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OBJECTIVE: It is important to discriminate different headaches in clinical practice, and neurocognitive biomarkers may serve as objective tools. Several reports have suggested potential cognitive impairment for primary headaches, whereas cognitions within specific domains remain elusive, e.g., emotional processing. In this study, we aimed to characterize processing of facial expressions in migraine and tension-type headache (TTH) by analyzing expression-related visual mismatch negativity (EMMN) and explored whether their processing patterns were distinct. METHODS: Altogether, 73 headache patients (20 migraine with aura (MA), 28 migraine without aura (MwoA), 25 TTH) and 27 age-matched healthy controls were recruited. After a battery of mood/neuropsychological evaluations, an expression-related oddball paradigm containing multiple models of neutral, happy and sad faces was used to investigate automatic emotional processing. RESULTS: We observed cognitive impairment in all headache patients, especially in attention/execution subdomains, but no discrepancy existed among different headaches. Although analyses of P1/N170 did not reach significant levels, amplitude of early and late EMMN was markedly diminished in MA and MwoA compared with controls and TTH, regardless of happy or sad expression. Moreover, sad EMMN was larger (more negative) than happy EMMN only in controls, while not in all headache groups. CONCLUSIONS: Our findings implied that migraine, rather than TTH, might lead to more severe impairment of automatic emotional processing, which was manifested as no observable EMMN elicitation and disappearance of negative bias effect. The EMMN component could assist in discrimination of migraine from TTH and diagnosis of undefined headaches, and its availability needed further validations.
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Monofluoromethyl (CH2F) motifs exhibit unique bioactivities and are considered privileged units in drug discovery. The radical monofluoromethylative difunctionalization of alkenes stands out as an appealing approach to access CH2F-containing compounds. However, this strategy remains largely underdeveloped, particularly under metal-free conditions. In this study, we report on visible light-mediated three-component monofluoromethylation/acylation of styrene derivatives employing NHC and organic photocatalyst dual catalysis. A diverse array of α-aryl-ß-monofluoromethyl ketones was successfully synthesized with excellent functional group tolerance and selectivity. The mild and metal-free CH2F radical generation strategy from NaSO2CFH2 holds potential for further applications in fluoroalkyl radical chemistry.
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ß-halogenated enol esters and ethers are versatile building blocks in organic synthesis, which has attracted increasing attention. In this study, we report the facile trans-oxyiodination and oxychlorination of alkynes, leading to the direct construction of versatile halogenated enol esters and ethers. This transformation features an easy operation, optimal atomic economy, a strong functional group tolerance, broad substrate scope, and excellent trans-selectivity. Employing highly electrophilic bifunctional N-X (halogen) reagents was the key to achieving broad reaction generality. To our knowledge, this transformation represents the first oxyhalogenation system employing N-X (halogen) reagents as both oxylation and halogenation sources.
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Objectives: Following cerebral ischemia, microRNA- (miR-) 29b in circulating blood is downregulated. This study investigates the underlying mechanism and implications of miR-29b in leukocyte induction. Methods: miR-29b from stroke patients and rats with middle cerebral artery occlusion (MCAO) were assessed using real-time polymerase chain reaction (PCR). miR-29b agomir was used to increase miR-29b expression in leukocytes via intravenous injection. C1q and tumor necrosis factor (C1QTNF) 6, interleukin- (IL-) 1ß, zonula occludens- (ZO-) 1, occludin, and ischemic outcomes were assessed in MCAO rats. Additionally, hCMEC/D3 cells were subjected to oxygen-glucose deprivation (OGD) and cocultured with HL-60 cells. Results: miR-29b levels in neutrophils were found to be significantly lower in stroke patients compared with healthy controls, which may indicate its high diagnostic sensitivity and specificity for stroke. Moreover, miR-29b levels in leukocytes showed a negative correlation with National Institute of Health Stroke Scale (NIHSS) scores and C1QTNF6 levels. In MCAO rats, miR-29b overexpression reduced brain infarct volume and brain edema, decreasing IL-1ß levels in leukocytes and in the brain 24 hours poststroke. miR-29b attenuated IL-1ß expression via C1QTNF6 inhibition, leading to decreased blood-brain barrier (BBB) disruption and leukocyte infiltration. Moreover, miR-29b overexpression in HL-60 cells downregulated OGD-induced hCMEC/D3 cell apoptosis and increased ZO-1 and occludin levels in vitro. Conclusion: Leukocytic miR-29b attenuates inflammatory response by augmenting BBB integrity through C1QTNF6, suggesting a novel miR-29b-based therapeutic therapy for ischemic stroke.
