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PURPOSE: Microglia-mediated inflammation is associated with perioperative neurocognitive disorders (PNDs) caused by sevoflurane. Dexmedetomidine has been reported to protect against sevoflurane-induced cognitive impairment. In this study, we investigated the effects and underlying mechanisms of dexmedetomidine on sevoflurane-induced microglial neuroinflammation and PNDs. METHODS: Wild-type and purinergic ionotropic 4 receptor (P2X4R) overexpressing C57/BL6 mice were intraperitoneally injected with 20 µg/kg dexmedetomidine or an equal volume of normal saline 2 h prior to sevoflurane exposure. The Morris water maze (MWM) test was performed to assess cognitive function. Immunofluorescence staining was employed to detect microglial activation. The expression levels of proinflammatory cytokines were measured by real-time quantitative PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). The protein levels of P2X4R and NOD-like receptor protein 3 (NLRP3) were detected by Western Blotting. RESULTS: Sevoflurane increased the number of microglia, upregulated the levels of proinflammatory cytokines, elevated the protein levels of P2X4R and NLRP3 in the hippocampus and induced cognitive decline, while pretreatment with dexmedetomidine downregulated the protein levels of P2X4R and NLRP3, alleviated sevoflurane-induced microglial neuroinflammation and improved cognitive dysfunction. Moreover, overexpression of P2X4R weakened the neuroprotective effect of dexmedetomidine. CONCLUSIONS: Dexmedetomidine protected against sevoflurane-induced neuroinflammation and neurocognitive disorders by suppressing the P2X4R/NLRP3 pathway.
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OBJECTIVE: To investigate the effect of sevoflurane on inflammation of microglia in hippocampus of neonatal rats, and to investigate whether the related mechanism is related to Wnt/ß-Catenin/CaMKIV pathway. METHODS: Neonatal rats were anesthetized with 2% or 3% sevoflurane for 4 h a day for 3 consecutive days. Water maze test was used to detect the effect of sevoflurane anesthesia on memory function of neonatal rats. H&E and Nissl staining were used to observe the pathological damage of hippocampal area of neonatal rats induced by sevoflurane anesthesia. The expression of microglial marker Iba-1 was detected by Immunofluorescence. Immunofluorescence and WB were used to detect the expression CD32b, CD86, TNF-α, IL-6, Wnt3a, ß-Catenin and CaMKIV in hippocampus. To further explore the related mechanism, Wnt-3α inhibitor and activator was treated to study the effect of sevoflurane on microglial inflammation in hippocampus of neonatal rats. RESULTS: Sevoflurane anesthesia significantly increased escape latency time, reduced platform crossing times, and damaged the learning and memory ability of neonatal rats. H&E and Nissl staining results showed that sevoflurane anesthesia caused obvious damage to the hippocampus of neonatal rats. Sevoflurane anesthesia promoted the expression of Iba-1 and activated microglia. Sevoflurane anesthesia not only significantly increased the positive expression of CD32b, CD86, TNF-α and IL-6, but also decreased the expression of Wnt3a, ß-Catenin and CaMKIV. These results suggested that sevoflurane inhibited Wnt/ß-Catenin/CaMKIV pathway. CONCLUSION: Sevoflurane induces inflammation of microglia in hippocampus of neonatal rats by inhibiting Wnt/ß-Catenin/CaMKIV pathway.
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Anestésicos Inalatórios/efeitos adversos , Animais Recém-Nascidos/genética , Animais Recém-Nascidos/metabolismo , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo , Hipocampo/citologia , Hipocampo/metabolismo , Inflamação/etiologia , Microglia/metabolismo , Microglia/patologia , Sevoflurano/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Expressão Gênica/efeitos dos fármacos , Inflamação/genética , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Accumulating evidence has already indicated that traditional Chinese medicine (TCM) possesses tremendous potential for treating neurodegenerative diseases. Astragalus, also named Huangqi, is a famous traditional medical herb that can be applied to treat cerebral ischemia and prevent neuronal degeneration. Nevertheless, the underlying mechanisms remain largely unexplored. In the present study, Astragalus-containing serum (ASMES) was prepared and added into the culture medium of PC12 cells to explore its neuroprotective effect on 6-hydroxydopamine (6-OHDA)-caused neuronal toxicity. Our data showed that ASMES significantly ameliorated the cellular viability of cultured PC12 cells against the neurotoxicity induced by 6-OHDA (P < 0.05). Moreover, ASMES significantly decreased the cell apoptosis triggered by 6-OHDA (P < 0.01). Furthermore, 2',7'-dichlorofluorescin diacetate assay was performed to detect the changes in oxidative stress, and we showed that 6-OHDA elevated the production of reactive oxygen species (ROS), whereas ASMES significantly reversed these changes (P < 0.01). Besides, mitochondrial membrane potential (MMP) assay showed that ASMES could restore 6-OHDA-damaged MMP in cultured PC12 cells (P < 0.05). In conclusion, Astragalus could protect PC12 cells from 6-OHDA-caused neuronal toxicity, and possibly, the ROS-mediated apoptotic pathway participated in this process. Collectively, our findings provided valuable insights into the potential in treatment of neurodegenerative diseases.
