RESUMO
BACKGROUND: Tau pathology is a hallmark of Alzheimer's disease (AD) and other tauopathies. During disease progression, abnormally phosphorylated forms of tau aggregate and accumulate into neurofibrillary tangles, leading to synapse loss, neuroinflammation, and neurodegeneration. Thus, targeting of tau pathology is expected to be a promising strategy for AD treatment. METHODS: The effect of rutin on tau aggregation was detected by thioflavin T fluorescence and transmission electron microscope imaging. The effect of rutin on tau oligomer-induced cytotoxicity was assessed by MTT assay. The effect of rutin on tau oligomer-mediated the production of IL-1ß and TNF-α in vitro was measured by ELISA. The uptake of extracellular tau by microglia was determined by immunocytochemistry. Six-month-old male Tau-P301S mice were treated with rutin or vehicle by oral administration daily for 30 days. The cognitive performance was determined using the Morris water maze test, Y-maze test, and novel object recognition test. The levels of pathological tau, gliosis, NF-kB activation, proinflammatory cytokines such as IL-1ß and TNF-α, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunolabeling, immunoblotting, or ELISA. RESULTS: We showed that rutin, a natural flavonoid glycoside, inhibited tau aggregation and tau oligomer-induced cytotoxicity, lowered the production of proinflammatory cytokines, protected neuronal morphology from toxic tau oligomers, and promoted microglial uptake of extracellular tau oligomers in vitro. When applied to Tau-P301S mouse model of tauopathy, rutin reduced pathological tau levels, regulated tau hyperphosphorylation by increasing PP2A level, suppressed gliosis and neuroinflammation by downregulating NF-kB pathway, prevented microglial synapse engulfment, and rescued synapse loss in mouse brains, resulting in a significant improvement of cognition. CONCLUSION: In combination with the previously reported therapeutic effects of rutin on Aß pathology, rutin is a promising drug candidate for AD treatment based its combinatorial targeting of tau and Aß.
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Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/prevenção & controle , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/prevenção & controle , Rutina/farmacologia , Rutina/uso terapêutico , Proteínas tau/antagonistas & inibidores , Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Técnicas de Cultura de Células , Modelos Animais de Doenças , Humanos , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/imunologia , Microglia/metabolismo , Microscopia Eletrônica de Transmissão , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/patologia , Rutina/administração & dosagem , Transdução de Sinais , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. No disease-modifying strategy to prevent or delay AD progression currently exists. Aß oligomers (AßOs), rather than monomers or fibrils, are considered as the primary neurotoxic species. Therapeutic approaches that direct against AßOs and promote Aß clearance may have great value for AD treatment. RESULTS: We here reported a multifunctional superparamagnetic iron oxide nanoparticle conjugated with Aß oligomer-specific scFv antibody W20 and class A scavenger receptor activator XD4 (W20/XD4-SPIONs). Besides the diagnostic value, W20/XD4-SPIONs retained the anti-Aß properties of W20 and XD4 by inhibiting Aß aggregation, attenuating AßO-induced cytotoxicity and increasing microglial phagocytosis of Aß. When applied to APP/PS1 mice, W20/XD4-SPIONs significantly rescued cognitive deficits and alleviated neuropathology of AD mice. CONCLUSION: These results suggest that W20/XD4-SPIONs show therapeutic benefits for AD. In combination with the early diagnostic property, W20/XD4-SPIONs present as a promising agent for early-stage AD diagnosis and intervention.
