RESUMEN
Cholinergic system dysfunction has been considered as a critical feature of neurodegenerative progression in Alzheimer's disease (AD). The α7 nicotinic acetylcholine receptors (α7-nAChRs) are widely expressed in the hippocampus cortex and play an important role in memory formation, considered as potential therapeutic agents targets. However, underlying mechanisms have not been fully elucidated. Here, we combine behavioral, molecular biological methods with in vitro slice and in vivo multichannel electrophysiological recording techniques to investigate the molecular, cellular synaptic and neuronal mechanisms of activating α7-nAChR by PHA-543613 (a selective α7-nAChR agonist), which influences the impaired cognitive function using presenilin 1 (PS1) and presenilin 2 (PS2) conditional double knockout (cDKO) mice. Our results demonstrated that PHA-543613 treatment significantly improved the impaired hippocampus-related memory via recovering the reduced the hippocampal synaptic protein levels of α7-nAChR, NMADAR and AMPAR, thereby restoring the impaired post-tetanic potentiation (PTP), long-term potentiation (LTP), activation of molecular signaling pathway for neuronal protection, theta power and strength of theta-gamma phase-amplitude coupling (PAC) at hippocampus in 6-month-old cDKO mice. For the first time, we systematically reveal the mechanisms by which PHA-543613 improves memory deficits at different levels. Therefore, our findings may be significant for the development of therapeutic strategies for AD.
Asunto(s)
Enfermedad de Alzheimer , Receptor Nicotínico de Acetilcolina alfa 7 , Ratones , Animales , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Presenilina-1/genética , Presenilina-1/metabolismo , Presenilina-2/genética , Presenilina-2/metabolismo , Ratones Noqueados , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Hipocampo/metabolismo , Enfermedad de Alzheimer/metabolismoRESUMEN
Traumatic stress exposure can form persistent trauma-related memories. However, only a minority of individuals develop post-traumatic stress disorder (PTSD) symptoms upon exposure. We employed a rat model of PTSD, which enables differentiating between exposed-affected and exposed-unaffected individuals. Two weeks after the end of exposure, male rats were tested behaviorally, following an exposure to a trauma reminder, identifying them as trauma 'affected' or 'unaffected.' In light of the established role of hippocampal synaptic plasticity in stress and the essential role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in hippocampal based synaptic plasticity, we pharmacologically inhibited CaMKII or knocked-down (kd) αCaMKII (in two separate experiments) in the dorsal dentate gyrus of the hippocampus (dDG) following exposure to the same trauma paradigm. Both manipulations brought down the prevalence of 'affected' individuals in the trauma-exposed population. A day after the last behavioral test, long-term potentiation (LTP) was examined in the dDG as a measure of synaptic plasticity. Trauma exposure reduced the ability to induce LTP, whereas, contrary to expectation, αCaMKII-kd reversed this effect. Further examination revealed that reducing αCaMKII expression enables the formation of αCaMKII-independent LTP, which may enable increased resilience in the face of a traumatic experience. The current findings further emphasize the pivotal role dDG has in stress resilience.