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Fármacos Neuroprotetores , Animais , Apoptose , Sobrevivência Celular , Potencial da Membrana Mitocondrial , Fármacos Neuroprotetores/farmacologia , Oxidopamina/toxicidade , Células PC12 , Ratos , Espécies Reativas de OxigênioRESUMO
Postoperative cognitive dysfunction (POCD) is a common complication induced by anesthesia or surgery, which affects the concentration, cognition and memory of patients. Sevoflurane, a clinical anesthetic, could stimulate neuro-inflammation and lead to POCD. Recent studies found that specificity protein 1 (SP1) participates in the development of neurological diseases. Our study aims to elucidate the role of SP1 in sevoflurane-induced POCD pathogenesis. We anesthetized Sprague-Dawley rats and treated the primary hippocampal neurons with sevoflurane to construct the in vivo and in vitro POCD models. Besides, the expression and regulatory mechanism of SP1 in the pathogenesis of POCD were explored. According to the results, sevoflurane anesthesia impaired the cognitive functions of rat, significantly elevated SP1 expression and inactivated the cholinergic anti-inflammatory pathway (CAP) both in vivo and in vitro. Moreover, the sevoflurane-treated rats and neurons also exhibited obvious inflammatory responses and enhanced apoptosis. Loss-of-function assay indicated that SP1 knockdown rescued the deactivation of CAP and alleviated the sevoflurane-induced neuro-inflammation and apoptosis in rat hippocampus. Generally, our study documented that the sevoflurane-induced SP1 up-regulation affected the activation of CAP, leading to the aggravated neuro-inflammation and apoptosis. This may provide a novel sight for POCD therapy.
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Anestésicos Inalatórios/efeitos adversos , Inflamação/etiologia , Complicações Cognitivas Pós-Operatórias/etiologia , Sevoflurano/efeitos adversos , Fator de Transcrição Sp1/metabolismo , Animais , Apoptose/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Inativação Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Inflamação/induzido quimicamente , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Complicações Cognitivas Pós-Operatórias/induzido quimicamente , Ratos Sprague-Dawley , Fator de Transcrição Sp1/genética , Receptor Nicotínico de Acetilcolina alfa7/metabolismoRESUMO
Melatonin (MLT) is widely used to treat sleep disorders although the underlying mechanism is still elusive. In mice, using wheel-running detection, we found that exogenous MLT could completely recover the period length prolonged by N-methyl-D-aspartate receptor (NMDAR) impairment due to the injection of the NMDAR antagonist MK-801, a preclinical model of psychosis. The analysis of the possible underlying mechanisms indicated that MLT could regulate the homeostatic state in the ventrolateral preoptic nucleus (VLPO) instead of the circadian process in the suprachiasmatic nucleus (SCN). In addition, our data showed that MK-801 decreased Ca2+ -related CaMKII expression and CREB phosphorylation levels in the VLPO, and MLT could rescue these intracellular impairments but not NMDAR expression levels. Accordingly, Gcamp6 AAV virus was injected in-vivo to further monitor intracellular Ca2+ levels in the VLPO, and MLT demonstrated a unique ability to increase Ca2+ fluorescence compared with MK-801-injected mice. Additionally, using the selective melatonin MT2 receptor antagonist 4-phenyl-2-propionamidotetralin (4P-PDOT), we discovered that the pharmacological effects of MLT upon NMDAR impairments were mediated by melatonin MT2 receptors. Using electroencephalography/electromyography (EEG/EMG) recordings, we observed that the latency to the first nonrapid eye movement (NREM) sleep episode was delayed by MK-801, and MLT was able to recover this delay. In conclusion, exogenous MLT by acting upon melatonin MT2 receptors rescues sleep phase delayed by NMDAR impairment via increasing intracellular Ca2+ signaling in the VLPO, suggesting a regulatory role of the neurohormone on the homeostatic system.
