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Specification of Sox2+ proneurosensory progenitors within otic ectoderm is a prerequisite for the production of sensory cells and neurons for hearing. However, the underlying molecular mechanisms driving this lineage specification remain unknown. Here, we show that the Brg1-based SWI/SNF chromatin-remodeling complex interacts with the neurosensory-specific transcriptional regulators Eya1/Six1 to induce Sox2 expression and promote proneurosensory-lineage specification. Ablation of the ATPase-subunit Brg1 or both Eya1/Six1 results in loss of Sox2 expression and lack of neurosensory identity, leading to abnormal apoptosis within the otic ectoderm. Brg1 binds to two of three distal 3' Sox2 enhancers occupied by Six1, and Brg1-binding to these regions depends on Eya1-Six1 activity. We demonstrate that the activity of these Sox2 enhancers in otic neurosensory cells specifically depends on binding to Six1. Furthermore, genome-wide and transcriptome profiling indicate that Brg1 may suppress apoptotic factor Map3k5 to inhibit apoptosis. Together, our findings reveal an essential role for Brg1, its downstream pathways, and their interactions with Six1/Eya1 in promoting proneurosensory fate induction in the otic ectoderm and subsequent neuronal lineage commitment and survival of otic cells.
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Montagem e Desmontagem da Cromatina , Cromatina/genética , Cromatina/metabolismo , Ectoderma/embriologia , Ectoderma/metabolismo , Diferenciação Celular/genética , Linhagem da Célula/genética , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismoRESUMO
The formation and maintenance of synapses are precisely regulated, and the misregulation often leads to neurodevelopmental or neurodegenerative disorders. Besides intrinsic genetically encoded signaling pathways, synaptic structure and function are also regulated by extrinsic factors, such as nutrients. O-GlcNAc transferase (OGT), a nutrient sensor, is abundant in the nervous system and required for synaptic plasticity, learning, and memory. However, whether OGT is involved in synaptic development and the mechanism underlying the process are largely unknown. In this study, we found that OGT-1, the OGT homolog in C. elegans, regulates the presynaptic assembly in AIY interneurons. The insulin receptor DAF-2 acts upstream of OGT-1 to promote the presynaptic assembly by positively regulating the expression of ogt-1. This insulin-OGT-1 axis functions most likely by regulating neuronal activity. In this study, we elucidated a novel mechanism for synaptic development, and provided a potential link between synaptic development and insulin-related neurological disorders.
Assuntos
Caenorhabditis elegans , Insulina , Animais , Insulina/metabolismo , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Transdução de SinaisRESUMO
Exploiting ingenious photoelectrodes and innovative signal amplification strategies has the potential to achieve high sensitivity in self-powered cathodic photoelectrochemical (PEC) analysis. In this work, a novel self-powered PEC sensing platform was constructed by integrating a synergistic signal amplification of an ingenious photocathode with a high light-harvesting photoanode. In the dual photoelectrode-based PEC system, the amplified photocurrent signals were induced by a synergistic enhancement: (1) the photocurrent of the BiOBr photocathode was improved by the incorporation of nitrogen-doped graphene; (2) the photocurrent of the self-powered sensor was activated by the high-light-harvesting Bi2S3-C3N4 photoanode. Subsequently, the rational mechanism for synergistic signal amplification was investigated. For the construction of the sensing interface, an aptamer was introduced as the recognition element to specifically capture the streptomycin (STR) target. Under optimal conditions, the constructed self-powered aptasensor has the merits of good linear range (1 × 10-11 to 5 × 10-7 M), acceptable limit of detection (1.18 × 10-12 M), and excellent stability and selectivity for STR detection. Additionally, the proposed self-powered aptasensor showed acceptable accuracy for the detection of STR in water. Hopefully, this might stimulate more interest in designing and constructing novel platforms for exquisite photocathodic monitoring of various contaminants in the environment.
