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Objective: To investigate the clinical, radiological, and pathological features of anaplastic gangliogliomas (AGGs) and to determine whether these tumors represent a distinct entity. Methods: Consecutive 667 cases of ganglioglioma (GG) diagnosed at the Xuanwu Hospital, Capital Medical University, Beijing, China between January 2015 and July 2023 were screened. Among these cases, 9 pathologically confirmed AGG cases were identified. Their clinical, radiological, treatment, and outcome data were analyzed retrospectively. Most of the tumor samples were subject to next-generation sequencing, while a subset of them were subject to DNA methylation profiling. Results: Among the 9 patients, there were five males and four females, with a median age of 8 years. Epileptic seizures (5/9) were the most frequently presented symptom. Radiological examinations showed three types of radiological manifestations: four cases showed abnormal MRI signals with no significant mass effects and mild enhancement; two cases demonstrated a mixed solid-cystic density lesion with peritumoral edema, which showed significant heterogeneous enhancement and obvious mass effects, and one case displayed cystic cavity formation with nodules on MRI, which showed evident enhancements. All cases exhibited mutations that were predicted to activate the MAP kinase signaling pathway, including seven with BRAF p.V600E mutation and two with NF1 mutation. Five AGGs with mutations involving the MAP kinase signaling pathway also had concurrent mutations, including three with CDKN2A homozygous deletion, one with a TERT promoter mutation, one with a H3F3A mutation, and one with a PTEN mutation. Conclusions: AGG exhibits a distinct spectrum of pathology, genetic mutations and clinical behaviors, differing from GG. Given these characteristics suggest that AGG may be a distinct tumor type, further expansion of the case series is needed. Therefore, a comprehensive integration of clinical, histological, and molecular analyses is required to correctly diagnose AGG. It will also help guide treatments and prognostication.
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Neoplasias Encefálicas , Metilación de ADN , Ganglioglioma , Imagen por Resonancia Magnética , Mutación , Fosfohidrolasa PTEN , Proteínas Proto-Oncogénicas B-raf , Humanos , Ganglioglioma/patología , Ganglioglioma/genética , Masculino , Femenino , Niño , Estudios Retrospectivos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/diagnóstico por imagen , Proteínas Proto-Oncogénicas B-raf/genética , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Telomerasa/genética , Histonas/genética , Histonas/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Epilepsia/patología , Epilepsia/genéticaRESUMEN
Sixteen patients with recurrent high-grade glioma who were treated by domestic magnetic resonance-guided laser interstitial thermotherapy (MRgLITT) in the Neurosurgery Department of Xuanwu Hospital of Capital Medical University from 1st January 2021 to 31st December 2021 were prospectively included, with 11 males and 5 females, and aged 27-74 (50±16) years. The duration of surgery, the rate of ablation after surgery, and perioperative complications were assessed. The patients were followed up every 3 months to assess survival and progression. A total of 5 WHO grade â ¢ patients and 11 WHO grade â £ patients were included. The operation time was 144 (109, 176) min, 28 targeted lesions were detected, and the ablation rate [M (Q1, Q3)] was 91.0% (87.4%, 93.3%). After surgery, 2 patients (2/16) had decreased limb muscle strength, and no perioperative death or other serious complications occurred. The median time to a complete response was 12 (5, 14) months in WHO Grade â ¢ patients, and one died 12 months after surgery, while the median time to a complete response was 3 (1, 8) months in 11 WHO Grade â £ patients, with a total of 8 deaths at the last follow-up. Therefore, domestic MRgLITT has certain efficacy and safety in the treatment of recurrent high-grade glioma, providing a new option for patients with recurrent glioma.
