RESUMO
In the current study, bioinformatics analysis of the hepatocellular carcinoma (HCC) dataset was conducted with the hepatoprotective effect of the Fuzheng Huayu (FZHY) capsule against the diethylnitrosamine-induced HCC progression analyzed. Eight cell clusters were defined and tanshinone IIA, arachidonic acid, and quercetin, compounds of the FZHY capsule, inhibit HCC progression-related fibrosis by regulating the expression of PLAU and IGFBP3. Combined with the ameliorative effect of the FZHY capsule against liver dysfunctions and expression of PLAU and IGFBP3, our study confirmed the effect of the FZHY capsule on inhibiting the fibrosis-associated HCC progression via regulating the expression of PLAU and IGFBP3.
Assuntos
Carcinoma Hepatocelular , Medicamentos de Ervas Chinesas , Neoplasias Hepáticas , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Carcinoma Hepatocelular/tratamento farmacológico , Animais , Neoplasias Hepáticas/tratamento farmacológico , Estrutura Molecular , Humanos , Masculino , Dietilnitrosamina , Abietanos/farmacologia , Cápsulas , Carcinogênese/efeitos dos fármacos , Quercetina/farmacologia , Cirrose Hepática/tratamento farmacológicoRESUMO
BACKGROUND: The role of physical exercise in the prevention of Alzheimer's disease (AD) has been widely studied. Microglia play an important role in AD. Triggering receptor expressed in myeloid cells 2 (TREM2) is expressed on microglia and is known to mediate microglial metabolic activity and brain glucose metabolism. However, the relationship between brain glucose metabolism and microglial metabolic activity during running exercise in APP/PS1 mice remains unclear. METHODS: Ten-month-old male APP/PS1 mice and wild-type mice were randomly divided into sedentary groups or running groups (AD_Sed, WT_Sed, AD_Run and WT_Run, n = 20/group). Running mice had free access to a running wheel for 3 months. Behavioral tests, [18]F-FDG-PET and hippocampal RNA-Seq were performed. The expression levels of microglial glucose transporter (GLUT5), TREM2, soluble TREM2 (sTREM2), TYRO protein tyrosine kinase binding protein (TYROBP), secreted phosphoprotein 1 (SPP1), and phosphorylated spleen tyrosine kinase (p-SYK) were estimated by western blot or ELISA. Immunohistochemistry, stereological methods and immunofluorescence were used to investigate the morphology, proliferation and activity of microglia. RESULTS: Long-term voluntary running significantly improved cognitive function in APP/PS1 mice. Although there were few differentially expressed genes (DEGs), gene set enrichment analysis (GSEA) showed enriched glycometabolic pathways in APP/PS1 running mice. Running exercise increased FDG uptake in the hippocampus of APP/PS1 mice, as well as the protein expression of GLUT5, TREM2, SPP1 and p-SYK. The level of sTREM2 decreased in the plasma of APP/PS1 running mice. The number of microglia, the length and endpoints of microglial processes, and the ratio of GLUT5+/IBA1+ microglia were increased in the dentate gyrus (DG) of APP/PS1 running mice. Running exercise did not alter the number of 5-bromo-2'-deoxyuridine (BrdU)+/IBA1+ microglia but reduced the immunoactivity of CD68 in the hippocampus of APP/PS1 mice. CONCLUSIONS: Running exercise inhibited TREM2 shedding and maintained TREM2 protein levels, which were accompanied by the promotion of brain glucose metabolism, microglial glucose metabolism and morphological plasticity in the hippocampus of AD mice. Microglia might be a structural target responsible for the benefits of running exercise in AD. Promoting microglial glucose metabolism and morphological plasticity modulated by TREM2 might be a novel strategy for AD treatment.