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Sinalização do Cálcio/efeitos dos fármacos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Maleato de Dizocilpina/farmacologia , Melatonina/farmacologia , Área Pré-Óptica/metabolismo , Receptor MT2 de Melatonina/metabolismo , Fases do Sono/efeitos dos fármacos , Animais , Eletroencefalografia , Eletromiografia , Masculino , Melatonina/metabolismo , CamundongosRESUMO
Allostery is the most direct and efficient way for regulation of biological macromolecule function and is induced by the binding of a ligand at an allosteric site topographically distinct from the orthosteric site. AlloSteric Database (ASD, http://mdl.shsmu.edu.cn/ASD) has been developed to provide comprehensive information on allostery. Owing to the inherent high receptor selectivity and lower target-based toxicity, allosteric regulation is expected to assume a more prominent role in drug discovery and bioengineering, leading to the rapid growth of allosteric findings. In this updated version, ASD v2.0 has expanded to 1286 allosteric proteins, 565 allosteric diseases and 22 008 allosteric modulators. A total of 907 allosteric site-modulator structural complexes and >200 structural pairs of orthosteric/allosteric sites in the allosteric proteins were constructed for researchers to develop allosteric site and pathway tools in response to community demands. Up-to-date allosteric pathways were manually curated in the updated version. In addition, both the front-end and the back-end of ASD have been redesigned and enhanced to allow more efficient access. Taken together, these updates are useful for facilitating the investigation of allosteric mechanisms, allosteric target identification and allosteric drug discovery.
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Regulação Alostérica , Bases de Dados de Proteínas , Sítio Alostérico , Descoberta de Drogas , Internet , Proteínas/química , Proteínas/metabolismoRESUMO
BACKGROUND AND AIMS: It is suggested that regulatory immune cells play a critical role in cancer cell growth by facilitating cancer cells to escape from the immune surveillance. The generation of the immune regulatory cells in cancer has not been fully understood yet. This study aims to investigate the role of the hepatoma-derived growth factor (HDGF) in the generation of regulatory T cells (Treg). METHODS: CCL-9.1 cells (A mouse hepatoma cell line), were cultured. The expression of HDGF in CCL-9.1 cells was assessed by quantitative RT-PCR and Western blotting. The generation of Foxp3(+) T cells was assessed by cell culture and flow cytometry. The immune suppressor function of the Foxp3(+) T cells on CD8(+) T cell activities was assessed by the carboxyfluorescein succinimidyl ester (CFSE)-dilution assay and enzyme-linked immunosorbent assay. RESULTS: The results showed that exposure to PolyIC markedly increased the expression of HDGF in CCL-9.1 cells. Coculture of CCL-9.1 cells and CD4(+) CD25(-) T cells in the presence of PolyIC generated the Forkhead box protein (Foxp)3(+) T cells. The exposure to HDGF increased the expression of Foxp3 and decreased the expression of GATA3 in CD4(+) T cells. After activation, the Foxp3(+) T cells suppressed the CD8(+) T cell proliferation and the release of the cytotoxic cytokines. CONCLUSIONS: Liver cancer cell-derived HDGF can induce Foxp3(+) T cells; the latter has the immune suppressor functions on CD8(+) T cell activities.
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Carcinoma Hepatocelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Western Blotting , Linhagem Celular Tumoral , Técnicas de Cocultura , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/isolamento & purificação , Neoplasias Hepáticas/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Poli I-C/farmacologia , Reação em Cadeia da Polimerase em Tempo Real , Linfócitos T Reguladores/fisiologiaRESUMO
The miR-92a family, including miR-25, miR-92a-1, miR-92a-2 and miR-363, arises from three different paralog clusters miR-17-92, miR-106a-363, and miR-106b-25 that are highly conservative in the process of evolution, and it was thought as a group of microRNAs (miRNAs) correlated with endothelial cells. Aberrant expression of miR-92a family was detected in multiple cancers, and the disturbance of miR-92a family was related with tumorigenesis and tumor development. In this review, the progress on the relationship between miR-92a family and their target genes and malignant tumors will be summarized.