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Glioma , Hipertermia Inducida , Femenino , Masculino , Humanos , Imagen por Resonancia Magnética , Rayos Láser , Espectroscopía de Resonancia MagnéticaRESUMEN
Objective: To investigate the safety and short-term efficacy of domestic magnetic resonance-guided laser interstitial thermotherapy (MRgLITT) in the treatment of drug-resistant epilepsy. Methods: Patients with drug-resistant epilepsy treated with a domestic MRgLITT system in the Department of Neurosurgery, Xuanwu Hospital, Capital Medical University from October 2020 to April 2021 were prospectively enrolled. The damage volume ratio was assessed immediately after surgery, and perioperative complications were recorded and followed up. The clinical safety and short-term efficacy were evaluated using the Engel classification. Results: A total of 22 patients were included, including 12 males and 10 females, aged from 3 to 45 years old [(24±13) years]. There were 5 cases of medial temporal lobe epilepsy (MTLE), 3 cases of hypothalamic hamartoma (HH), 7 cases of focal cortical dysplasia (FCD), and 7 cases of other types, respectively. The mean operation time and blood loss was (173±49) min and (3.7±1.6) ml. The postoperative length of hospital stay was (5.5±1.8) days, and the average damage volume ratio was 92.6%. Among them, only 2 patients (FCD of the parietal lobe) showed transient contralateral limb weakness, without any serious complications such as symptomatic intracranial hemorrhage and cerebral infarction. The follow-up time was 14 to 168 days. There were 13 Engel class â cases (59.1%), 2 Engel class â ¡ cases (9.1%), 2 Engel class â ¢ cases (9.1%) and 5 Engel class â £ cases (22.7%), respectively. Short-term incident-free rates were MTLE 5/5and FCD4/7, respectively. Conclusion: Domestic MRgLITT system is stable, reliable and safe in the treatment of drug-refractory epilepsy, and has better short-term efficacy in MTLE and FCD patients.
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Epilepsia Refractaria , Hipertermia Inducida , Terapia por Láser , Preparaciones Farmacéuticas , Adolescente , Adulto , Niño , Preescolar , Epilepsia Refractaria/cirugía , Femenino , Humanos , Rayos Láser , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Objective: To investigate the safety and efficacy of stereotactic-EEG (SEEG)-guided radiofrequency thermocoagulation (RF-TC) with three-dimensional lesioning in the treatment of drug-resistant insular epilepsy. Methods: Seven patients with drug-resistant insular epilepsy who underwent SEEG-guided RF-TC with three-dimensional ablation at the Department of Neurosurgery of Xuanwu Hospital, Capital Medical University from February 2017 to June 2019 were retrospectively enrolled. Presurgical evaluation including semiology, EEG and imaging results suggested that the epileptogenic zone was located in the insular lobe. All patients underwent SEEG recording and three-dimensional RF-TC. Postoperative follow-up was conducted by outpatient visits or telephone, the clinical efficacy was evaluated based on Engel classification and the relevant complications were documented. Results: Seven patients were followed up at 18 months after surgery. Among them, 4 were seizure free (Engel â A), 2 had nondisabling simple partial seizures (Engel â B) and 1 achieved 75% decrease (Engel â ¢A) in seizure frequency. Postoperative complications occurred in 3 patients which included decreased sensation in the right lower extremity, decreased strength in the right upper extremity, glossolalia, decline in memory and comprehension. No permanent neurological dysfunction was detected. Conclusion: SEEG-guided RF-TC with three-dimensional lesioning is minimally invasive, safe and effective in the treatment of drug-resistant insular epilepsy and can serve as a complementary method for resection surgery.