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Barreira Hematoencefálica , Isquemia Encefálica , AVC Isquêmico , MicroRNAs , Animais , Barreira Hematoencefálica/metabolismo , Isquemia Encefálica/metabolismo , Glucose/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Inflamação/patologia , AVC Isquêmico/metabolismo , MicroRNAs/metabolismo , Ocludina/metabolismo , RatosRESUMO
Evodiamine (EVO) exerts anti-cancer effect in a majority of cancer cells. BGC-823 and SGC-7901 cells were used to study EVO-induced cytotoxicity in human gastric cancer cell. Our results demonstrated that EVO exposure elicited cell vialibility decrease and G2/M arrest caused by induction of cdc2/cyclin B1 complex activation. EVO also induced caspase-dependent apoptosis and necroptosis caused by induction of actication of RIP, RIP3 and MLKL. Moreover, increase of reactive oxygen species (ROS) levels and cytotoxicity induced by EVO were significantly attenuated by co-treatment with a ROS scavenger, EUK134. In conclusion, EVO induced ROS-dependent cytotoxicity, which may involve apoptosis and necroptosis, in human gastric cancer cells.
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Apoptose , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Espécies Reativas de Oxigênio , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo CelularRESUMO
Liver fibrosis, with the characterization of progressive accumulation of extracellular matrix (ECM), is the common pathologic feature in the process of chronic liver disease. Hepatic stellate cells (HSCs) which are activated and differentiate into proliferative and contractile myofibroblasts are recognized as the main drivers of fibrosis. Obesity-related adipocytokine dysregulation is known to accelerate liver fibrosis progression, but the direct fibrogenic effect of mature adipocytes on HSCs has been rarely reported. Therefore, the purpose of this study was to explore the fibrogenic effect of adipocyte 3T3-L1 cells on hepatic stellate LX-2 cells. The results showed that incubating LX-2 cells with the supernatant of 3T3-L1 adipocytes triggered the expression of ECM related proteins, such as α-smooth muscle actin (α-SMA), type I collagen (CO-I), and activated TGF ß/Smad2/3 signaling pathway in LX-2 cells. In addition, 3T3-L1 cells inhibited insulin sensitivity, activated endoplasmic reticulum stress and autophagy to promote the development of fibrosis. These results supported the notion that mature adipocytes can directly activate hepatic stellate cells, and the establishment of an in vitro model of adipocytes on HSCs provides an insight into screening of drugs for liver diseases, such as nonalcoholic fatty liver disease.
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Adipócitos/metabolismo , Autofagia , Estresse do Retículo Endoplasmático , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/metabolismo , Células 3T3-L1 , Adipócitos/patologia , Animais , Células Estreladas do Fígado/patologia , Humanos , Cirrose Hepática/patologia , CamundongosRESUMO
PURPOSE: According to the cognitive processing perspectives, patients with insomnia have insufficient neural management of expressional information. In this study, we compared the pre-attentive processing function of task-irrelevant facial expressions in patients with primary insomnia (PI) and matched healthy controls, with expression-related mismatch negativity (EMMN) elicited by emotional faces as the indicator. METHODS: Using three schematic facial expressions (neutral, happy, and sad) as task-irrelevant stimuli, we investigated the visual processing of PI patients (n = 22) and healthy subjects (n = 22) in an expression-related oddball paradigm designed to elicit the visual N170 and EMMN component. After recording and analyzing the electroencephalogram of all participants, amplitude analysis of N170 and EMMN was eventually conducted under corresponding time window. RESULTS: Compared with control group, the amplitude of sad-EMMN component was significantly attenuated in patients with PI, while no remarkable difference was observed under the happy condition. In addition, negative cognitive bias was further validated in the control group, but not presented in the PI group. CONCLUSION: The current data suggest dysfunctional expressional information processing in PI patients, accompanied by the disorganization of high level perceptual strategy of processing facial emotional expression.
