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BACKGROUND: Symptoms of depression and anxiety are common complications of narcolepsy. Earlier studies have shown that narcolepsy type 1 (NT1) is an autoimmune inflammatory disease and symptoms of depression and anxiety are closely related to fluctuations in inflammatory cytokines. The objective of the current research was to investigate the potential correlation between cytokines and symptoms of depression and anxiety in patients with NT1. METHODS: We collected demographic and clinical data and information on cytokine levels from 50 patients with NT1 and used Self-Rating Depression Scale (SDS) and Self-Rating Anxiety Scale (SAS) to assess the severity of depression and anxiety symptoms. Patients with SDS scores ≥ 53 points were defined as depressive narcolepsy type 1 (D-NT1) and those with SDS scores < 53 points as non-depressive narcolepsy type 1 (ND-NT1). Patients with SAS scores ≥ 50 points were defined as anxious narcolepsy type 1 (A-NT1) and those with SAS scores < 50 points as non-anxious narcolepsy type 1 (NA-NT1). A binary logistic regression model was employed to identify the influencing factors of depressive and anxiety symptoms. RESULTS: Levels of IL-10 (p = 0.02), IL-4 (p = 0.049) and disease duration (p = 0.049) were decreased, while SAS scores (p < 0.001) and total sleep duration (p = 0.03) were increased in D-NT1 relative to ND-NT1 patients. A-NT1 patients had higher SDS scores (p < 0.001) compared to NA-NT1 patients. Binary logistic regression analysis revealed associations of longer disease duration (OR=0.83; 95 % CI: 0.70-0.97) and increased IL-10 (OR=0.40; 95 % CI: 0.17-0.90) with reduced risk of depression and worsening anxiety (SAS score; OR=1.17; 95 % CI: 1.06-1.30) with increased risk of depression in patients with NT1. Consistently, worsening depression (SDS score; OR=1.22; 95 % CI: 1.07-1.39) was correlated with increased risk of anxiety in the NT1 group. CONCLUSION: Our finding that higher IL-10 levels correlate with a lower risk of depression in NT1 patients provides a reference for further exploration of the pathophysiological mechanisms of depressive symptoms in NT1 patients.
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Ansiedade , Citocinas , Depressão , Narcolepsia , Humanos , Narcolepsia/psicologia , Narcolepsia/complicações , Masculino , Feminino , Adulto , Depressão/etiologia , Ansiedade/etiologia , Ansiedade/psicologia , Citocinas/sangue , Adulto Jovem , Adolescente , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Pessoa de Meia-IdadeRESUMO
Eighteen S rRNA factor 1 (ESF1) is a predominantly nucleolar protein essential for embryogenesis. Our previous studies have suggested that Esf1 is a negative regulator of the tumor suppressor protein p53. However, it remains unclear whether ESF1 contributes to tumorigenesis. In this current research, we find that increased ESF1 expression correlates with poor survival in multiple tumors including pancreatic cancer. ESF1 is able to regulate cell proliferation, migration, DNA damage-induced apoptosis, and tumorigenesis. Mechanistically, ESF1 physically interacts with MDM2 and is essential for maintaining the stability of MDM2 protein by inhibiting its ubiquitination. Additionally, ESF1 also prevented stress-induced stabilization of p53 in multiple cancer cells. Hence, our findings suggest that ESF1 is a potent regulator of the MDM2-p53 pathway and promotes tumor progression.
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STUDY OBJECTIVES: Narcolepsy type 1 is attributed to a deficiency in cerebrospinal fluid orexin and is considered linked to autoimmunity. The levels of anti-Tribbles homolog 2 (TRIB2) autoantibodies are elevated in the sera of some patients with narcolepsy with cataplexy. Additionally, injecting mice with serum immunoglobulin from patients with narcolepsy with positive anti-TRIB2 antibodies can induce hypothalamic neuron loss and alterations in sleep patterns. Consequently, we hypothesized the existence of a potential association between anti-TRIB2 antibodies and narcolepsy. To test this possibility, we used cell-based assays (CBAs) and enzyme-linked immunosorbent assays (ELISAs) to detect the presence of anti-TRIB2 antibodies in Chinese patients with narcolepsy. METHODS: We included 68 patients with narcolepsy type 1, 39 patients with other central disorders of hypersomnolence, and 43 healthy controls. A CBA and a conventional ELISA were used to detect anti-TRIB2 antibody levels in patients' sera. RESULTS: CBA was used to detect serum anti-TRIB2 antibodies in Chinese patients with narcolepsy, and the results were negative. However, when the ELISA was used, only 2 patients with narcolepsy type 1 had TRIB2 antibody titers higher than the mean titer plus 2 standard deviations of the healthy controls. CONCLUSIONS: In our study, ELISA identified TRIB2 autoantibodies in sera of patients with narcolepsy where CBA failed to demonstrate them. Contrary to our hypothesis, this intriguing finding deserves further research to elucidate the potential association between TRIB2 and narcolepsy type 1. Exploring the implications of TRIB2 autoantibodies in narcolepsy and disparate outcomes between ELISA and CBA could provide crucial insights. CITATION: Zhong X, Yuan Y, Zhan Q, et al. Cell-based vs enzyme-linked immunosorbent assay for detection of anti-Tribbles homolog 2 autoantibodies in Chinese patients with narcolepsy. J Clin Sleep Med. 2024;20(6):941-946.