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Epilepsia Refractaria , Preparaciones Farmacéuticas , Epilepsia Refractaria/cirugía , Electrocoagulación , Electroencefalografía , Humanos , Imagen por Resonancia Magnética , Estudios Retrospectivos , Técnicas Estereotáxicas , Resultado del TratamientoRESUMEN
In Alzheimer's disease (AD), neurodegenerative signals such as amyloid-beta (Aß) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aß and mediates Aß-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer's patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aß. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aß deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aß deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing ß-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aß toxicity and would be a novel therapeutic target and biomarker for AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Encéfalo/patología , Proteínas del Tejido Nervioso/química , Estructura Terciaria de Proteína/fisiología , Receptores de Factor de Crecimiento Nervioso/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Factores de Edad , Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/toxicidad , Precursor de Proteína beta-Amiloide/genética , Animales , Apoptosis/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Estudios de Casos y Controles , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/terapia , Modelos Animales de Enfermedad , Regulación hacia Abajo/genética , Humanos , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Transgénicos , Mutación/genética , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Presenilina-1/genética , Receptores de Factor de Crecimiento Nervioso/deficiencia , Receptores de Factor de Crecimiento Nervioso/genética , Proteínas Recombinantes/uso terapéutico , Transducción GenéticaRESUMEN
Modern Bai Jiu(liquor) was called Shao Jiu in ancient times.By consulting ancient books, it was found that there was a distillation and preparation process of Shao Jiu before the Ming Dynasty, but due to its high toxicity, the scope of application was limited, and there were few records of its medicinal use.However many records of its medicinal use was found in the Compendium of Materia Medica(«¼).By comparing the medical books that recorded Shao Jiu in previous dynasties, it is found that the Compendium of Materia Medica comprehensively records the relevant cognition and application of the medicinal use of Shao Jiu for the first time. The book lists in detail the causes of the toxicity of Shao Jiu and the methods to avoid it, comprehensively expounds its characteristics, efficacy and indications, lists a variety of ways to use it, skillfully uses Shao Jiu to treat syphilis sores, and proposes that high-concentration Shao Jiu can be used as a solvent for medical liquor.The record of Shao Jiu in the Compendium of Materia Medica had a profound impact on the medical liquor of later generations.The use of Shao Jiu in the Qing Dynasty continued to expand, and the types of medicinal liquor were also constantly enriched. The record of Shao Jiu in the Compendium of Materia Medica can also provide a reference for the medicinal use of modern liquor.
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Materia Medica , Libros , China , Medicina Tradicional ChinaRESUMEN
Objective: To evaluate the immunogenicity and protective effect of a multicomponent recombinant protein vaccine EPRHP014 constructed independently and provide a scientific basis for developing new tuberculosis (TB) vaccine and effective prevention and control of TB. Methods: Three full-length Mycobacterium (M.) tuberculosis protein antigens (EsxH, Rv2628, and HspX) and two epitope-predicted and optimized epitope-dominant protein antigens (nPPE18 and nPstS1) were selected, from which five protein antigens were used to construct a protein antigen composition EPRHP014, including a fusion expression multi-component protein antigen (EPRHP014f) and a multi-component mixed protein antigen (EPRHP014m) formed with the five single protein using clone, purification, and purification respectively. Multicomponent protein vaccines EPRHP014f and EPRHP014m were prepared with aluminum adjuvant, and the BCG vaccine was used as a control. ELISA detected the titer of serum-specific antibodies, the secretion of various cytokines was detected by ELISpot and Luminex, and immune protection was observed by the M. tuberculosis growth inhibition test in vitro. The results were statistically analyzed by t-test or rank sum test, and P<0.05 was considered a statistically significant difference. Results: Mice Immunized with EPRHP014m and EPRHP014f could produce highly effective IgG antibodies and their subtypes IgG1 and IgG2a, and the antibody titers were similar to those of mice immunized with BCG, with no statistical significance (P>0.05). The number of spot-forming cells (SFC) secreting IFN-γ and IL-4 induced by EPRHP014f group was significantly higher than those by EPRHP014m group and BCG group (P<0.05), but there was no significant difference in the number of SFC for IFN-γ and IL-4 induced between EPRHP014m group and BCG group (P>0.05). The secretion levels of GM-CSF and IL-12p70 induced by the EPRHP014m group were higher than those of the BCG group (P<0.05), but there was no significant difference in the levels of IL-6 and IL-10 induced between EPRHP014m group and BCG group (P>0.05). There was no significant difference in the secretions of IL-6, IL-10, IL-12, and GM-CSF between the EPRHP014f and BCG groups (P>0.05). EPRHP014m group, EPRHP014f group, and BCG group had obvious antibacterial effects in vitro, and the difference was insignificant (P>0.05). Conclusion: Both EPRHP014f and EPRHP014m can induce strong humoral and cellular immune responses in mice after immunization, and have a strong ability to inhibit the growth of M. tuberculosis in vitro, indicating that the antigen composition EPRHP014 has good potential in the development and application of TB vaccine.