Assuntos
Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , Grafite , Técnicas Eletroquímicas , Eletrodos , Limite de DetecçãoRESUMO
The development of multifunctional materials for the synchronous detection and removal of mercury ions (Hg2+) is in high demand. Although a few multifunctional materials as a fluorescent indicator and adsorbent have achieved this aim, the feedback of their removal efficiency still depends on other methods. Herein, magnetic Fe3O4 nanoparticles (MNPs) and 6-aza-2-thiothymine-protected gold nanoclusters (ATT-AuNCs) were rationally assembled into a zeolitic imidazolate framework 8 (ZIF-8) structure via a one-pot method. The coordination assembly of ATT-AuNCs and ZIF-8 not only strengthened the aurophilic interactions of adjacent ATT-AuNCs but also induced the restriction of intramolecular motion of ATT with a six-membered heterocyclic structure. As a consequence, the fluorescence (FL) quantum yield of MNPs/ATT-AuNCs@ZIF-8 was 12.5-fold higher than that of pristine ATT-AuNCs. Benefiting from the enhanced FL emission, MNPs/ATT-AuNCs@ZIF-8 showed improved sensitivity for Hg2+ detection and therefore could evaluate the removal efficiency via FL detection, without relying on another detection method. Additionally, the nanocomposite also displayed a satisfactory removal capability for Hg2+, including a short capture time (20 min), a high removal efficiency (>96.9%), and excellent reusability (10 cycles). This work provides an approach for customizing functional nanocomposites to concurrently detect and remove Hg2+ with superior performance, especially for high detection sensitivity.
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BACKGROUND: PER2 gene methylation is closely related to the occurrence and progress of some cancers, but there is no method to quantitatively detect PER2 methylation in conventional laboratories. So, we established a TaqMan real-time fluorescence quantitative methylation specific PCR (TaqMan real-time FQ-MSP) assay and use it for quantitative detection of PER2 methylation in leukemia patients. METHODS: According to the PER2 sequence searched by GenBank, a CpG sequence enrichment region of the PER2 gene promoter was selected, and the methylated and unmethylated target sequences were designed according to the law of bisulfite conversion of DNA to construct PER2 methylation positive and negative reference materials. Specific primers and probe were designed. The reference materials were continuously diluted into gradient samples by tenfold ratio to evaluate the analytical sensitivity, specificity, accuracy and reproducibility of the method, and the analytical sensitivity of TaqMan real-time FQ-MSP assay was compared with that of the conventional MSP assay. At the same time, the new-established TaqMan real-time FQ-MSP assay and the conventional MSP assay were used to detect the PER2 methylation level of 81 patients with leukemia, and the samples with inconsistent detection results of the two assays were sent to pyromethylation sequencing to evaluate the clinical detection performance. RESULTS: The minimum detection limit of TaqMan real-time FQ-MSP assay for detecting PER2 methylation level established in this study was 6 copies/uL, and the coefficient of variation(CV) of intra-assay and inter-assay was less than 3%. Compared with the conventional MSP assay, it has higher analytical sensitivity. For the samples with inconsistent detection results, the results of pyrosequencing and TaqMan real-time FQ-MSP assay are consistent. CONCLUSION: TaqMan real-time FQ-MSP assay of PER2 methylation established in this study has high detection performance and can be used for the detection of clinical samples.
