Glucose/sangue , Gordura Intra-Abdominal/diagnóstico por imagem , Hormônios Peptídicos/sangue , Gordura Subcutânea/diagnóstico por imagem , Tecido Adiposo/diagnóstico por imagem , Proteína 8 Semelhante a Angiopoietina , Estudos de Casos e Controles , Estudos Transversais , Extremidades , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-IdadeRESUMO
Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is a phosphorus-based flame retardant common in consumer goods and baby products. Concerns have been raised about TDCPP exposure and neurodevelopmental toxicity. However, the mechanism and early response for TDCPP-induced neurotoxicity are poorly understood. This study investigates the role of microglia-mediated neuroinflammation in TDCPP-induced neurotoxicity in mice and primary cells. TDCPP was administered to C57BL/6 pups (0, 5, or 50 mg/kg/day) via an oral gavage from postnatal days 10-38 (28 days). The results showed that TDCPP exposure for 28 days altered the gene expression of neuronal markers Tubb3, Nefh, and Nes, and led to apoptosis in the hippocampus. The mRNA levels of pro-inflammatory factors Il-1ß, Tnfα and Ccl2 dose dependently increased in the hippocampus at both 24 h and 28 days following exposure, accompanied by microglia activation characterized by an amoeboid-like phenotype. In in vitro studies using the primary microglia isolated from neonatal mice, exposure to TDCPP (0-100 µM) for 24 h resulted in cellular activation. It also increased the expression of genes responsible for inflammatory responses including surface markers and pro-inflammatory cytokines. These changes occurred in a dose-dependent fashion. Neurite outgrowth of primary mouse hippocampal neurons was inhibited by treatment with the conditioned medium harvested from microglia exposed to TDCPP. These results reveal that neonatal exposure to TDCPP induces neuronal damage through microglia-mediated inflammation. This provides insight into the mechanism of TDCPP's neurodevelopmental toxicity, and suggests that microglial cell is a sensitive responder for OPFRs exposure.
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Retardadores de Chama/toxicidade , Hipocampo/efeitos dos fármacos , Microglia/efeitos dos fármacos , Síndromes Neurotóxicas/patologia , Compostos Organofosforados/toxicidade , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Peso Corporal/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiologia , Inflamação/induzido quimicamente , Masculino , Camundongos Endogâmicos C57BL , Microglia/patologia , Síndromes Neurotóxicas/etiologia , Testes de Toxicidade/métodosRESUMO
Polybrominated diphenyl ethers (PBDEs) are distributed throughout the environment. Despite a moratorium on their use, concentrations of PBDEs in the atmosphere and in residential environments remain high due to their persistence. The environmental health risks remain concerning and one of the major adverse effects is neurodevelopmental toxicity. However, the early response and effects of PBDEs exposure on the developing brain remain unknown. In the present study, we investigated the impacts of 2,2',4,4',5-pentabrominated diphenyl ether (BDE-99) on vascular growth and vascular barrier function with an emphasis on cerebral blood vessels, in the early life stages, using a zebrafish model. No general toxicity was observed in exposing zebrafish larvae to 0-0.5⯵Mâ¯BDE-99 at 72 hpf. BDE-99 exposure resulted in neither general toxicity nor pronounced developmental impairment in somatic blood vessels, including intersegmental vessels (ISV) and common cardinal veins (CCV). Meanwhile, both 0.05⯵M and 0.5⯵M of BDE-99 reduced cerebrovascular density as well as down-regulation of VEGFA and VEGFR2 in the head. In addition, BDE-99 exposure increased vascular leakage, both in cerebral and truncal vasculature at 72 hpf. The accentuated vascular permeability was observed in the head. The mRNA levels of genes encoding tight junction molecules decreased in the BDE-99-exposed larvae, and more robust reductions in Cldn5, Zo1 and Jam were detected in the head than in the trunk. Moreover, proinflammatory factors including TNF-α, IL-1ß and ICAM-1 were induced, and the expression of neurodevelopment-related genes was suppressed in the head following BDE-99 exposure. Taken together, these results reveal that developmental exposure to BDE-99 impedes cerebrovascular growth and disturbs vascular barrier formation. The cerebral vasculature in developing zebrafish, a more sensitive target for BDE-99, may be a promising tool for the assessment of the early neurodevelopmental effects due to PBDEs exposure.