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Mycobacterium tuberculosis , Vacunas contra la Tuberculosis , Tuberculosis , Animales , Ratones , Vacuna BCG , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Interleucina-10 , Interleucina-4 , Interleucina-6 , Tuberculosis/prevención & control , Antígenos Bacterianos , Interleucina-12 , Proteínas Recombinantes , Epítopos , Proteínas BacterianasRESUMEN
The North China Medical College typically represented medical colleges for traditional Chinese medicine in the 1930s when many of them were set up. It was based on the principles of centring on traditional Chinese medicine, following western medicine and integrated medicine in teaching. This led to the emergence of a great number of people with a high level of traditional Chinese medicine and strong belief in it. In terms of the textbooks and handouts for western medicine, compared to similar textbooks in other medical colleges, such as the Medical College of Xie He, at that time, the textbooks in the North China Medical College covered a variety of perspectives and categories. It was found that 20 textbooks for western medicine in the North China Medical College were designed reasonably in content and were simple and applicable in teaching. More importantly, it contained some traditional Chinese medicine in different degrees, with its typical characteristics. The course design and textbook compilation provided references for the teaching in contemporary medical universities.
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Medicina , Humanos , Universidades , China , Medicina Tradicional ChinaRESUMEN
Objective: To observe the position of the electrode in the cochlea following cochlear implantation by cone beam computed tomography (CBCT). Methods: Twenty-five children who received cochlear implantation and CBCT examinations in the Department of Otorhinolaryngology Head and Neck Surgery from the Second Hospital of Shandong University between January 2016 and December 2017 were selected. There were 15 males (17 ears) and 10 females (10 ears). The age ranged from 0.5 to 7.0 years old, with a median age of 1.6 years. 23 patients with unilateral implantation and two patients with bilateral implantation. The implants were all Med-El standard 12-electrode contact arrays. The CBCT was used to determine the position of the electrode in the cochlea, the distance between the electrode contacts and modiolus, and intracochlear insertion length of the electrode arrays. SPSS Statistics, version 22.0 was used for data processing and statistical analysis. Results: CBCT images could clearly demonstrate the structure of round window, oval window, modiolus, osseous cochlear duct, osseous spiral lamina, and electrodes. The electrode arrays of all the children were fully implanted into the cochlea. 26 of the electrode arrays were located in the scala tympani and one of them was inserted into the scala vestibular. The mean intracochlear insertion length of the electrode arrays was 30.23 (95%CI, 30.04-30.71) mm. The distance between the electrode contacts and modiolus gradually increased at the 1-4th electrode contacts and reached the maximum at the 4th electrode contacts with an average of 1.10 mm (95%CI, 1.02 to 1.18 mm), and then gradually decreased from the 5th electrode contacts. Conclusions: CBCT can clearly show cochlear fine structures and therefore accurately assess the electrode position following cochlear implantation.
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Cóclea/diagnóstico por imagen , Cóclea/cirugía , Implantación Coclear , Implantes Cocleares , Tomografía Computarizada de Haz Cónico Espiral , Niño , Preescolar , Oído Interno/diagnóstico por imagen , Femenino , Humanos , Lactante , MasculinoRESUMEN
The present study provides evidence that rat brain protein kinase C elicits a phosphotransferase activity towards histone and undergoes autophosphorylation in the absence of phosphatidylserine. The tumor promoter 12-O-tetradecanoylphorbol-13-acetate binds to and activates protein kinase C in a phospholipid-free reaction. The apparent activation constant (Ka = 2.7 nM) is not modified by the absence of phospholipid but the maximum velocity is greatly decreased. The phosphotransfer reaction to exogenous substrates occurs in 0.5 mM ethylene-bis(oxyethylenenitrilo)tetraacetic acid, although autophosphorylation in these conditions requires the presence of Ca2+. The protein kinase C inhibitor (1-(5-isoquinolinesulfonyl)-2-methylpiperazine inhibits the reaction, whereas the cAMP-dependent protein kinase inhibitor is ineffective. In contrast to diacylglycerol, which is a poor activator, unsaturated fatty acids potently activate the phospholipid-free reaction. Moreover, the substrate specificity is markedly changed, e.g., myelin basic protein and histone types VI-S and VII-S appear to be relatively better substrates in the phospholipid-free reaction. The data presented indicate that protein kinase C (or some individual isoforms) may function, at least partially, without binding to membrane phospholipid and suggest that this novel characteristic of phorbol esters may account for their tumor-promoting activity.