Assuntos
Doença de Alzheimer , Microglia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/terapia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Cognição , Modelos Animais de Doenças , Glucose/metabolismo , Hipocampo/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismoRESUMO
In view of the negative regulatory effect of leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1) on neurons, an antibody against LINGO-1 (anti-LINGO-1 antibody) was herein administered to 10-month-old APP/PS1 transgenic Alzheimer's disease (AD) mice for 2 months as an experimental intervention. Behavioral, stereology, immunohistochemistry and immunofluorescence analyses revealed that the anti-LINGO-1 antibody significantly improved the cognitive abilities, promoted adult hippocampal neurogenesis (AHN), decreased the amyloid beta (Aß) deposition, enlarged the hippocampal volume, and increased the numbers of total neurons and GABAergic interneurons, including GABAergic and CCK-GABAergic interneurons rich in cannabinoid type 1 receptor (CB1R), in the hippocampus of AD mice. In contrast, this intervention significantly reduced the number of GABAergic interneurons expressing LINGO-1 and CB1R in the hippocampus of AD mice. More importantly, we also found a negative correlation between LINGO-1 and CB1R on GABAergic interneurons in the hippocampus of AD mice, while the anti-LINGO-1 antibody reversed this relationship. These results indicated that LINGO-1 plays an important role in the process of hippocampal neuron loss in AD mice and that antagonizing LINGO-1 can effectively prevent hippocampal neuron loss and promote AHN. The improvement in cognitive abilities may be attributed to the improvement in AHN, and in the numbers of GABAergic interneurons and CCK-GABAergic interneurons rich in CB1Rs in the hippocampus of AD mice induced by the anti-LINGO-1 antibody. Collectively, the double target effect (LINGO-1 and CB1R) initiated by the anti-LINGO-1 antibody may provide an important basis for the study of drugs for the prevention and treatment of AD in the future.
Assuntos
Anticorpos Monoclonais/farmacologia , Disfunção Cognitiva/metabolismo , Neurônios GABAérgicos/metabolismo , Hipocampo/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Anticorpos Monoclonais/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Neurônios GABAérgicos/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Masculino , Proteínas de Membrana/antagonistas & inibidores , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Receptor CB1 de Canabinoide/genética , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismoRESUMO
Background: Ketamine has been shown to possess lasting antidepressant properties. However, studies of the mechanisms involved in its effects on poststroke depression are nonexistent. Methods: To investigate these mechanisms, Sprague-Dawley rats were treated with a single local dose of ketamine after middle cerebral artery occlusion and chronic unpredicted mild stress. The effects on the hippocampal dentate gyrus were analyzed through assessment of the N-methyl-D-aspartate receptor/calcium/calmodulin-dependent protein kinase II (NMDAR/CaMKII) pathway, synaptic plasticity, and behavioral tests. Results: Ketamine administration rapidly exerted significant and lasting improvements of depressive symptoms. The biochemical analysis showed rapid, selective upregulation and downregulation of the NMDAR2-ß and NMDAR2-α subtypes as well as their downstream signaling proteins ß-CaMKII and α-phosphorylation in the dentate gyrus, respectively. Furthermore, the colocalization analysis indicated a significant and selectively increased conjunction of ß-CaMKII and postsynaptic density protein 95 (PSD95) coupled with a notable decrease in NMDAR2-ß association with PSD95 after ketamine treatment. These changes translated into significant and extended synaptic plasticity in the dentate gyrus. Conclusions: These findings not only suggest that ketamine represents a viable candidate for the treatment of poststroke depression but also that ketamine's lasting antidepressant effects might be achieved through modulation of NMDAR/CaMKII-induced synaptic plasticity in key brain regions.
Assuntos
Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Depressão/tratamento farmacológico , Ketamina/farmacologia , Ketamina/uso terapêutico , Plasticidade Neuronal/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Acidente Vascular Cerebral/fisiopatologia , Sinapses/efeitos dos fármacos , Animais , Giro Denteado/fisiopatologia , Depressão/etiologia , Proteína 4 Homóloga a Disks-Large/genética , Infarto da Artéria Cerebral Média/complicações , Masculino , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/complicações , Estresse Psicológico/fisiopatologia , Acidente Vascular Cerebral/complicaçõesRESUMO
BACKGROUND: Hyperglycemia impaired hippocampal network via triggering suicide program of immanent neurons, this is regarded as an etiological factor for diabetic cognition deficits. AIM: To investigate the occurrence of apoptosis in the hippocampal dentate gyrus of streptozotocin (STZ)-induced diabetic rats with cognitive impairment and assess the gene and protein expression of the apoptotic proteins bax, bcl-2, and caspase-3. MATERIALS AND METHODS: Four weeks after the verification of STZ-induced diabetes, diabetic rats with and without cognitive decline subgroups were subsequently assigned according to Morris water maze test. The expression levels of apoptotic proteins were measured using real-time RT-PCR and western blotting, respectively. Neuronal apoptosis was detected by TUNEL staining and electron microscopy. RESULTS: In the dentate gyrus of the rats with cognitive decline, Bcl-2 exhibited lower gene and protein levels, whereas a higher expression of bax was detected contributing to a significant increase in their mean bax/bcl-2 ratio. However, caspase-3 was not activated. Statistically different numbers of TUNEL-staining cells and features of apoptosis were no found. CONCLUSIONS: The higher bax/bcl ratio probably represents neurons of dentate gyrus vulnerable to apoptosis in the diabetes with cognitive decline. However, the normal caspase-3 level suggests that apoptosis is not active in this illness phase.