Assuntos
Metilação de DNA , Proteínas Circadianas Period , Reação em Cadeia da Polimerase em Tempo Real , Metilação de DNA/genética , Humanos , Regiões Promotoras Genéticas/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Eya1 is a critical regulator of nephron progenitor cell specification and interacts with Six2 to promote NPC self-renewal. Haploinsufficiency of these genes causes kidney hypoplasia. However, how the Eya1-centered network operates remains unknown. METHODS: We engineered a 2×HA-3×Flag-Eya1 knock-in mouse line and performed coimmunoprecipitation with anti-HA or -Flag to precipitate the multitagged-Eya1 and its associated proteins. Loss-of-function, transcriptome profiling, and genome-wide binding analyses for Eya1's interacting chromatin-remodeling ATPase Brg1 were carried out. We assayed the activity of the cis-regulatory elements co-occupied by Brg1/Six2 in vivo. RESULTS: Eya1 and Six2 interact with the Brg1-based SWI/SNF complex during kidney development. Knockout of Brg1 results in failure of metanephric mesenchyme formation and depletion of nephron progenitors, which has been linked to loss of Eya1 expression. Transcriptional profiling shows conspicuous downregulation of important regulators for nephrogenesis in Brg1-deficient cells, including Lin28, Pbx1, and Dchs1-Fat4 signaling, but upregulation of podocyte lineage, oncogenic, and cell death-inducing genes, many of which Brg1 targets. Genome-wide binding analysis identifies Brg1 occupancy to a distal enhancer of Eya1 that drives nephron progenitor-specific expression. We demonstrate that Brg1 enrichment to two distal intronic enhancers of Pbx1 and a proximal promoter region of Mycn requires Six2 activity and that these Brg1/Six2-bound enhancers govern nephron progenitor-specific expression in response to Six2 activity. CONCLUSIONS: Our results reveal an essential role for Brg1, its downstream pathways, and its interaction with Eya1-Six2 in mediating the fine balance among the self-renewal, differentiation, and survival of nephron progenitors.
Assuntos
Montagem e Desmontagem da Cromatina , DNA Helicases/fisiologia , Elementos Facilitadores Genéticos , Proteínas de Homeodomínio/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Néfrons/citologia , Proteínas Nucleares/metabolismo , Proteínas Nucleares/fisiologia , Proteínas Tirosina Fosfatases/metabolismo , Células-Tronco/citologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/fisiologia , Animais , Sequência de Bases , Diferenciação Celular , Autorrenovação Celular , Imunoprecipitação da Cromatina , Técnicas de Introdução de Genes , Células HEK293 , Proteínas de Homeodomínio/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Rim/embriologia , Mesoderma/citologia , Mesoderma/metabolismo , Camundongos , Complexos Multiproteicos , Proteínas Nucleares/genética , Mapeamento de Interação de Proteínas , Proteínas Tirosina Fosfatases/genética , Células-Tronco/metabolismo , Fatores de Transcrição/genética , TranscriptomaRESUMO
Currently, researchers use modern analytical techniques in a unique perspective of physical pharmacy to analyze the phase composition of traditional Chinese medicine (TCM) and have discovered that natural nanoparticles commonly exist in decoctions. This study aims to isolate and characterize the structure and composition of nanoparticles in Naoluo Xintong (NLXT) and investigate whether the brain protection effect of NLXT is closely related to NLXT-Nanoparticles (NLXT-NPs). Firstly, the dialysis-centrifugation method was used to separate the nanoparticles and then their size distribution, potential, and morphology were characterized. In addition, infrared spectroscopy and ultra-high performance liquid chromatography-quadrupole-time of flight-mass spectrometer (UPLC-Q-TOF-MS) technology were used to analyze the composition of nanoparticles. As for the pharmacodynamic experiment, Sprague Dawley (SD) rats were randomly divided into sham, Middle cerebral artery occlusion (MCAO) model, NLXT, NLXT with nanoparticles removing (NLXT-RN), NLXT-RN+Nanoparticles (NLXT-RN+NPs), and NLXT-NPs groups. After administration, the neurological function, histopathological changes, oxidative stress, and apoptosis level were measured. Our research showed that NLXT-NPs are mainly composed of polysaccharides, proteins, and saponins, with typical characteristics of two hundred-nanometer size and negatively loaded. NLXT can improve nerve function, reduce oxidative stress, and inhibit cell apoptosis. However, removing nanoparticles can significantly reduce the brain-protective effect of NLXT, which indicates that NLXT-NPs play an essential role in the efficacy of NLXT.
