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Dysregulation of energy balance leading to obesity is a significant risk factor for cardiometabolic diseases such as diabetes, non-alcoholic fatty liver disease and atherosclerosis. In rodents and several other vertebrates, feeding has been shown to induce a rapid rise in the intestinal levels of N-acyl-ethanolamines (NAEs) and the chronic consumption of a high fat diet abolishes this rise. Administering NAEs to rodents consuming a high fat diet reduces their adiposity, in part by reducing food intake and enhancing fat oxidation, so that feeding-induced intestinal NAE biosynthesis appears to be critical to appropriate regulation of energy balance. However, the contribution of feeding-induced intestinal NAE biosynthesis to appropriate energy balance remains poorly understood in part because there are multiple enzymes that can contribute to NAE biosynthesis and the specific enzyme(s) that are responsible for feeding-induced intestinal NAE biosynthesis have not been identified. The rate-limiting step in the intestinal biosynthesis of NAEs is formation of their immediate precursors, the N-acyl-phosphatidylethanolamines (NAPEs), by phosphatidylethanolamine N-acyltransferases (NATs). At least six NATs are found in humans and multiple homologs of these NATs are found in most vertebrate species. In recent years, the fecundity and small size of zebrafish (Danio rerio), as well as their similarities in feeding behavior and energy balance regulation with mammals, have led to their use to model key features of cardiometabolic disease. We therefore searched the Danio rerio genome to identify all NAT homologs and found two additional NAT homologs besides the previously reported plaat1, rarres3, and rarres3l, and used CRISPR/cas9 to delete these two NAT homologs (plaat1l1 and plaat1l2). While wild-type fish markedly increased their intestinal NAPE levels in response to a meal after fasting, this response was completely ablated in plaat1l1-/-fish. Furthermore, plaat1l1-/- fish fed a standard flake diet had increased weight gain and glucose intolerance compared to wild-type fish. The results support a critical role for feeding-induced NAPE and NAE biosynthesis in regulating energy balance and suggest that restoring this response in obese animals could potentially be used to treat obesity and cardiometabolic disease.
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Metabolismo Energético , Peixe-Zebra , Animais , Peixe-Zebra/metabolismo , Etanolaminas/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Aciltransferases/metabolismo , Aciltransferases/genéticaRESUMO
BACKGROUND: Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disease characterized by complex neuropsychiatric syndrome and cerebrospinal fluid (CSF) NMDAR antibodies. Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to be associated with inflammation of the central nervous system (CNS). Matrix metalloproteinase-9 (MMP9) and cluster of differentiation (CD44) were measured to evaluate bloodâbrain barrier (BBB) permeability in anti-NMDAR encephalitis. The roles of microglial activation and BBB disruption in anti-NMDAR encephalitis are not well known. FINDINGS: In this work, we detected increased expression levels of CSF sTREM2, CSF and serum CD44, and serum MMP9 in anti-NMDAR encephalitis patients compared with controls. CSF sTREM2 levels were positively related to both CSF CD44 levels (r = 0.702, p < 0.0001) and serum MMP9 levels (r = 0.428, p = 0.021). In addition, CSF sTREM2 levels were related to clinical parameters (modified Rankin Scale scores, r = 0.422, p = 0.023, and Glasgow Coma Scale scores, r = - 0.401, p = 0.031). CONCLUSION: Increased sTREM2 levels in CSF as well as increased CD44 and MMP9 in serum and CSF reflected activation of microglia and disruption of the BBB in anti-NMDAR encephalitis, expanding the understanding of neuroinflammation in this disease. The factors mentioned above may have potential as novel targets for intervention or novel diagnostic biomarkers.