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Autoanticorpos , Ensaio de Imunoadsorção Enzimática , Narcolepsia , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Autoanticorpos/sangue , Proteínas Quinases Dependentes de Cálcio-Calmodulina/imunologia , China , População do Leste Asiático , Ensaio de Imunoadsorção Enzimática/métodos , Narcolepsia/imunologiaRESUMO
BACKGROUND: Infection is the most common adverse event of acute lymphoblastic leukemia (ALL) treatment and is also one of the main causes of death. METHODS: To investigate the clinical characteristics and risk factors of severe infections during the maintenance phase of ALL treatment, we conducted a retrospective study. RESULTS: A total of 181 children were eligible and 46 patients (25.4%) suffered from 51 events of severe infection, most of which occurred in the first half year of the maintenance phase (52.9%). The most common infection was pulmonary infection (86.3%) followed by bloodstream infection (19.6%). The main symptoms of ALL patients with pulmonary infection were fever, cough, and shortness of breath. The main manifestations of computer tomography (CT) were ground glass shadow (56.8%), consolidation shadow (27.3%), and streak shadow (25%). Multivariate binary logistic regression analysis showed that agranulocytosis, agranulocytosis ≥7 days, anemia, and low globulin level were independent risk factors for severe infection during the maintenance phase (all p < 0.05). CONCLUSIONS: Taken together, blood routine examinations and protein levels should be monitored regularly for ALL patients in the maintenance phase, especially in the first 6 months. For ALL patients with risk factors, preventive anti-infective or supportive therapies can be given as appropriate to reduce the occurrence of severe infections.
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Agranulocitose , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Criança , Estudos Retrospectivos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Fatores de Risco , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Agranulocitose/tratamento farmacológico , Agranulocitose/etiologiaRESUMO
Background: Type II diabetes mellitus (T2DM) has become a worldwide public health problem. Although it has been empirically established that physical activity is a promising therapeutical approach to the prevention and management of T2DM, the effectiveness of yoga on T2DM has not yet reached an agreement across studies and also needs an updated synthetic examination. Purpose: The purpose of this study was to examine the effect of yoga training on diabetes-related indicators compared with usual care. Methods: The review protocol of this study has been registered in the PROSPERO with a registration number CRD42021267868. A systematic literature search through electronic databases was conducted to identify yoga-based intervention (i.e., randomized controlled trial [RCT]; e.g., yogic postures, movements, breathing, and meditation) studies reporting outcomes on glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG), postprandial blood glucose (PPBG), total cholesterol (TC), triglycerides (TG), and body mass index (BMI). A number of two researchers manually reviewed and assessed each article using the Cochrane Risk of Bias Tool 2.0. The literature search identified 296 eligible entries, of which 13 were finalized after screening using predefined inclusion and exclusion criteria. The extracted data (group mean and standard deviation at posttest) were synthesized using random-effects meta-analyses. Finally, potential moderators were explored using subgroup analysis and sensitivity analysis. Results: The standardized mean difference for the effects of yoga was significant on HbA1c (MD = -0.47; 95%CI: -0.77, -0.16; Z = 3.02, p = 0.003), FBG (SMD = -0.92; 95%CI: -1.55, -0.29; Z = 2.87, p = 0.004), PPBG (SMD = -0.53; 95%CI: -0.86, -0.21; Z = 3.20, p = 0.001), and TG (SMD = -0.32; 95%CI: -0.54, -0.10; Z = 2.86, p = 0.004). However, yoga effect was not observed on TC (SMD = -0.84; 95%CI: -1.71, 0.04; Z = 1.87, p = 0.06) and BMI (MD = -0.63; 95%CI: -1.42, 0.16; Z = 1.57, p = 0.12). Conclusion: The findings suggest that yoga can improve the biochemical indices of blood glucose and the lipid profile of patients with T2DM. Therefore, yoga can be prescribed as an effective and active complementary treatment for T2DM. However, this study only tested yoga as a short-term treatment. In the future, rigorous RCTs with a larger sample size may be carried out to examine the long-term effect of yoga on T2DM. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=267868, identifier: CRD42021267868.
