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The evolutionarily conserved Polycomb repressive complexes (PRC) mediate genome-wide transcriptional silencing and regulate a plethora of development, as well as environmental responses in multicellular organisms. The PRC2-catalyzed trimethylation of lysine 27 on histone H3 (H3K27me3) is recognized by reader-effector modules of PRC1 to implement gene repression. Here, we report that the Arabidopsis (Arabidopsis thaliana) H3K27me3 effector EMBRYONIC FLOWER 1 (EMF1) interacts with and constrains the R2R3 DNA binding transcription factor MYB26 by a eudicot-conserved motif in the stamen. MYB26 activates the transcription of two NAC domain genes, NAC SECONDARY WALL THICKENING PROMOTING FACTOR1 (NST1) and NST2, whose encoded proteins mediate anther secondary cell thickening in jasmonate (JA)-regulated stamen maturation. In this process, the transcriptional activity of MYB26 is negatively modulated by the JAZ-PRC repressive complex to precisely regulate the expression of NST1 and NST2. Disruption of EMF1 repression stimulates MYB26, leading to the excessive transcription of the two NAC genes and male sterility. Our results reveal a novel mechanism in polycomb-mediated gene silencing and illustrate that the plant Polycomb complex regulates stamen development by preventing the hypersensitivity of JA responses in male reproduction.
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Objective: This study aims to investigate the efficacy of bevacizumab (BEV) in combination with chemotherapy for metastatic colorectal cancer (mCRC). Methods: A cohort of 121 patients diagnosed with mCRC and admitted to our hospital from May 2018 to October 2019 were selected for the study. The control group, comprising 64 patients, received chemotherapy alone, while the research group, consisting of 57 patients, underwent a combination of BEV and chemotherapy. Comparative analyses included an assessment of clinical outcomes, monitoring of tumor markers including Carcinoembryonic Antigen (CEA), Cancer Antigen 74-2 (CA74-2), and Carbohydrate Antigen 19-9 (CA19-9) before and after treatment, and a count of adverse effects during the treatment phase. A 3-year post-discharge follow-up was conducted to compare the survival prognosis between the two groups. Results: The research group exhibited a significantly higher objective response rate (ORR) and clinical benefit rate (CBR) compared to the control group (P < .05). Furthermore, CEA, CA74-2, and CA19-9 post-treatment levels were markedly lower in the research group (P < .05). No notable difference in the incidence of adverse reactions was observed between the two groups (P > .05). Importantly, the 3-year overall survival prognosis was superior in the research group (P < .05). Within the research group, patients treated with BEV combined with the XELIRI regimen chemotherapy demonstrated a higher CBR rate (P < .05). Conclusions: The combination of BEV and chemotherapy proves to be highly effective in treating mCRC, significantly enhancing the prognostic survival cycle of patients. This treatment modality holds promise for future clinical applications in managing patients with mCRC.
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Alisol B 23-acetate (AB23A) is a natural triterpenoid isolated from Rhizoma alisamatis that has been widely used as a traditional Chinese medicine (TCM). Previous studies have documented the beneficial effect of AB23A on non-alcoholic fatty liver disease (NAFLD), but the functional interactions between gut microbiota and the anti-NAFLD effect of AB23A remain unclear. In this study, we investigated the benefits of experimental treatment with AB23A on gut microbiota dysbiosis in NAFLD with an obesity model. C57BL/6J mice were administrated a high-fat diet (HFD) with or without AB23A for 12 weeks. AB23A significantly improved metabolic phenotype in the HFD-fed mice. Moreover, results of 16S rRNA gene-based amplicon sequencing in each group reveled that AB23A not only reduced the abundance of the Firmicutes/Bacteroidaeota ratio and Actinobacteriota/Bacteroidaeota ratio, but regulated the abundance of the top 10 genera, including norank_f__Muribaculaceae, Lactobacillus, Ileibacterium, Turicibacter, Faecalibaculum, the Lachnospiraceae_NK4A136_group, unclassified_f__Lachnospiraceae, and norank_f__Lachnospiraceae. AB23A significantly reduced the serum levels of lipopolysaccharide and branched-chain amino acids, which are positively correlated with the abundances of Ileibacterium and Turicibacter. Moreover, AB23A led to remarkable reductions in the activation of TLR4, NF-κB, and mTOR, and upregulated the expression of tight junction proteins, including ZO-1 and occludin. These results revealed that AB23A displayed a prebiotic capacity in HFD-fed NAFLD mice.