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Encefalite Antirreceptor de N-Metil-D-Aspartato , Barreira Hematoencefálica , Humanos , Metaloproteinase 9 da Matriz , Microglia , BiomarcadoresRESUMO
Homogeneous and nanometric metal clusters with unique electronic structures are promising for catalysis, however, common synthesis techniques for metal clusters suffer from large size and even metal nanocrystals attributing to their high surface energy and unsaturated configurations. Herein, a generalized rapid annealing strategy for synthesizing a series of supported metal clusters as superior catalysts is developed. Remarkably, TiO2 supported platinum nanoclusters (Pt NC/TiO2 ) exhibits the excellent catalytic activity to realize phenol hydrogenation under mild conditions. The complete phenol conversion rate and 100% selectivity toward KA oil are achieved in aqueous solution at room temperature and normal pressure. Semi-continuous scale up production of KA oil is successfully performed under mild conditions. Such excellent performance mainly originates from the partial reconstruction of Pt NC/TiO2 in aqueous phenol solution. Considering that the phenol can be produced from lignin, this study underpins a facile, sustainable, and economical route to synthesize nylon from biomass.
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BACKGROUND: Systematic and comparative studies on CD4+ T-lymphocytes in aplastic anemia (AA), myelodysplastic syndrome (MDS), and acute myelogenous leukemia (AML) are scarce. This study aimed to investigate the importance of CD4+ T-cells in bone marrow (BM) failure. METHODS: The proportions of Th1, Th2, Th17, and Treg cells in peripheral blood mononuclear cells (PBMCs) were examined by flow cytometry (FCM). The mRNA expression levels of transcription factors were measured using real-time PCR. RESULTS: The proportions of Th1, Th17 cells, and Th1/Th2 in the AA group were higher, whereas Th2 and Tregs were lower compared to controls. The proportions of Th17 and Treg cells accompanied by RORγt, and Foxp3 expression were significantly higher in the MDS group. The proportions of Th1, Th17, and Th1/Th2 were higher, whereas Th2 cells and GATA3 expression were significantly lower in MDS-multilineage dysplasia group, than in control group. The proportions of Th1, Th17, and Th1/Th2 were lower in MDS-excess blasts, and AML groups, than in controls, whereas that of Th2 and Treg cells accompanied by GATA3, and Foxp3 expression were significantly higher. CONCLUSIONS: Imbalance in CD4+ T-cell subsets may play a critical role in the pathogenesis and BM failure in the investigated diseases.
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Anemia Aplástica , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Linfócitos T CD4-Positivos/metabolismo , Leucócitos Mononucleares/metabolismo , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Síndromes Mielodisplásicas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Fatores de Transcrição Forkhead , Células Th1/metabolismoRESUMO
Our lineage tracing studies using multiple Cre mouse lines showed a concurrent labeling of abundant taste bud cells and the underlying connective tissue with a neural crest (NC) origin, warranting a further examination on the issue of whether there is an NC derivation of taste bud cells. In this study, we mapped NC cell lineages in three different models, Sox10-iCreERT2/tdT mouse, GFP+ neural fold transplantation to GFP- chickens, and Sox10-Cre/GFP-RFP zebrafish model. We found that in mice, Sox10-iCreERT2 specifically labels NC cell lineages with a single dose of tamoxifen at E7.5 and that the labeled cells were widely distributed in the connective tissue of the tongue. No labeled cells were found in taste buds or the surrounding epithelium in the postnatal mice. In the GFP+/GFP- chicken chimera model, GFP+ cells migrated extensively to the cranial region of chicken embryos ipsilateral to the surgery side but were absent in taste buds in the base of oral cavity and palate. In zebrafish, Sox10-Cre/GFP-RFP faithfully labeled known NC-derived tissues but did not label taste buds in lower jaw or the barbel. Our data, together with previous findings in axolotl, indicate that taste buds are not derived from NC cells in rodents, birds, amphibians or teleost fish.