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BACKGROUND: Particulate matter≤ 2.5 µm (PM2.5) is a type of environmental agent associated with air pollution, which induces hepatic fibrosis. However, the function and mechanism of PM2.5 on hepatic stellate cell (HSC) proliferation and fibrosis remain largely unknown. METHODS: Human HSC line (LX-2) and murine HSCs were exposed to various doses of PM2.5. microRNA (miR)-411 expression was detected via quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell proliferation, fibrosis, mitochondrial dynamics dysfunction and mitophagy were determined via cell counting kit-8 (CCK-8), qRT-PCR, Western blotting and immunofluorescence. RESULTS: PM2.5 facilitated HSC proliferation and fibrosis via increasing the levels of ACTA2, Collagen 1, TIMP1 and TGF-ß1. PM2.5 reduced miR-411 expression, and contributed to mitochondrial dynamics dysfunction via increasing Drp1 and decreasing OPA1, TOM20 and PGC-1α levels. PM2.5 promoted mitophagy by upregulating the levels of Beclin-1, LC3II/I, PINK1 and Parkin. miR-411 overexpression or autophagy blockage using 3-methyladenine (3-MA) relieved PM2.5-mediated cell proliferation and fibrosis-associated factor expression in HSCs. Drp1 was targeted by miR-411. miR-411 mitigated PM2.5-induced mitophagy via targeting Drp1. Drp1 overexpression abolished the inhibitory role of miR-411 in cell proliferation and fibrosis-associated factor levels in HSCs. CONCLUSION: PM2.5 induced HSC activation and fibrosis via promoting Drp1-mediated mitophagy by decreasing miR-411, thereby causing liver fibrosis.
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Dinaminas/metabolismo , Células Estreladas do Fígado/patologia , Cirrose Hepática/patologia , MicroRNAs/genética , Dinâmica Mitocondrial , Mitofagia , Material Particulado/efeitos adversos , Animais , Autofagia , Proliferação de Células , Dinaminas/genética , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Humanos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Camundongos , Transdução de Sinais , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND: Long non-coding RNA (lncRNA) HULC (highly upregulated in liver cancer) is considered as an oncogenic factor for various malignant tumors. This study aimed to reveal the role of lncRNA HULC in the malignant behavior of glioblastoma (GBM) by exploring its effects on the epithelial-mesenchymal transition (EMT) and vasculogenic mimicry (VM) of human GBM. MATERIALS AND METHODS: The contents of VM in 27 GBM samples were assessed by immunohistochemistry-histology and their association with progress-free survival (PFS) was analyzed. Human GBM SHG44 and U87 cells were manipulated to establish stable lncRNA HULC overexpressing and silencing cells by lentivirus-based technology. The effects of altered lncRNA HULC on vasculogenic tubular formation, invasion, and EMT process in GBM cells were tested in vitro and the growth of implanted GBM tumors and their EMT process were examined in vivo. RESULTS: The numbers of VM were positively associated with disease progression, but negatively with PFS periods of GBM patients. Compared with the control vec cells, lncRNA HULC overexpression significantly increased the tubular formation, invasion, and EMT process of both SHG44 and U87 cells, accompanied by promoting the growth of implanted GBM tumors and EMT process in mice. LncRNA HULC silencing had opposite effects on the tubular formation, invasion, and EMT process as well as tumor growth of GBM cells. CONCLUSION: LncRNA HULC stimulates the EMT process and VM in human GBM, and may be a therapeutic target for intervention of GBM.