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Doença de Alzheimer/terapia , Nanopartículas Magnéticas de Óxido de Ferro/química , Receptores Depuradores/química , Anticorpos de Cadeia Única/química , Doença de Alzheimer/diagnóstico , Amiloide , Peptídeos beta-Amiloides/farmacologia , Animais , Encéfalo/patologia , Citocinas , Cinética , Masculino , Camundongos , Camundongos Transgênicos , Microglia , Fragmentos de Peptídeos/farmacologia , FagocitoseRESUMO
It has been suggested that aggregation of α-synuclein (α-syn) into oligomers leads to neurodegeneration in Parkinson's disease (PD), but intravenous immunoglobulin (IVIG) which contains antibodies against α-syn monomers and oligomers fails to treat PD mouse model. The reason may be because IVIG contains much low level of antibodies against α-syn, and of which only a small part can penetrate the blood-brain barrier, resulting in an extremely low level of effective antibodies in the brain, and limiting the beneficial effect of IVIG on PD mice. Here, we first isolated naturally occurring autoantibodies against α-syn (NAbs-α-syn) from IVIG. Our further investigation results showed that NAbs-α-syn inhibited α-syn aggregation and attenuated α-syn-induced cytotoxicity in vitro. Compared with vehicles, NAbs-α-syn significantly attenuated the memory and motor deficits by reducing the levels of soluble α-syn, total human α-syn and α-syn oligomers, decreasing the intracellular p-α-synser129 deposits and axonal pathology, inhibiting the microgliosis and astrogliosis, as well as the production of proinflammatory cytokines, increasing the levels of PSD95, synaptophysin and TH in the brain of A53T transgenic mice. These findings suggest that NAbs-α-syn overcomes the deficiency of IVIG and exhibits a promising therapeutic potential for the treatment of PD.
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Autoanticorpos/administração & dosagem , Encéfalo/imunologia , Atividade Motora , Doença de Parkinson/imunologia , Memória Espacial , alfa-Sinucleína/imunologia , Animais , Autoanticorpos/isolamento & purificação , Encéfalo/patologia , Modelos Animais de Doenças , Imunização Passiva , Imunoglobulinas Intravenosas/isolamento & purificação , Camundongos Transgênicos , Microglia/imunologia , Doença de Parkinson/patologia , Agregação Patológica de Proteínas/imunologiaRESUMO
OBJECTIVE: Periodontitis and peri-implantitis are oral infectious-inflammatory diseases that share similarities in their pathology and etiology. Our objective was to characterize the single-site subgingival and submucosal microbiomes of implant-rehabilitated, partially dentate Chinese subjects (n = 18) presenting with both periodontitis and peri-implantitis. MATERIALS AND METHODS: Subgingival/submucosal plaque samples were collected from four clinically distinct sites in each subject: peri-implantitis submucosa (DI), periodontal pocket (DT), clinically healthy (unaffected) peri-implant submucosa (HI), and clinically healthy (unaffected) subgingival sulcus (HT). The bacterial microbiota present was analyzed using Illumina MiSeq sequencing. RESULTS: Twenty-six phyla and 5,726 operational taxonomic units (OTUs, 97% sequence similarity cutoff) were identified. Firmicutes, Proteobacteria, Fusobacteria, Bacteroidetes, Actinobacteria, Synergistetes, TM7, and Spirochaetes comprised 99.6% of the total reads detected. Bacterial communities within the DI, DT, HI, and HT sites shared high levels of taxonomic similarity. Thirty-one "core species" were present in >90% sites, with Streptococcus infantis/mitis/oralis (HMT-070/HMT-071/HMT-638/HMT-677) and Fusobacterium sp. HMT-203/HMT-698 being particularly prevalent and abundant. Beta-diversity analyses (PERMANOVA test, weighted UniFrac) revealed the largest variance in the microbiota was at the subject level (46%), followed by periodontal health status (4%). Differing sets of OTUs were associated with periodontitis and peri-implantitis sites, respectively. This included putative "periodontopathogens," such as Prevotella, Porphyromonas, Tannerella, Bacteroidetes [G-5], and Treponema spp. Interaction network analysis identified several putative patterns underlying dysbiosis in periodontitis/peri-implantitis sites. CONCLUSIONS: Species (OTU) composition of the periodontal and peri-implant microbiota varied widely between subjects. The inter-subject variations in subgingival/submucosal microbiome composition outweighed differences observed between implant vs. tooth sites, or between diseased vs. healthy (unaffected) peri-implant/periodontal sites.
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Placa Dentária , Microbiota , Peri-Implantite , Periodontite , Bactérias , HumanosRESUMO
Arabidopsis CKI1 (cytokinin independent 1) is a histidine kinase protein involved in the two-component system, which can activate two-component signaling via the downstream histidine phospho-transfer proteins, playing the essential roles in central cell fate determination and development regulation in embryo sacs. However, studies on CKI1 upstream transcription regulators are still limited. In the present study, promoter activities with varying fragments were investigated, and CKI1 upstream transcription regulators were screened and identified by the yeast-one hybrid technique. Results indicated F5/R2 fragments located in the intron region showed promoter activities in embryo sacs, which is consistent with CKI1 full-length promoters. Then three tandem repeats of F5/R2 fragments were used to construct the bait expression vector, and Arabidopsis pistils were collected for cDNA library construction. Totally, 226 positive clones were screened by the yeast-one hybrid technique, 66 readable sequences were retrieved after removing sequences with low quality and redundant repeats, among which eight proteins could act as DNA-binding proteins. These results provided some important clues to study the molecular function of CKI1 in the transcription regulation network.