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Aminoácidos de Cadeia Ramificada/sangue , Colestenonas/farmacologia , Dieta Hiperlipídica , Lipopolissacarídeos/sangue , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Probióticos , Animais , Peso Corporal/efeitos dos fármacos , Microbioma Gastrointestinal , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , RNA Ribossômico 16S/genética , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/metabolismo , Aumento de Peso/efeitos dos fármacosRESUMO
Repulsive electrostatic forces between prion-like proteins are a barrier against aggregation. In neuropharmacology, however, a prion's net charge (Z) is not a targeted parameter. Compounds that selectively boost prion Z remain unreported. Here, we synthesized compounds that amplified the negative charge of misfolded superoxide dismutase-1 (SOD1) by acetylating lysine-NH3+ in amyloid-SOD1, without acetylating native-SOD1. Compounds resembled a "ball and chain" mace: a rigid amyloid-binding "handle" (benzothiazole, stilbene, or styrylpyridine); an aryl ester "ball"; and a triethylene glycol chain connecting ball to handle. At stoichiometric excess, compounds acetylated up to 9 of 11 lysine per misfolded subunit (ΔZfibril =-8100 per 103 subunits). Acetylated amyloid-SOD1 seeded aggregation more slowly than unacetylated amyloid-SOD1 in vitro and organotypic spinal cord (these effects were partially due to compound binding). Compounds exhibited reactivity with other amyloid and non-amyloid proteins (e.g., fibrillar α-synuclein was peracetylated; serum albumin was partially acetylated; carbonic anhydrase was largely unacetylated).
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Amiloide/metabolismo , Lisina/metabolismo , Príons/metabolismo , Superóxido Dismutase-1/metabolismo , Acetilação , Amiloide/química , Humanos , Lisina/química , Estrutura Molecular , Príons/química , Superóxido Dismutase-1/químicaRESUMO
The most aggressive and invasive tumor cells often reside in hypoxic microenvironments and rely heavily on rapid anaerobic glycolysis for energy production. This switch from oxidative phosphorylation to glycolysis, along with up-regulation of the glucose transport system, significantly increases the release of lactic acid from cells into the tumor microenvironment. Excess lactate and proton excretion exacerbate extracellular acidification to which cancer cells, but not normal cells, adapt. We have hypothesized that carbonic anhydrases (CAs) play a role in stabilizing both intracellular and extracellular pH to favor cancer progression and metastasis. Here, we show that proton efflux (acidification) using the glycolytic rate assay is dependent on both extracellular pH (pHe) and CA IX expression. Yet, isoform-selective sulfonamide-based inhibitors of CA IX did not alter proton flux, which suggests that the catalytic activity of CA IX is not necessary for this regulation. Other investigators have suggested the CA IX co-operates with the MCT transport family to excrete protons. To test this possibility, we examined the expression patterns of selected ion transporters and show that members of this family are differentially expressed within the molecular subtypes of breast cancer. The most aggressive form of breast cancer, triple-negative breast cancer, appears to co-ordinately express the monocarboxylate transporter 4 (MCT4) and carbonic anhydrase IX (CA IX). This supports a possible mechanism that utilizes the intramolecular H+ shuttle system in CA IX to facilitate proton efflux through MCT4.
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Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX/metabolismo , Glicólise , Proteínas de Neoplasias/metabolismo , Neoplasias de Mama Triplo Negativas/enzimologia , Animais , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
BACKGROUND: Since vagus nerve stimulation (VNS) was approved by the Food and Drug Administration (FDA). A number of studies show that VNS was effective to reduce seizure frequency. However, there was still some patients treated with VNS having poor or even no clinical effect. OBJECTIVES: The purpose of the present review was to identify factors predicting the effect of VNS therapy and to select patients suitable for VNS treatment. METHOD: PubMed and Medline was searched with this terms "epilepsy," "vagus nerve stimulation," "vagal nerve stimulation," "VNS," "intractable," and "refractory".We selected studies by predefining inclusion and exclusion criteria. RESULTS: the effectiveness of VNA was confirmed by a number of studies. We find many studies exploring the predictive factors to VNS. However there was no any study finding factors correlating clearly with the outcome of VNS. Although, we find these factors, such as post-traumatic epilepsy, temporal lobe epilepsy and focal interictal epileptiform discharges (IEDs), were favorable for the treatment of VNS, while comprehensive IEDs and neuronal migration disorders were indicative of the poor effect. Also, temporal lobe epilepsy was generally effectively controlled by this therapy and yougers seemed to get more benefit from VNS. Additionally, other indexes, such as cytokine profile, slow cortical potential (SCP) shift, preoperative heart rate variability (HRV), EEG reactivity and connectomic profiling, maybe predict the results of VNS. CONCLUSION: In summary, these conventional and other new factors should be analyzed further by more science and rigorous experimental design to identify the clear correlation with the outcome of VNS therapy.