Assuntos
Diálise RenalRESUMO
BACKGROUND: The high incidence and mortality of lung cancer have seriously affected human life and health. Nivolumab is a monoclonal antibody that can inhibit programmed death 1 (PD-1) and Ipilimumab is a monoclonal antibody against CTLA-4(cytotoxic T lymphocyte-associated antigen 4), both of which can prevent the immune escape of tumor cells. Our goal was to synthesize evidence from published randomized controlled trials involving the safety and efficacy of either Nivolumab alone or in combination for the treatment of unresectable lung cancer. METHODS: We searched the following electronic databases: PubMed, Embase, and Cochrane libraries, and screened the retrieved records for eligibility. We used the Stata16 software for the analyses. The results of the analysis are expressed as hazard ratios (HRs) or risk ratios (RRs) and their corresponding 95% confidence intervals (CI). RESULTS: The final analysis included seven trials involving 3817 patients. Among patients with advanced lung cancer, patients using immunotherapy had better overall survival (OS), progression-free survival (PFS), and an objective response rate (ORR) than patients receiving chemotherapy. The HR of Nivolumab monotherapy or combination therapy with OS was compared with that of chemotherapy (HR: 0.73, 95% CI 0.64-0.83; HR: 0.67, 95% CI 0.55-0.81), and the HR of PFS was (HR: 0.81, 95% CI 0.69-0.94; HR: 0.67, 95% CI 0.55-0.82). CONCLUSIONS: Immunotherapy has been shown to have more clinically meaningful survival benefits for patients with lung cancer, whether monotherapy or combination immunotherapy. CRD42020213440.
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Circadian rhythm is a periodic change of organism according to the law of external environment, which is manifested in metabolism, cell proliferation, physiology and behavior. In recent years, the role of circadian genes in the occurrence and progression of hematological malignancies have been continuously demonstrated. PER2 is the core component of the circadian rhythm playing an important role in regulating the circadian rhythm of the biological clock. This review summarizes the research progress of PER2 in hematological malignancies, especially leukemia, in order to better understand its role in hematological malignancies, and provide new ideas for clinical diagnosis and treatment.
Assuntos
Proliferação de Células , Ritmo Circadiano , Neoplasias Hematológicas/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Circadianas Period/metabolismo , Animais , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Proteínas de Neoplasias/genética , Proteínas Circadianas Period/genéticaRESUMO
We aimed to investigate how estrogen (ES) is implicated in the pathogenesis of pulmonary arterial hypertension (PAH) potentially by reducing the extent of vascular remodeling in females. HE assay, Western Blot, IHC, and real-time PCR were carried out to observe the role of ES in regulating miR-133a expression and the levels of MYOSLID, SRF, CTGF, and vascular remodeling in rats. In addition, MTT assay and flow cytometry were utilized to observe how ES affects cell proliferation and cell cycle in PAH. Moreover, luciferase assays were carried out to clarity the regulatory relationship between miR-133a and its downstream targets. ES administration relieved the deregulation of miR-133a, MYOSLID, SRF, and CTGF in PAH rats. In addition, ES also reduced the thickening of blood vessels in PAH rats. ES could activate miR-133a promoter and arrest the cells in the G0/G1 cycle, thus dose-dependently suppressing the proliferation of cells. In addition, the presence of ES, MYOSLID siRNA, or miR-133a precursor all altered the expression of MYOSLID, SP1, SRF, and CTGF, thus establishing a molecular signaling pathway among these factors. Furthermore, miR-133a could bind to SP1, MYOSLID, SRF, and CTGF to reduce their expression. Moreover, SRF was proved to function as an activator of miR-133a promoter. Two feedback loops were established in this study: a negative feedback loop between SRF and miR-133a, and a positive loop among miR-133a/SRF/MLK1/MYOSLID. ES treatment upregulates miR-133a expression and reduces the incidence of PAH and vascular remodeling.