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Proteínas de Arabidopsis/genética , Arabidopsis/genética , Proteínas Quinases/genética , Flores/genética , Regulação da Expressão Gênica de PlantasRESUMO
Bacterial taxa belonging to the phylum Synergistetes are commonly detected within diseased periodontal niches, but are rarely found within healthy oral sites. However, as they typically constitute a minor fraction of the oral microbiota, their precise distributions and disease-associations remain to be fully established. Here, we surveyed the Synergistetes taxa present within individual periodontal/subgingival and peri-implant/submucosal sites, within Chinese subjects (n = 18) affected by both peri-implantitis and periodontitis. Four individual, clinically-distinct sites were analyzed in each patient: healthy sulcus; periodontitis lesion; healthy peri-implant space; peri-implantitis lesion. We employed a clone library-based approach, using PCR-primers that specifically amplified ca. 650bp regions of the 16S rRNA gene from oral cluster A and B Synergistetes taxa. Twenty-one of the 72 sites (from 12/18 subjects) yielded Synergistetes 16S rRNA PCR products. Sequencing of cloned amplicon libraries yielded 1338 quality-filtered 16S rRNA sequences, which were assigned to 26 Synergistetes operational taxonomic units (OTUs; oral taxon SH01-SH26) using a 98.5% identity cut-off. We identified 25 Synergistetes oral cluster A OTUs (genus Fretibacterium; corresponding to Human Oral Taxon (HOT) numbers 358, 359, 360, 361, 362, 363, 452, and 453), and one oral cluster B OTU (Pyramidobacter piscolens oral taxon SH04, HOT-357). Three OTUs predominated: Fretibacterium oral taxon SH01 (HOT-360), Fretibacterium oral taxon SH02 (HOT-452), and Fretibacterium fastidiosum oral taxon SH03 (HOT-363). The Synergistetes community compositions within the respective periodontal and peri-implant sites were variable and complex, and no statistically-significant correlations could be established. However, the detection frequency of F. fastidiosum SH03 and Fretibacterium oral taxon SH01 were both positively associated with plaque index at healthy subgingival sites. Taken together, our results show that diverse Synergistetes populations inhabit both diseased and healthy periodontal and peri-implant niches, with considerable site-to-site variations in composition occurring within the same oral cavity.
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Bactérias Anaeróbias Gram-Negativas/isolamento & purificação , Boca/microbiologia , Peri-Implantite/microbiologia , Doenças Periodontais/microbiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biofilmes , China , DNA Bacteriano/genética , Placa Dentária/microbiologia , Feminino , Bactérias Anaeróbias Gram-Negativas/genética , Humanos , Masculino , Microbiota , Pessoa de Meia-Idade , Periodonto/microbiologia , Filogenia , RNA Ribossômico 16S/genéticaRESUMO
The elderly frequently present impaired blood-brain barrier which is closely associated with various neurodegenerative diseases. However, how the albumin, the most abundant protein in the plasma, leaking through the disrupted BBB, contributes to the neuropathology remains poorly understood. We here demonstrated that mouse serum albumin-activated microglia induced astrocytes to A1 phenotype to remarkably increase levels of Elovl1, an astrocytic synthase for very long-chain saturated fatty acids, significantly promoting VLSFAs secretion and causing neuronal lippoapoptosis through endoplasmic reticulum stress response pathway. Moreover, MSA-activated microglia triggered remarkable tau phosphorylation at multiple sites through NLRP3 inflammasome pathway. Intracerebroventricular injection of MSA into the brains of C57BL/6J mice to a similar concentration as in patient brains induced neuronal apoptosis, neuroinflammation, increased tau phosphorylation, and decreased the spatial learning and memory abilities, while Elovl1 knockdown significantly prevented the deleterious effect of MSA. Overall, our study here revealed that MSA induced tau phosphorylation and neuron apoptosis based on MSA-activated microglia and astrocytes, respectively, showing the critical roles of MSA in initiating the occurrence of tauopathies and cognitive decline, and providing potential therapeutic targets for MSA-induced neuropathology in multiple neurodegenerative disorders.