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Epilepsia Resistente a Medicamentos/terapia , Avaliação de Resultados em Cuidados de Saúde , Estimulação do Nervo Vago , Humanos , PrognósticoRESUMO
Many plants sense the seasonal cues, day length or photoperiod changes, to align the timing of the developmental transition to flowering with changing seasons for reproductive success. Inductive day lengths through the photoperiod pathway induce the expression of FLOWERING LOCUS T (FT) or FT relatives that encode a major mobile florigen to promote flowering. In Arabidopsis thaliana, under inductive long days the photoperiod pathway output CONSTANS (CO) accumulates toward the end of the day, and associates with the B and C subunits of Nuclear Factor Y (NF-Y) to form the NF-CO complex that acts to promote FT expression near dusk, whereas Polycomb group (PcG) proteins function to silence FT expression. How NF-CO acts to antagonize the function of PcG proteins to regulate FT expression remains unclear. Here, we show that the NF-CO complex bound to the proximal FT promoter, through chromatin looping, acts in concert with an NF-Y complex bound to a distal enhancer to reduce the levels of PcG proteins, including both Polycomb repressive complex 1 (PRC1) and PRC2 at the FT promoter, leading to a relieving of Polycomb silencing and thus FT de-repression near dusk. Thus, our study provides molecular insights on how the 'active' photoperiod pathway and the 'repressive' Polycomb silencing system interact to control temporal FT expression, conferring the long-day induction of flowering in Arabidopsis.
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Proteínas de Arabidopsis/genética , Arabidopsis/genética , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica de Plantas/genética , Fatores de Transcrição/genética , Arabidopsis/metabolismo , Arabidopsis/fisiologia , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/fisiologia , Proteínas de Ligação a DNA/fisiologia , Flores/crescimento & desenvolvimento , Glucosiltransferases/metabolismo , Fotoperíodo , Complexo Repressor Polycomb 2 , Proteínas do Grupo Polycomb/genética , Proteínas do Grupo Polycomb/metabolismo , Proteínas do Grupo Polycomb/fisiologia , Proteínas Repressoras/metabolismo , Fatores de Transcrição/fisiologiaRESUMO
PURPOSE: The aim of this study was to evaluate the relationship between olfactory function and hippocampal volume in patients with mild cognitive impairment (MCI). METHODS: We enrolled a total of 31 MCI patients and 9 normal control subjects. All participants underwent 3.0 T-magnetic resonance imaging scanning. The scan results were processed using GE ADW4.6 processing software and V0xar 3D workstation to acquire the hippocampal volume. The University of Pennsylvania Smell Identification Test (UPSIT) was used to evaluate the olfactory function of MCI patients. The correlations of UPSIT score with hippocampal volume and hippocampal head volume were evaluated by Pearson correlation coefficient analysis. RESULTS: MCI patients had significantly smaller left (2.78±0.50 vs. 3.19±0.31 cm(3)) and right (2.97±0.42 vs. 3.31±0.25 cm(3)) hippocampal volumes compared with normal controls (P<0.05). In addition, patients with olfactory dysfunction had smaller volumes of the hippocampus (left hippocampal volume, 2.57±0.39 vs. 3.23±0.40 cm(3); right hippocampal volume, 2.86±0.43 vs. 3.22±0.30 cm(3)) and hippocampal head (left hippocampal head volume, 1.18±0.16 vs. 1.53±0.25 cm(3); right hippocampal head volume, 1.25±0.22 vs. 1.54±0.22 cm(3)) compared with those with normal olfactory function (P<0.05). No significant difference in the hippocampal body volume and hippocampal tail volume was found between MCI patients with olfactory loss and those with normal olfactory function. The UPSIT score was significantly positively correlated with left hippocampal volume (r=0.55, P<0.05), right hippocampal volume (r=0.42, P<0.05), left hippocampal head volume (r=0.53, P<0.05), and right hippocampal head volume (r=0.45, P<0.05). CONCLUSIONS: Olfactory function correlates well with hippocampal volume among patients with MCI.