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Linhagem da Célula , Crista Neural/embriologia , Papilas Gustativas/embriologia , Animais , Embrião de Galinha , Galinhas , Camundongos , Camundongos Transgênicos , Crista Neural/citologia , Papilas Gustativas/citologia , Peixe-ZebraRESUMO
BACKGROUND: This study aimed to investigate whether CXCL1/CXCR2 mediates intestinal injury or white matter injury by delivering inflammatory mediators through the gut-brain regulation axis. METHODS: Neonatal SD rats, regardless of sex, were administered 3% dextran sulfate sodium via intragastric administration at different time points to construct necrotizing enterocolitis (NEC) models. Meanwhile, hypoxia and ischemia were induced in 3 day-old SD rats to construct hypoxic-ischemic brain injury (HIBI) and NEC + HIBI models, without gender discrimination. Hematoxylin-eosin staining was used to observe pathological changes in neonatal rat intestinal and brain tissues. Western blotting detected CXCL1 and CXCR2 expression in NEC, HIBI, and NEC + HIBI rat intestinal and brain tissues. RESULTS: Compared with normal rats, pathological damage to periventricular white matter was observed in the NEC group. In addition to the increased mortality, the histopathological scores also indicated significant increases in brain and intestinal tissue damage in both HIBI and NEC + HIBI rats. Western blotting results suggested that CXCL1 and CXCR2 expression levels were upregulated to varying degrees in the intestinal and brain tissues of NEC, HIBI, and NEC + HIBI neonatal rats compared to that in the normal group. Compared with the HIBI group, the expression of CXCL1 and CXCR2 continued to increase in NEC + HIBI rats at different time points. CONCLUSIONS: CXCL1/CXCR2 may be involved in white matter injury in neonatal rats by delivering intestinal inflammatory mediators through the gut-brain axis.
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Lesões Encefálicas , Enterocolite Necrosante , Hipóxia-Isquemia Encefálica , Substância Branca , Animais , Ratos , Animais Recém-Nascidos , Ratos Sprague-Dawley , Eixo Encéfalo-Intestino , Modelos Animais de Doenças , Hipóxia-Isquemia Encefálica/metabolismo , Enterocolite Necrosante/metabolismo , Quimiocina CXCL1/metabolismoRESUMO
Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Here, using H3K27ac and BRD4 chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors, validated by ChIP-seq, that is responsible for subgroup divergence, and implicates candidate cells of origin for Group 4. Our integrated analysis of enhancer elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins.
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Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Elementos Facilitadores Genéticos/genética , Regulação Neoplásica da Expressão Gênica/genética , Meduloblastoma/classificação , Meduloblastoma/patologia , Fatores de Transcrição/metabolismo , Animais , Neoplasias Cerebelares/classificação , Feminino , Redes Reguladoras de Genes/genética , Genes Neoplásicos/genética , Genes Reporter/genética , Humanos , Masculino , Meduloblastoma/genética , Camundongos , Reprodutibilidade dos Testes , Peixe-Zebra/genéticaRESUMO
BACKGROUND: With the rapid development of endoscopic technology, endoscopic therapy (ET) has gradually become a new treatment choice for gastrointestinal stromal tumors (GISTs). However, due to the low incidence of duodenal GIST and the difficulty of ET, there is a lack of data to compare the long-term results of ET and surgical resection. METHODS: Duodenal GIST patients from 2004 to 2015 were selected from the surveillance, epidemiology, and end result (SEER) database. We used the Kaplan-Meier method and log-rank test to describe the 5- and 10-year survival differences between the ET and the surgery groups. The multivariate Cox proportional hazard model was used for analyzing the risk factors influencing the prognosis of patients. We used a 1:1 propensity score-matched (PSM) to reduce confounding factors, and then we compared survival differences between the two groups again. RESULTS: A total of 294 patients with duodenal GIST were enrolled, including 41 (13.9%) patients with ET and 253 (86.1%) patients with surgical resection. Before PSM, the long-term survival of patients with duodenal GIST after ET and surgical resection was similar [5-year overall survival (OS) (79.7 vs. 79.3%, p = 0.876), 10-year OS (66.5 vs. 68.1%, p = 0.876)]. After adjusting the relevant variables using multivariate Cox analysis, we found that the ET and surgery groups were comparable in OS and cancer-specific survival (CSS). After PSM, there was also no significant difference between ET and surgical resection for long-term OS and CSS. CONCLUSION: Our study found no significant difference in long-term survival between ET and surgical resection in patients with duodenal GIST. However, to obtain high-quality evidence, more extensive sample size studies are needed in the future to evaluate the long-term effects of ET on patients.