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Transformação Celular Neoplásica/genética , MicroRNAs/genética , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Neoplasias/genética , Apoptose/genética , Células Endoteliais/citologia , Regulação Neoplásica da Expressão Gênica , HumanosRESUMO
MicroRNAs (miRNAs) are a class of endogenous, non-coding, 18-24 nucleotide length single-strand RNAs that could modulate gene expression at post-transcriptional level. Previous studies have shown that miR-128 enriched in the brain plays an important role in the development of nervous system and the maintenance of normal physical functions. Aberrant expression of miR-128 has been detected in many types of human tumors and its validated target genes are involved in cancer-related biological processes such as cell proliferation, differentiation and apoptosis. In this review, we will summarize the roles of miR-128 and its target genes in tumorigenesis and metastasis.
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Carcinogênese/genética , MicroRNAs/genética , Metástase Neoplásica/genética , Neoplasias/genética , Animais , Apoptose , Diferenciação Celular , Proliferação de Células , Humanos , Camundongos , Neoplasias/patologiaRESUMO
Exposure to cigarette smoke directly damages the lungs and causes lung inflammation. The anti-inflammatory properties of edible bird's nest (EBN) have been reported. We aimed to determine the effect of EBN on pneumonia in a mouse model exposed to cigarette smoke. Fifty BALB/c mice were randomly divided into control, model, positive drug, low-dose EBN, and high-dose EBN groups (n = 10 each). Except for the control group, the mice in each group were exposed to four cigarettes once a day for 8 days. In addition, we validated the effects of EBN on A549 cells and investigated the mechanism by which EBN alleviates lung inflammation. Edible bird's nest (EBN) could alleviate the structural damage of lung tissue and the smoke-induced inflammatory response in mice. The best effect was observed at the high dose of EBN (0.019 g). The mice treated with EBN had a stronger ability than those in the model group to resist cigarette smoke stimulation, as indicated by a decrease in serum and lung inflammatory markers (interleukin 6 [IL-6], tumor necrosis factor-α [TNF-α], and interleukin 8 [IL-8]), an increase in serum interleukin 10 (IL-10) levels, and a decrease in the expression of inflammasome NOD-like receptor pyrin 3 (NLRP3). In addition, our cell experiments showed that EBN attenuated cigarette smoke-induced pulmonary inflammation mainly by inhibiting the tumor necrosis factor receptor 1 (TNFR1)/nuclear factor-kappa B (NF-κB)/NLRP3 pathway. These findings provide theoretical evidence for the positive nutritional qualities of EBN for the lung by demonstrating that it inhibits the TNFR1/NF-κB/NLRP3 signaling pathway, which prevents the development of cigarette smoke-induced pulmonary inflammation.
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The immune system of infants is partly weak and immature, and supplementation of infant formula can be of vital importance to boost the development of the immune system. Lactoferrin (LF) and osteopontin (OPN) are essential proteins in human milk with immunoregulation function. An increasing number of studies indicate that proteins have interactions with each other in milk, and our previous study found that a ratio of LF : OPN at 1 : 5 (w/w, denoted as LOP) had a synergistic effect on intestinal barrier protection. It remains unknown whether LOP can also exert a stronger effect on immunoregulation. Hence, we used an in vitro model of LPS-induced macrophage inflammation and in vivo models of LPS-induced intestinal inflammation and early life development. We showed that LOP increased the secretion of the granulocyte-macrophage colony-stimulating factor (132%), stem cell factor (167%) and interleukin-3 (176%) in bone marrow cells, as well as thymosin (155%) and interleukin-10 (161%) in the thymus, more than LF or OPN alone during development, and inhibited changes in immune cells and cytokines during the LPS challenge. In addition, analysis of the components of digested proteins in vitro revealed that differentially expressed peptides may provide immunoregulation. Lastly, LOP increased the abundance of Rikenellaceae, Muribaculum, Faecalibaculum, and Elisenbergiella in the cecum content. These results imply that LOP is a potential immunomodifier for infants and offers a new theoretical basis for infant formula innovation.