RESUMEN
Growing evidence has suggested the poor correlation between brain amyloid plaque and Alzheimer's disease (AD). Presenilin1 (PS1) and presenilin2 (PS2) conditional double knockout (cDKO) mice exhibited the reduced 42-amino acid amyloid-ß peptide (Aß1-42) level and AD-like symptoms, indicating a different pathological mechanism from the amyloid cascade hypothesis for AD. Here we found that exogenous synthetic Aß1-42 monomers could improve the impaired memory not only in cDKO mice without Aß1-42 deposition but also in the APP/PS1/Tau triple transgenic 3 × Tg-AD mice with Aß1-42 deposition, which were mediated by α7-nAChR. Our findings demonstrate for the first time that reduced soluble Aß1-42 level is the main cause of cognitive dysfunction in cDKO mice, and support the opinions that low soluble Aß1-42 level due to Aß1-42 deposition may also cause cognitive deficits in 3 × Tg-AD mice. Therefore, "loss-of-function" of Aß1-42 should be avoided when designing therapies aimed at reducing Aß1-42 burden in AD.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides , Precursor de Proteína beta-Amiloide , Animales , Cognición , Modelos Animales de Enfermedad , Ratones , Ratones Transgénicos , Fragmentos de Péptidos , Placa Amiloide/patología , Presenilina-1/genéticaRESUMEN
AIMS: Propofol, the most commonly used intravenous anesthetic, is known for its protective effect in various human and animal disease models such as post-traumatic stress disease (PTSD). However, it still needs efforts to clarify the effect of propofol on fear memory extinction and the relevant mechanisms. METHODS: Fear memory extinction was examined in PTSD mice model. Thirty-six mice were randomly divided into three groups: a shock + propofol group (sh + Pro), shock + normal saline group (sh + NS), and sham group. The mice were treated with propofol (150 mg/kg) or normal saline (of the same volume) intraperitoneally 30 min after the conditioning. These mice's behavior was analysed with contextual test, sucrose preference test (SPT) and Morris water maze (MWM). Additionally, the synaptic plasticity of the hippocampus was examined by long-term potentiation (LTP) and long-term depression (LTD). KEY FINDINGS: Compared with the sham group, the sh + NS group showed increased freezing time and depressive behavior, meanwhile the sh + Pro group showed minor behavioral changes. What's more, we found that propofol rescued the impaired long-term potentiation (LTP) and long-term depression (LTD) in hippocampus of PTSD mice. All these suggest that propofol can accelerate fear memory extinction and change synaptic plasticity of PTSD mice. SIGNIFICANCE: The study proved that propofol can protect the mice from PTSD by reserving synaptic plasticity and brought a new insight into PTSD treatment indicating that propofol maybe a potential cure for PTSD.
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Hipocampo/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Propofol/uso terapéutico , Trastornos por Estrés Postraumático/tratamiento farmacológico , Animales , Hipocampo/fisiología , Hipnóticos y Sedantes/farmacología , Hipnóticos y Sedantes/uso terapéutico , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Masculino , Aprendizaje por Laberinto/fisiología , Memoria/fisiología , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal/fisiología , Propofol/farmacología , Trastornos por Estrés Postraumático/fisiopatología , Trastornos por Estrés Postraumático/psicologíaRESUMEN
Post-traumatic stress disorder (PTSD) is a psychiatric disorder that afflicts many individuals. However, its molecular and cellular mechanisms remain largely unexplored. Here, we found PTSD susceptible mice exhibited significant up-regulation of alpha-Ca2+/calmodulin-dependent kinase II (αCaMKII) in the lateral amygdala (LA). Consistently, increasing αCaMKII in the LA not only caused PTSD-like behaviors such as impaired fear extinction and anxiety-like behaviors, but also attenuated N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD) at thalamo-lateral amygdala (T-LA) synapses, and reduced GluA1-Ser845/Ser831 dephosphorylation and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization. Suppressing the elevated αCaMKII to normal levels completely rescued both PTSD-like behaviors and the impairments in LTD, GluA1-Ser845/Ser831 dephosphorylation, and AMPAR internalization. Intriguingly, deficits in GluA1-Ser845/Ser831 dephosphorylation and AMPAR internalization were detected not only after impaired fear extinction, but also after attenuated LTD. Our results suggest that αCaMKII in the LA may be a potential molecular determinant of PTSD. We further demonstrate for the first time that GluA1-Ser845/Ser831 dephosphorylation and AMPAR internalization are molecular links between fear extinction and LTD.