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Vasos Sanguíneos/efeitos dos fármacos , Exposição Ambiental , Éteres Difenil Halogenados/toxicidade , Peixe-Zebra/crescimento & desenvolvimento , Animais , Encéfalo/irrigação sanguínea , Encéfalo/crescimento & desenvolvimento , Permeabilidade Capilar/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Inflamação/genética , Inflamação/patologia , Larva/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/genéticaRESUMO
Dermatopontin (DPT), a noncollagenous extracellular matrix component, has been illustrated to regulate cellular proliferation and invasiveness in several types of neoplasms. Nevertheless, the biological functions of DPT in cell proliferation, especially papillary thyroid cancer (PTC) cell proliferation, remain unknown, as do the mechanisms underlying its effects. In this study, we detected low DPT expression in PTC, which was related to higher T classifications. Ectopic DPT expression impeded cell proliferation both in vitro and in vivo. Furthermore, we illustrated that DPT down-regulated MYC, which in turn targeted CDK4, CDK6 and p21, through the ERK pathway. These results suggest that DPT regulates CDK4, CDK6 and p21, through MEK-ERK-MYC signaling to repress PTC proliferation.
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Proteoglicanas de Sulfatos de Condroitina/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Animais , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteoglicanas de Sulfatos de Condroitina/genética , Regulação para Baixo/genética , Proteínas da Matriz Extracelular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Estadiamento de NeoplasiasRESUMO
BACKGROUND: It has been reported that CBP/p300-Interacting Transactivator with glutamic acid [E]/aspartic acid [D]-rich C-terminal domain 1 (CITED1) is overexpressed in papillary thyroid cancer (PTC). However, the functional significance and underlying mechanisms of CITED1 in PTC are largely unknown. METHODS: The Cancer Genome Atlas dataset and real-time PCR were used to determine the expression of CITED1 in PTC. The role of CITED1 in PTC cell proliferation was determined conducted using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, and flow cytometry assays in vitro, and a subcutaneous xenotransplantation tumor model in nude mice was established to analyze tumor growth in vivo. We studied the potential mechanisms underlying the contribution of CITED1 to PTC proliferation using western blotting and luciferase assays. RESULTS: We found that CITED1 was highly expressed in PTC. In vitro and in vivo experiments demonstrated that CITED1 was involved in PTC cell proliferation and tumorigenesis. Then, gain- and loss-of-function experiments revealed that CITED1 decreased the expression of p21 and p27, and thereby increased the phosphorylation of pRb as well as E2F1 transcriptional activity. CONCLUSIONS: Our results suggest that CITED1 is overexpressed in PTC and that CITED1 promotes the proliferation of PTC cells via the regulation of p21 and p27, which indicates that CITED1 might be a potential therapeutic target in the treatment of PTC.
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AIMS/INTRODUCTION: Optimal glycemic targets during short-term intensive insulin therapy in patients with newly diagnosed type 2 diabetes are not standardized. The present study was carried out to determine the optimal glycemic targets during therapy by analyzing the impacts of glucose levels on therapeutic outcomes. MATERIALS AND METHODS: A total of 95 individuals with newly diagnosed type 2 diabetes were enrolled. Short-term intensive insulin therapy was carried out using an insulin pump to achieve and maintain glycemic targets (fasting blood glucose ≤6.0 mmol/L, 2-h postprandial blood glucose ≤7.8 mmol/L) for 14 days, with daily eight-point capillary blood glucose profiles recorded. Patients were followed up for 1 year after discharge. RESULTS: In most participants, the mean blood glucose and glycemic excursion parameters during the therapy were controlled within the normal range. Mean blood glucose was independently associated with amelioration of acute insulin response (r = -0.25, P = 0.015) and 1-year remission (odds ratio 0.12, 95% confidence interval 0.034-0.426), but negatively associated with more level 1 hypoglycemia (r = -0.34, P = 0.001), although major hypoglycemia was rare. Among mean blood glucose tertiles, patients in the middle (68.7%) and lower (75.0%) tertiles had a higher 1-year remission rate compared with the upper tertile (32.3%, both P < 0.001), whereas only the middle tertile did not have increased hypoglycemia compared with the upper tertile (8.1 ± 5.4 vs 7.2 ± 3.9 events/person, P = 0.48). CONCLUSIONS: Stricter glycemic control during short-term intensive insulin therapy produced more remission despite self-manageable hypoglycemia. Based on glycemic parameters in the middle mean tertile, we propose new glycemic targets that are approximately 0.4 mmol/L lower than current the targets, as long-term benefit outweighs short-term risks.