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Tumores do Estroma Gastrointestinal , Humanos , Tumores do Estroma Gastrointestinal/patologia , Estudos Retrospectivos , Prognóstico , Modelos de Riscos Proporcionais , Pontuação de Propensão , Programa de SEERRESUMO
BACKGROUND AND AIMS: With the development of endoscopic technology, endoscopic treatment has been widely used in Gastrointestinal stromal tumors (GISTs). However, population-based studies comparing the long-term results of patients who received endoscopic treatment vs. Surgery are lacking. We used the Surveillance, Epidemiology, and End Results (SEER) database to analyze the long-term survival of colorectal or gastric GISTs who underwent primary tumor resection (endoscopic therapy or surgery) in the USA. METHODS: Patients with colorectal or gastric GISTs were selected from the SEER database between 2010 and 2015. Kaplan-Meier analyses and log-rank tests were used to evaluate the difference in the long-term survival between the endoscopic therapy group and the surgery group. We examined the association between different treatments and survival after using the multivariate cox proportional hazards model to adjust the relevant covariates. Besides, we used Propensity score matching (PSM) to overcome the different distributions of covariates between the two groups and then further compare the survival difference. RESULTS: In total, 2355 patients were enrolled in our study, of which 1999 (84.9%) received surgical treatment and 356 (15.1%) received endoscopic treatment. There was no significant difference in overall survival (OS) between the two groups before PSM. The median OS (73.5 months vs. 72.2 months) and 5-year OS rate (85.7% vs. 81.5%) of endoscopic therapy were similar to surgical patients (P = 0.34). The median Cancer-specific survival (CSS) and 5-year CSS rate in the endoscopic treatment group were higher than the surgical group before PSM, with 81.3 months, 97.1% versus 78.8 months, 92.7% (P = 0.011). After adjusting for other clinical factors and PSM, the long-term OS and CSS did not significantly differ between those treated surgically and treated endoscopically. CONCLUSION: Based on the American population, we preliminarily found that the long-term OS and CSS did not differ between patients undergoing endoscopic therapy and surgery.
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Neoplasias Colorretais , Tumores do Estroma Gastrointestinal , Neoplasias Gástricas , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Pontuação de Propensão , Estudos Retrospectivos , Neoplasias Gástricas/cirurgiaRESUMO
BACKGROUND: With the rapid advances in endoscopic technology, endoscopic therapy (ET) is increasingly applied to the treatment of small (≤ 20 mm) colorectal neuroendocrine tumors (NETs). However, long-term data comparing ET and surgery for management of T1N0M0 colorectal NETs are lacking. The purpose of this work was to compare overall survival (OS) and cancer-specific survival (CSS) of such patients with ET or surgery. METHODS: Patients with T1N0M0 colorectal NETs were identified within the Surveillance Epidemiology and End Results (SEER) database (2004-2016). Demographics, tumor characteristics, therapeutic methods, and survival were compared. Propensity score matching (PSM) was used 1:3 and among this cohort, Cox proportional hazards regression models were performed to evaluate correlation between treatment and outcomes. RESULTS: Of 4487 patients with T1N0M0 colorectal NETs, 1125 were identified in the matched cohort, among whom 819 (72.8%) underwent ET and 306 (27.2%) underwent surgery. There was no difference in the 5-year and 10-year OS and CSS rates between the 2 treatment modalities. Likewise, analyses stratified by tumor size and site showed that patients did not benefit more from surgery compared with ET. Moreover, multivariate analyses found no significant differences in OS [Hazard Ratio (HR) = 0.857, 95% Confidence Interval (CI): 0.513-1.431, P = 0.555] and CSS (HR = 0.925, 95% CI: 0.282-3.040, P = 0.898) between the 2 groups. Similar results were observed when comparisons were limited to patients with different tumor size and site. CONCLUSIONS: In this population-based study, patients with lesions < 10 mm treated endoscopically had comparable long-term survival compared with those treated surgically, which demonstrates ET as an alternative to surgery in T1N0M0 colorectal NETs of < 10 mm. Further high-quality prospective studies are warranted to comprehensively evaluate the role of ET in patients with tumors 10 to 20 mm.