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Apoptose , Camundongos Endogâmicos C57BL , Neurônios , Albumina Sérica , Tauopatias , Animais , Humanos , Masculino , Camundongos , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Astrócitos/metabolismo , Astrócitos/patologia , Astrócitos/efeitos dos fármacos , Elongases de Ácidos Graxos/metabolismo , Microglia/metabolismo , Microglia/efeitos dos fármacos , Microglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Neurônios/efeitos dos fármacos , Albumina Sérica/metabolismo , Albumina Sérica/farmacologia , Proteínas tau/metabolismo , Tauopatias/patologia , Tauopatias/metabolismoRESUMO
BACKGROUND: Deoxyribonuclease 2 (DNase II) plays a key role in clearing cytoplasmic double-stranded DNA (dsDNA). Deficiency of DNase II leads to DNA accumulation in the cytoplasm. Persistent dsDNA in neurons is an early pathological hallmark of senescence and neurodegenerative diseases including Alzheimer's disease (AD). However, it is not clear how DNase II and neuronal cytoplasmic dsDNA influence neuropathogenesis. Tau hyperphosphorylation is a key factor for the pathogenesis of AD. The effect of DNase II and neuronal cytoplasmic dsDNA on neuronal tau hyperphosphorylation remains unclarified. METHODS: The levels of neuronal DNase II and dsDNA in WT and Tau-P301S mice of different ages were measured by immunohistochemistry and immunolabeling, and the levels of DNase II in the plasma of AD patients were measured by ELISA. To investigate the impact of DNase II on tauopathy, the levels of phosphorylated tau, phosphokinase, phosphatase, synaptic proteins, gliosis and proinflammatory cytokines in the brains of neuronal DNase II-deficient WT mice, neuronal DNase II-deficient Tau-P301S mice and neuronal DNase II-overexpressing Tau-P301S mice were evaluated by immunolabeling, immunoblotting or ELISA. Cognitive performance was determined using the Morris water maze test, Y-maze test, novel object recognition test and open field test. RESULTS: The levels of DNase II were significantly decreased in the brains and the plasma of AD patients. DNase II also decreased age-dependently in the neurons of WT and Tau-P301S mice, along with increased dsDNA accumulation in the cytoplasm. The DNA accumulation induced by neuronal DNase II deficiency drove tau phosphorylation by upregulating cyclin-dependent-like kinase-5 (CDK5) and calcium/calmodulin activated protein kinase II (CaMKII) and downregulating phosphatase protein phosphatase 2A (PP2A). Moreover, DNase II knockdown induced and significantly exacerbated neuron loss, neuroinflammation and cognitive deficits in WT and Tau-P301S mice, respectively, while overexpression of neuronal DNase II exhibited therapeutic benefits. CONCLUSIONS: DNase II deficiency and cytoplasmic dsDNA accumulation can initiate tau phosphorylation, suggesting DNase II as a potential therapeutic target for tau-associated disorders.
Assuntos
Doença de Alzheimer , Endodesoxirribonucleases , Neurônios , Proteínas tau , Animais , Proteínas tau/metabolismo , Proteínas tau/genética , Fosforilação , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Doença de Alzheimer/patologia , Endodesoxirribonucleases/genética , Endodesoxirribonucleases/deficiência , Endodesoxirribonucleases/metabolismo , Camundongos Transgênicos , DNA/genética , Masculino , Feminino , Encéfalo/metabolismo , Encéfalo/patologia , Camundongos Endogâmicos C57BLRESUMO
Passive immunotherapy is one of the most promising interventions for Alzheimer's disease (AD). However, almost all immune-modulating strategies fail in clinical trials with unclear causes although they attenuate neuropathology and cognitive deficits in AD animal models. Here, we showed that Aß-targeting antibodies including their lgG1 and lgG4 subtypes induced microglial engulfment of neuronal synapses by activating CR3 or FcγRIIb via the complex of Aß, antibody, and complement. Notably, anti-Aß antibodies without Fc fragment, or with blockage of CR3 or FcγRIIb, did not exert these adverse effects. Consistently, Aß-targeting antibodies, but not their Fab fragments, significantly induced acute microglial synapse removal and rapidly exacerbated cognitive deficits and neuroinflammation in APP/PS1 mice post-treatment, whereas the memory impairments in mice were gradually rescued thereafter. Since the recovery rate of synapses in humans is much lower than that in mice, our findings may clarify the variances in the preclinical and clinical studies assessing AD immunotherapies. Therefore, Aß-targeting antibodies lack of Fc fragment, or with reduced Fc effector function, may not induce microglial synaptic pruning, providing a safer and more efficient therapeutic alternative for passive immunotherapy for AD.