Assuntos
Estrogênios/farmacologia , Hipertensão Pulmonar/prevenção & controle , MicroRNAs/metabolismo , Transdução de Sinais , Animais , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Proliferação de Células , Células Cultivadas , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Estrogênios/uso terapêutico , Feminino , Hipertensão Pulmonar/tratamento farmacológico , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Ratos , Ratos Wistar , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Remodelação Vascular/efeitos dos fármacosRESUMO
MicroRNAs (miRNAs) are important regulators of mouse brain development. However, their precise roles in this context remain to be elucidated. Through screening of expression profiles from a miRNA microarray and experimental analysis, we show here that miR-15b controls several aspects of cortical neurogenesis. miR-15b inhibits cortical neural progenitor cell (NPC) proliferation and promotes cell-cycle exit and neuronal differentiation. Additionally, miR-15b expression decreases the number of apical progenitors and increases basal progenitors in the VZ/SVZ. We also show that miR-15b binds to the 3' UTR of TET3, which plays crucial roles during embryonic development by enhancing DNA demethylation. TET3 promotes cyclin D1 expression, and miR-15b reduces TET3 expression and 5hmC levels. Notably, TET3 expression rescues miR-15b-induced impaired NPC proliferation and increased cell-cycle exit in vivo. Our results not only reveal a link between miRNAs, TET, and DNA demethylation but also demonstrate critical roles for miR-15b and TET3 in maintaining the NPC pool during early neocortical development.
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Proteínas de Ligação a DNA/metabolismo , MicroRNAs/fisiologia , Neocórtex/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia , Proteínas Proto-Oncogênicas/metabolismo , Animais , Proliferação de Células/fisiologia , Metilação de DNA , Proteínas de Ligação a DNA/genética , Dioxigenases , Feminino , Regulação da Expressão Gênica no Desenvolvimento , MicroRNAs/genética , Neurogênese/genética , Gravidez , Proteínas Proto-Oncogênicas/genéticaRESUMO
BACKGROUND: The growing number of people living with HIV/AIDS (PLWHA) in China points to an increased need for case management services of HIV/AIDS. This study sought to explore the challenges and enablers in shifting the HIV/AIDS case management services from Centers for Disease Control and Prevention (CDCs) to Community Health Service Centers (CHSCs) in urban China. METHODS: A qualitative method based on the Health Policy Triangle (HPT) framework was employed to gain in-depth insights into four elements of the task shifting strategy. This included a review on published literature and health policy documents, 15 focus group discussions (FGDs) and 30 in-depth interviews (IDIs) with four types of key actors from three cities in China. A total of 78 studies and 17 policy files at the national, municipal and local levels were obtained and reviewed comprehensively. Three semi-structured interview guides were used to explore key actors' views on shifting the HIV/AIDS case management services to CHSCs. RESULTS: It is necessary and feasible for CHSCs to engage in case management services for PLWHA in local communities. The increasing number of PLWHA and shortage of qualified health professionals in CDCs made shifting case management services downwards to CHSCs an urgent agenda. CHSCs' wide distribution, technical capacity, accessibility and current practice enabled them to carry out case management services for PLWHA. However our findings indicated several challenges in this task shifting process. Those challenges included lack of specific policy and stable financial support for CHSCs, inadequate manpower, relatively low capacity for health service delivery, lack of coordination among sectors, PLWHA's fear for discrimination and privacy disclosure in local communities, which may compromise the effectiveness and sustainability of those services. CONCLUSIONS: Shifting the HIV/AIDS case management services from CDCs to CHSCs is a new approach to cope with the rising number of PLWHA in China, but it should be implemented alongside with other efforts and resources such as increasing public funding, planned team building, professional training, coordination with other sectors and education on privacy protection as well as non-discrimination to make this approach more effective and sustainable. Policy makers need to ensure both political feasibility and resources accessibility to facilitate this shifting process.