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Neoplasias Encefálicas , Transição Epitelial-Mesenquimal/fisiologia , Glioblastoma , RNA Longo não Codificante/metabolismo , Adolescente , Adulto , Idoso , Animais , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Feminino , Inativação Gênica , Glioblastoma/irrigação sanguínea , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioblastoma/secundário , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Transplante de Neoplasias , Neovascularização Patológica/etiologia , Intervalo Livre de Progressão , RNA Longo não Codificante/genética , Adulto JovemRESUMO
Glioblastoma multiforme (GBM) is a life-threatening brain tumor. This study aimed to identify potential targets of the long noncoding RNA (lncRNA) HULC that promoted the progression of GBM. Two U87 cell lines were constructed: HULC-siRNA and negative control (NC). Quantitative real-time PCR (qRT-PCR) was performed to validate the transfection efficiency of HULC silencing vector. Mass spectrometry (MS) was used to generate proteomic profiles for the two cell lines. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to distinguish HULC-related genes and pathway mapping. Colony formation, Transwell, and wound-healing assays were used to investigate the functional effects of HULC knockdown on GBM. We identified 112 up-regulated proteins and 24 down-regulated proteins from a total of 4360 quantified proteins. GO enrichment illustrated that these proteins were mainly involved in organelle structure, catalysis, cell movement, and material metabolism. KEGG pathway analysis indicated that some of these proteins were significantly enriched in tight junction, metabolic pathways, and arachidonic acid metabolism. In vitro experiments demonstrated that HULC knockdown inhibited GBM cell proliferation, invasion, and migration. Our KEGG analyses revealed that PLA2G4A was a shared protein in several enriched pathways. HULC silencing significantly down-regulated the expression of PLA2G4A. Knockdown of HULC changed the proteomic characteristics of GBM and altered the behaviors of GBM cells. Specifically, we identified PLA2G4A as an HULC target in GBM. This study provides a new perspective on the mechanisms and potential drug targets of GBM treatment.
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Inativação Gênica , Glioblastoma/genética , Fosfolipases A2 do Grupo IV/genética , Proteômica , RNA Longo não Codificante/genética , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/patologia , Humanos , MicroRNAs/genética , Transdução de Sinais/genéticaRESUMO
A series of dibenzodiazepine 2-position derivatives, bearing N-methylpiperazine at the C-11 position, were prepared by using a concise approach. Their inhibitory activities of tumor cell proliferation in vitro were tested in five cell lines, including breast cancer cell BCAP37, gastric cancer cell SGC7901, liver cancer cell HepG2, cervical cancer cell HeLa and acute promyelocytic leukemia cell HL-60. Several compounds showed efficient tumor activity with IC50 values down to 0.30 µM. These compounds are expected to be a new class of potential anticancer lead compounds.
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Antineoplásicos , Benzodiazepinas , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzodiazepinas/síntese química , Benzodiazepinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , ProibitinasRESUMO
PURPOSE: Glioblastoma (GBM) is an aggressive central nervous system (CNS) cancer and a serious threat to human health. The long noncoding RNA (lncRNA) HULC has been implicated in GBM, but the molecular mechanism is uncertain. This study used quantitative proteomic analysis for global identification of HULC-regulated proteins in glioblastoma cells and identification of potential biomarkers. MATERIALS AND METHODS: qRT-PCR was used to determine the expression of HULC in U87 cells stably transfected with HULC or an empty vector (control). The CCK-8 assay, transwell assay, and wound-scratch assay were used to measure cell proliferation, invasion, and migration. Quantitative proteomics using Tandem Mass Tag (TMT) labeling, high-performance liquid chromatography (HPLC) fractionation, and liquid chromatography-mass spectrometry (LC-MS/MS) analysis were used to identify differentially expressed proteins (DEPs). Screened proteins were validated by parallel reaction monitoring (PRM) and Western blotting. RESULTS: Overexpression of HULC led to increased cell proliferation, invasion, and migration. HULC overexpression also led to significant upregulation of 37 proteins and downregulation of 78 proteins. Bioinformatics analysis indicated these proteins had roles in cellular component, biological process, and molecular function. PRM results of 8 of these proteins (PTK2, TNC, ITGAV, LASP1, MAPK14, ITGA1, GNA13, RRAS) were consistent with the LC-MS/MS and Western blotting results. CONCLUSION: The results of present study suggest that lncRNA HULC promotes GBM cell proliferation, invasion, and migration by regulating RRAS expression, suggesting that RRAS may be a potential biomarker or therapeutic target for this cancer.
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At present, autophagic dysfunction has been considered to be involved in the pathogenesis of Alzheimer's disease (AD). Thus, the activation of autophagy provides a potential means of eliminating the intracellular amyloid-ß (Aß) and slows down the neurotoxicity induced by Aß. Here, we synthesize a Quercetin (Qu) modified polysorbate 80 (P-80)-coated AuPd core-shell structure. Our results indicate that Concave cubic Qu@P-80@AuPd can activate autophagy of SH-SY5Y cells, promote the fusion of autophagosomes and lysosomes, accelerate the clearance of Aß, and protect SH-SY5Y cells from Aß-induced cytotoxicity damage. Furthermore, Concave cubic Qu@P-80@AuPd also has good biocompatibility and high blood-brain barrier (BBB) permeability. Therefore, we anticipate that Concave cubic Qu@P-80@AuPd will be used as a potential autophagy inducer to treat AD.