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Doença de Alzheimer , Disfunção Cognitiva , Camundongos , Humanos , Animais , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Disfunção Cognitiva/patologia , Sinapses/patologia , Anticorpos/uso terapêutico , CogniçãoRESUMO
Abscisic acid (ABA) is a phytohormone that plays critical roles in numerous developmental stages as well as in adaptive responses to biotic and abiotic stresses. Recent breakthroughs in the field of ABA signaling have indicated that there are three major components, PYR/PYL/RCAR (an ABA receptor), type 2C protein phosphates (PP2C, a negative regulator), and SNF1-related protein kinase 2 (SnRK2, a positive regulator). Further results show that these three proteins construct a double negative regulatory system, PYR/PYL/RCAR-| PP2C-| SnRK2, to regulate ABA signal responses in plant cells. Moreover, the combination patterns of these components in vivo are restricted by spatio-temporal and biochemical determinants and the combinational variation in the ABA signalosome is specific to different ABA signal responses. This review summarizes recent advances of study on the molecular basis and regulatory mechanism of PYR/PYL/RCAR-mediated ABA signaling pathway and PYR/PYL/RCAR-PP2C-SnRK2 complex-mediated ABA signal regulation network in plants. The perspectives related to this study are proposed.
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Ácido Abscísico/fisiologia , Proteínas de Plantas/fisiologia , Transdução de Sinais/fisiologia , Sequência de Aminoácidos , Dados de Sequência Molecular , Fosfoproteínas Fosfatases/fisiologia , Proteína Fosfatase 2CRESUMO
Genome-wide association studies (GWAS) have identified a large number of schizophrenia risk variants, and most of them are mapped to noncoding regions. By leveraging multiple joint-tissue gene expression data and GWAS data, we herein performed a transcriptome-wide association study (TWAS) and Mendelian randomization (MR) analysis and identified 144 genes whose mRNA levels were related to genetic risk of schizophrenia. Most of these genes exhibited diametrically opposite trends of expression in prenatal and postnatal brain tissues, despite that their expression levels in dorsolateral prefrontal cortex (DLPFC) tissues did not significantly differ between schizophrenics and healthy controls. We then found significant enrichment of these genes in dopamine-related pathways that were repeatedly implicated in schizophrenia pathogenesis and in the action of antipsychotic drugs. Gene expression analysis using single cell RNA-sequencing (scRNA-seq) data of mid-gestation fetal brains further revealed enrichment of these genes in glutamatergic excitatory neurons and cycling progenitors. These lines of evidence, in consistency with previous findings, confirmed the polygenic nature of schizophrenia and highlighted involvement of early neurodevelopment aberrations in this disorder. Further investigations using advanced algorithms in both bulk brain tissues and in single cells and at different developmental stages are necessary to characterize transcriptomic features of schizophrenia pathogenesis along brain development.