Assuntos
Apoptose/fisiologia , Transtornos Cognitivos/metabolismo , Giro Denteado/patologia , Diabetes Mellitus Experimental/patologia , Animais , Caspase 3/biossíntese , Giro Denteado/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Masculino , Aprendizagem em Labirinto , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Proteína X Associada a bcl-2/metabolismoRESUMO
Spastic paraplegia type 4 (SPG4), the predominant form of Autosomal Dominant Hereditary spastic paraplegia (AD-HSP), is characterized by variants in the SPAST gene. This study reports a unique case of a late-onset SPG4 in a Han Chinese male, manifesting primarily as gait disturbances from lower extremity spasticity. Uncovered through whole-genome sequencing, a previously undocumented frameshift variant, c.1545dupA in exon 14 of the SPAST gene, was identified. Notably, this variant was absent in asymptomatic parents with confirmed paternity and maternity status, suggesting a de novo variant occurrence. This discovery emphasizes the potential of de novo variants to exhibit a late-onset pure pattern, extending the SPG4 variant spectrum, and consideration of such variants should be given in HSP patients with a negative family history.
RESUMO
Pathological changes in the medial prefrontal cortex (mPFC) and astrocytes are closely associated with Alzheimer's disease (AD). Voluntary running has been found to effectively delay AD. However, the effects of voluntary running on mPFC astrocytes in AD are unclear. A total of 40 10-month-old male amyloid precursor protein/presenilin 1 (APP/PS1) mice and 40 wild-type (WT) mice were randomly divided into control and running groups, and the running groups underwent voluntary running for 3 months. Mouse cognition was assessed by the novel object recognition (NOR), Morris water maze (MWM), and Y maze tests. The effects of voluntary running on mPFC astrocytes were investigated using immunohistochemistry, immunofluorescence, western blotting, and stereology. APP/PS1 mice performed significantly worse than WT mice in the NOR, MWM, and Y maze tests, and voluntary running improved the performance of APP/PS1 mice in these tests. The total number of mPFC astrocytes was increased, cell bodies were enlarged, and protrusion number and length were increased in AD mice compared with WT mice, but there was no difference in component 3 (C3) levels in the mPFC (total mPFC level); however, C3 and S100B levels in astrocytes were increased in AD mice. Voluntary running reduced the total number of astrocytes and S100B levels in astrocytes and increased the density of PSD95+ puncta in direct contact with astrocyte protrusions in the APP/PS1 mouse mPFC. Three months of voluntary running inhibited astrocyte hyperplasia and S100B expression in astrocytes, increased the density of synapses in contact with astrocytes, and improved cognitive function in APP/PS1 mice.
Assuntos
Doença de Alzheimer , Astrócitos , Cognição , Condicionamento Físico Animal , Córtex Pré-Frontal , Corrida , Masculino , Animais , Camundongos , Camundongos Transgênicos , Astrócitos/patologia , Córtex Pré-Frontal/patologia , Sinapses , Modelos Animais de Doenças , Doença de Alzheimer/patologiaRESUMO
We investigated the hypothesis that hippocampal neurogenesis related to Notch1 signaling could be a valid index for a combined citalopram and WAY100635 pharmacotherapy for the treatment of depression arising after stroke. Adult rats were exposed to a chronic mild stress paradigm after ischemic surgery. Behavioral tests included the open-field test and a sucrose consumption test. Proliferating cells in the hippocampus ipsilateral to ischemia and their fate were monitored by bromodeoxyuridine labeling and confocal laser scanning microscopy for up to 28 days (day 28) after ischemia. Expression of the Notch1 signaling cascade, including its ligand and downstream target genes, was also examined. WAY100635 shortened the onset of citalopram action to less than the day 21 required with citalopram alone and also proved more effective. The activity of the Notch1 signaling pathway in the hippocampus fluctuated in its function in proliferation (day 21) and differentiation (day 28) of newly formed cells in animals receiving the combination treatment. This indicated that augmentation of citalopram by cotreatment with a selective 5-hydroxytryptamine 1A antagonist would be an efficacious strategy for poststroke depression. The observed effects are most likely because of enhanced poststroke neurogenesis mediated by the Notch1 signaling cascade.