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Disfunção Cognitiva/fisiopatologia , Emoções/fisiologia , Potenciais Evocados/fisiologia , Reconhecimento Facial/fisiologia , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Adulto , Disfunção Cognitiva/etiologia , Eletroencefalografia , Expressão Facial , Feminino , Humanos , Masculino , Índice de Gravidade de Doença , Distúrbios do Início e da Manutenção do Sono/complicações , Percepção SocialRESUMO
Objective: To investigate the effects of lycopene-loaded microemulsion (LME) on the cognitive function and neurogenesis in the dentate gyrus (DG) of the hippocampus and subventricular (SVZ) region of rats with amyloid ß- (Aß-) induced Alzheimer's disease (AD) and its mechanism based on the Wnt/ß-catenin pathway. Methods: Healthy Wistar rats were divided into four groups: the blank control (CON), AD control, traditional lycopene (LOO), and LME groups. The CON and AD groups were fed with normal saline, while the LOO group was fed with traditional lycopene, and the LME group was fed with lycopene-loaded microemulsion. Behavioral tests were performed after three weeks of gastric administration. Immunofluorescence-labeled cells were used to observe the differentiation and maturation of new nerve cells in the DG of the hippocampus and SVZ region. qRT-PCR and Western blotting detected the expression of neurogenesis genes and Wnt/ß-catenin pathway-related proteins, respectively. Results: On the Morris water maze test, LME rats had significantly shortened movement trajectory on the searching platform, reduced escape latency time, and increased residence time on the original platform quadrant. In addition, more LME rats crossed the platform when it was removed. Thus, LME can improve the spatial learning and memory of Aß-induced AD rats. On qRT-PCR, LME significantly increased Reelin, Nestin, and Pax6 gene expressions, which regulate neurogenesis. Immunofluorescence showed that LME could significantly increase BrdU+, Dcx+, BrdU+/Neun+, BrdU+/Dcx+ cells in the DG and SVZ regions, thus promoting neurogenesis. LME also reduced the number of Iba1+ and Iba1+/BrdU+ cells, thus reducing the neuroinflammatory response. On Western blot, LME upregulated the Wnt/ß-catenin pathway by upregulating Wnt3a, ß-catenin, Disheveled (Dvl), and p-GSK3ß and downregulating p-ß-catenin and GSK3ß. Conclusion: LME attenuates cognitive impairment in Aß-induced AD rats by promoting neurogenesis in the hippocampus and SVZ region through upregulating the Wnt/ß-catenin pathway.
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Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/toxicidade , Licopeno/administração & dosagem , Neurogênese/efeitos dos fármacos , Fragmentos de Peptídeos/toxicidade , Via de Sinalização Wnt/efeitos dos fármacos , Doença de Alzheimer/fisiopatologia , Animais , Antioxidantes/administração & dosagem , Emulsões , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Ventrículos Laterais/efeitos dos fármacos , Masculino , Neurogênese/fisiologia , Ratos , Ratos Wistar , Via de Sinalização Wnt/fisiologiaRESUMO
Studies have found that salidroside, isolated from Rhodiola rosea L, has various pharmacological activities, but there have been no studies on the effects of salidroside on brain hippocampal senescence. The purpose of this study was to investigate the mechanistic role of salidroside in hippocampal neuron senescence and injury. In this study, long-term cultured primary rat hippocampal neurons and naturally aged C57 mice were treated with salidroside. The results showed that salidroside increased the viability and MAP2 expression, reduced ß-galactosidase (ß-gal) levels of rat primary hippocampal neurons. Salidroside also improved cognition dysfunction in ageing mice and alleviated neuronal degeneration in the ageing mice CA1 region. Moreover, salidroside decreased the levels of oxidative stress and p21, p16 protein expressions of hippocampal neurons and ageing mice. Salidroside promoted telomerase reverse transcriptase (TERT) protein expression via the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway. In conclusion, our findings suggest that salidroside has the potential to be used as a therapeutic strategy for anti-ageing and ageing-related disease treatment.