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Disfunção Cognitiva/fisiopatologia , Hipocampo/fisiopatologia , Processamento de Imagem Assistida por Computador , Transtornos do Olfato , Idoso , Estudos de Casos e Controles , China , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Olfato/fisiologiaRESUMO
To investigate the discrepancy between 11C-methionine (MET) positron emission tomography (PET) and MRI results in primary glioblastoma multiforme (GBM) through three-dimensional (3D) volumetric analysis, we retrospectively analysed patients with primary GBM who underwent preoperative 3D MRI and MET PET and were operated between June 2016 and January 2017. Tumour delineation and volumetric analysis were conducted using MRIcron software. Tumour volumes defined by MRI (VMRI) were manually drawn slice by slice in axial and sagittal or coronal images of enhanced T1 sequence, while metabolic tumour volumes were automatically segmented in MET PET (VMET) based on three (frontal, occipital and temporal) 3D reference volumes of interest (VOI). Discrepancies were evaluated in terms of both absolute volume and percentage on the combined images. MET PET contours contained and extended beyond MRI contours in all five patients; in a subset of cases, MET PET contours extended to the contralateral hemisphere. The discrepancy between MET uptake and MRI results was 27.67 cm3 (4.20-51.20 cm3), i.e. approximately 39.0% (17.4-64.3%) of the metabolic tumour volume was located outside the volumes of the Gd-enhanced area. Metabolic tumour volume is substantially underestimated by Gd-enhanced area in patients with primary GBM. Quantitative volumetric information derived from MET uptake is useful in defining tumour targets and designing individualised therapy strategies in primary GBM.
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Neoplasias Encefálicas , Glioblastoma , Radioisótopos de Carbono , Humanos , Imageamento por Ressonância Magnética , Metionina , Tomografia por Emissão de Pósitrons , Estudos RetrospectivosRESUMO
INTRODUCTION: Runt-related transcription factor 3 (RUNX3) exerts a tumor suppressor gene associated with gastric and other cancers, including glioma. However, how its anti-tumor mechanism in functions glioma is unclear. METHODS: We assayed expression of RUNX3 with a tissue microarray (TMA), frozen cancer tissues and malignant glioma cell lines using immunohistochemistry, qRT-PCR and Western bolt analysis. Cell proliferation, invasion, cell cycle distribution and apoptosis were also examined to confirm the effect of RUNX3 medicated malignant phenotype. TOP/FOP experiment was used to detect the ß-catenin/Tcf-4 transcription activity by RUNX3. RESULTS: Enforced RUNX3 expression inhibited proliferation and invasion, induced cell cycle arrest and promoted apoptosis in vitro and in vivo, Bim siRNA partically reversed the effect of RUNX3-induced apoptosis in LN229 and U87 cells, suggesting a dependent role of Bim-caspase pathway. Moreover, Mechanism investigations revealed that restoration of RUNX3 suppressed ß-catenin/Tcf-4 transcription activity. CONCLUSIONS: RUNX3 plays a pivotal role in glioma initiation and progression as a tumor suppressor via attenuation of Wnt signaling, highlighting it as a potential therapeutic target for glioma.