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Lactoferrina , Osteopontina , Lactente , Humanos , Lactoferrina/química , Osteopontina/genética , Osteopontina/metabolismo , Lipopolissacarídeos/metabolismo , Leite Humano/química , Inflamação/metabolismo , Sistema Imunitário/metabolismoRESUMO
BACKGROUND: Cranial radiation therapy has been used for the treatment of primary and metastatic brain tumors. A prominent feature of brain injury induced by the radiation therapy is hippocampal dysfunction, characterized by a decline in memory. Cdk5 plays an important role in memory formation. Abnormal Cdk5 activity is associated with neuronal apoptosis induced by neurotoxic stimuli. However, the roles of Cdk5 in hippocampal apoptosis in response to X-ray irradiation have not been explored. METHODS: The expression of Cdk5 activators, p35 and p25, in hippocampal neurons was tested in both in vivo animal and in vitro couture after X-ray irradiation. RESULTS: After X-ray irradiation at 20 Gy and 30 Gy in rats, the number of hippocampal neuronal pyknosis was increased, but the number of hippocampal neuron was decreased, in the hippocampal CA1 region of rats. In these animals undergone with X-ray irradiation, the expression of p35 was significantly down-regulated, but it was up-regulated in p25. These opposite expressions were also shown in the primary cultured hippocampal neurons with 30 Gy irradiation. The apoptosis induced by X-ray irradiation were significantly prevented by the pretreatment of Cdk5 inhibitor, roscovitine, in both in vivo and in vitro settings. CONCLUSIONS: X-ray irradiation resulted in a hippocampal neuronal apoptosis through up-regulation of p25, the Cdk5 activator. Hyperactivity of Cdk5 was involved in the pathogenesis of X-ray irradiation-induced hippocampal neuronal apoptosis. Blockade of Cdk5 signal pathway effectively protected neurons from the irradiation-induced brain injury.
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Sevoflurane, a commonly used anesthetic in surgery, is considered as an inducer of neurodegenerative diseases and postoperative complications including postoperative cognitive dysfunction. Evidence showed that specificity protein 1 (SP1) participated in the regulation of various cellular processes. Also, SP1 was found to modulate sevoflurane-induced hippocampal inflammatory injury both in vitro and in vivo. Our study aimed to illustrate the role of SP1 in mediating mitochondrial stress and autophagy in neurons under sevoflurane exposure. SiRNA for SP1 was transfected in to hippocampus neurons for the loss-of-function assay before sevoflurane stimulation. Meanwhile, recilisib was utilized for PI3K/Akt/mTOR signaling activation, GTS-21 and MLA (methylycaconitine citrate) were used to activate or inactivate alpha 7 nicotinic acetylcholine receptor (α7-nAChR), respectively. Sevoflurane induced SP1 upregulation and autophagy suppression. Interfering SP1 dramatically depressed the promoted oxidative stress and mitochondrial dysfunction induced by sevoflurane. Additionally, SP1 silence blocked sevoflurane-induced activation of PI3K/Akt/mTOR signaling and inhibition of α7-nAChR. Restoring PI3K/Akt/mTOR signaling or depressing CAP significantly reversed the repressive effects of SP1 knockdown on mitochondrial stress and autophagy imbalance in hippocampal cells. In conclusions, our research indicated that SP1 regulated sevoflurane-induced oxidative stress dysregulation, mitochondrial function and cell autophagy in hippocampus via mediating the PI3K/Akt/mTOR and α7-nAChR pathways. Therefore, it might provide a novel sight for sevoflurane-induced hippocampus injury and POCD therapy.
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Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Sevoflurano/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Hipocampo/metabolismo , Autofagia , Neurônios/metabolismo , Mitocôndrias/metabolismoRESUMO
Several studies indicate that the disruption of the intestinal epithelial barrier can lead to inflammatory bowel disease (IBD). Recent evidence has increasingly demonstrated that lactoferrin (LF) and osteopontin (OPN) can alleviate intestinal barrier injury. However, the potential synergistic effects of these two proteins and the mechanisms underlying their effects remain unclear. To address this question, we developed a lipopolysaccharide-induced intestinal barrier injury model in C57BL/6 N mice. Our findings demonstrated that the combination of LF and OPN at a 1:5 ratio exerts the strongest protective effect on the intestinal barrier, and it is more effective than LF or OPN alone. This protection is evidenced by the decrease in serum diamine oxidase (DAO) activity (1.66-fold decrease) and D-lactic content (1.51-fold decrease) and the reduced rate of FITC-labeled glucan transport across the jejunum (3.18-fold decrease). Moreover, the protein combination significantly promoted villi length (1.66-fold increase) and crypt depth (1.57-fold increase), improved tight junction protein structure and expression, and boosted the number of absorptive cells (4.34-fold increase) in the intestinal epithelium. Furthermore, the combination promoted crypt cell proliferation and differentiation via Notch signaling. In summary, our findings provide scientific evidence supporting the use of dietary intervention strategies for preventing IBD.