RESUMEN
N-methyl-d-aspartic acid receptor (NMDAR)-dependent synaptic plasticity at the thalamus-lateral amygdala (T-LA) synapses is related to acquisition and extinction of auditory fear memory. However, the roles of the NMDAR GluN2A subunit in acquisition and extinction of auditory fear memory as well as synaptic plasticity at T-LA synapses remain unclear. Here, using electrophysiologic, molecular biological techniques and behavioral methods, we found that the forebrain specific GluN2A overexpression transgenic (TG) mice exhibited normal acquisition but impaired extinction of auditory fear memory. In addition, in vitro electrophysiological data showed normal basal synaptic transmission and NMDAR-dependent long-term potentiation (LTP) at T-LA synapses, but deficit in NMDAR-dependent long-term depression (LTD) at T-LA synapses in GluN2A TG mice. Consistent with the reduced NMDAR-dependent LTD, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization was also weakened during NMDAR-dependent LTD in GluN2A TG mice. Taken together, our findings for the first time indicate that GluN2A overexpression impairs extinction of auditory fear memory and NMDAR-dependent LTD at T-LA synapses, which further confirms the close relationship between NMDAR-dependent LTD and fear extinction.
Asunto(s)
Amígdala del Cerebelo/fisiología , Extinción Psicológica/fisiología , Miedo/psicología , Depresión Sináptica a Largo Plazo/genética , Depresión Sináptica a Largo Plazo/fisiología , Prosencéfalo/metabolismo , Receptores de N-Metil-D-Aspartato/fisiología , Estimulación Acústica , Animales , Conducta Animal , Fenómenos Electrofisiológicos , Expresión Génica , Potenciación a Largo Plazo/genética , Potenciación a Largo Plazo/fisiología , Ratones , Plasticidad Neuronal , Receptores AMPA/genética , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/biosíntesis , Receptores de N-Metil-D-Aspartato/genéticaRESUMEN
Never in mitosis (NIMA) related kinase 2 (Nek2) is involved in multiple cellular processes such as cell cycle checkpoint regulation, cell division, DNA damage response and cell apoptosis. Nek2 has been reported to be overexpressed in various tumors and correlated with poor prognosis. Herein, a series of imidazo[1,2-a] pyridines Nek2 inhibitors were designed, synthesized, and their biological activities were investigated. Besides, structure activity relationship analysis of these compounds were performed in the MGC-803 cell. The screening results are promising, and compound 28e shows good proliferation inhibitory activity with an IC50 of 38 nM. The results would be helpful to design and develop more effective Nek2 inhibitors for the treatment of gastric cancer.
Asunto(s)
Diseño de Fármacos , Quinasas Relacionadas con NIMA/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Piridinas/química , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Quinasas Relacionadas con NIMA/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/metabolismo , Piridinas/farmacología , Relación Estructura-ActividadRESUMEN
Voltage-gated potassium (Kv) channels are widely expressed in the central and peripheral nervous system and are crucial mediators of neuronal excitability. Importantly, these channels also actively participate in cellular and molecular signaling pathways that regulate the life and death processes of neurons. The current study used a kainic acid (KA)-induced temporal lobe epilepsy model to examine the role of the Kv10.2 gene in status epilepticus (SE). Lentiviral plasmids containing the coding sequence region of the KCNH5 gene (LV-KCNH5) were injected into the CA3 subarea of the right dorsal hippocampus within 24â¯h in post-SE rats to rescue Kv10.2 protein expression. Open-field and elevated plus maze test results indicated that anxiety-like behavior was ameliorated in the KAâ¯+â¯LV-KCNH5 group rats compared with the SE group rats, and working memory was improved in the Y-maze test. However, the spatial reference memory of the LV-KCNH5 group rats did not improve in the Morris water maze test, and no difference was found in the light-dark transition box test. The results of this study indicate that Kv10.2 protein may play an important role in epilepsy, providing new potential therapeutic directions and drug targets for epilepsy treatment.