Assuntos
Citalopram/administração & dosagem , Depressão/tratamento farmacológico , Hipocampo/metabolismo , Infarto da Artéria Cerebral Média/complicações , Neurogênese/efeitos dos fármacos , Piperazinas/administração & dosagem , Piridinas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Depressão/complicações , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptor Notch1/genética , Receptor Notch1/metabolismo , Antagonistas da Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagemRESUMO
Isolated cerebral mucormycosis is a clinical type of mucormycosis that is estimated to account for 8% of all mucormycosis cases. The clinical symptoms of isolated cerebral mucormycosis are elusive, and thus conventional techniques often lake sensitivity and specificity. Moreover, cultures are often negative, even when direct microscopy examination is positive. Although histopathology will probably remain the gold standard for the diagnosis of mucormycosis, obtaining a biopsy specimen is not always feasible in most vulnerable populations. Thus, molecular approaches are currently used as an advantageous assistant examination method to improve the early identification of the causative agent and subsequently guide therapy to improve the prognosis of patients. Here, we report a case of isolated cerebral mucormycosis caused by Rhizopus microspores in a healthy young adult that was identified using next-generation sequencing technology.
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Plantaginis Semen (PS) is well recognized in traditional Chinese medicine (TCM) and health products. Crude PS (CPS) and salt-processed CPS (SPS) are the two most commonly used decoction pieces of PS, and are included in the 2020 edition of Chinese Pharmacopoeia. Although they all have multiple effects, the mechanisms for treating diseases are different and remain unclear, the processing mechanism of SPS is also indeterminate, which hinders their clinical application to a certain extent. In order to solve these problems and further develop PS in the clinical application. Here, we used saline-loaded model rats for experiments, and utilized an integrated approach consisting of pharmacological methods and metabolomics, which could assess the diuretic impact of CPS and SPS ethanol extracts on saline-loaded rats and elucidate the underlying mechanism. The results showed that CPS and SPS both produced increased urine volume excretion and urine electrolyte excretion, but the levels of aldosterone (ALD) and aquaporin 2 (AQP2) were decreased. And 30 differential metabolites such as linoleic acid, lysoPC(O-18:0), sphingosine-1-phosphate, lysoPC(18:0) were found, mainly involving three metabolic pathways. In conclusion, CPS and SPS both have a diuretic effect, and that of SPS is better. This work investigated the possible diuretic mechanisms of CPS and SPS which may also be the mechanism of PS for anti-hypertension. In addition, a holistic approach provided novel and helpful insights into the underlying processing mechanisms of TCM.
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Alterations of serotonin (5-HT) neurotransmission are implicated in post-stroke depression (PSD). Serotonin 1A (5-HT(1A)) receptor-based abnormalities have been the focus of intensive study in depression. Here we investigated the expression of the 5-HT(1A) receptor and gene in the hippocampal dentate gyrus (DG) by chronic mild stress (CMS) after stroke and the effect of citalopram. Male Sprague-Dawley rats were separated into control, stress only, ischemic stroke, PSD and citalopram-treated groups. The putative PSD animal model involved cerebral ischemia induced by left middle cerebral artery occlusion (MCAO) followed by exposure to CMS combined with single housing. All animals were assessed for depression-like behavior. The 5-HT(1A) receptor and mRNA level in DG were quantified by Western immunoblotting and Real-time RT-PCR, respectively, on the 19th and 28th days after initiating CMS. PSD animals displaying a behavioral index of depression (anhedonia) have significantly decreased protein expression of 5-HT(1A) receptors and mRNA level relative to ischemic stroke animals at each timepoint, respectively, and all these were reversed by citalopram. The dysfunction of the of 5-HT(1A) receptor in DG may play an important role in the pathogenesis of PSD and become a potential target for therapeutic intervention in the rat. The results provide partial support for the psychosocial and biological etiology of PSD and further predict the etiologic validity of the PSD model.