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Neoplasias Encefálicas , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Glioma , Transdução de Sinais/fisiologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/fisiopatologia , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , Glioma/patologia , Glioma/fisiopatologia , Humanos , Invasividade Neoplásica/fisiopatologia , Análise Serial de Tecidos , Fator de Transcrição 4/metabolismo , beta Catenina/metabolismoRESUMO
OBJECTIVE: The purpose of this study was to investigate the relationship between alterations of functional brain network and cognition in patients with benign epilepsy with centrotemporal spikes (BECTS) as a function of spike-wave index (SWI) during slow wave sleep. METHODS: Resting-state functional magnetic resonance imaging (RS-fMRI) data and Intelligence Quotient (IQ) were collected from two groups of patients with BECTS, including a SWI<50% group (5 cases) and a SWI≥50% group (7 cases). The SWI was calculated from the long-term video-electroencephalogram monitoring (one sleep cycle was included at least). The RS-fMRI data were analyzed by regional homogeneity (ReHo) method. RESULTS: There were three main findings. Firstly, Full Intelligence Quotient (FIQ), Verbal Intelligence Quotient (VIQ), and Performance Intelligence Quotient (PIQ) of the SWI≥50% group were significantly lower than SWI<50% group (p<0.05). Secondly, there was a negative correlation between the FIQ, VIQ, PIQ, and SWI (p<0.05), and the FIQ, VIQ, and PIQ were not dependent on age, age of onset, disease course, years of education, and total number of seizures (p>0.05). Finally, compared with the SWI<50% group, the SWI≥50% group showed increased ReHo in the bilateral precentral gyrus, bilateral premotor area, bilateral subcortical structure, right temporal lobe, and bilateral insular lobe, while they showed decreased ReHo in the posterior cingulate cortex and posterior of right inferior temporal lobe. CONCLUSIONS: The alterations of functional brain network caused by the frequent discharges during slow wave sleep could affect cognition in patients with BECTS.
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Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Cognição/fisiologia , Eletroencefalografia/métodos , Epilepsia Rolândica/diagnóstico por imagem , Epilepsia Rolândica/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Descanso , Adolescente , Mapeamento Encefálico , Córtex Cerebral/fisiopatologia , Feminino , Lobo Frontal/fisiopatologia , Humanos , Testes de Inteligência , Masculino , Lobo Temporal/fisiopatologiaRESUMO
BACKGROUND: In recent years, the prevalence of hand-foot-mouth disease (HFMD) in China and some other countries has caused worldwide concern. Mild cases tend to recover within a week, while severe cases may progress rapidly and tend to have bad outcome. Since there is no vaccine for HFMD and anti-inflammatory treatment is not ideal. In this study, we aimed to establish a valid forecasting model for severe HFMD using common laboratory parameters. METHODS: Retrospectively, 77 severe HFMD cases from Zhengzhou Children's hospital in the peaking period between years 2013 to 2015 were collected, with 77 mild HFMD cases in the same area. The study recorded common laboratory parameters to assist in establishment of the severe HFMD model. After screening the important variables using Mann-Whitney U test, the study also matched the logistic regression (LR), discriminant analysis (DA), and decision tree (DT) to make a comparison. RESULTS: Compared with that of the mild group, serum levels of WBC, PLT, PCT, MCV, MCH, LCR, SCR, LCC, GLO, CK-MB, K, S100, and B in the severe group were higher (p < 0.05), while MCR, EOR, BASOR, SCC, MCC, EO, BASO, NA, CL, T, Th, and Th/Ts were lower (p < 0.05). Five indicators including MCR, LCC, Th, CK-MB, and CL were screened out by LR and the same for DA, and five variables including EO, LCC, CL, GLO, and MCC screened out by DT. The area under the curve (AUC) of LR, DA, and DT was 0.805, 0.779 and 0.864, respectively. CONCLUSIONS: The findings were that common laboratory indexes were effectively used to distinguish the mild HFMD cases and severe HFMD cases by LR, DA, and DT, and DT had the best classification effect with an AUC of 0.864.
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Técnicas de Apoio para a Decisão , Árvores de Decisões , Febre Aftosa/diagnóstico , Febre Aftosa/epidemiologia , Previsões , Algoritmos , Animais , Área Sob a Curva , Biomarcadores/sangue , Pré-Escolar , China/epidemiologia , Mineração de Dados , Análise Discriminante , Feminino , Febre Aftosa/sangue , Febre Aftosa/virologia , Humanos , Lactente , Modelos Logísticos , Masculino , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Estudos Retrospectivos , Fatores de TempoRESUMO
CONTEXT: Hypertension is the single most important risk factor for intracerebral hemorrhage (ICH) and often leads to solitary hematoma. Multiple spontaneous simultaneous ICH is not common, and bilateral hemorrhages occurred in symmetrical basal ganglia is extremely rare. Most reported cases accepted conservative treatment and suffered extremely poor outcome. CASE REPORT: A 57-year-old male became unconscious when having supper and was transported to our emergency room immediately. Non-contract CT brain scanning showed simultaneous bilateral hypertensive basal ganglia hemorrhage; he was treated by stereotactic aspiration and thrombolysis for both sides, with subsequent thrombolysis and clot aspiration through hematoma-indwelling catheter. The hematomas were almost totally cleared within a week. His condition improved gradually. Nearly 10 months after onset, he could chow and swallow food, controlling bowels and bladder all by himself, but need some help when feeding and using toilet. CONCLUSION: Simultaneous bilateral hypertensive basal ganglia hemorrhage is a devastating cerebrovascular disease with significant high morbidity and mortality. Stereotactic aspiration and thrombolysis is a safe and effective way to clear hematomas within short time, thus reducing the neurological impairment from hematoma mass effect and secondary brain injury, improving prognosis.