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Neoplasias Colorretais , Tumores Neuroendócrinos , Neoplasias Colorretais/patologia , Humanos , Estadiamento de Neoplasias , Tumores Neuroendócrinos/patologia , Prognóstico , Modelos de Riscos Proporcionais , Programa de SEERRESUMO
Hospital-acquired pneumonia (HAP) is one of the common infections in hospitalized patients. Early and prompt diagnosis of HAP is important because it aids in the appropriate selection of antibiotics and decreases the mortality and morbidity of patients. The investigation on serum procalcitonin (PCT) levels in pediatric patients is limited. Herein we aimed to evaluate the role of PCT in the early diagnosis of children with bacterial HAP. The study enrolled 264 children (< 14 years old) who were radiographically detected by pulmonary condensation chest X-rays. The HAP patients were stratified by patterns of microbiological detection of pathogens. Baseline white blood cell (WBC) count, neutrophil proportion, PCT, and C-reactive protein (CRP) were measured on admission. The laboratory findings and microbiological findings were analyzed and compared among groups. The median PCT concentration of patients with typical bacterial pathogens (3.95 ± 3.75 ng/mL) was significantly higher than the one of the patients with other pathogen types (median lower than 1.20 ng/mL). Correlation analysis indicated a significant correlation between PCT concentrations and the main inflammation makers including WBC count, neutrophil proportion, and CRP. PCT level was significantly decreased to 0.86 ± 1.46 ng/mL in post-treatment patients (p < 0.001). This cohort study with 264 pediatric HAP patients demonstrated the reliability of PCT level as a biomarker in patients with typical bacterial pathogens. Specifically, PCT cutoffs of 2 ng/mL accurately identified HAP children with typical bacterial pathogens. This finding suggested that PCT may serve as a reliable biomarker for the early diagnosis and treatment indicator of children with HAP.
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Infecção Hospitalar/sangue , Pneumonia Bacteriana/sangue , Pró-Calcitonina/sangue , Adolescente , Antibacterianos/farmacologia , Biomarcadores/sangue , Criança , Pré-Escolar , Infecção Hospitalar/diagnóstico , Infecção Hospitalar/microbiologia , Feminino , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva , Masculino , Admissão do Paciente , Pediatria , Pneumonia Bacteriana/diagnóstico , Pneumonia Bacteriana/microbiologia , Radiografia TorácicaRESUMO
Phenol is considered as an important platform molecule for synthesizing value-added chemical intermediates and products. To date, various strategies for phenol transformation have been developed, and among them, selective hydrogenation of phenol toward cyclohexanone (K), cyclohexanol (A) or the mixture KA oil has been attracted great interest because they are both the key raw materials for the synthesis of nylon 6 and 66, as well as many other chemical products, including polyamides. However, until now it is still challengeable to realize the industrilized application of phenol hydrogenation toward KA oils. To better understand the selective hydrogenation of phenol and fabricate the enabled nanocatalysts, it is necessary to summarize the recent progress on selective hydrogenation of phenol with different catalysts. In this review, we first summarize the selective hydrogenation of phenol toward cyclohexanone or cyclohexanol by different nanocatalysts, and simultaneously discuss the relationship among the active components, type of supports and their performances. Then, the possible reaction mechanism of phenol hydrogenation with the typical metal nanocatalysts is summarized. Subsequently, the possible ways for scale-up hydrogenation of phenol are discussed. Finally, the potential challenges and future developments of metal nanocatalysts for the selective hydrogenation of phenol are proposed.