Assuntos
Giro Denteado/metabolismo , Depressão/patologia , Regulação para Baixo/fisiologia , Receptor 5-HT1A de Serotonina/metabolismo , Estresse Psicológico/patologia , Animais , Citalopram/farmacologia , Citalopram/uso terapêutico , Giro Denteado/efeitos dos fármacos , Depressão/tratamento farmacológico , Depressão/etiologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Comportamento Exploratório , Preferências Alimentares/efeitos dos fármacos , Lateralidade Funcional , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/genética , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Estresse Psicológico/fisiopatologia , Acidente Vascular Cerebral/complicações , Fatores de TempoRESUMO
Stress and antidepressants have been shown to influence hippocampal neurogenesis, which is hypothesized to be an etiological factor of depression. Robust ischemia-stimulated neurogenesis implies the existence of an innate response and rehabilitation mechanism to injury repair, i.e. cognitive recovery. We investigated whether unpredictable chronic mild stress (CMS) influences ischemia-stimulated compensatory neurogenesis in the hippocampus and also studied the therapeutic effect of citalopram. Adult rats were exposed to the CMS paradigm after left middle cerebral artery occlusion (MCAO). The open-field test (OFT) and the sucrose consumption test were employed to assess depression-like behaviour. The survival and fate of proliferating cells was monitored by labelling with bromodeoxyuridine (BrdU) and other cell markers. Cell proliferation was examined 1 day after the last BrdU injection, and survival and differentiation were determined up to 45 days after ischemia. The number of BrdU-positive cells that were labelled using the 2 protocols and the proportion of newborn neurons in the dentate gyrus (DG) ipsilateral to ischemia were higher than in the control. CMS induced depressive behaviours in ischemic rats, and this was accompanied by reduced proliferation and survival/neurogenic fate. All these effects were reversed by citalopram administration. These results support a putative role for ischemia-induced neurogenesis in what may be an adaptive or compensatory process, which is influenced by post-stroke stressors. This may contribute to the onset of Post-stroke depression (PSD) and thus represents a potential target for therapy.
Assuntos
Isquemia Encefálica/patologia , Comportamento Exploratório/fisiologia , Hipocampo/citologia , Neurônios/citologia , Estresse Psicológico/patologia , Adaptação Fisiológica/efeitos dos fármacos , Adaptação Psicológica/fisiologia , Animais , Antidepressivos de Segunda Geração/farmacologia , Isquemia Encefálica/complicações , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Doença Crônica , Citalopram/farmacologia , Depressão/prevenção & controle , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/patologia , Masculino , Análise por Pareamento , Atividade Motora/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Estresse Psicológico/complicaçõesRESUMO
OBJECTIVE: To detect the expression patterns of Notch(1) and Jagged(1) in the hippocampus of focal ischemia and find out whether the Notch pathway is involved in the regulation of the differentiation of the proliferated neural precursor cells in the dentate gyrus under ischemic conditions. METHODS: 42 SD rats were randomly divided into 3 equal groups: middle cerebral artery occlusion (MCAO) group undergoing MCAO by intraluminal thread technique so as to cause focal cerebral infarction, sham operation group, and normal control group.19 and 28 days after the operation 6 rats in each group were killed with their hippocampus taken out. The protein and mRNA levels of Notch(1) and Jagged(1) in hippocampus were assayed respectively by Western blotting and real-time reverse-transcription PCR. RESULTS: The protein and mRNA expression levels of Notch(1) on the 19th day of the MCAO group were up-regulated, both significantly higher than those of the sham operation and control groups (all P < 0.05). The protein and mRNA expression levels of Notch(1) on the 28th day of the MCAO group were both significantly lower than those of the same group on the 19th day (both P < 0.01), and were lower than those of the sham operation and control groups on the 28th day, however, not significantly (all P > 0.05). The protein and mRNA expression levels of Jagged(1) on the 19th and 28th days of the MCAO group were significantly higher than those of the sham and control groups (all P < 0.05), however, there were not significant differences in the protein and mRNA expression levels of Jagged(1) on the 19th and 28th days of the MCAO group (all P > 0.05). CONCLUSION: The protein and gene expression of Notch(1) and Jagged(1) vary dynamically in the hippocampus of focal ischemia, which suggests that the Notch pathway may be a potential mechanism in the regulation of the neurogenesis in the dentate gyrus of hippocampus.