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Hemorragia dos Gânglios da Base/etiologia , Encéfalo/diagnóstico por imagem , Hipertensão/complicações , Hemorragia dos Gânglios da Base/diagnóstico por imagem , Hemorragia dos Gânglios da Base/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Técnicas Estereotáxicas , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
αB-crystallin (CRYAB) is present at a high frequency in poor prognosis basal-like breast tumours, which are largely absent of oestrogen, progesterone receptors and HER2 known as triple-negative breast cancer (TNBC). CRYAB functions as a molecular chaperone to bind to and correct intracellular misfolded/unfolded proteins such as vascular endothelial growth factor (VEGF), preventing non-specific protein aggregations under the influence of the tumour microenvironment stress and/or anti-cancer treatments including bevacizumab therapy. Directly targeting CRYAB can sensitize tumour cells to chemotherapeutic agents and decrease tumour aggressiveness. However, growing evidence shows that CRYAB is a critical adaptive response element after ischemic heart disease and stroke, implying that directly targeting CRYAB might cause serious unwanted side effects. Here, we used structure-based molecular docking of CRYAB and identified a potent small molecular inhibitor, NCI-41356, which can strongly block the interaction between CRYAB and VEGF165 without affecting CRYAB levels. The disruption of the interaction between CRYAB and VEGF165 elicits in vitro anti-tumour cell proliferation and invasive effects through the down-regulation of VEGF signalling in the breast cancer cells. The observed in vitro anti-tumour angiogenesis of endothelial cells might be attributed to the down-regulation of paracrine VEGF signalling in the breast cancer cells after treatment with NCI-41356. Intraperitoneal injection of NCI-41356 greatly inhibits the tumour growth and vasculature development in in vivo human breast cancer xenograft models. Our findings provide 'proof-of-concept' for the development of highly specific structure-based alternative targeted therapy for the prevention and/or treatment of TNBC.
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Antineoplásicos/farmacologia , Ácido Glutâmico/análogos & derivados , Neoplasias de Mama Triplo Negativas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Cadeia B de alfa-Cristalina/antagonistas & inibidores , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Descoberta de Drogas , Ensaio de Imunoadsorção Enzimática , Feminino , Ácido Glutâmico/química , Ácido Glutâmico/farmacologia , Humanos , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Neovascularização Patológica/metabolismo , Estrutura Quaternária de Proteína , Ensaios Antitumorais Modelo de Xenoenxerto , Cadeia B de alfa-Cristalina/químicaRESUMO
Although anti-vascular endothelial growth factor (VEGF) treatments reduce pathological neovascularization in the eye and in tumors, the regression is often not sustainable or is incomplete. We investigated whether vascular endothelial cells circumvent anti-VEGF therapies by activating the unfolded protein response (UPR) to override the classic extracellular VEGF pathway. Exposure of endothelial cells to VEGF, high glucose, or H2O2 up-regulated the X-box binding protein-1/inositol-requiring protein-1 (IRE1) α and activating transcription factor 6 (ATF6) arms of the UPR compared with untreated cells. This was associated with increased expression in α-basic crystallin (CRYAB), which has previously bound VEGF. siRNA knockdown or pharmacological blockade of IRE1α, ATF6, or CRYAB increased intracellular VEGF degradation and decreased full-length intracellular VEGF. Inhibition of IRE1α, ATF6, or CRYAB resulted in an approximately 40% reduction of in vitro angiogenesis, which was further reduced in combination with a neutralizing antibody against extracellular VEGF. Blockade of IRE1α or ATF6 in the oxygen-induced retinopathy or choroidal neovascularization mouse models caused an approximately 35% reduction in angiogenesis. However, combination therapy of VEGF neutralizing antibody with UPR inhibitors or siRNAs reduced retinal/choroidal neovascularization by a further 25% to 40%, and this inhibition was significantly greater than either treatment alone. In conclusion, activation of the UPR sustains angiogenesis by preventing degradation of intracellular VEGF. The IRE1α/ATF6 arms of the UPR offer a potential therapeutic target in the treatment of pathological angiogenesis.