Asunto(s)
Cognición/fisiología , Emociones/fisiología , Canales de Potasio Éter-A-Go-Go/biosíntesis , Ácido Kaínico/toxicidad , Estado Epiléptico/inducido químicamente , Estado Epiléptico/metabolismo , Animales , Cognición/efectos de los fármacos , Emociones/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go/genética , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Lentivirus/genética , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratas , Memoria Espacial/efectos de los fármacos , Memoria Espacial/fisiología , Estado Epiléptico/genéticaRESUMEN
Natural bioactive compounds have increasingly proved to be promising in evidence- or target-directed treatment or modification of a spectrum of diseases including cerebral ischemic stroke. Hydroxysafflor yellow A (HSYA), a major active component of the safflower plant, has drawn more interests in recent year for its multiple pharmacological actions in the treatment of cerebrovascular and cardiovascular diseases. Although the Janus kinase signaling, such as JAK2/STAT3 pathway, has been implicated in the modulation of the disease, the inhibition or activation of the pathway that contributed to the neuronal prevention from ischemic damages remains controversial. In this study, a series of experiments were performed to examine the dose- and therapeutic time window-related pharmacological efficacies of HSYA with emphasis on the HSYA-modulated interaction of JAK2/STAT3 and SOCS3 signaling in the MCAO rats. We found that HSYA treatment significantly rescued the neurological and functional deficits in a dose-dependent manner in the MCAO rats within 3 h after ischemia. HSYA treatment with a dosage of 8 mg/kg or higher markedly downregulated the expression of the JAK2-mediated signaling that was activated in response to ischemic insult, while it also promoted the expression of SOCS3 coordinately. In the subsequent experiments with the use of the JAK2 inhibitor WP1066, we found that the treatment of WP1066 alone or combination of WP1066/HSYA all exhibited inhibitory effects on JAK2-mediated signaling, while there was no influence on the SOCS3 activity of corresponding efficacious data in the MCAO rats, suggesting that excessive activation of JAK2/STAT3 might be necessary for HSYA to provoke SOCS3-negative feedback signaling. Taking together, our study demonstrates that HSYA might modulate the crosstalk between JAK2/STAT3 and SOCS3 signaling pathways that eventually contributed to its therapeutic roles against cerebral ischemic stroke.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Chalcona/análogos & derivados , Janus Quinasa 2/metabolismo , Quinonas/farmacología , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Animales , Chalcona/farmacología , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuroprotección/efectos de los fármacos , Accidente Cerebrovascular/tratamiento farmacológico , Proteínas Supresoras de la Señalización de Citocinas/metabolismoRESUMEN
Alzheimer's disease (AD) is the most common degenerative disease of the central nervous system. It is associated with abnormal accumulation of amyloid-ß (Aß) plaques, impaired neurogenesis, and damaged cognitive functions. We have known for a long time that natural compounds and their derivatives have gained increasing attention in AD drug research due to their multiple effects and inherently enormous chemicals. In this study, we will demonstrate that polysaccharides from L. barbarum (LBP1), a traditional natural compound, can reduce Aß level and improve the cognitive functions in APP/PS1 transgenic mouse. LBP1 can enhance neurogenesis as indicated by BrdU/NeuN double labeling. Furthermore, it can restore synaptic dysfunction at hippocampus CA3-CA1 pathway. Additionally, in vitro cell assay indicates that LBP1 may affect Aß processing. In conclusion, our study indicates that LBP1 might be a potential therapeutic agent for the treatment of AD against multiple targets that include synaptic plasticity, Aß pathology and neuropathology.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/fisiopatología , Amiloide/metabolismo , Cognición/efectos de los fármacos , Lycium/química , Polisacáridos/farmacología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/patología , Humanos , Ratones , Ratones Transgénicos , Peso Molecular , Monosacáridos/análisis , Plasticidad Neuronal/efectos de los fármacos , Polisacáridos/uso terapéuticoRESUMEN
MicroRNA-501-3p (miR-501-3p) has been reported to play tumor-suppressive roles in different cancers; however, its expression pattern and biological function in non-small cell lung cancer (NSCLC) remain unknown. In this study, we noted downregulation of miR-501-3p in NSCLC tissues and cell lines. Functional assays showed that overexpression of miR-501-3p suppressed NSCLC cell proliferation, clonogenicity, migration, and invasion. Moreover, miR-501-3p overexpression attenuated in vivo tumor growth in a nude mouse model. In terms of the mechanism, RAP1A was identified as a novel target of miR-501-3p. Overexpression of RAP1A strongly attenuated the inhibitory effects of miR-501-3p on the capacity of NSCLC cells for proliferation and motility. In the clinical samples of NSCLC, miR-501-3p levels negatively correlated with RAP1A expression, which was upregulated in NSCLC. Collectively, these results indicate that miR-501-3p acts as a tumor suppressor in NSCLC by directly targeting RAP1A mRNA and may serve as a theranostic biomarker for patients with NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Regulación hacia Abajo/genética , Neoplasias Pulmonares/genética , MicroARNs/genética , Proteínas de Unión al GTP rap1/genética , Animales , Línea Celular , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Genes Supresores de Tumor/fisiología , Células HEK293 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Regulación hacia Arriba/genéticaRESUMEN