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Córtex Pré-Frontal Dorsolateral , Predisposição Genética para Doença , Esquizofrenia/genética , Transcriptoma , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Metabolic syndrome (MetS) is a major risk factor for cardiovascular disease and negatively affecting the prognosis of patients with ST elevation myocardial infarction (STEMI). Macrophage migration inhibitory factor (MIF) is a multipotent cytokine involved in various cardiovascular and inflammatory diseases. In this prospective study, we investigate the value of MIF in the long-term prognosis of STEMI combined with MetS after emergency PCI. Circulating MIF levels were measured at admission, and major adverse cardiovascular and cerebrovascular events (MACCE) were monitored during the follow-up period of 4.9 (3.9-5.8) years. MACCE occurred in 92 patients (22.9%), which was significantly higher in MetS (69/255, 27.1%) than in the non-MS subgroup (23/146, 15.8%, P < 0.05). Patients with MetS developed MACCE had the highest admission MIF level. Kaplan-Meier survival analysis using the cutoff value of admission MIF (143 ng/ml) showed that patients with a higher MIF level had a greater incidence of MACCE than those with lower MIF levels in both the MetS (P < 0.0001) and non-MetS groups (P = 0.016). After adjustment for clinical variables, the value of MIF ≥ 143 ng/ml still had the predictive power for the MetS group [HR 9.56, 95% CI (5.397-16.944),P < 0.001]; nevertheless, it was not the case in the non-MetS group. Our findings indicated that MetS is a critical risk factor for adverse clinical outcomes in patients with STEMI, and a high admission MIF level has predictive power for the long-term MACCE, which is superior in STEMI patients with MetS and better than other traditional predictors.
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OBJECTIVE: To investigate whether genomic instability (GI)-derived long non-coding RNAs (lncRNAs) have a prognostic impact on the patients with endometrial cancer. MATERIAL AND METHODS: Patients with Uterine Corpus Endometrial Carcinoma (UCEC) were selected from The Cancer Genome Atlas (TCGA) database. Systematic bioinformatics analyses were performed, including Pearson correlations, GO and KEGG enrichment analysis, bivariate and multiple logistic regression analysis, and Kaplan-Meier (KM) method. RESULTS: A total of 552 UCEC samples were included in the study. The differentially expressed lncRNAs (DELs) were identified, including 79 down-regulated lncRNAs and 31 up-regulated lncRNAs. Bivariate logistic regression analysis showed that 19 GI-derived lncRNAs were prognostic factors. By further multivariate logistic regression analysis, AC005256.1 (estimated coefficient = -0.474), AC026336.3 (estimated coefficient = -0.030), AL161618.1 (estimated coefficient = -1.661), and BX322234.1 (estimated coefficient = 1.511) were used to construct a prognostic risk model. In the train set and test set, the risk model was shown to have both a high prognostic and a diagnostic value. CONCLUSION: We developed a novel GI-derived 4-lncRNA signature for the diagnosis and prognosis of patients with endometrial cancer. These findings offered a novel perspective in the clinical management of endometrial cancer.
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Carcinoma Endometrioide/genética , Neoplasias do Endométrio/genética , Instabilidade Genômica , RNA Longo não Codificante/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/patologia , Bases de Dados Genéticas , Intervalo Livre de Doença , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Genoma , Humanos , Estimativa de Kaplan-Meier , Prognóstico , Fatores de RiscoRESUMO
Insulin resistance (IR) plays a critical role in cardiovascular diseases and metabolic diseases. In this study, we identified the downregulation of DMRT2 in adipose tissues from insulin-resistant subjects through bioinformatics analysis and in an insulin-resistant mouse model through experimental analysis. DMRT2 overexpression significantly attenuated HDF-induced insulin resistance and inflammation in mice. Moreover, in control and insulin-resistant differentiated mouse 3T3-L1 adipocytes, DMRT2 overexpression attenuated but DMRT2 knockdown enhanced the insulin resistance of 3T3-L1 adipocytes. DMRT2 interacted with FXR and positively regulated FXR level and transcription activity. In both control and insulin-resistant differentiated mouse 3T3-L1 adipocytes, FXR knockdown enhanced the insulin resistance and attenuated the effects of DMRT2 overexpression upon 3T3-L1 adipocyte insulin resistance. In conclusion, we identify the downregulation of DMRT2 in the insulin-resistant mouse model and cell model. DMRT2 interacts with FXR and improves insulin resistance in adipocytes.