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Fator 6 Ativador da Transcrição/metabolismo , Neovascularização de Coroide/prevenção & controle , Proteínas de Ligação a DNA/metabolismo , Neovascularização Retiniana/prevenção & controle , Fatores de Transcrição/metabolismo , Resposta a Proteínas não Dobradas , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Bovinos , Neovascularização de Coroide/patologia , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Técnicas de Silenciamento de Genes , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Lasers , Dose Letal Mediana , Camundongos , Camundongos Endogâmicos C57BL , Microvasos/patologia , Proteólise/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Fatores de Transcrição de Fator Regulador X , Retina/patologia , Neovascularização Retiniana/patologia , Transdução de Sinais/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologia , Proteína 1 de Ligação a X-Box , Cadeia B de alfa-Cristalina/metabolismoRESUMO
OBJECTIVE: To explore the changes of executive function in patients with temporal lobe epilepsy and analyze its correlation with P300 event-related potentials. METHODS: Fifty patients with temporal lobe epilepsy and 30 age, gender and education-matched healthy control subjects were assessed by neuropsychological tests, including Montreal cognitive assessment (MoCA), working memory, verbal fluency, trail making, digit span, digit symbol and Stroop color-word interference to detect P300 event-related potentials. RESULTS: In temporal lobe epilepsy group, the scores in MoCA, verbal and non-verbal working memory, verbal fluency, digit span, digit symbol and Stroop test were lower than those of the normal control group. And trail making tests A and B became prolonged (P < 0.05). Comparing with normal control group, temporal lobe epilepsy patients had prolonged latency [(332 ± 33)ms] and decreased P300 amplitude [(10 ± 8)µV] (P < 0.05). Comparing epileptogenic focus group on the left and right sides, there was statistically significant difference in verbal working memory (P < 0.05). There was a negative correlation of P300 latency and MoCA, non-verbal working memory, digit span and digit symbol test scores (r = -0.29--0.45, P < 0.05). And a positive correlation of P300 amplitude and MoCA, non-verbal working memory, digit symbol conversion and Stroop scores was also found (r = 0.37-0.47, P < 0.05). P300 amplitude was more relevant to overall cognitive level and executive functions. CONCLUSION: Temporal lobe is involved in the regulation of executive functions. Besides a wide range of cognitive impairment, temporal lobe epilepsy patients have a number of executive dysfunctions, including working memory, cognitive flexibility, attention and inhibitory control ability. And an impairment of verbal working memory is evident in left-sided lesion. Their manifestations include decreased latency and amplitude of P300 on executive function tests. Therefore these two objective parameters may be employed to evaluate the cognitive impairment in patients with temporal lobe epilepsy.
Assuntos
Epilepsia do Lobo Temporal/fisiopatologia , Epilepsia do Lobo Temporal/psicologia , Potenciais Evocados P300 , Função Executiva , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Adulto JovemRESUMO
OBJECTIVE: To explore the diagnostic and therapeutic values of stereotactic guidance of intraoperative high-field magnetic resonance imaging (iMRI) for multiple intracranial lesions. METHODS: We retrospectively assessed 18 patients with multiple intracranial lesions undergoing stereotactic guidance of high-field iMRI between June 2011 and May 2013. The procedures included biopsy of stereotactic guidance (n = 6), stereotactic aspiration and drainage for brain abscess (n = 4), stereotactic aspiration and intracavitary irradiation with (32)P for mixed solid and cystic craniopharyngiomas (n = 3) and stereotactic hematoma evacuation (n = 5). RESULTS: For 6 cases with high-field iMRI stereotactic guidance, the target lesions were precisely predetermined and pathological specimens confirmed by clinical follow-up results. For 12 cases with multiple cystic lesions and multiple intracranial hematoma, aspiration of hematoma and liquids was satisfactory. And the course of clinical treatment was significantly shortened. And there was a lower incidence of postoperative complications. CONCLUSION: iMRI may guide precisely stereotactic surgery. And it has important clinical significance for confirming the diagnosis of multiple intracranial lesions and shortening their treatment courses.