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Fármacos Neuroprotetores , Proteínas Proto-Oncogênicas c-akt , Envelhecimento , Animais , Glucosídeos , Hipocampo/metabolismo , Camundongos , Neurônios , Fármacos Neuroprotetores/farmacologia , Fenóis , Fosfatidilinositol 3-Quinase , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RatosRESUMO
The water-soluble polysaccharide EP2, from Enteromorpha prolifera, belongs to the group of polysaccharides known as glucuronoxylorhamnan, which mainly contains glucuronic acid (GlcA), xylose (Xyl), and rhamnose (Rha). The aim of this study was to detect the immunomodulatory effects of EP2 on RAW 264.7 macrophages and cyclophosphamide (CYP)-induced immunosuppression mouse models. The cells were treated with EP2 for different time periods (0, 0.5, 1, 3, and 6 h). The results showed that EP2 promoted nitric oxide production and up-regulated the expression of pro-inflammatory cytokines, such as IL-1ß, IL-6, and TNF-α, in a time-dependent manner. Furthermore, we found that EP2-activated iNOS, COX2, and NLRP3 inï¬ammasomes, and the TLR4/MAPK/NF-κB signaling pathway played an important role. Moreover, EP2 significantly increased the body weight, spleen index, thymus index, inflammatory cell counts, and the levels of IL-1ß, IL-6, and TNF-α in CYP-induced immunosuppression mouse models. These results indicate that EP2 might be a potential immunomodulatory drug and provide the scientific basis for the comprehensive utilization and evaluation of E. prolifera in future applications.
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Clorófitas/química , Ciclofosfamida/toxicidade , Polissacarídeos/farmacologia , Animais , Terapia de Imunossupressão , Imunossupressores/toxicidade , Camundongos , Camundongos Endogâmicos ICR , Polissacarídeos/química , Células RAW 264.7 , Distribuição AleatóriaRESUMO
BACKGROUND: Several studies have suggested that migraineurs suffer from neurocognitive abnormalities, but this phenomenon and exact mechanisms remain controversial. In this study, we aimed to reevaluate visual spatial attention via event-related potential (ERP) examinations and explore further correlations between ERP data and migraine characteristics. METHODS: Altogether, 25 migraine patients (9 males, 16 females; mean age 35.240 years) in the interictal period and 21 age-matched healthy controls (8 males, 13 females; mean age 35.286 years) were recruited. A modified visual oddball paradigm which contained standard, target and novel stimuli was used in the test, and amplitudes and latencies of corresponding original/difference ERP components were measured and analyzed independently. RESULTS: We found that P3 amplitude was markedly reduced in migraineurs. This phenomenon was further validated in analysis of difference P3 components (target minus standard and novel minus standard). Additionally, the N1 and N2 latencies elicited by novel stimulus were both delayed in patients compared with controls. Furthermore, these deviant cognitive ERPs were correlated with frequency and duration of migraine attacks. CONCLUSIONS: These results indicated impaired visual spatial attention in migraine patients, which could be related to frequency and duration of attacks.