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Resistência à Insulina , Células 3T3-L1 , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Animais , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Humanos , Insulina/metabolismo , Resistência à Insulina/genética , Camundongos , Fatores de Transcrição/metabolismoRESUMO
Background: Obesity is an independent risk factor for cardiovascular disease. We investigated whether and to what extent visceral obesity-related indices were associated with coronary collateralization (CC) in chronic total occlusion (CTO) patients. Methods: This retrospective cohort study involved 1,008 consecutive patients with CTO who underwent CTO-percutaneous coronary artery intervention (PCI). CC was graded according to the Rentrop scoring system. Data on demographic and clinical characteristics were collected by cardiovascular doctors. Logistic regression, receiver operating characteristic (ROC) curve and Kaplan-Meier analyses were performed to assess the predictive value of visceral obesity-related indices for CC. Results: Overall, 1,008 inpatients were assigned to the poor CC group (n = 592) and good CC group (n = 416). In multivariate-adjusted logistic regression analyses, all visceral obesity-related indices (P-value < 0.001) were significantly associated with CC. After ROC analysis and the Delong test, the Chinese visceral adiposity index (CVAI) had the largest area under the curve (AUC) of 0.741 (0.711-0.771). Further analysis revealed that CVAI quartile remained a risk factor for poor CC in all groups, CVAI was associated with a 1.018-fold higher risk of poor CC (OR = 1.018, 95% CI: 1.014-1.021, P < 0.001). Individuals in the top CVAI quartile group had the highest risk of poor CC (OR = 10.657, 95% CI: 6.492-17.493, P < 0.001). Subgroup analyses showed similar results, and CVAI quartile remained a risk factor for poor CC. Moreover, increased CVAI predicted poor prognosis in CTO patients. Conclusion: In summary, this study indicated that all the increased visceral obesity-related indices were significantly associated with increased poor CC risk. After adjusting for potential risks, CVAI had the best performance for estimating CC and predicting prognosis in CTO patients.
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Although vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are under development, the antigen epitopes on the virus and their immunogenicity are poorly understood. Here, we simulate the 3D structures and predict the B cell epitopes on the spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins of SARS-CoV-2 using structure-based approaches and validate epitope immunogenicity by immunizing mice. Almost all 33 predicted epitopes effectively induce antibody production, six of these are immunodominant epitopes in individuals, and 23 are conserved within SARS-CoV-2, SARS-CoV, and bat coronavirus RaTG13. We find that the immunodominant epitopes of individuals with domestic (China) SARS-CoV-2 are different from those of individuals with imported (Europe) SARS-CoV-2, which may be caused by mutations on the S (G614D) and N proteins. Importantly, we find several epitopes on the S protein that elicit neutralizing antibodies against D614 and G614 SARS-CoV-2, which can contribute to vaccine design against coronaviruses.
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Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Epitopos de Linfócito B/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Proteínas da Matriz Viral/imunologia , Proteínas Viroporinas/imunologia , Adolescente , Adulto , Idoso , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , COVID-19/imunologia , COVID-19/terapia , Vacinas contra COVID-19/imunologia , Criança , Epitopos de Linfócito B/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. Diagnosing AD before symptoms arise will facilitate earlier intervention. The early diagnostic approaches are thus urgently needed. METHODS: The multifunctional nanoparticles W20/XD4-SPIONs were constructed by the conjugation of oligomer-specific scFv antibody W20 and class A scavenger receptor (SR-A) activator XD4 onto superparamagnetic iron oxide nanoparticles (SPIONs). The SPIONs' stability and uniformity in size were measured by dynamic light scattering and transmission electron microscopy. The ability of W20/XD4-SPIONs for recognizing Aß oligomers (AßOs) and promoting AßOs phagocytosis was assessed by immunocytochemistry and flow cytometry analysis. The blood-brain barrier permeability of W20/XD4-SPIONs was determined by a co-culture transwell model. The in vivo probe distribution of W20/XD4-SPIONs in AD mouse brains was detected by magnetic resonance imaging (MRI). RESULTS: W20/XD4-SPIONs, as an AßOs-targeted molecular MRI contrast probe, readily reached pathological AßOs regions in brains and distinguished AD transgenic mice from WT controls. W20/XD4-SPIONs retained the property of XD4 for SR-A activation and significantly promoted microglial phagocytosis of AßOs. Moreover, W20/XD4-SPIONs exhibited the properties of good biocompatibility, high stability and low cytotoxicity. CONCLUSION: Compared with W20-SPIONs or XD4-SPIONs, W20/XD4-SPIONs show the highest efficiency for AßOs-targeting and significantly enhance AßOs uptake by microglia. As a molecular probe, W20/XD4-SPIONs also specifically and sensitively bind to AßOs in AD brains to provide an MRI signal, demonstrating that W20/XD4-SPIONs are promising diagnostic agents for early-stage AD. Due to the beneficial effect of W20 and XD4 on neuropathology, W20/XD4-SPIONs may also have therapeutic potential for AD .
Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/imunologia , Imunoconjugados/química , Nanopartículas de Magnetita/química , Receptores Depuradores/metabolismo , Anticorpos de Cadeia Única/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Especificidade de Anticorpos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Diagnóstico Precoce , Imunoconjugados/farmacologia , Imageamento por Ressonância Magnética , Camundongos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/patologia , Nanopartículas Multifuncionais/química , Fagocitose/efeitos dos fármacos , Anticorpos de Cadeia Única/imunologiaRESUMO
BACKGROUND AND PURPOSE: Immunotherapeutic intervention is one of the most promising strategies for the prevention and treatment of Alzheimer's disease (AD). Although they showed great success in AD mouse models, the clinical trials of many immune approaches failed due to low efficacy and safety. Thus, an animal model which can show the potential side effects of vaccines or antibodies is urgently needed. In this study, we generated EAE/AD mice by crossing APP/PS1 mice with experimental autoimmune encephalomyelitis (EAE) mice. We then investigated the efficacy and safety of two vaccines: the immunogens of which were Aß1-42 aggregates (Aß42 vaccine) and an oligomer-specific conformational epitope (AOE1 vaccine), respectively. EXPERIMENTAL APPROACH: EAE/AD mice were immunized with the Aß42 vaccine or AOE1 vaccine five times at biweekly intervals. After the final immunization, cognitive function was evaluated by the Morris water maze, Y maze, and object recognition tests. Neuropathological changes in the mouse brains were analysed by immunohistochemistry and ELISA. KEY RESULTS: In contrast to previous findings in conventional AD animal models, Aß42 immunization promoted neuroinflammation, enhanced Aß levels and plaque burden, and failed to restore cognitive deficits in EAE/AD mice. By contrast, AOE1 immunization dramatically attenuated neuroinflammation, reduced Aß levels, and improved cognitive performance in EAE/AD mice. CONCLUSION AND IMPLICATIONS: These results suggest that the EAE/AD mouse model can exhibit the potential side effects of AD immune approaches that conventional AD animal models fail to display. Furthermore, strategies specifically targeting Aß oligomers may be safe and show clinical benefit for AD treatment.
Assuntos
Doença de Alzheimer , Encefalomielite Autoimune Experimental , Vacinas , Sequência de Aminoácidos , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide , Animais , Cognição , Modelos Animais de Doenças , Epitopos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fragmentos de PeptídeosRESUMO
Huntington's disease (HD) is a genetic neurodegenerative disorder caused by a highly polymorphic CAG trinucleotide repeat expansion encoding an extended polyglutamine (polyQ) tract at the N-terminus of huntingtin protein (HTT). The polyQ tract promotes the formation of toxic oligomers and aggregates of HTT, which leads to neuronal dysfunction and death. Therapies to lower mutant HTT (mHTT) and its aggregates appear to be the most promising strategies. Ellagic acid (EA) has been marketed as a dietary supplement with various claimed benefits and neuroprotective effects on several neurodegenerative disorders, while its effect on mHTT pathology is still unknown. Here we reported that EA significantly attenuated motor and cognitive deficits in R6/2 mice. Moreover, EA significantly lowered mHTT levels, reduced neuroinflammation, rescued synapse loss, and decreased oxidative stress in R6/2 mouse brains. These findings indicated that EA has promising therapeutic potential for HD treatment.
Assuntos
Disfunção Cognitiva/tratamento farmacológico , Ácido Elágico/farmacologia , Proteína Huntingtina/efeitos dos fármacos , Doença de Huntington/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Animais , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Feminino , Proteína Huntingtina/genética , Doença de Huntington/metabolismo , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacosRESUMO
In the study the changes of scalp potential and cardiac autonomic nervous system during volitional control of heart beat are explored with the wavelet packet parameters and approximate entropy (ApEn) of Electroencephalogram (EEG) and heart rate variability. The results show that volition can control heart beat and the changes of brain activity are earlier than that of autonomic activity. But its control of heart beat is very different from the motor nervous system because different cortical positions are respectively concerned during the quick and slow control of heart beat. The pre-central areas of brain are correlated with parasympathetic activity by which HR is controlled to slow down. The post-central areas of brain are correlated with sympathetic activity by which HR is controlled to accelerate.