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BACKGROUND: Glucocorticoid (GC) is the first-line therapy in acute attacks of multiple sclerosis (MS), but its efficacy is individually variable and may be associated with glucocorticoid receptor (GR) gene. OBJECTIVE: To establish the association between GR gene sequence and clinical GC sensitivity in Chinese MS patients. And to investigate the expression differences of serum GRα and FK506 binding protein 5 (FKBP5) in GC responders and non-responders. MATERIALS AND METHODS: Coding exons 2-9 of the GR gene from 97 MS patients were sequenced. We performed ELISA to detect serum GRα and FKBP5 before the GC impulse therapy in patients with different GC sensitivities (according to the EDSS changes before and after the GC medication). RESULTS: Seven new mutations were located in exon 2, but the presence or absence of mutations was not associated with the response to GC therapy (P = 0.416). The GC-sensitive patients had higher GRα (P = 0.011) but lower FKBP5 (P = 0.025) levels in the serum. CONCLUSIONS: The GR mutations detected in our study were not associated with the response to GC in Chinese MS patients. Higher GRα and lower FKBP5 levels in the serum might predict the response to GC, which may provide potential therapeutic target for GC-resistant patients with acute MS attack.
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Glucocorticoides , Esclerose Múltipla , China , Glucocorticoides/uso terapêutico , Humanos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/genética , Mutação , Receptores de Glucocorticoides/genéticaRESUMO
Long-term uninterrupted therapy is essential for maximizing clinical benefits of antiangiogenic drugs (AADs) in cancer patients. Unfortunately, nearly all clinically available AADs are delivered to cancer patients using disrupted regimens. We aim to develop lifetime, nontoxic, effective, orally active, and low-cost antiangiogenic and antitumor drugs for treatment of cancer patients. Here we report our findings of long-term maintenance therapy with orally active, nontoxic, low cost antiangiogenic chemotherapeutics for effective cancer treatment. In a sequential treatment regimen, robust antiangiogenic effects in tumors were achieved with an anti-VEGF drug, followed by a low-dose chemotherapy. The nontoxic, low dose of the orally active prodrug capecitabine was able to sustain the anti-VEGF-induced vessel regression for long periods. In another experimental setting, maintenance of low-dose capecitabine produced greater antiangiogenic and antitumor effects after AAD plus chemotherapy. No obvious adverse effects were developed after more than 2-mo of consecutive treatment with a low dose of capecitabine. Together, our findings provide a rationalized concept of effective cancer therapy by long-term maintenance of AAD-triggered antiangiogenic effects with orally active, nontoxic, low-cost, clinically available chemotherapeutics.
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Capecitabina/farmacologia , Neoplasias Experimentais , Neovascularização Patológica , Células A549 , Administração Oral , Animais , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Fatores de TempoRESUMO
Anti-VEGF drugs are commonly used for treatment of a variety of cancers in human patients, and they often develop resistance. The mechanisms underlying anti-VEGF resistance in human cancer patients are largely unknown. Here, we show that in mouse tumor models and in human cancer patients, the anti-VEGF drug-induced kidney hypoxia augments circulating levels of erythropoietin (EPO). Gain-of-function studies show that EPO protects tumor vessels from anti-VEGF treatment and compromises its antitumor effects. Loss of function by blocking EPO function using a pharmacological approach markedly increases antitumor activity of anti-VEGF drugs through inhibition of tumor angiogenesis. Similarly, genetic loss-of-function data shows that deletion of EpoR in nonerythroid cells significantly increases antiangiogenic and antitumor effects of anti-VEGF therapy. Finally, in a relatively large cohort study, we show that treatment of human colorectal cancer patients with bevacizumab augments circulating EPO levels. These findings uncover a mechanism of desensitizing antiangiogenic and anticancer effects by kidney-produced EPO. Our work presents conceptual advances of our understanding of mechanisms underlying antiangiogenic drug resistance.