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Atenção/fisiologia , Potenciais Evocados/fisiologia , Transtornos de Enxaqueca/fisiopatologia , Adulto , Eletroencefalografia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Migraine is a primary neuropsychological disorder, although its etiology and pathogenesis are unknown. It has been reported that using contingent negative variation, the periodicity of migraine attacks is three days in adults. However, there is still a lack of relevant reports about the periodicity of migraine without aura in adults. Therefore, we investigated the changes of contingent negative variation in adults with migraine without aura from three to seven days after migraine attacks in order to provide the basis for exploring the circulation periodicity of migraine without aura. This prospective, observational study involved a group of 34 individuals with migraine without aura, who were screened during the three to seven days after a migraine attack without aura. A healthy group (31 individuals) was used as controls to assess the amplitudes of contingent negative variation and habituation of early contingent negative variation. Indices of the amplitudes included overall contingent negative variation, initial contingent negative variation, terminal contingent negative variation, and postoperative negative contingent variation. Differences between these indicators were analyzed. No significant difference was found between the patient and control groups for either the amplitudes of these measures of contingent negative variation or habituation of the early contingent negative variation for three to seven days after a migraine attack without aura (all P > 0.05). Thus, the study reported here found that the periodicity of migraine attacks without aura in adults is more than three days.
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Variação Contingente Negativa/fisiologia , Enxaqueca sem Aura/fisiopatologia , Periodicidade , Adulto , Eletroencefalografia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Several studies have suggested cognitive deficits in migraineurs, and sex differences have also been observed in migraine, such as a higher prevalence in females. Nevertheless, little is known about gender-related differences in cognitive processing. In this study, we aimed to investigate the effect of gender on neurocognitive processing in migraineurs. METHODS: Altogether, 46 migraine patients without aura (23 females; mean age 32.848 years) during the interictal period and 46 age-matched healthy controls (23 females; mean age 32.652 years) were recruited. The emotional characteristics of participants were evaluated, and attentive processing was analyzed via event-related potential examinations using a three-stimulus visual oddball paradigm. RESULTS: We found that migraineurs suffered from emotional and visual cognitive processing abnormalities compared with healthy controls, including higher levels of anxiety and reduced P3 amplitude. These parameters were modulated by gender in migraine patients, but not in healthy participants. Our findings indicated that female patients seemed to be more anxious and have more severe impairment in attentive processing of visual stimuli than their male counterparts. The gender-related differences in migraineurs were further validated using event-related potential difference waveforms. CONCLUSIONS: These results suggested that migraine might have an additional influence on females and lead to more dysfunction in their interictal neurocognitive processing. Our findings provide evidence that a gender effect exists in migraineurs, which should be considered when designing experiments and exploring treatment approaches. The gender-related differences and underlying mechanisms deserve further investigation for patients with migraine.
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Cognição/fisiologia , Potenciais Evocados Visuais/fisiologia , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/fisiopatologia , Caracteres Sexuais , Adulto , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/psicologiaRESUMO
Angiogenesis is recognized as an important hallmark of cancer. Although telomerase is thought to be involved in tumor angiogenesis, the evidence and underlying mechanism remain elusive. Here, we demonstrate that human telomerase reverse transcriptase (hTERT) activates vascular epithelial growth factor (VEGF) gene expression through interactions with the VEGF promoter and the transcription factor Sp1. hTERT binds to Sp1 in vitro and in vivo and stimulates angiogenesis in a manner dependent on Sp1. Deletion of the mTert gene in the first generation of Tert null mice compromised tumor growth, with reduced VEGF expression. In addition, we show that hTERT expression levels are positively correlated with those of VEGF in human gastric tumor samples. Together, our results demonstrate that hTERT facilitates tumor angiogenesis by up-regulating VEGF expression through direct interactions with the VEGF gene and the Sp1 transcription factor. These results provide novel insights into hTERT function in tumor progression in addition to its role in telomere maintenance.