Assuntos
Administração de Caso , Centros Comunitários de Saúde , Infecções por HIV/tratamento farmacológico , Formulação de Políticas , Serviços Urbanos de Saúde , Síndrome da Imunodeficiência Adquirida , Pessoal Administrativo , Adolescente , Adulto , China , Doenças Transmissíveis , Atenção à Saúde , Feminino , Grupos Focais , Pessoal de Saúde , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: Dysfunction of vascular endothelium is implicated in many pathological situations. Cytoskeleton plays an importance role in vascular endothelial permeability barrier and inflammatory response. Many Chinese herbs have the endothelial protective effect, of which, "Astragalus membranaceus" is a highly valued herb for treatment of cardiovascular and renal diseases in traditional Chinese medicine, In this study, we tested whether calycosin-7-O-ß-D-glucoside (Calycosin), a main effective monomer component of "Astragalus membranaceus", could protect endothelial cells from bacterial endotoxin (LPS)-induced cell injury. METHODS: Endothelial cell injury was induced by exposing human umbilical vein endothelial cells (HUVECs) to LPS. The effects of calycosin on LPS-induced changes in cell viability, apoptosis rate, cell migration, nitric oxide synthase (NOS), generationof intracellular reactive oxygen species (ROS) and cytoskeleton organization were determined. Microarray assay was employed to screen the possible gene expression change. Based on the results of microarray assay, the expression profile of genes involved in Rho/ROCK pathway and AKT pathway were further evaluated with quantitative real-time RT-PCR or western blot methods. RESULTS: Calycosin improved cell viability, suppressed apoptosis and protected the cells from LPS-induced reduction in cell migration and generation of ROS, protein level of NOS at a comparable magnitude to that of Y27632 and valsartan. Similar to Y27632 and valsartan, Calycosin, also neutralized LPS-induced actomyosin contraction and vinculin protein aggregation. Microarray assay, real-time PCR and western blot results revealed that LPS induced expression of FN, ITG A5, RhoA, PI3K (or PIP2 in western blotting), FAK, VEGF and VEGF R2, and inhibited expression of MLCP. We believed multiple pathways involved in the regulation of calycosin on HUVECs. Calycosin are considered to be able to activate MLCP through promoting the generation of NO, decreasing PMLC, suppressing the cytoskeleton remodeling caused by activation of Rho/ROCK pathway and inhibiting AKT pathway by decreasing VEGF, VEGF R2 and PI3K level. CONCLUSION: Calycosin protected HUVEC from LPS-induced endothelial injury, possibly through suppression of Rho/ROCK pathway and regulation of AKT pathway.
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Citoesqueleto/metabolismo , Glucosídeos/metabolismo , Isoflavonas/metabolismo , Estresse Oxidativo/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/fisiologia , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana , HumanosRESUMO
Electrical stimulation of ventral division of medial geniculate body (MGBv) neurons evokes a shift of the frequency-tuning curves of auditory cortical (AC) neurons toward the best frequency (BF) of the stimulated MGBv neurons (frequency-specific plasticity). The shift of BF is induced by inhibition of responses at the BF of the recorded AC neuron, with coincident facilitation of responses at the BF of the stimulated MGBv neuron. However, the synaptic mechanisms are not yet understood. We hypothesize that activation of thalamocortical synaptic transmission and receptor function may contribute to MGBv stimulation-induced frequency-specific auditory plasticity and the shift of BF. To test this hypothesis, we measured changes in the excitatory postsynaptic currents in pyramidal neurons of layer III/IV in the auditory cortex following high-frequency stimulation (HFS) of the MGBv, using whole cell recordings in an auditory thalamocortical slice. Our data showed that in response to the HFS of the MGBv the excitatory postsynaptic currents of AC neurons showed long-term bidirectional synaptic plasticity and long-term potentiation and depression. Pharmacological studies indicated that the long-term synaptic plasticity was induced through the activation of different sets of N-methyl-d-aspartate-type glutamatergic receptors, γ-aminobutyric acid-type receptors, and type 5 metabotropic glutamate receptors. Our data further demonstrated that blocking of different receptors with specific antagonists significantly inhibited MGBv stimulation-induced long-term plasticity as well as the shift of BF. These data indicate that these receptors have an important role in mediating frequency-specific auditory cortical plasticity.