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Doença de Alzheimer/tratamento farmacológico , Autofagia/efeitos dos fármacos , Materiais Biocompatíveis/farmacologia , Ouro/química , Nanopartículas Metálicas/química , Paládio/química , Quercetina/farmacologia , Doença de Alzheimer/patologia , Materiais Biocompatíveis/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ouro/farmacologia , Humanos , Paládio/farmacologia , Tamanho da Partícula , Quercetina/química , Relação Estrutura-Atividade , Propriedades de SuperfícieRESUMO
BACKGROUND The aim of this study was to explore the influence of ubiquitin associated protein 2-like (UBAP2L) on the growth and metastasis of hepatocellular carcinoma (HCC) and its potential underlying mechanism. MATERIAL AND METHODS UBAP2L gene was knocked down in SMMC-7721 by RNA interference and cell function experiments were performed. A subcutaneous xenograft tumor model was constructed to examine the effect of UBAP2L silence on HCC growth. Finally, the whole genomic microarrays were used to screen the potential mechanism of UBAP2L in regulating the biological function of HCC. RESULTS Compared with those in the control group, the cell proliferation and clone formation were significantly reduced, cell cycle was arrested in G2/M phase, the number of apoptotic cells was remarkably increased, and the abilities of vascular formation and cell migration and metastasis were dramatically weakened in the shUBAP2L group (All P<0.05). UBAP2L knockdown significantly suppressed the tumor growth of HCC in vivo. Moreover, a total of 320 genes changed significantly after UBAP2L knockdown, among which, 159 genes were upregulated and 161 genes were downregulated. Then, gene enrichment analysis revealed that PI3K/AKT and P53 signal pathway were the most significant in the top 10 enrichments. Finally, Western blot analysis verified that UBAP2L knockdown caused the increase of P21 and PTEN and decrease of CDK1, CCNB1, p-PI3K, and p-AKT. CONCLUSIONS UBAP2L plays an oncogenic role in HCC, and knockdown of its expression significantly inhibits HCC growth and metastasis, which may be related to the regulation of PI3K/AKT and P53 signaling pathways by UBAP2L.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proteínas de Transporte/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas de Transporte/genética , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Regulação para Baixo , Genes p53 , Humanos , Neoplasias Hepáticas/patologia , Metástase Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , Transdução de SinaisRESUMO
The elastic cellulose-based aerogels (CBAs) with highly porous (99.56%) and low-density (0.0065gcm-1) were prepared using Eichhornia crassipes as cellulose source and polyvinyl alcohol directly as cross-linker via a facile and environment-friendly process. The prepared CBAs exhibited excellent oil/solvent sorption capacities (60.33-152.21gg-1), super-hydrophobicity (water contact angle of 156.7°) as well as remarkable reusability. More importantly, the absorbed oil could be quickly recovered by simple squeezing without significantly structure damage (at least 16 times). All these merits make CBAs very promising materials for oil spillage cleaning.
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Eichhornia , Poluição por Petróleo , Poluentes Químicos da Água/isolamento & purificação , Biodegradação Ambiental , Celulose/química , Interações Hidrofóbicas e Hidrofílicas , PorosidadeRESUMO
Poultry are the main source of Campylobacter infection worldwide. To obtain information on Campylobacter-infected flocks and create a reference for preventing and controlling Campylobacter at farm level, Campylobacter isolates were recovered from broilers and the environments of nine chicken flocks in two farms during growth. The genetic relationship between the Campylobacter isolates was determined using multilocus sequence typing. Flocks were colonized as early as 3 weeks after introduction to the farm. The highest colonization rate was more than 90% and occurred 4-6 weeks after introduction to the farm. Quantitative data showed that the highest Campylobacter loads appeared at 1-2 weeks after initial colonization. Campylobacter loads in cloacal swabs in four flocks were significantly higher at 5 weeks than at 3 weeks (P < 0.05). Multilocus sequence typing of 171 selected isolates revealed 20 sequence types (STs), which consisted of 12 STs for Campylobacter jejuni and eight for Campylobacter coli isolates. The STs of the Campylobacter isolates recovered from farm 1 were more diversified than those from farm 2. The STs of environmental samples were highly consistent with those of the cloacal swab samples. The consistency between Campylobacter STs in the environmental and cloacal swab samples suggested that the environment might be one of the main sources of infection. Thus, our study highlights the prevalence and contamination load of Campylobacter in broilers during their rearing period and emphasizes the need for control and prevention measures for Campylobacter infection in broilers, which is also important for human health.