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Ésteres del Forbol/farmacología , Proteína Quinasa C/metabolismo , Animales , Encéfalo/enzimología , Ácido Egtácico/farmacología , Activación Enzimática/efectos de los fármacos , Cinética , Fosfolípidos/fisiología , Fosforilación , Ratas , Solubilidad , Especificidad por Sustrato , Acetato de Tetradecanoilforbol/metabolismo , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
In order to understand and imitate the more complex bio-processes and fascinating functions in nature, protein self-assembly has been studied and has attracted more and more interest in recent years. Artificial self-assemblies of proteins have been constructed through many strategies. However, the design of complicated protein self-assemblies utilizing the special profile of building blocks remains a challenge. We herein report linear and 2D nanostructures constructed from a V shape SMAC protein and induced by metal coordination. Zigzag nanowires and wavy 2D nanostructures have been demonstrated by AFM and TEM. The zigzag nanowires can translate to a 2D nanostructure with an excess of metal ions, which reveals the step by step assembly process. Fluorescence and UV/Vis spectra have also been obtained to further study the mechanism and process of self-assembly. Upon the protein nanostructure, fluorescence resonance energy transfer (FRET) could also be detected using fluorescein modified proteins as building blocks. This article provides an approach for designing and controlling self-assembled protein nanostructures with a distinctive topological morphology.
RESUMEN
Arachidonic acid (AA) activates brain protein kinase C (PKC) in a specific manner, and which differs from that of diacylglycerol (DG)-mediated PKC activation in cofactor Ca2+ and phosphatidylserine (PtdSer) requirements. We presently report that characteristics of AA-mediated activation are heterogenous, and are dependent upon the concentrations of AA. Highly sensitive PKC activation (HS) occurring at concentrations of 20 microM AA can be distinguished from less sensitive PKC activation (LS) requiring concentrations of at least 160 microM AA, on the basis of the effects of phorbol ester TPA or DG, phosphatidylcholine (PtdCho) and sodium deoxycholate (DOC). TPA, like DG suppressed the HS reaction whereas it enhanced the LS reaction. PtdCho, a phospholipid which does not affect DG-mediated activation, also prevented the HS reaction without affecting the LS reaction. This latter was inhibited at 100 microM DOC, a concentration which slightly stimulated the HS reaction. The substrate specificity was also different in the two reactions: the preferential substrate for PKC in HS was histone type VII-S, while it was histone type V-S in LS. Both reactions were similarly affected by PtdSer. In 0.1 mM CaCl2, PtdSer stimulated AA-mediated activation without evoking additive responses while this phospholipid prevented this activation in 0.5 mM EGTA, suggesting that AA and PtdSer bind PKC on the same or related sites. Together these results provide evidence for the existence of different modes of AA-mediated PKC activation with unique characteristics which presumably involve two different binding sites for AA on the same molecule and/or different PKC isoforms.
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Ácido Araquidónico/farmacología , Química Encefálica , Proteína Quinasa C/metabolismo , Animales , Sitios de Unión , Ácido Desoxicólico/metabolismo , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Masculino , Fosfatidilcolinas/farmacología , Fosfatidilserinas/farmacología , Ratas , Transducción de Señal , Especificidad por Sustrato , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
Extracellular ligands transfer information into the cell through several pathways that operate in an integrated fashion. Protein kinase C, and enzyme that plays a pivotal role in signal transduction, is the molecular target for tumor promoters from the series of phorbol esters. A number of structurally unrelated tumor promoters also enhance protein kinase C, interacting or not interacting with the phorbol ester binding site. Evidence is provided that benzene potently activate protein kinase C in vitro, as well as in intact platelets. The drug does not compete for the phorbol ester binding site and probably affects the hydrophobic environment requires for full enzyme activation. Toluene is equally active. The relevance of the presented findings in the carcinogenic effects of benzene is discussed.