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Doenças Inflamatórias Intestinais , Osteopontina , Camundongos , Animais , Osteopontina/metabolismo , Lactoferrina/farmacologia , Lactoferrina/metabolismo , Camundongos Endogâmicos C57BL , Intestinos , Mucosa Intestinal/metabolismo , Doenças Inflamatórias Intestinais/metabolismoRESUMO
BACKGROUND AND AIMS: Epithelial barrier dysfunction is involved in a number of diseases in the body. The mechanism is to be further understood. The present study aimed to investigate the role of one of the common microbial products, flagellin (FGN), in the induction of intestinal epithelial barrier dysfunction. METHODS: We collected the colon epithelium specimens from 40 patients with ulcerative colitis (UC), 40 patients with Crohn's disease (CD) and 40 healthy volunteers. The expression of toll like receptors (TLR)5 of the specimens was assessed by RT-PCR and western blotting. The expression of tumor necrosis factor alpha (TNFα) and its role in compromising the barrier function in the intestinal epithelial cells, T84 cells, were observed by a cell culture model. RESULTS: The results showed that the expression of TLR5 was observed in the colon epithelium of healthy subjects that was increased in UC patients and further increased in CD patients. Treating T84 cells with FGN increased the expression of TNFα in the cells that caused the T84 cell apoptosis as well as compromised the T84 monolayer barrier function, which could be prevented by knocking down the gene of TNFα in T84 cells. CONCLUSIONS: We conclude that the human colon epithelial cells express detectable TLR5 that is increased in patients with CD and UC. The exposure to FGN can increase the expression of TNFα that further compromises the intestinal epithelial barrier function.
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Mucosa Intestinal/fisiopatologia , Fator de Necrose Tumoral alfa/fisiologia , Adulto , Western Blotting , Estudos de Casos e Controles , Imunoprecipitação da Cromatina , Colite Ulcerativa/metabolismo , Colite Ulcerativa/fisiopatologia , Feminino , Citometria de Fluxo , Inativação Gênica , Humanos , Mucosa Intestinal/metabolismo , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Receptor 5 Toll-Like/genética , Receptor 5 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/genéticaRESUMO
OBJECTIVE: To develop a novel chronic intermittent hypoxia chamber for rat models. DESIGN: The intermittent hypoxia chamber included two animal cabins (28 × 20 × 15 cm) and a hypoxia chamber (80 × 80 × 60 cm) between them, as well as the actuating device. Pure nitrogen was fed into the hypoxia chamber continuously in order to keep the low O(2) concentration. Each animal cabin could move in and out of the hypoxia chamber with precise timing function. As a result, the animal cabins could be covered by the hypoxia chamber and got the same low O(2) concentration as in the hypoxia chamber and normal O(2) concentration as out of the hypoxia chamber. Twelve healthy, male Sprague-Dawley rats (200~250 g) were selected to test the effect of the intermittent hypoxia chamber. The O(2) concentration in the hypoxia chamber was 10 ± 0.5%, and the cycle time of intermittent hypoxia was 180 s (the hypoxia and normoxic time was 90 s, respectively). The hypoxia chamber ran 8 h per day. The arterial blood gas analysis (ABSA) of rats was conducted when the animal cabin was located inside and outside the hypoxia chamber. RESULTS: The chronic intermittent hypoxia chamber ran safely and reliably. The ABSA showed that the lowest PaO(2) was 35.75 ± 4.02 mmHg and the lowest SaO(2) was 68.62 ± 8.36% when the animal cabin was covered by the hypoxia chamber. CONCLUSIONS: The chronic intermittent hypoxia chamber designed by us was suitable to establish a chronic intermittent hypoxia model for rats.