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Córtex Auditivo/fisiologia , Potenciais Pós-Sinápticos Excitadores , Corpos Geniculados/fisiologia , Potenciação de Longa Duração , Sinapses/fisiologia , Animais , Córtex Auditivo/citologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas GABAérgicos/farmacologia , Corpos Geniculados/citologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Ratos , Ratos Sprague-Dawley , Sinapses/efeitos dos fármacosRESUMO
Accumulated soluble amyloid beta- (Aß-) induced aberrant neuronal network activity may directly contribute to cognitive deficits, which are the most outstanding characteristics of Alzheimer's disease (AD). The entorhinal cortex (EC) is one of the earliest affected brain regions in AD. Impairments of EC neurons are responsible for the cognitive deficits in AD. However, little effort has been made to investigate the effects of soluble Aß on the discharge properties of EC neurons in vivo. The present study was designed to examine the effects of soluble Aß(1-42) on the discharge properties of EC neurons, using in vivo extracellular single unit recordings. The protective effects of gastrodin (GAS) were also investigated against Aß(1-42)-induced alterations in EC neuronal activities. The results showed that the spontaneous discharge of EC neurons was increased by local application of soluble Aß(1-42) and that GAS can effectively reverse Aß(1-42)-induced facilitation of spontaneous discharge in a concentration-dependent manner. Moreover, whole-cell patch clamp results indicated that the protective function of GAS on abnormal hyperexcitability may be partially mediated by its inhibitory action on Aß(1-42)-elicited inward currents in EC neurons. Our study suggested that GAS may provide neuroprotective effects on Aß(1-42)-induced hyperactivity in EC neurons of rats.
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Peptídeos beta-Amiloides/farmacologia , Álcoois Benzílicos/farmacologia , Córtex Entorrinal/efeitos dos fármacos , Córtex Entorrinal/fisiologia , Glucosídeos/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Immunohistochemistry (IHC) is widely used in the management of patients with cervical intraepithelial neoplasia (CIN) but still has many limitations in clinical practice. We analyzed the correlation of new biomarkers with the severity of CIN and follow-up outcomes in patients after conization to improve the management of patients with CIN. METHODS: IHC staining of Eag1 and p16/Ki-67 was performed on cervical tissue sections from 234 patients with suspected CIN2/3. After a series of follow-ups, including human papillomavirus (HPV) test and thinprep cytologic test (TCT) for 1-2 years, the outcomes were collected. IHC scores of biomarkers and follow-up results were used to analyze the correlation and assess the diagnostic efficiency of biomarkers. RESULTS: The IHC staining intensity of Eag1 and p16/Ki-67 was significantly different from that of the CIN1-3 groups (p < 0.05). Eag1 expression scores were significantly different in the distribution between the two follow-up groups (p < 0.001). ROC curves based on the correlations between the follow-up outcomes and the Eag1 scores and IS of p16/ki-67 showed that Eag1 had a greater AUC (0.767 vs. 0.666). Logistic regression analysis of the combination of biomarkers revealed a greater AUC value than any single biomarker. CONCLUSIONS: Eag1 expression was significantly correlated with CIN grade and follow-up outcomes after conization. IHC staining of combinations of biomarkers of Eag1, p16 and Ki-67 may help us to improve the ability to identify risk groups with abnormal follow-up outcomes after treatment for CIN.