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Infecções por Campylobacter/veterinária , Campylobacter/genética , Galinhas/microbiologia , Doenças das Aves Domésticas/microbiologia , Criação de Animais Domésticos , Animais , Técnicas de Tipagem Bacteriana/veterinária , Campylobacter/isolamento & purificação , Infecções por Campylobacter/epidemiologia , Infecções por Campylobacter/microbiologia , Campylobacter coli/genética , Campylobacter coli/isolamento & purificação , Campylobacter jejuni/genética , Campylobacter jejuni/isolamento & purificação , Cloaca/microbiologia , Microbiologia Ambiental , Fazendas , Genótipo , Tipagem de Sequências Multilocus/veterinária , Filogenia , Doenças das Aves Domésticas/epidemiologia , Análise de Sequência de DNA/veterináriaRESUMO
Metal ions promote Alzheimer's disease (AD) pathogenesis by accelerating amyloid-ß (Aß) aggregation and inducing formation of neurotoxic reactive oxygen species (ROS) such as hydrogen peroxide (H2O2). Although metal chelators can block these effects, their therapeutic potential is marred by their inability to cross the blood-brain barrier (BBB) and by their non-specific interactions with metal ions necessary for normal cellular processes, which could result in adverse side effects. To overcome these limitations, we created a novel gold nanoparticle-capped mesoporous silica (MSN-AuNPs) based H2O2-responsive controlled release system for targeted delivery of the metal chelator CQ. In this system, CQ is released only upon exposure to conditions in which H2O2 levels are high, such as those in Aß plaques. The conjugation of AuNPs on the surface of MSN did not affect their ability to cross the BBB. The AuNPs also help in decrease the Aß self-assembly, due to this, MSN-CQ-AuNPs were more efficient than MSN-CQ in inhibiting Cu2+-induced Aß40 aggregation. Furthermore, MSN-CQ-AuNPs reduced the cell membrane disruption, microtubular defects and ROS-mediated apoptosis induced by Aß40-Cu2+ complexes. The high BBB permeability, efficient anti-Aß aggregation, and good biocompatibility of MSN-CQ-AuNPs, together with the specific conditions necessary for its release of CQ, demonstrate its potential for future biomedical applications. STATEMENT OF SIGNIFICANCE: Due to the low ability to cross the blood-brain barrier (BBB) and non-specific interactions with metal ions necessary for normal cellular processes of metal chelator or Aß inhibitors, we created a novel gold nanoparticle-capped mesoporous silica (MSN-AuNPs)-based H2O2-responsive controlled release system for targeted delivery of the metal chelator CQ and AuNPs (Aß inhibitor). In this system, CQ and AuNPs are released only upon exposure to conditions in which H2O2 levels are high, such as those in Aß plaques. The AuNPs on the surface of MSN also help in decrease the Aß self-assembly, due to this, MSN-CQ-AuNPs were more efficient than MSN-CQ in inhibiting Cu2+-induced Aß40 aggregation. Furthermore, MSN-CQ-AuNPs reduced the cell membrane disruption, microtubular defects and ROS-mediated apoptosis induced by Aß40-Cu2+ complexes. Our data suggest that this controlled release system may have widespread application in the field of medicine for Alzheimer's disease.
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Doença de Alzheimer/tratamento farmacológico , Ouro/química , Peróxido de Hidrogênio/farmacologia , Nanopartículas Metálicas/química , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Animais , Barreira Hematoencefálica/metabolismo , Morte Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Forma Celular/efeitos dos fármacos , Quelantes/farmacologia , Cobre/farmacologia , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Imunofluorescência , Nanopartículas Metálicas/ultraestrutura , Camundongos , Neurotoxinas/toxicidade , Células PC12 , Porosidade , Ratos , Rodaminas/análise , Dióxido de Silício/química , Tubulina (Proteína)/metabolismo , Difração de Raios XRESUMO
The structural changes of amyloid-beta (Aß) from nontoxic monomers into neurotoxic aggregates are implicated with pathogenesis of Alzheimer's disease (AD). Over the past decades, weak disaggregation ability and low permeability to the blood-brain barrier (BBB) may be the main obstacles for major Aß aggregation blockers. Here, we synthesized penetratin (Pen) peptide loaded poly(ethylene glycol) (PEG)-stabilized gold nanostars (AuNS) modified with ruthenium complex (Ru@Pen@PEG-AuNS), and Ru(II) complex as luminescent probes for tracking drug delivery. We revealed that Ru@Pen@PEG-AuNS could obviously inhibit the formation of Aß fibrils as well as dissociate preformed fibrous Aß under the irradiation of near-infrared (NIR) due to the NIR absorption characteristic of AuNS. More importantly, this novel design could be applied in medicine as an appropriate nanovehicle, being highly biocompatible and hemocompatible. In addition, Ru@Pen@PEG-AuNS had excellent neuroprotective effect on the Aß-induced cellular toxicity by applying NIR irradiation. Meanwhile, Pen peptide could effectively improve the delivery of nanoparticles to the brain in vitro and in vivo, which overcame the major limitation of Aß aggregation blockers. These consequences illustrated that the enhanced BBB permeability and efficient photothermolysis of Ru@Pen@PEG-AuNS are promising agents in AD therapy.