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Neovascularização Patológica/metabolismo , Fator de Transcrição Sp1/metabolismo , Telomerase/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Carcinogênese/metabolismo , Carcinogênese/patologia , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Células HeLa , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica/genética , Neoplasias Gástricas/irrigação sanguínea , Neoplasias Gástricas/genética , Transcrição Gênica , Regulação para Cima/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND/AIMS: Bleomycin is a clinically used anti-cancer drug that produces DNA breaks once inside of cells. However, bleomycin is a positively charged molecule and cannot get inside of cells by free diffusion. We previously reported that the cell surface negatively charged glycosaminoglycans (GAGs) may be involved in the cellular uptake of bleomycin. We also observed that a class of positively charged small molecules has Golgi localization once inside of the cells. We therefore hypothesized that bleomycin might perturb Golgi-operated GAG biosynthesis. METHODS: We used stable isotope labeling coupled with LC/MS analysis of GAG disaccharides simultaneously from bleomycin-treated and non-treated cancer cells. To further understand the cytotoxicity of bleomycin and its relationship to GAGs, we used sodium chlorate to inhibit GAG sulfation and commercially available GAGs to compete for cell surface GAG/bleomycin interactions in seven cell lines including CHO745 defective in both heparan sulfate and chondroitin sulfate biosynthesis. RESULTS: we discovered that heparan sulfate GAG was significantly undersulfated and the quantity and disaccharide compositions of GAGs were changed in bleomycin-treated cells in a concentration- and time-dependent manner. We revealed that bleomycin-induced cytotoxicity was directly related to cell surface GAGs. CONCLUSION: GAGs were targeted by bleomycin both at cell surface and at Golgi. Thus, GAGs might be the biological relevant molecules that might be related to the bleomycin-induced fibrosis in certain cancer patients, a severe side effect with largely unknown molecular mechanism.
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Bleomicina/química , Sulfatos de Condroitina/química , Heparitina Sulfato/química , Animais , Antipirina/análogos & derivados , Antipirina/química , Bleomicina/toxicidade , Células CHO , Sulfatos de Condroitina/análise , Sulfatos de Condroitina/metabolismo , Cromatografia Líquida de Alta Pressão , Cricetinae , Cricetulus , Deutério/química , Edaravone , Células HCT116 , Células HT29 , Heparitina Sulfato/análise , Heparitina Sulfato/metabolismo , Humanos , Marcação por Isótopo , Espectrometria de MassasRESUMO
Chitin is the second most abundant biopolymer on Earth and is mainly comprised of a marine invertebrate, consisting of repeating ß-1,4 linked N-acetylated glucosamine units, whereas its N-deacetylated product, chitosan, has broad medical applications. Interestingly, chitosan oligosaccharides have therapeutic effects on different types of neuronal disorders, including, but not limited to, Alzheimer's disease, Parkinson's disease, and nerve crush injury. A common link among neuronal disorders is observed at a sub-cellular level, such as atypical protein assemblies and induced neuronal death. Chronic activation of innate immune responses that lead to neuronal injury is also common in these diseases. Thus, the common mechanisms of neuronal disorders might explain the general therapeutic effects of chitosan oligosaccharides and their derivatives in these diseases. This review provides an update on the pathogenesis and therapy for neuronal disorders and will be mainly focused on the recent progress made towards the neuroprotective properties of chitosan and acetylated chitosan oligosaccharides. Their structural features and the underlying molecular mechanisms will also be discussed.
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Quitosana/farmacologia , Quitosana/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Oligossacarídeos/farmacologia , Oligossacarídeos/uso terapêutico , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Acetilação , Animais , Humanos , Neurônios/efeitos dos fármacosRESUMO
Acute carbon monoxide (CO) poisoning is the most common cause of death from poisoning all over the world and may result in neuropathologic and neurophysiologic changes. Acute brain damage and delayed encephalopathy are the most serious complication, yet their pathogenesis is poorly understood. The present study aimed to evaluate the neuroprotective effects of Edaravone against apoptosis and oxidative stress after acute CO poisoning. The rat model of CO poisoning was established in a hyperbaric oxygen chamber by exposed to CO. Ultrastructure changes were observed by transmission electron microscopy (TEM). TUNEL stain was used to assess apoptosis. Immunohistochemistry and immunofluorescence double stain were used to evaluate the expression levels of heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf-2) protein and their relationship. By dynamically monitored the carboxyhemoglobin (HbCO) level in blood, we successfully established rat model of severe CO poisoning. Ultrastructure changes, including chromatin condensation, cytoplasm dissolution, vacuoles formation, nucleus membrane and cell organelles decomposition, could be observed after CO poisoning. Edaravone could improve the ultrastructure damage. CO poisoning could induce apoptosis. Apoptotic cells were widely distributed in cortex, striatum and hippocampus. Edaravone treatment attenuated neuronal apoptosis as compared with the poisoning group (P < 0.01). Basal expressions of HO-1 and Nrf-2 proteins were found in normal brain tissue. CO poisoning could activate HO-1/Nrf-2 pathway, start oxidative stress response. After the administration of Edaravone, the expression of HO-1 and Nrf-2 significantly increased (P < 0.01). These findings suggest that Edaravone may inhibit apoptosis, activate the Keapl-Nrf/ARE pathway, and thus improve the ultrastructure damage and neurophysiologic changes following acute CO poisoning.