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Biomarcadores Tumorais , Inibidor p16 de Quinase Dependente de Ciclina , Imuno-Histoquímica , Antígeno Ki-67 , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Humanos , Feminino , Displasia do Colo do Útero/patologia , Displasia do Colo do Útero/diagnóstico , Displasia do Colo do Útero/virologia , Displasia do Colo do Útero/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/análise , Antígeno Ki-67/análise , Antígeno Ki-67/metabolismo , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/cirurgia , Adulto , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Pessoa de Meia-Idade , Conização/métodos , Adulto JovemRESUMO
The complexities of acute kidney injury (AKI), a multifaceted pathological occurrence, are not fully understood. At present, there is a lack of effective pharmaceutical treatments in clinical practice. Studies have shown that icariin has beneficial effects in models of acute kidney injury (AKI) caused by cisplatin and lipopolysaccharide (LPS). The aim is to explore the mechanisms that cause folic acid (FA)-induced AKI and examine the protective effects of icariin against this condition. To establish a mouse model of AKI, FA was administered via intraperitoneal injection. Icariin was used as the drug intervention. The model and the impact of drug intervention were assessed using measurements of renal function parameters, staining with hematoxylin and eosin, and Q-PCR. The analysis of protein expression changes in the control, model, and icariin treatment groups was conducted using proteomics. KEGG signaling pathway analysis indicates that differential expressed proteins are enriched in the component and coagulation cascades signaling pathway. Through protein-protein interaction network analysis, it was found that compared to the normal group, the expression of Fibrinogen and other proteins was significantly upregulated at the center of the protein interaction network in the model group. After drug treatment, the expression of these proteins was significantly downregulated. The validation experiment supports the above results. In conclusion, this study clarified the molecular mechanism of FA induced acute renal injury from the proteomics level, and provided target selection for AKI; At the same time, the mechanism of icariin in the treatment of AKI was analyzed from the proteomics level.
Assuntos
Injúria Renal Aguda , Ácido Fólico , Camundongos , Animais , Ácido Fólico/farmacologia , Ácido Fólico/uso terapêutico , Proteômica , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Flavonoides/farmacologia , Flavonoides/uso terapêutico , RimRESUMO
Acute kidney injury (AKI) is characterized by a rapid decline in renal function and is associated with a high morbidity and mortality rate. At present, the underlying mechanisms of AKI remain incompletely understood. Immune disorder is a prominent feature of AKI, and dendritic cells (DCs) play a pivotal role in orchestrating both innate and adaptive immune responses, including the induction of protective proinflammatory and tolerogenic immune reactions. Emerging evidence suggests that DCs play a critical role in the initiation and development of AKI. This paper aimed to conduct a comprehensive review and analysis of the role of DCs in the progression of AKI and elucidate the underlying molecular mechanism. The ultimate objective was to offer valuable insights and guidance for the treatment of AKI.
Assuntos
Injúria Renal Aguda , Humanos , Injúria Renal Aguda/etiologia , Cognição , Células DendríticasRESUMO
Repair of acute kidney injury (AKI) is a typical example of renal regeneration. AKI is characterized by tubular cell death, peritubular capillary (PTC) thinning, and immune system activation. After renal tubule injury, resident renal progenitor cells, or renal tubule dedifferentiation, give rise to renal progenitor cells and repair the damaged renal tubule through proliferation and differentiation. Mesenchymal stem cells (MSCs) also play an important role in renal tubular repair. AKI leads to sparse PTC, affecting the supply of nutrients and oxygen and indirectly aggravating AKI. Therefore, repairing PTC is important for the prognosis of AKI. The activation of the immune system is conducive for the body to clear the necrotic cells and debris generated by AKI; however, if the immune activation is too strong or lengthy, it will cause damage to renal tubule cells or inhibit their repair. Macrophages have been shown to play an important role in the repair of kidney injury. Traditional Chinese medicine (TCM) has unique advantages in the treatment of AKI and a series of studies have been conducted on the topic in recent years. Herein, the role of TCM in promoting the repair of renal injury and its molecular mechanism is discussed from three perspectives: repair of renal tubular epithelial cells, repair of PTC, and regulation of macrophages to provide a reference for the treatment and mechanistic research of AKI.