Assuntos
Doença de Alzheimer/terapia , Barreira Hematoencefálica/metabolismo , Proteínas de Transporte/química , Ouro/química , Nanopartículas/química , Fototerapia/métodos , Animais , Proteínas de Transporte/farmacologia , Linhagem Celular , Peptídeos Penetradores de Células , Humanos , Raios Infravermelhos , Camundongos , Camundongos Nus , Peptídeos/química , Permeabilidade/efeitos dos fármacosRESUMO
Drug resistance mediated by P-glycoprotein (P-gp) and class III ß-tubulin (ß-tubulin III) is a major barrier in microtubule-targeting cancer chemotherapy. In this study, layered double hydroxide nanoparticles (LDHs) were employed to simultaneously deliver selenium (Se) and pooled small interfering RNAs (siRNAs) to achieve therapeutic efficacy. LDH-supported Se nanoparticles (Se@LDH) were compacted with siRNAs (anti-P-gp and anti-ß-tubulin III) via electrostatic interactions, which could protect siRNA from degradation. Se@LDH showed excellent abilities to deliver siRNA into cells, including enhancing siRNA internalization, and promoting siRNA escape from endosomes. siRNA transfection experiments further confirmed a higher gene silencing efficiency of Se@LDH than LDH. Interestingly, we found Se@LDH may be a microtubule (MT) stabilizing agent which could inhibit cell proliferation by blocking cell cycle at G2/M phase, disrupting normal mitotic spindle formation and inducing cell apoptosis. When complexed with different specific siRNAs, Se@LDH/siRNA nanoparticles, especially the Se@LDH-pooled siRNAs, exhibit an efficient gene-silencing effect that significantly downregulate the expression of P-gp and ß-tubulin III. Moreover, Se@LDH-pooled siRNAs could induce cell apoptosis, change cell morphology and increase cellular ROS levels through change the expression of Bcl-2/Bax, activation of caspase-3, PI3K/AKT/mTOR and MAPK/ERK pathways. These results suggested that co-delivery of Se and pooled siRNAs may be a promising strategy for overcoming the drug resistance mediated by P-gp and ß-tubulin III in drug-resistant breast cancers.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Nanopartículas Metálicas/química , RNA Interferente Pequeno/administração & dosagem , Selênio/administração & dosagem , Tubulina (Proteína)/química , Anexina A5/química , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Feminino , Células HEK293 , Células Hep G2 , Humanos , L-Lactato Desidrogenase/química , Células MCF-7 , Microscopia de Fluorescência , Microtúbulos/química , Oxirredução , RNA Interferente Pequeno/química , Espécies Reativas de Oxigênio/química , Selênio/química , Espectroscopia de Infravermelho com Transformada de Fourier , Fuso AcromáticoRESUMO
Pomelo peel (PP), as one of the well-known agricultural wastes, is cost-effective and environmentally friendly. Based on PP, two new kinds of oil sorbents were prepared by using acetic anhydride and styrene. The structures of raw pomelo peel (RP), acetic anhydride-treated pomelo peel (AP) and styrene-treated pomelo peel (SP) were characterized by Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM), contact-angle (CA) measurements. The optimum reaction conditions for preparation of AP and SP were also investigated. The resulting products exhibited better oil sorption capacity than that of RP for diesel and lubricating oil, also SP had better oil sorption capacity than AP, while the oil sorption capacities of SP for diesel and lubricating oil reached 18.91 and 26.36 g/g, respectively. Adsorption kinetics was well described by the pseudo-second-order model. The results indicated that AP and SP, especially SP could be used as the substitute for non-biodegradable oil sorption materials.