Alzheimer's disease (AD) is characterized by memory impairments in its earliest clinical phase. The synaptic loss and dysfunction leading to failures of synaptic networks in AD brain directly cause cognitive deficits of patient. However, it remains unclear whether the synaptic networks in AD brain could be repaired. In this study, we generated functional human induced neural progenitor/stem cells (iNPCs) that had been transplanted into the hippocampus of immunodeficient wild-type and AD mice. The grafted human iNPCs efficiently differentiated into neurons that displayed long-term survival, progressively acquired mature membrane properties, formed graft-host synaptic connections with mouse neurons and functionally integrated into local synaptic circuits, which eventually reinforced and repaired the neural networks of host hippocampus. Consequently, AD mice with human iNPCs exhibited enhanced synaptic plasticity and improved cognitive abilities. Together, our results suggest that restoring synaptic failures by stem cells might provide new directions for the development of novel treatments for human AD.
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Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/metabolismo , Disfunción Cognitiva , Hipocampo/metabolismo , Células-Madre Neurales/metabolismo , Plasticidad Neuronal , Sinapsis/metabolismo , Enfermedad de Alzheimer/fisiopatología , Animales , Biomarcadores , Supervivencia Celular , Modelos Animales de Enfermedad , Técnica del Anticuerpo Fluorescente , Hipocampo/fisiopatología , Humanos , Ratones , Ratones Transgénicos , Modelos Biológicos , Neuronas/metabolismoRESUMEN
Hydroxysafflor yellow A (HSYA) is the major active chemical component of the safflower plant flower, which is widely used in Chinese medicine for cerebrovascular and cardiovascular disease treatment. Recent studies have demonstrated that HSYA exerts neuroprotective effect on cerebral ischemia, such as neuronal anti-apoptosis, antioxidant activity and oxygen free radical-scavenging. However, whether and how HSYA has a protective effect on cognitive impairment induced by cerebral ischemia reperfusion remains elusive. In the present study, by using the middle cerebral artery occlusion (MCAO) model, we found that 8 mg/kg and 16 mg/kg HSYA administration by common carotid artery (CCA) injection improved impaired cognitive function in Morris water maze (MWM) and passive avoidance tasks, but not 4 mg/kg HSYA treatment, suggesting that HSYA treatment in a certain concentration can improve cognitive impairment in MCAO rats. Furthermore, we found that 8 mg/kg HSYA treatment rescued the impaired long-term potentiation (LTP) in hippocampus of MCAO rats. Taken together, these results for the first time demonstrate that HSYA has the capacity to protect cognitive function and synaptic plasticity against cerebral ischemia-reperfusion injury, and provide a new insight that HSYA may be a promising alternative for recovery of cognitive dysfunction after brain ischemic injury.
RESUMEN
Although the striatum has a well-documented role in procedural learning and memory, the underlying mechanisms remain poorly understood. GluN2B subunit is abundantly expressed in striatum, however, the function of striatal GluN2B subunit in striatum-related learning is also unclear. In the present study, using transgenic mice with forebrain-specific overexpression of the GluN2B subunit, we observed that up-regulation of GluN2B subunit expression results in enhanced dorsal striatum-related motor skill learning and stimulus-response (S-R) learning as well as cortico-dorsomedial striatal (cortico-DMS) long-term potentiation (LTP). Consistent with the above results, we also found that GluN2B transgenic mice exhibited a remarkable increase in N-methyl-d-aspartic acid receptor (NMDAR) mediated currents in the dorsomedial striatum. In addition, in order to further verify that striatal GluN2B is involved in the dorsal striatum-related cognitive function, lentivirus-mediated short hairpin RNA (shRNA) was used to silence the expression of GluN2B gene in the dorsomedial striatum. As a consequence of down-regulation of dorsomedial striatal GluN2B subunit expression, defective motor skill learning and S-R learning were observed in the GluN2B-shRNA mice. Furthermore, the impaired cortico-DMS LTP, as well as decreased NMDAR mediated currents in the dorsomedial striatum were also detected. Taken together, our findings demonstrate for the first time that striatal GluN2B subunit plays an important role in the dorsal striatum-related motor skill learning and S-R learning and provide further evidence that the cortico-DMS LTP underlies dorsal striatum-related motor skill learning and S-R learning.