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Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Eritropoetina/metabolismo , Rim/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Animais , Bevacizumab/farmacologia , Estudos de Coortes , Neoplasias Colorretais/metabolismo , Humanos , Rim/metabolismo , Camundongos , Neovascularização Patológica/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVE: We investigated the contribution of several cytokines in the pathogenesis of first-onset neuromyelitis optica spectrum disorder (NMOSD) and determined the differences between aquaporin 4 immunoglobulin G (AQP4-IgG)-positive and AQP4-IgG-negative subtypes. METHODS: We enrolled 18 NMOSD (10 AQP4-IgG-positive and 8 AQP4-IgG-negative) and 8 multiple sclerosis (MS) patients, whose serum and cerebrospinal fluid (CSF) samples were collected during the acute phase of the first onset before immunotherapy. Fifteen patients with other noninflammatory neurological diseases (OND) were also included. The serum and CSF levels of interleukin (IL)-6, IL-10, IL-17, IL-21, IL-23, transforming growth factor (TGF)-ß1 and the CSF levels of 3 biomarkers of axonal loss and astrocytic damage were measured using the human cytokine multiplex assay or ELISA. RESULTS: Serum levels of IL-10 and TGF-ß1 and CSF levels of IL-6, IL-10, and TGF-ß1 were significantly increased in first-onset NMOSD compared to in OND patients. In a subgroup analysis, the CSF levels of IL-6, neurofilament light protein (NFL), S100B, and glial fibrillary acidic protein (GFAP) were significantly more elevated in the AQP4-IgG-positive patients than in the AQP4-IgG-negative NMOSD patients. Correlations were found between the CSF cytokines and tissue damage biomarkers and the clinical findings in NMOSD patients. Notably, the CSF IL-6 level had the strongest correlation with the tissue damage biomarkers and it also correlated with CSF white blood cell (WBC) count. CONCLUSIONS: IL-6 plays a role in the pathogenetic process of NMOSD, especially in the AQP4-IgG-positive subtype. Distinct pathogenesis exists between AQP4-IgG-positive and AQP4-IgG-negative NMOSD in the initial phase of the disease.
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Citocinas/sangue , Citocinas/líquido cefalorraquidiano , Interleucina-6/sangue , Interleucina-6/líquido cefalorraquidiano , Neuromielite Óptica/sangue , Neuromielite Óptica/líquido cefalorraquidiano , Adulto , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/diagnóstico , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Adulto JovemRESUMO
OBJECTIVE: To investigate the relationship between serum level of Apelin-13 and bone mineral density (BMD) as well as other parameters, and determine the influence of Apelin-13 on osteoporosis in patients with Type-2 diabetes mellitus. METHODS: Seventy-six patients with Type-2 diabetes mellitus were recruited from Department of Endocrinology of our hospital between January 2013 and July2017. The clinical data, including age, gender, height, weight, body mass index (BMI) and disease duration were recorded for all patients. Blood sample was collected for measurement of Apelin-13, Procollagen type-I N propeptide (PINP) and Cross-linked carboxy terminal telopeptide of type-I collagen (ICTP), and BMD was tested with a dual-energy X-ray absorptiometry scanner. RESULTS: The patients were divided into three groups, in which 19 patients were assigned in osteoporosis group, 25 in osteopenia group and 32 in normal group. The level of Apelin-13 in osteoporosis group was significantly lower than that in osteopenia and normal groups (p<0.05), and the value in osteopenia group was significant lower than that in normal group (p<0.05). Correlation analysis showed in the included patients the level of Apelin-13 was positively correlated to the value of BMD and PINP (p<0.05), but negatively correlated to age and ICTP (p<0.05). CONCLUSION: In conclusion, this study demonstrated that there was a close relationship among Apelin-13, BMD, ICTP and PINP, and Apelin-13 plays an important role in the occurrence of osteoporosis in patients with Type-2 diabetes mellitus.