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Antipirina/análogos & derivados , Encefalopatias/etiologia , Encefalopatias/prevenção & controle , Encéfalo/efeitos dos fármacos , Intoxicação por Monóxido de Carbono/complicações , Fármacos Neuroprotetores/farmacologia , Doença Aguda , Animais , Antipirina/farmacologia , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Encefalopatias/metabolismo , Intoxicação por Monóxido de Carbono/metabolismo , Intoxicação por Monóxido de Carbono/patologia , Edaravone , Heme Oxigenase-1/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: To explore the effect of minimally invasive hematoma aspiration (MIHA) on the c-Jun NH2-terminal kinase (JNK) signal transduction pathway after intracerebral hemorrhage (ICH). METHODS: In this experiment, 300 adult male Wistar rats were randomly and averagely divided into sham-operated group, ICH group and MIHA group. In each group, 60 rats were used in the detection of indexes in this experiment, while the other 40 rats were used to replace rats which reached the exclusion criteria (accidental death or operation failure). In ICH group and MIHA group, ICH was induced by injection of 70 µL of autologous arterial blood into rat brain, while only the rats in MIHA group were treated by MIHA 6 h after ICH. Rats in sham-operated group were injected nothing into brains, and they were not treated either, like rats in ICH group. In each group, six rats were randomly selected to observe their Bederson's scales persistently (6, 24, 48, 72, 96, 120 h after ICH). According to the time they were sacrificed, the remaining rats in each group were divided into 3 subgroups (24, 72, 120 h). The change of brain water content (BWC) was measured by the wet weight to dry weight ratio method. The morphology of neurons in cortex was observed by the hematoxylin-eosin (HE) staining. The expressions of phospho-c-Jun NH2-terminal kinase (pJNK) and JNK in peri-hematomal brain tissue were determined by the immunohistochemistry (IHC) and Western blotting (WB). RESULTS: At all time points, compared with the ICH groups, the expression of pJNK decreased obviously in MIHA groups (p < 0.05), while their Bederson's scales and BWC declined, and neuron injury in the cortex was relieved. The expression level of JNK was not altered at different groups. The data obtained by IHC and WB indicated a high-level of consistency, which provided a certain dependability of the test results. CONCLUSION: The JNK signal transduction pathway could be activated after intracerebral hemorrhage, with the expressions of pJNK increasing. MIHA could relieve the histo-pathological damage of nerve cells, reducing brain edema and neurological deficits, and these neuroprotective effects might be associated with suppression of JNK signal transduction pathway.