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Aprendizaje/fisiología , Destreza Motora/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Animales , Cuerpo Estriado/fisiología , Regulación hacia Abajo , Potenciación a Largo Plazo/fisiología , Masculino , Ratones , Ratones Transgénicos , Neostriado/metabolismo , ARN Interferente Pequeño/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/biosíntesis , Receptores de N-Metil-D-Aspartato/genética , Regulación hacia ArribaRESUMEN
OBJECTIVE: The study aimed to determine the effect of electroacupuncture (EA) on Wistar Kyoto (WKY) depressive model rats and explore the possible mechanism of EA on hippocampal CA1 region neuronal synaptic plasticity. METHODS: The male WKY rats were randomized to three experimental groups (EA, Sham EA, and Model group, nâ¯=â¯8/group), and Wistar rats as the normal control group (nâ¯=â¯8). EA treatment was administered once daily for 3 weeks at acupuncture points Baihui (GV20) and Yintang (EX-HN3). In the Sham EA group, acupuncture needles were inserted superficially into the acupoints without electrical stimulation. On day 21, the forced swimming test (FST), open field test (OFT) and sucrose preference test (SPT) were conducted. After the behavioral tests, long-term potentiation (LTP) was evoked at Schaffer collateral-CA1 synapses in hippocampal slices in vitro by electrophysiological recording, 5-HTT, 5-HT1A and 5-HT1â¯B protein levels in the hippocampus CA1 region were examined by using Western blot. RESULT: EA significantly decreased immobility in FST and improved sucrose intake compared with the Sham EA and Model groups. The center time and total move time in OFT were significantly increased in the EA group compared to the Model group. Compared with those of the Sham EA and Model groups, the fEPSP slope of the EA group increased significantly, and the LTP induction was successful. EA significantly decreased 5-HTT protein expression in the hippocampus CA1 region in comparison to the Sham EA and Model groups. Additionally, EA down regulated the 5-HT1A protein expression in the hippocampus CA1 region in comparison to the Sham EA group. CONCLUSION: EA could ameliorate depressive-like behaviors by restoring hippocampus CA1 synaptic plasticity, which might be mainly mediated by regulating 5-HT receptor levels.
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Depresión/terapia , Electroacupuntura/métodos , Hipocampo/fisiología , Potenciación a Largo Plazo/fisiología , Receptores de Serotonina/metabolismo , Puntos de Acupuntura , Animales , Depresión/patología , Modelos Animales de Enfermedad , Estimulación Eléctrica , Conducta Exploratoria/fisiología , Preferencias Alimentarias/fisiología , Técnicas In Vitro , Masculino , Proteínas de la Membrana/metabolismo , Ratas , Ratas Endogámicas WKY , Ratas Wistar , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Sacarosa/administración & dosificación , Natación/psicologíaRESUMEN
BACKGROUND/AIMS: The transcription factor CCAAT/enhancer-binding protein α (C/EBPα) is a basic leucine zipper transcription factor that plays essential roles in tumor progression. Although decreased or absent C/EBPα expression in many cancers suggests a possible role for C/EBPα as a tumor suppressor, the functions of C/EBPα in lung adenocarcinoma remain unclear. METHODS: Here, C/EBPα expression levels in 26 lung adenocarcinoma and para-carcinoma tissue samples were detected by qRT-PCR and immunohistochemistry. Cell transwell assays, wound healing assay and three-dimensional spheroid invasion assay were performed to assess the effects of C/EBPα on migration and invasion in lung adenocarcinoma cells in vitro. Western blotting was applied to analyze the potential mechanisms. RESULTS: C/EBPα was found to be decreased in lung adenocarcinoma tissues compared to para-carcinoma tissues. Overexpression of C/EBPα significantly inhibited the migration and invasion of lung adenocarcinoma cells. In addition, C/EBPα overexpression suppressed the epithelial-mesenchymal transition (EMT) that was characterized by a gain of epithelial and loss of mesenchymal markers. Further study showed that C/EBPα suppressed the transcription of ß-catenin and downregulated the levels of its downstream targets. CONCLUSION: Our data suggest that C/EBPα inhibits lung adenocarcinoma cell invasion and migration by suppressing ß-catenin-mediated EMT in vitro. Thus, C/EBPα may be helpful as a potential target for treatment of lung adenocarcinoma.