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The sulfur distributions and evolution of sulfur-containing compounds in the char, tar and gas fractions were investigated during the microwave and conventional pyrolysis of sewage sludge. Increased accumulation of sulfur in the char and less production of H2S were obtained from microwave pyrolysis at higher temperatures (500-800 °C). Three similar conversion pathways were identified for the formation of H2S during microwave and conventional pyrolysis. The cracking of unstable mercaptan structure in the sludge contributed to the release of H2S below 300 °C. The decomposition of aliphatic-S compounds in the tars led to the formation of H2S (300-500 °C). The thermal decomposition of aromatic-S compounds in the tars generated H2S from 500 to 800 °C. However, the secondary decomposition of thiophene-S compounds took place only in conventional pyrolysis above 700 °C. Comparing the H2S contributions from microwave and conventional pyrolysis, the significant increase of H2S yields in conventional pyrolysis was mainly attributed to the decomposition of aromatic-S (increasing by 10.4%) and thiophene-S compounds (11.3%). Further investigation on the inhibition mechanism of H2S formation during microwave pyrolysis confirmed that, with the special heating characteristics and relative shorter residence time, microwave pyrolysis promoted the retention of H2S on CaO and inhibited the secondary cracking of thiophene-S compounds at higher temperatures.
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Micro-Ondas , Esgotos/química , Temperatura Alta , Enxofre , AlcatrõesRESUMO
OBJECTIVE: To observe the effect of Zishen Huoxue Recipe (ZHR) on pathomorphology in coronary heart disease (CHD) rats with Shen deficiency blood stasis syndrome (SDBSS). METHODS: Totally 60 healthy Wistar rats were divided into the blank control group, the model group, high, middle, and low dose ZHR groups according to random digit table, 12 in each group. Myocardial ischemia SDBSS rat model was prepared by ligating the left anterior descending coronary artery and injecting hydrocortisone. ZHR physic liquor was administered to rats in high, middle, and low dose ZHR groups at the daily dose of 21.6, 10.8, 5.4 g/kg by gastrogavage for 7 successive days, equal volume of pure water was administered to rats in the blank control group and the model group by gastrogavage for 7 successive days. Rat heart was collected for pathomorphological observation under light microscope. RESULTS: In the model group the heart muscle fiber was swollen and deformed with widened space, loose and dropsy tissues. Blood vessels in myocardial mesenchymal were dilated, infiltrated with more inflammatory cells. Myocardial cells were markedly swollen, degenerated, or necrotic, with caryolysis or disappearance of partial nuclear. A large amount of collagen fibrous tissue became hyperplasia. Endocardial blood vessels were swollen and degenerated with infiltration of few inflammatory cells. Epicardium tissue and structure were destroyed and got hyperplasia. Swollen, degenerated, or necrotic vessels could be seen, with infiltration of more inflammatory cells and collagen deposition. Pathomorphological injuries were alleviated in each ZHR group. The higher ZHR concentration, the milder the injury degree of myocardial tissue, the more limited range of damage. CONCLUSION: ZHR could attenuate pathomorphological injuries of myocardial ischemia rats with SDBSS and regulate myocardial function, thus improving myocardial ischemia in CHD rats with SDBSS.
Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Animais , Medicamentos de Ervas Chinesas/farmacologia , Isquemia Miocárdica , Miocárdio , Ratos , Ratos WistarRESUMO
The MADS box transcription factors are critical regulators of rice (Oryza sativa) reproductive development. Here, we here report the functional characterization of a rice MADS box family member, MADS29, which is preferentially expressed in the nucellus and the nucellar projection. Suppressed expression of MADS29 resulted in abnormal seed development; the seeds were shrunken, displayed a low grain-filling rate and suppressed starch biosynthesis, and contained abnormal starch granules. Detailed analysis indicated that the abnormal seed development is due to defective programmed cell death (PCD) of the nucellus and nucellar projection, which was confirmed by a TUNEL assay and transcriptome analysis. Further studies showed that expression of MADS29 is induced by auxin and MADS29 protein binds directly to the putative promoter regions of genes that encode a Cys protease and nucleotide binding site-Leu-rich repeat proteins, thereby stimulating the PCD. This study identifies MADS29 as a key regulator of early rice seed development by regulating the PCD of maternal tissues. It provides informative clues to elucidate the regulatory mechanism of maternal tissue degradation after fertilization and to facilitate the studies of endosperm development and seed filling.