Assuntos
Isquemia Encefálica/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Hipocampo/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/metabolismo , Receptor Notch1/metabolismo , Animais , Isquemia Encefálica/fisiopatologia , Proteínas de Ligação ao Cálcio/genética , Regulação da Expressão Gênica , Hipocampo/fisiopatologia , Infarto da Artéria Cerebral Média/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteína Jagged-1 , Masculino , Proteínas de Membrana/genética , Ratos , Ratos Sprague-Dawley , Receptor Notch1/genética , Proteínas Serrate-Jagged , Transdução de SinaisRESUMO
OBJECTIVE: To survey the effects of citalopram on proliferation and differentiation of neural precursor cells (NPCs) from embryonic rat hippocampus. METHODS: Single cell suspensions were prepared from the hippocampus of 14.5 days embryos rat. After formation of the primary neurospheres, single cell clone was obtained with limited dilution method. Then the single cell clone spheres were digested and induced to proliferate and differentiate using non-serum medium and bovine serum. The effects of varied concentration citalopram on the proliferation and differentiation of NPCs were investigated by using mononuclear cell direct cytotoxicity (MTT) reduction assay and immunofluorescence method respectively. RESULTS: MTT showed that citalopram (1.0 micromol/L) could increase the absorbance (A(570) nm) from 3 days to 7 days after intervention significantly (all P < 0.0001). Immunofluorescence showed that percentage of NeuN positive cells were 59.5% +/- 2.8% and 57.8% +/- 2.1% respectively after 7-day intervention of 1.0 micromol/L and 0.5 micromol/L citalopram, more than 47.3% +/- 4.3% of control group (all P < 0.05). CONCLUSION: Citalopram promotes proliferation and differentiation of NPCs from embryonic rat hippocampus.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citalopram/farmacologia , Células-Tronco Embrionárias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Células-Tronco Embrionárias/citologia , Feminino , Imunofluorescência , Hipocampo/citologia , Hipocampo/embriologia , Neurônios/citologia , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: To establish an animal model of post-stroke depression (PSD) and assess the effects of citalopram on PSD. METHODS: Fifty-two male SD rats were randomly divided into 3 groups. Normal group (n = 6) underwent sham operation. Chronic unpredictable mild stress (CMS) group (n = 6), underwent separate raising and CMS. Middle cerebral artery occlusion (MCAO) group (n = 24) underwent MCAO and then re-divided into 3 equal subgroups: stroke subgroup, PSD model subgroup (undergoing isolated raising and CMS so as to establish PSD models), and citalopram subgroup (treated with intraperitoneal injection of citalopram, a selective serotonin reuptake inhibitor for 6 weeks). The rats were examined dynamically at the 19th, 28th, and 42nd days after CMS by open-field test (OFT) and sucrose consumption test. RESULTS: On the 19th day after CMS the locomotor activity score of the PSD models was significantly lower (P < 0.001 compared to the baseline level of the same subgroup and to those of the control and stroke rats, P < 0.01 compared to the CMS group); and the frequency of rearing score of the PSD models was significantly decreased (P < 0.001 compared to its baseline level and to those of the control and stroke groups, and P < 0.05 compared to the CMS group). During the days 19 - 42, the frequency of locomotor and exploratory activities of the PSD model rats declined continually, from 37.8 +/- 1.7 to 34.2 +/- 1.2 and from 9.7 +/- 0.8 to 7.8 +/- 0.8 respectively, showing a tendency in just the reverse direction in the CMS group (from 41.0 +/- 1.3 to 42.3 +/- 0.8 and from 11.2 +/- 0.4 to 11.7 +/- 0.8 respectively). The PSD rats showed a reduction in sucrose preference at week 3 and afterwards (P < 0.001 compared with other groups). The levels of open-field activities and proportion of rats with sucrose preference in the citalopram subgroup were all significantly higher than those in other groups (all P < 0.001). CONCLUSION: Anhedonia and underactivity, the core symptoms in the PSD patients, can be found completely and persistently in the PSD rats. With good operability and repeatability, the PSD rat model is an ideal model for PSD research. Citalopram can improve the behavior abnormality in PSD.