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Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , beta Catenina/metabolismo , Células A549 , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Proteína alfa Potenciadora de Unión a CCAAT/genética , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Movimiento Celular , Regulación hacia Abajo , Transición Epitelial-Mesenquimal , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Reacción en Cadena en Tiempo Real de la Polimerasa , Transcripción Genética , Vía de Señalización WntRESUMEN
The present study aimed to identify genes and microRNAs (miRNAs or miRs) that were abnormally expressed in the vastus lateralis muscle of patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The gene expression profile of GSE10828 was downloaded from the Gene Expression Omnibus database, and this dataset was comprised of 4 samples from patients with AECOPD and 5 samples from patients with stable COPD. Differentially expressed genes (DEGs) were screened using the Limma package in R. A proteinprotein interaction (PPI) network of DEGs was built based on the STRING database. Module analysis of the PPI network was performed using the ClusterONE plugin and functional analysis of DEGs was conducted using DAVID. Additionally, key miRNAs were enriched using gene set enrichment analysis (GSEA) software and a miR-gene regulatory network was constructed using Cytoscape software. In total, 166 up- and 129 downregulated DEGs associated with muscle weakness in AECOPD were screened. Among them, NCL, GOT1, TMOD1, TSPO, SOD2, NCL and PA2G4 were observed in the modules consisting of upregulated or downregulated genes. The upregulated DEGs in modules (including KLF6 and XRCC5) were enriched in GO terms associated with immune system development, whereas the downregulated DEGs were enriched in GO terms associated with cell death and muscle contraction. Additionally, 39 key AECOPDrelated miRNAs were also predicted, including miR-1, miR-9 and miR-23a, miR-16 and miR-15a. In conclusion, DEGs (NCL, GOT1, SOD2, KLF6, XRCC5, TSPO and TMOD1) and miRNAs (such as miR-1, miR-9 and miR-23a) may be associated with the loss of muscle force in patients during an acute exacerbation of COPD which also may act as therapeutic targets in the treatment of AECOPD.
Asunto(s)
Progresión de la Enfermedad , MicroARNs/genética , Músculos/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfermedad Aguda , Fenómenos Biomecánicos/genética , Análisis por Conglomerados , Perfilación de la Expresión Génica , Ontología de Genes , Redes Reguladoras de Genes , Humanos , MicroARNs/metabolismo , Anotación de Secuencia Molecular , Mapas de Interacción de Proteínas/genéticaRESUMEN
Increasing evidences show that hippocampal synaptic plasticity plays a crucial role in the pathogenesis of depression. The objective of this study was to determine whether electroacupuncture (EA) in the Wistar Kyoto (WKY) rat model of depression would exert antidepressant effects and whether this effect would be associated with changes in hippocampal synaptic plasticity. Male WKY rats were randomly divided into three groups (EA, sham EA, and blank control); Wister rats were used as normal control group. Treatment with EA was performed at Baihui (GV20) and Yintang (EX-HN3) once daily for 3 weeks. Forced swimming test (FST), open field test (OFT), and Morris water maze (MWM) were evaluated after 21-day intervention. Long-term potentiation (LTP) was evoked at Schaffer collateral-CA1 synapses in hippocampal slices in vitro. EA treatment significantly reduced immobility time in FST. MWM test showed a significant downward trend in escape latency time from the second to fifth days of experiment, and a higher frequency of crossing the missing quadrant platform in normal control and EA vs other groups. Impaired LTP was detected in Schaffer collateral-CA1 synapses in blank control and sham EA groups. In the western blot, the expression of GluN2B showed significant increase in EA vs sham EA and blank control groups. EA was able to improve depression-like behaviors and reverse the impairment of LTP, which were likely mediated by GluN2B in the hippocampus.