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Benceno/farmacología , Carcinógenos/farmacología , Proteína Quinasa C/metabolismo , Animales , Plaquetas/enzimología , Activación Enzimática/efectos de los fármacos , Técnicas In Vitro , Ésteres del Forbol/farmacologíaRESUMEN
The SC administration of either typical mu-agonists such as morphine, pethidine, fentanyl and levorphanol or a mixed mu- and delta-agonist like [D-Ala2, D-Leu5]-enkephalin to 10-day-old rats produced loss of righting reflex. Additionally, the loss of righting reflex induced by these opioid agonists was antagonized by naloxone, an opioid antagonist having a preference for mu-receptors, but by neither nor-binaltorphimine nor naltrindole, a specific kappa- or delta-antagonist, respectively, indicating that the loss of righting reflex was produced by the interaction of an opioid with mu-receptors. Moreover, the potency of each opioid agonist relative to that of morphine estimated by the present in vivo method was similar to that determined by the traditional in vitro isolated preparation. In contrast to mu-agonists, neither typical kappa-agonists such as U-50, 488H, ketocyclazocine, pentazocine and butorphanol, nor a selective delta-agonist like [D-Pen2, D-Pen5]-enkephalin affected the righting reflex of 10-day-old rats, indicating that mu-agonists, but neither kappa- nor delta-agonists, produced the naloxone-reversible loss of righting reflex in infant rats. By employing the present in vivo method to estimate the mu-agonist activity of an opioid with mixed agonist activities, it was indicated that the mu-agonist activity of ethylketocyclazocine, which had been employed as a representative kappa-agonist, was essentially the same as that of morphine, a representative mu-agonist.
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Receptores Opioides delta/agonistas , Receptores Opioides kappa/agonistas , Receptores Opioides mu/agonistas , Animales , Leucina Encefalina-2-Alanina/farmacología , Etilcetociclazocina/farmacología , Femenino , Masculino , Ratones , Ratones Endogámicos ICR , Morfina/farmacología , Naloxona/farmacología , Equilibrio Postural/efectos de los fármacos , Ratas , Ratas Wistar , Reflejo/efectos de los fármacosRESUMEN
Using altitude hypoxia model, in situ hybridization and NADPH-d histochemistry, we investigated the effects of ketamine and L-NAME (blocker of NOS) on NOS and somatostatin mRNA (SS mRNA) expression in the rat hypothalamus following acute altitude hypoxia. It was revealed that acute altitude hypoxia induced NOS and SS mRNA overexpression in the rat hypothalamus. When pretreated with NMDA receptor antagonist ketamine and L-NAME, NOS and SS mRNA expression were inhibited significantly. These results suggest that NMDA receptor activation participates in the expression of NOS and SS mRNA in the rat hypothalamus subjected to acute altitude hypoxia. Meanwhile, hypothalamic endogenous NO may mediate expression of SS mRNA.
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Mal de Altura/metabolismo , Hipotálamo/metabolismo , Ketamina/farmacología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/biosíntesis , Somatostatina/biosíntesis , Animales , Hipoxia/metabolismo , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo I , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Distribución Aleatoria , Ratas , Ratas Wistar , Somatostatina/genéticaRESUMEN
While Parkinson's disease is the result of dopaminergic dysfunction of the nigrostriatal system, the clinical manifestations of Parkinson's disease are brought about by alterations in multiple neural components, including cortical areas. We examined how 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration affected extracellular cortical glutamate levels by comparing glutamate levels in normal and MPTP-lesioned nonhuman primates (Macaca mulatta). Extracellular glutamate levels were measured using glutamate microelectrode biosensors. Unilateral MPTP-administration rendered the animals with hemiparkinsonian symptoms, including dopaminergic deficiencies in the substantia nigra and the premotor and motor cortices, and with statistically significant decreases in basal glutamate levels in the primary motor cortex on the side ipsilateral to the MPTP-lesion. These results suggest that the functional changes of the glutamatergic system, especially in the motor cortex, in models of Parkinson's disease could provide important insights into the mechanisms of this disease.
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Dopamina/deficiencia , Ácido Glutámico/análisis , Macaca mulatta/metabolismo , Corteza Motora/química , Trastornos Parkinsonianos/metabolismo , Sustancia Negra/química , Animales , Técnicas Biosensibles , Recuento de Células , Neuronas Dopaminérgicas/enzimología , Electrodos Implantados , Femenino , Microelectrodos , Corteza Motora/patología , Proteínas del Tejido Nervioso/análisis , Sustancia Negra/patología , Tirosina 3-Monooxigenasa/análisisRESUMEN
Ca2+ requirement for protein kinase C activation is a matter of controversy. In this report we have examined Ca2+ dependency of the reaction in different assay systems and shown that the enzyme response to Ca2+, as well as diacylglycerol, depends upon phospholipid species, protein substrate and lipid conformation (micelles or sonicates). These results emphasize that the enzyme characteristics as defined in reconstituted membrane systems may not have a physiological relevance.