Assuntos
Imageamento por Ressonância Magnética , Monitorização Intraoperatória , Biópsia , Craniofaringioma , Drenagem , Hematoma , Humanos , Imageamento Tridimensional , Hemorragias Intracranianas , Neoplasias Hipofisárias , Complicações Pós-OperatóriasRESUMO
This study proposed an innovative strategy of catalytic cracking of tar during biomass pyrolysis/gasification using furfural residue derived biochar-based catalysts. Fe, Co, and Ni modified furfural residue char (FRC-Fe, FRC-Co, and FRC-Ni) were prepared by one-step impregnation method. The influences of cracking temperature and metal species on the tar cracking characteristics were investigated. The results showed that the tar conversion efficiency for all catalysts were improved with the cracking temperature increasing, the higher tar conversion efficiency achieved at 800 °C were 66.72 %, 89.58 %, 84.58 %, and 94.70 % for FRC, FRC-Fe, FRC-Co, and FRC-Ni respectively. FRC-Ni achieved the higher gas (H2, CO, CH4, CO2) yield 681.81 mL/g. At 800 °C, the catalyst (FRC-Ni) still reached a high tar conversion efficiency over 85.90 % after 5 cycles. SEM-EDS results showed that the distribution of Ni particles on the biochar support was uniform. TGA results demonstrated that FRC-Ni exhibited better thermal stability. XRD results indicated that there was no significant change in the grain size of Ni before and after the reaction. The FRC-Ni catalyst was reasonably stable due to its better anti-sintering and coke-resistant capabilities.
Assuntos
Carvão Vegetal , Furaldeído , Gases , Biomassa , Metais , CatáliseRESUMO
The effect of aggregation configuration of molecular fluorophore citrazinic acid (CZA) on the photoluminescence (PL) properties of carbon dots (CDs) has been investigated using first-principles method. The structural stability of all aggregates has been analyzed, and the results show that the most stable structures are J-type CZA aggregates with head-to-tail configurations and the CZA/CD aggregates are bonded by replacing H atoms on the CD edges with de-OH from the pyridine ring of CZA. The luminescent properties of CZA/CD aggregates are mainly affected by the binding modes and binding sites. When the sites belong to electron-donating groups, electron-withdrawing groups or sp2 domain, the PL spectra of CDs are shifted and the luminescent intensities are significantly enhanced. The results suggest that covalently bonded CZA/CD aggregates are responsible for the high fluorescence quantum yield of CD. Moreover, the distance between the centers of the two pyridine rings in H-type CZA dimers less than 3.5 Å is prone to π-π stacking, leading to fluorescence quenching of aggregates. The present work is helpful in understanding the effect of molecular fluorophores on the PL properties of CDs and provides theoretical guidance for the controllable synthesis of CDs.
RESUMO
OBJECTIVE: To explore the methods and applications of intraoperative magnetic resonance imaging (iMRI)-guided functional neuronavigation plus intraoperative neurophysiological monitoring (IONM) for microsurgical resection of lesions involving hand motor area. METHODS: A total of 16 patients with brain lesions adjacent to hand motor area were recruited from January 2011 to April 2012. All of them underwent neuronavigator-assisted microsurgery. Also IONM was conducted to further map hand motor area and epileptogenic focus. High-field iMRI was employed to update the anatomical and functional imaging date and verify the extent of lesion resection. RESULTS: Brain shifting during the functional neuronavigation was corrected by iMRI in 5 patients. Finally, total lesion resection was achieved in 13 cases and subtotal resection in 3 cases. At Months 3-12 post-operation, hand motor function improved (n = 10) or remained unchanged (n = 6). None of them had persistent neurological deficit. The postoperative seizure improvement achieved Enge II level or above in 9 cases of brain lesions complicated with secondary epilepsy. CONCLUSION: Intraoperative MRI, functional neuronavigation and neurophysiological monitoring technique are complementary in microsurgery of brain lesions involving hand motor area. Combined use of these techniques can obtain precise location of lesions and hand motor functional structures and allow a maximum resection of lesion and minimization of postoperative neurological deficits.