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Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Adulto , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
AIMS/INTRODUCTION: To explore angiopoietin-like protein 8 (ANGPTL-8) levels, and its association with hepatocellular lipid content (HCL) and insulin resistance in patients with different extents of non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: In 48 adults were recruited, of which 12 had no NAFLD (HCL < 5.5%; group 1), 18 had mild NAFLD (5.5% ≤ HCL < 10.0%; group 2) and 18 had moderate-to-severe NAFLD (HCL ≥ 10.0%; group 3). The peripheral insulin sensitivity of all participants was monitored by a hyperinsulinemic-euglycemic clamp (M value), as well as the magnetic resonance image of HCL. Serum ANGPTL-8, blood glucose levels and lipid profiles were also recorded in the study. RESULTS: Group 3 had a worse metabolic profile, and had the highest ANGPTL-8 level (1,129 ± 351 pg/mL vs 742 ± 252 pg/mL, 765 ± 301 pg/mL, P = 0.001) compared with those in group 1 and group 2. In all metabolic profiles, HCL positively correlated the strongest with ANGPTL-8 (r = 0.436, P = 0.042). Multivariate stepwise linear regression analysis showed ANGPTL-8 and alanine aminotransferase were independent determinants of HCL (P = 0.002, P < 0.001, respectively), and these two indexes explained 67.4% of the variation of HCL (P < 0.001). CONCLUSIONS: ANGPTL-8 was positively correlated with hepatocellular lipid content independent of obesity and insulin resistance, indicating that ANGPTL-8 might be a new and important important predictor of the severity of NAFLD.
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Proteínas Semelhantes a Angiopoietina/sangue , Hepatócitos/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hormônios Peptídicos/sangue , Adulto , Idoso , Proteína 8 Semelhante a Angiopoietina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Obesidade/complicações , Obesidade/metabolismoRESUMO
AIMS: We explored whether red blood cell distribution width (RDW), a routinely checked item of complete blood cell counts, was an indicator of long-term euglycemia remission in patients with type 2 diabetes after short-term continuous subcutaneous insulin infusion (CSII). METHODS: We analyzed the original data of patients enrolled in three randomized control trials from 2002 to 2014. CSII was administered to drug-naÑve patients with newly diagnosed type 2 diabetes to achieve and maintain euglycemia for 2weeks. RESULTS: A total of 185 patients were involved and 98 patients (52.97%) who achieved and maintained euglycemia for at least 12months were classified as the remission group, and the others as the non-remission group. Patients in remission group had a relatively lower value for baseline RDW (38.82±2.76vs 39.89±2.78fL, p=0.017) compared with those in non-remission group. A graded decrease of remission rate (67.50%, 55.00%, 53.66% and 30.77% for Quartile 1 to Quartile 4 respectively, P<0.05) was observed with the increasing of RDWs. The risk of hyperglycemic relapse was significantly increased for those in the highest quartile compared with the lowest (hazard ratio=2.68; 95% CI, 1.38-5.22). Those who achieved euglycemia within 7days or obtained a better fasting glucose after therapy had preferable remission rates. CONCLUSIONS: Patients with lower baseline RDWs are more likely to maintain a one-year euglycemia remission after short-term CSII. A faster normalization of glucose during treatment and a lower fasting glucose after therapy are correlated with a long-term glucose control.