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Hemorragia Cerebral/cirurgia , MAP Quinase Quinase 4/metabolismo , Sistema de Sinalização das MAP Quinases , Procedimentos Cirúrgicos Minimamente Invasivos/efeitos adversos , Paracentese/efeitos adversos , Animais , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Hematoma/metabolismo , Hematoma/cirurgia , MAP Quinase Quinase 4/genética , Masculino , Ratos , Ratos WistarRESUMO
OBJECTIVE: To explore the neuroprotective effect and mechanism of picroside II on extracellular regulated protein kinases1/2 (ERK1/2) signal transduction pathway in cerebral ischemia injuryrats. METHODS The middle cerebral artery occlusion (MCAO) model was established by inserting a monofilament into middle cerebral artery. Totally 96 successfully modeled Wistar rats were divided into the modelgroup, the treatment (picroside II) group, the Lipopolysachcaride (LPS) group, and the U0126 group according to random digit table. Each group was further divided into 3 subgroups, i.e. 6, 12, and 24 h sub-groups. Picroside II (20 mg/kg) was peritoneally injected to rats in the treatment group 2 h after ischemia.LPS (20 mg/kg) and Picroside II (20 mg/kg) were peritoneally injected to rats in the LPS group 2 h after ischemia. U0126-EtOH (20 mg/kg)and Picroside II (20 mg/kg) were peritoneally injected to rats in the U0126group 2 h after ischemia. Equal volume of normal saline was peritoneally injected to rats in the control groupand the model group. The neurobehavioral function was evaluated by modified neurological severity score(mNSS) test. The structure of neurons was observed using hematoxylin-eosinstaining (HE) staining. Theapoptotic cells were detected using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The expression of phosphorylated extracellular signal-regulated protein kinase1,2 (pERK1,2) in cortex was detected using immunohistochemistry (IHC) and Western blot. RESULTS: After cerebral ischemia injury neurological impairment score increased, the damage of neuron in the cortical area was aggravated, apoptotic cells increased in the model group as time went by. The expression of pERK1/2 increased more significantly in the model group than in the control group (P <0.05). The damage of neuron in the cortical area was milder, while apoptotic cells decreased, the expression of pERK1f2 obviously decreased more in the treatment group and the U0126 group (P < 0.05). The early damage of neuron in the cortical area was more severe, apoptotic cells and the expression of pERK12 were comparatively higher in early stage of the LPS group, but the expression of pERK1/2 was somewhat decreased in late stage. CONCLUSIONS: Activating ERK12 pathway could mediate apoptosis and inflammatory reactions of neurons after cerebral ischemia injury. Picroside II could protect the nerve system possibly through reducing activation of ERKI2 pathway, inhibiting apoptosis of neurons and inflammation reaction.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Cinamatos/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Glucosídeos Iridoides/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Apoptose , Neurônios/patologia , Distribuição Aleatória , Ratos , Ratos WistarRESUMO
OBJECTIVE: To observe the effects of neuregulin1ß (NRG1ß) on the level of phosphorylated ERK1/2 (p-ERK1/2), and explore the therapeutic mechanism of NRG1ß on the cognitive dysfunction in rats with chronic omethoate poisoning. METHODS: Rats with strong learning and memory ability, 50 in total, were selected by Y-electric maze test. Among which, 15 rats were randomly selected into control group, and the rest 35 rats were used to establish experimental cognitive impairment models by being injected with omethoate subcutaneously. The 30 cases of successful cognitive impairment models were randomly divided into model group and treated group consisting of 15 rats, respectively. Then rats in treated group were injected with NRG1ß into their lateral ventricles, while rats in control and model groups were given equal volume of PBS simultaneously. The cognitive capacity of rats was evaluated with Y-electric maze. The morphology and ultrastructure of hippocampus were observed by hematoxylin eosin (HE) staining and transmission electron microscopy (TEM) respectively. The expression of p-ERK1/2 was determined by immunohistochemical (IHC) staining and Western blotting. RESULTS: Compared with rats in model group, the cognitive ability of rats with omethoate exposed (model and treated groups) reduced significantly, along with the obvious damage of hippocampal neurons and the expression of p-ERK1/2 decreased significantly (P < 0.05). And after treatment with NRG1ß, the cognitive activity of treated rats was improved obviously, and the injury of hippocampal neurons was milder and the expression of p-ERK1/2 increased significantly more than those in model rats (P < 0.05). CONCLUSION: In chronic omethoate poisoning rats, NRG1ß can promote the phosphorylation level of ERK1/2 in hippocampal neurons, and play an important role in the improvement of cognitive function.