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Modelos Animais de Doenças , Hipóxia/fisiopatologia , Nitrogênio/farmacologia , Oxigênio/sangue , Apneia Obstrutiva do Sono/fisiopatologia , Animais , Câmaras de Exposição Atmosférica , Doença Crônica , Desenho de Equipamento , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
In the diagnosis of Alzheimer's Disease (AD), the brain network analysis method is often used. The traditional network can only reflect the pairwise association between two brain regions, but ignore the higher-order relationship between them. Therefore, a brain network construction method based on hypergraph, called hyperbrain network, is adopted. The brain network constructed by the conventional static hyperbrain network cannot reflect the dynamic changes in brain activity. Based on this, the construction of a dynamic hyperbrain network is proposed. In addition, graph convolutional networks also play a huge role in AD diagnosis. Therefore, an evolving hypergraph convolutional network for the dynamic hyperbrain network is proposed, and the attention mechanism is added to further enhance the ability of representation learning, and then it is used for the aided diagnosis of AD. The experimental results show that the proposed method can effectively improve the accuracy of AD diagnosis up to 99.09%, which is a 0.3 percent improvement over the best existing methods.
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Interleukin 4 (IL-4) plays a major role in T-lymphocyte development and is thought to be a central regulator as a cofactor in resting B-lymphocyte proliferation. Primary infection with porcine reproductive and respiratory syndrome virus (PRRSV) induces minimal IL-4 production, whereas an IL-4 response occurs in the peripheral blood of piglets reinfected by PRRSV. The locations and interaction partners for the massive volume of IL-4 triggered by PRRSV reinfection remain unclear. This study aimed to investigate the characteristics of IL-4 secretion and location changes in peripheral immune organs induced by PRRSV infection and reinfection. Our results show that PRRSV reinfection induced higher levels of IL-4 mRNA and protein expression in the peripheral immune organs (e.g., lymph node and spleen) and peripheral blood compared with PRRSV primary infection. Importantly, we found that, following PRRSV reinfection, an obvious large-scale migration of IL-4 occurred in the lymph nodes. During PRRSV primary infection, IL-4 was mainly concentrated around the lymphoid follicles and paracortical regions of the lymph node and also located in the marginal area and periarterial lymphatic sheath region of the spleen. During PRRSV reinfection, the now abundant IL-4 gathered into the lymphoid follicles of the lymph node and spleen. Notably, IL-4 changed its location state from scattered and sparse during primary infection to clinging to B lymphocytes in the lymphoid follicles during reinfection. During reinfection, IL-4 was often co-localized with T and B lymphocytes; furthermore, the percentages of several T lymphocyte subsets, N protein-specific antibody levels, and viral load in the peripheral blood or lymph tissues underwent remarkable variation. Another important finding of this study was that the numbers of B lymphocytes and T lymphocytes in the lymphoid nodes were significantly reduced after PRRSV infection or reinfection, presumably due to PRRSV-induced acute bone marrow failure and autophagy in thymic epithelial cells. This study revealed the characteristics of IL-4 migration and distribution in the peripheral lymph organs induced by PRRSV reinfection and provides valuable clues for further exploration of the interactions between IL-4, B lymphocytes, and T lymphocytes during PRRSV infection and reinfection.
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Síndrome Respiratória e Reprodutiva Suína , Vírus da Síndrome Respiratória e Reprodutiva Suína , Doenças dos Suínos , Animais , Linfócitos B , Interleucina-4 , Reinfecção/veterinária , Suínos , Linfócitos TRESUMO
As cancer with the highest morbidity and mortality in the world, lung cancer is characterized by pulmonary nodules in the early stage. The detection of pulmonary nodules is an important method for the early detection of lung cancer, which can greatly improve the survival rate of lung cancer patients. However, the accuracy of conventional detection methods for lung nodules is low. With the development of medical imaging technology, deep learning plays an increasingly important role in medical image detection, and pulmonary nodules can be accurately detected by CT images. Based on the above, a pulmonary nodule detection method based on deep learning is proposed. In the candidate nodule detection stage, the multiscale features and Faster R-CNN, a general-purpose detection framework based on deep learning, were combined together to improve the detection of small-sized lung nodules. In the false-positive nodule filtration stage, a 3D convolutional neural network based on multiscale fusion is designed to reduce false-positive nodules. The experiment results show that the candidate nodule detection model based on Faster R-CNN integrating multiscale features has achieved a sensitivity of 98.6%, 10% higher than that of the other single-scale model, the proposed method achieved a sensitivity of 90.5% at the level of 4 false-positive nodules per scan, and the CPM score reached 0.829. The results are higher than methods in other works of literature. It can be seen that the detection method of pulmonary nodules based on multiscale fusion has a higher detection rate for small nodules and improves the classification performance of true and false-positive pulmonary nodules. This will help doctors when making a lung cancer diagnosis.