Assuntos
Anidridos Acéticos/química , Citrus/química , Recuperação e Remediação Ambiental/métodos , Poluição por Petróleo/análise , Estireno/química , AdsorçãoRESUMO
The blood-brain barrier (BBB) is a formidable gatekeeper toward exogenous substances, playing an important role in brain homeostasis and maintaining a healthy microenvironment for complex neuronal activities. However, it also greatly hinders drug permeability into the brain and limits the management of brain diseases. The development of new drugs that show improved transport across the BBB represents a promising strategy for Alzheimer's disease (AD) intervention. Whereas, previous study of receptor-mediated endogenous BBB transport systems has focused on a strategy of using transferrin to facilitate brain drug delivery system, a system that still suffers from limitations including synthesis procedure, stability and immunological response. In the present study, we synthetised sialic acid (SA)-modified selenium (Se) nanoparticles conjugated with an alternative peptide-B6 peptide (B6-SA-SeNPs, a synthetic selenoprotein analogue), which shows high permeability across the BBB and has the potential to serve as a novel nanomedicine for disease modification in AD. Laser-scanning confocal microscopy, flow cytometry analysis and inductively coupled plasma-atomic emission spectroscopy ICP-AES revealed high cellular uptake of B6-SA-SeNPs by cerebral endothelial cells (bEnd.3). The transport efficiency of B6-SA-SeNPs was evaluated in a Transwell experiment based on in vitro BBB model. It provided direct evidence for B6-SA-SeNPs crossing the BBB and being absorbed by PC12 cells. Moreover, inhibitory effects of B6-SA-SeNPs on amyloid-ß peptide (Aß) fibrillation could be demonstrated in PC12 cells and bEnd3 cells. B6-SA-SeNPs could not only effectively inhibit Aß aggregation but could disaggregate preformed Aß fibrils into non-toxic amorphous oligomers. These results suggested that B6-SA-SeNPs may provide a promising platform, particularly for the application of nanoparticles in the treatment of brain diseases. STATEMENT OF SIGNIFICANCE: Alzheimer's disease (AD) is the world's most common form of dementia characterized by intracellular neurofibrillary tangles in the brain. Over the past decades, the blood-brain barrier (BBB) limits access of therapeutic or diagnostic agents into the brain, which greatly hinders the development of new drugs for treating AD. In this work, we evaluated the efficiency of B6-SA-SeNPs across BBB and investigated the interactions between B6-SA-SeNPs and amyloid-ß peptide (Aß). We confirm that B6-SA-SeNPs could provide a promising platform because of its high brain delivery efficiency, anti-amyloid properties and anti-oxidant properties, which may serve as a novel nanomedicine for the application in the treatment of brain diseases.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Barreira Hematoencefálica/metabolismo , Materiais Revestidos Biocompatíveis/química , Ácido N-Acetilneuramínico/química , Nanopartículas/química , Oligopeptídeos/uso terapêutico , Peptídeos/uso terapêutico , Selênio/farmacologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/toxicidade , Animais , Transporte Biológico/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Microscopia Confocal , Nanopartículas/ultraestrutura , Oligopeptídeos/farmacologia , Células PC12 , Peptídeos/farmacologia , Permeabilidade , Agregados Proteicos/efeitos dos fármacos , RatosRESUMO
Human islet amyloid polypeptide (hIAPP) was found as amyloid aggregate deposits in the pancreatic islets of patients with type-2 diabetes and studies showed that insulin and its derivatives were the potent inhibitors of hIAPP aggregation. However, several emerging therapies with this goal showed limited success due to the instability and inefficiency of insulin derivatives. Nanosized graphene oxide (nGO) possesses high stability and affinity toward aromatic rings. In this study, an insulin-derived peptide, EALYLV, was stabilized by loading on nGO@PEG to inhibit aggregation and hIAPP-induced cytotoxicity. The results showed that nGO@PEG@EALYLV (abbreviated as nGO@PEG@E) can effectively inhibit the aggregation of hIAPP via electrostatic adsorption and specific binding to the active sites of hIAPP. We further evaluated the protective effect of nGO@PEG@E on INS-1 cells in the presence of hIAPP. Treatment with nGO@PEG@E could significantly elevate the viability of INS-1 cells, decrease the level of intracellular reactive oxygen species, and stabilize mitochondrial membrane potential. All the results indicated that nGO@PEG@E could inhibit the aggregation of hIAPP, which reduces its cytotoxicity.