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Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Eritrócitos/citologia , Adulto , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/administração & dosagem , Sistemas de Infusão de Insulina , Masculino , Modelos de Riscos ProporcionaisRESUMO
Purpose. This study aimed to explore the relationship among insulin sensitivity and ectopic fat depots in participants with different glucose status. Methods. Fifty-nine men and women were enrolled in this study: 29 with normal glucose tolerance (NGT), 17 with impaired glucose tolerance (IGT), and 13 with type 2 diabetes mellitus (T2DM). All participants underwent a hyperinsulinemic-euglycemic clamp to assess the insulin sensitivity index (M value) and magnetic resonance imaging to measure the hepatocellular lipid content (HCL), skeletal muscle fat content including intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) of tibialis anterior (ta), and soleus muscle (sol). Results. The M value of NGT group was higher than those of IGT and T2DM groups (P = 0.001). Participants with T2DM had the highest HCL and IMCL (ta) compared with those in NGT and IGT groups (P = 0.001). The M value had an inverse relationship with HCL (r = -0.789, P = 0.001), IMCL (sol) (r = -0.427, P = 0.002), and IMCL (ta) (r = -0.419, P = 0.002). Stepwise linear regression analysis showed that HCL (standardized ß = -0.416; P = 0.001) had an independent relationship with M value. Conclusions. Hepatocellular lipid content deposition happens earlier than skeletal muscle fat deposition. HCL is an independent risk factor for insulin resistance and may be used to evaluate the risk of developing T2DM as a noninvasive marker of insulin sensitivity index.
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Tecido Adiposo/diagnóstico por imagem , Diabetes Mellitus Tipo 2/metabolismo , Intolerância à Glucose/metabolismo , Hepatócitos/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos , Células Musculares/metabolismo , Músculo Esquelético/diagnóstico por imagem , Adulto , Estudos de Casos e Controles , Feminino , Técnica Clamp de Glucose , Humanos , Lipídeos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
The objective of this paper is to investigate the effects of liraglutide in combination with short-term continuous subcutaneous insulin infusion (CSII) therapy on glycemic control and beta cell function in patients with newly diagnosed type 2 diabetes mellitus (T2DM). Thirty-nine eligible newly diagnosed T2DM patients were recruited and randomized to receive either of two therapies: short-term CSII alone (CSII alone group) or CSII in combination with liraglutide (CSII + Lira group) for 12 weeks. Blood glucose control, homeostasis model assessment (HOMA) indices, and acute insulin response (AIR) were compared between the two groups. The patients in CSII + Lira group achieved euglycemia with equivalent insulin dosage in shorter time (1 (0) versus 2 (3) days, P = 0.039). HbA1c at the end of study was comparable between two groups (6.3 ± 0.7% versus 6.0 ± 0.5%, for CSII alone group and CSII + Lira group, resp., P = 0.325). The increment of AIR was higher in CSII + Lira group (177.58 (351.57) µU · min/mL versus 58.15 (51.30) µU · min/mL, P < 0.001). However, after stopping liraglutide, its effect on beta cell function disappeared completely. Liraglutide combined with short-term CSII was effective in further improving beta cell function, but the beneficial effects did not sustain after suspension of the therapy.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Insulina/uso terapêutico , Liraglutida/uso terapêutico , Adulto , Diabetes Mellitus Tipo 2/metabolismo , Quimioterapia Combinada , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Infusões Subcutâneas , Insulina/administração & dosagem , Células Secretoras de Insulina/metabolismo , Liraglutida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Resultado do TratamentoRESUMO
Sclerostin domain containing protein 1 (SOSTDC1) is down-regulated and acts as a tumor suppressor in some kinds of cancers. However, the expression pattern and biological significance of SOSTDC1 in thyroid cancer are largely unknown. We demonstrated that SOSTDC1 was significantly down-regulated in thyroid cancer. Ectopic over-expression of SOSTDC1 inhibited proliferation and induced G1/S arrest in thyroid cancer cells. Moreover, SOSTDC1 over-expression suppressed the growth of tumor xenografts in nude mice. We also found that elevated SOSTDC1 led to inhibition of cyclin A2 and cyclin E2. Together,our results demonstrate that SOSTDC1 is down-regulated in thyroid cancer and might be a potential therapeutic target in the treatment of thyroid cancer.