Assuntos
Comportamento Animal/efeitos dos fármacos , Citalopram/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Animais , Isquemia Encefálica/complicações , Citalopram/farmacologia , Transtorno Depressivo/etiologia , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
The research of alternative treatment for ischemic stroke and degenerative diseases has always been a priority in neurology. 3-N-Butylphthalide (NBP), a family of compounds initially isolated from the seeds of Apium graveolens Linn., has shown significant neuroprotective effects. Previous extensive studies have demonstrated that NBP promotes a better poststroke outcome and exerts a multitargeted action on several mechanisms, from oxidative stress to mitochondrial dysfunction to apoptosis to inflammation. Additionally, recent findings on several neurological disorders have shown that NBP's beneficial effects extend beyond the management of stroke. However, despite the increasing number of studies toward a better understanding and the rapid advances made in therapeutic options, to date, dl-3-N-butylphthalide, a synthetic variation of l-3-N-butylphthalide, remains the only clinically approved anti-ischemic agent in China, stressing the difficulties for a viable and effective transition from experimental to clinical practice. Events indicate that NBP, due to its multitargeted effect and the adaptability of its basic structure, can be an important game changer and a precursor to a whole new therapeutic approach to several neurological conditions. The present review discusses recent advances pertaining to the neuroprotective mechanisms of NBP-derived compounds and the possibility of their clinical implementation in the management of various neurological conditions.
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Benzofuranos/uso terapêutico , Inflamação/tratamento farmacológico , Doenças do Sistema Nervoso/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Apium/química , Apoptose/efeitos dos fármacos , Humanos , Inflamação/patologia , Doenças do Sistema Nervoso/patologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/uso terapêuticoRESUMO
BACKGROUND: Problem/case-based learning (PCBL) is one of the most commonly used educational methods in medical schools. AIM: To further improve PCBL in clinical course of severe infection by introducing competition mode. METHODS: Two classes of medical students were divided into two groups by class-based simple randomization and were taught the course of severe infection by PCBL. A team-based competition was introduced in the study group (n = 35) while not in the control group (n = 36). After the course, four closely associated references were recommended. All the students were notified about a group consultation on a similar case. In the final examination, a case with severe infection complicated with infectious shock was presented for the students to analyze and resolve listed questions. Their performances were qualitatively evaluated to justify the effectiveness of the competition-based PCBL. RESULTS: The students in the study group were more active and initiative in case discussion and interaction, in referring to case-related articles and attending clinical group-consultation. They had better performance in the case analysis in the final examination. The typical case analysis test easily figured out more excellent students in the study group. CONCLUSIONS: The PCBL with competition mode introduced in is an effective approach to guide students to fully understand the clinical diagnoses and treatment of severe infection. It also prompts medical students' initiative in referring to case-related articles and attending group-consultation, both of which are essential to equip medical students with sufficient competency for clinical practice.
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BACKGROUND: Hyperglycaemia is common among patients with critical neurological injury, even if they have no history of diabetes. The optimal target range for normalizing their blood glucose is unknown. METHODS: Retrospective data were extracted from 890 hyperglycaemic individuals (glucose > 200 mg/dL) admitted to neuroscience critical care unit (NCCU) and these patients were divided into two groups: intensive glucose control group with target glucose of < 140 mg/dL achieved and moderate control with glucose levels 140-180 mg/dL. The groups were also stratified according to the hyperglycaemia type (pre-existing diabetes or stress-related). We defined the primary endpoint as death from any cause during NCCU admission. RESULTS: In NCCU, tighter control of blood glucose at ≤ 140 mg/dL was associated with increased, mortality of individuals with pre-existing diabetes compared with moderate control [29 of 310 patients (9.4%) vs 15 of 304 patients (4.9%), p = 0.034]. Patient age [adjusted odds ratio (OR) = 1.12; 95% confidence interval (CI) = 1.05-1.19; p < 0.001], level of glycated haemoglobin (adjusted OR = 1.24; 95% CI = 1.04-1.48; p = 0.017) and hypoglycaemia (adjusted OR = 10.3; 95% CI = 2.92-36.6; p < 0.001) were positively associated with higher mortality. Death rate was lower among stress-related hyperglycaemic patients with tighter glucose controlled at ≤ 140 mg/dL [6 of 140 patients (4.3%) vs 15 of 136 patients (11.0%), p = 0.035]. CONCLUSION: A differential association is evident between glucose levels and mortality in diabetes and stress-related hyperglycaemia patients. However, given the observational nature of our work, no clinical recommendations can be given and prospective studies are required to further investigate these findings.