Asunto(s)
Depresión/terapia , Modelos Animales de Enfermedad , Electroacupuntura/métodos , Hipocampo/fisiología , Aprendizaje por Laberinto/fisiología , Plasticidad Neuronal/fisiología , Animales , Depresión/fisiopatología , Depresión/psicología , Potenciales Postsinápticos Excitadores/fisiología , Masculino , Ratas , Ratas Endogámicas WKY , Ratas WistarRESUMEN
N-methyl-d-aspartic acid (NMDA) receptor-dependent long-term potentiation (LTP) at the thalamus-lateral amygdala (T-LA) synapses is the basis for acquisition of auditory fear memory. However, the role of the NMDA receptor NR2B subunit in synaptic plasticity at T-LA synapses remains speculative. In the present study, using transgenic mice with forebrain-specific overexpression of the NR2B subunit, we have observed that forebrain NR2B overexpression results in enhanced LTP but does not alter long-term depression (LTD) at the T-LA synapses in transgenic mice. To elucidate the cellular mechanisms underlying enhanced LTP at T-LA synapses in these transgenic mice, AMPA and NMDA receptor-mediated postsynaptic currents have been measured. The data show a marked increasing in the amplitude and decay time of NMDA receptor-mediated currents in these transgenic mice. Consistent with enhanced LTP at T-LA synapses, NR2B-transgenic mice exhibit better performance in the acquisition of auditory fear memory than wild-type littermates. Our results demonstrate that up-regulation of NR2B expression facilitates acquisition of auditory cued fear memory and enhances LTP at T-LA synapses.
Asunto(s)
Amígdala del Cerebelo/fisiología , Miedo/fisiología , Aprendizaje/fisiología , Potenciación a Largo Plazo/fisiología , Prosencéfalo/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Amígdala del Cerebelo/efectos de los fármacos , Animales , Ansiedad/fisiopatología , Percepción Auditiva/efectos de los fármacos , Percepción Auditiva/fisiología , Depresión/fisiopatología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Aprendizaje/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Depresión Sináptica a Largo Plazo/fisiología , Ratones Transgénicos , Prosencéfalo/efectos de los fármacos , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiología , Receptores de N-Metil-D-Aspartato/genética , Sinapsis/efectos de los fármacos , Sinapsis/fisiología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Tálamo/efectos de los fármacos , Tálamo/fisiologíaRESUMEN
The effects of early deprivation (ED, which involves both dam and littermate deprivation) on anxiety and memory are less investigated in comparison with maternal separation (MS), and it is not yet clear how ED affects long-term potentiation (LTP) in the hippocampal Schaffer collateral pathway. By using a series of behavioral tests, enzyme-linked immunosorbent assay and field potential recording, we explored the effect of pre-weaning daily 3-h ED on anxiety, memory and potential mechanisms in adult male rats. Compared with control, ED rats spent longer time in open arms of elevated plus maze and in light compartment of light-dark transition box. Consistently, stress-induced blood plasma corticosterone level was also lower in ED rats. Moreover, ED rats showed better performance in social recognition and Morris water maze test. In accordance with results in memory tests, the threshold of LTP induction in hippocampal CA3-CA1 pathway of ED rats was also reduced. Our results indicate ED reduced anxiety, but enhanced social recognition and spatial reference memory. We suggest the diminished hypothalamic-pituitary-adrenal axis response and facilitated hippocampal LTP may contribute to the anxiety-reducing and memory-enhancing effects of ED, respectively.