Assuntos
Proliferação de Células , Ciclina A2/genética , Ciclinas/genética , Regulação Neoplásica da Expressão Gênica , Proteínas/metabolismo , Neoplasias da Glândula Tireoide/patologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Apoptose , Western Blotting , Ciclo Celular , Ciclina A2/metabolismo , Ciclinas/metabolismo , Regulação para Baixo , Feminino , Humanos , Técnicas Imunoenzimáticas , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Proteínas/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
AIMS: To investigate the insulin requirement profiles during short-term intensive continuous subcutaneous insulin infusion (CSII) in patients with newly diagnosed type 2 diabetes and its relationship with long-term glycemic remission. METHODS: CSII was applied in 104 patients with newly diagnosed type 2 diabetes. Daily insulin doses were titrated and recorded to achieve and maintain euglycemia for 2 weeks. Measurements of blood glucose, lipid profiles as well as intravenous glucose tolerance tests were performed before and after the therapy. Afterwards, patients were followed up for 1 year. RESULTS: Total daily insulin dose (TDD) was 56.6±16.1IU at the first day when euglycemia was achieved (TDD-1). Thereafter, TDD progressively decreased at a rate of 1.4±1.0IU/day to 36.2±16.5IU at the end of the therapy. TDD-1 could be estimated with body weight, FPG, triglyceride and waist circumference in a multiple linear regression model. Decrement of TDD after euglycemia was achieved (ΔTDD) was associated with reduction of HOMA-IR (r=0.27, P=0.008) but not with improvement in ß cell function. Patients in the lower tertile of ΔTDD had a significantly higher risk of hyperglycemia relapse than those in the upper tertile within 1 year (HR 3.4, 95%CI [1.4, 8.4], P=0.008). CONCLUSIONS: There is a steady decline of TDD after euglycemia is achieved in patients with newly diagnosed type 2 diabetes treated with CSII, and ΔTDD is associated with a better long-term glycemic outcome.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Adulto , Idoso , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Esquema de Medicação , Feminino , Teste de Tolerância a Glucose , Humanos , Hiperglicemia/sangue , Hiperglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Infusões Subcutâneas , Insulina/administração & dosagem , Sistemas de Infusão de Insulina , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Indução de RemissãoRESUMO
Fufang Xue Shuan Tong (FXST) capsules, a traditional Chinese medicine, have been used to treat diabetic nephropathy for many years. FXST has been shown to attenuate elevated levels of oxidative stress in the retina of diabetic rats. However, whether FXST protects kidneys through the same mechanism(s) remains unclear. In this study, diabetes was induced in rats by administration of a high-fat diet and low-dose streptozotocin. Rats were administered low (450 mg/kg/day), middle (900 mg/kg/day) or high (1800 mg/kg/day) doses of FXST orally for 3 months. Another group was administered 50 mg/kg/day orally for the same period. The results indicated that all doses of FXST reduced urinary protein excretion and creatinine clearance and ameliorated the diabetic nephropathy-related mesangial matrix expansion. However, only middle and high doses of FXST prevented glomerular hypertrophy in diabetic rats, and the high dose showed the greatest inhibitory effect with regard to mesangial matrix expansion. Furthermore, superoxide dismutase activities were significantly elevated, whereas malondialdehyde levels were significantly reduced in the renal cortex following FXST treatment. The kidney-protective role of FXST is not inferior to that of captopril, one of the most commonly used drugs for the treatment of diabetic nephropathy. In conclusion, FXST retards the progression of diabetic nephropathy, while high-dose FXST shows the most prominent effect in counteracting the pathological changes of diabetic nephropathy. The renoprotective action of FXST is induced by the reduction of oxidative stress in diabetic nephropathy.