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Glicemia/efeitos dos fármacos , Cuidados Críticos , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Doenças do Sistema Nervoso/terapia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Glicemia/metabolismo , Distribuição de Qui-Quadrado , Estado Terminal , Feminino , Mortalidade Hospitalar , Humanos , Hiperglicemia/sangue , Hiperglicemia/diagnóstico , Hiperglicemia/mortalidade , Unidades de Terapia Intensiva , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/mortalidade , Razão de Chances , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Accumulating evidence indicates that dyslipidaemia plays an important role in the progression of kidney disease in patients with diabetes. Hyperlipidaemia is a risk factor for microalbuminuria in patients with diabetes. Little information exists on the prevalence and control of dyslipidaemia among diabetic patients with microalbuminuria in China. The aims of this study were to investigate the prevalence and control of dyslipidaemia among diabetic patients with microalbuminuria in a Chinese hospital as well as factors affecting the disease. METHODS: A total of 1060 type 2 diabetic inpatients were assigned to the with-microalbuminuria group (n = 635) or the without-microalbuminuria group on the basis of urinary albumin-to-creatinine ratios (UACRs = 30-299 mg/g). Serum levels and the control of lipid profiles were assessed and classified according to the 2011 American Diabetes Association (ADA) guidelines, and low-density lipoprotein-cholesterol (LDL-C) was also assessed and classified according to Chinese intensified control criteria. Multiple regression analyses were performed to examine the factors affecting lipid variables. RESULTS: Among patients with microalbuminuria, a significantly lower prevalence was found (33.1% vs. 58.6%; 35.3% vs. 52.5%, all p < 0.001) at target levels [LDL-C < 2.60 mmol/L or high-density lipoprotein-cholesterol (HDL-C) > 1.0 mmol/L for men and >1.3 mmol/L for women]. According to the intensified LDL-C goal (<2.07 mmol/L), a lower prevalence was found in male patients (15.5% vs. 32.7%, p < 0.001). Fewer patients with microalbuminuria were adherent to the therapy prescribed for dyslipidaemia (28.8% vs. 43.3%, p < 0.001). Even among patients who were on lipid-lowering treatment, the majority of individuals remained uncontrolled for all three lipid fractions [LDL-C, HDL-C and triglyceride (TG)] (82.5% vs. 69.0%, p = 0.003). Lipid and lipoprotein parameters were associated with gender and age. CONCLUSION: In China, diabetic patients with microalbuminuria displayed typical dyslipidaemias and were not adequately controlled. Intensified LDL-C and overall lipid-lowering clinical goals are potential precautions taken against diabetic nephropathy.
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Albuminúria/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Dislipidemias/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Albuminúria/etiologia , China/epidemiologia , LDL-Colesterol/sangue , Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Feminino , Humanos , Hipolipemiantes/uso terapêutico , Masculino , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Resultado do TratamentoRESUMO
AIMS: To investigate the roles of PPARγ in advanced glycation end product (AGE)-mediated characteristics of neural stem cells (NSCs) and the molecular mechanisms of action. METHODS: We prepared pLentiLox3.7 lentiviral vectors expressing short hairpin RNA (shRNA) against PPARγ and transduced NSCs. MTT absorbance and cell counts were used to assay cell growth, and cell differentiation was analysed by confocal laser-scanning and western blots for the expression of MAP2/nestin. The protein and gene expression of the BDNF-CREB pathway components were examined by western blotting and real-time PCR. RESULTS: Immunoblot analysis indicated that shRNA delivered by lentiviral vectors silenced PPARγ expression in NSCs. The proliferation of NSCs and expression of BDNF pathway components dropped in AGE-BSA culture medium (400 mg/L and 200 mg/L) on Day 3 and Day 7, respectively (all P<0.001). PPARγ-silenced NSCs exhibited a significant increase in cell growth and expression of BDNF pathway components compared with NSCs incubated with AGE-BSA (all P<0.001). Immunocytochemistry and western blotting analysis showed that AGE-BSA (400 mg/L) induced a significant decrease in the expression of MAP2 both in NSCs and PPARγ-silenced NSCs, as standardised by nestin. There was no significant difference between NSCs and PPARγ-silenced NSCs in the presence of AGE-BSA. CONCLUSIONS: PPARγ plays roles in the AGE-mediated regulation of NSC proliferation but not neural differentiation through the BDNF-CREB pathway.