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Calcio/farmacología , Proteína Quinasa C/metabolismo , Técnicas In Vitro , Lípidos/farmacología , Fosfolípidos/farmacología , Especificidad por SustratoRESUMEN
Previous work has shown that guanosine 5'-[gamma-thio]triphosphate (GTP[S]) and GTP stimulate phospholipase D (PLD) in rabbit platelet membranes and that these effects are greatly enhanced by pretreatment of platelets with phorbol esters that activate protein kinase C [Van der Meulen and Haslam (1990), Biochem. J. 271, 693-700]. In the present study, the effects of Mg2+, various nucleoside triphosphates and phosphocreatine (PCr) were investigated. Platelet membranes containing phospholipids labelled with [3H]glycerol were assayed for PLD in the presence of an optimal Mg2+ concentration (10 mM) by measuring [3H]phosphatidylethanol formation in incubations that included 300 mM ethanol. In membranes from phorbolester-treated platelets, the same maximal increases in PLD activity (5-fold) were seen with 1 microM GTP[S]), and 100 microM GTP. Addition of adenosine 5'-[gamma-thio]triphosphate (ATP[S]), ITP, XTP, UTP and CTP had similar stimulatory effects, but only at > or = 1 mM. In contrast, ATP had a biphasic action, causing a maximal (2-fold) stimulation at 10 microM and smaller effects at higher concentrations; the inhibitory component of the action of ATP was blocked by 2 microM staurosporine. Guanosine 5'-[beta-thio]diphosphate decreased the stimulatory effects of ATP and ATP[S]. UDP, which can inhibit nucleoside diphosphate kinase (NDPK), decreased the activation of PLD by ATP[S], ATP, XTP, CTP and to a lesser extent ITP, but had no effect on the actions of GTP[S] and GTP. Rabbit platelet membranes contained NDPK and addition of [gamma-32P]ATP led to the formation of [32P]GTP in amounts sufficient to explain most or all of the activation of PLD; UDP prevented GTP formation. PCr (0.04-1 mM) also stimulated membrane PLD activity, an effect that was dependent on endogenous membrane-bound creatine kinase (CK). UDP and guanosine 5'-[beta-thio]diphosphate each inhibited this effect of PCr. The results show that in rabbit platelet membranes, CK, NDPK and the GTP-binding protein that activates PLD can be functionally coupled. However, assay of membrane preparations at increasing dilutions showed that stimulation of PLD by the compounds studied, with the partial exception of ATP[S], involved diffusible rather than protein-bound intermediates.
Asunto(s)
Plaquetas/enzimología , Creatina Quinasa/fisiología , Nucleósido-Difosfato Quinasa/fisiología , Nucleótidos/farmacología , Fosfocreatina/farmacología , Fosfolipasa D/metabolismo , Animales , Plaquetas/efectos de los fármacos , Calcio/farmacología , Membrana Celular/efectos de los fármacos , Membrana Celular/enzimología , Activación Enzimática , Guanosina Difosfato/farmacología , Técnicas In Vitro , Magnesio/farmacología , ConejosRESUMEN
The intra-third-ventricular (i.t.v.) administration of [Met5]-enkephalin (enk) to rats pretreated i.t.v. with three peptidase inhibitors (PIs), amastatin, captopril and phosphoramidon, inhibited the tail-flick response. The enk-induced inhibition was augmented by increasing the doses of the three PIs, with the maximum inhibition being attained at the doses of 10 nmol each. The enk-induced inhibition in rats pretreated with any combination of two PIs, however, were markedly smaller than that in rats pretreated with all three PIs, indicating that three kinds of enzymes all played important roles in the inactivation of enk. The inhibitory effect of enk on the tail-flick response in rats pretreated with the three PIs at doses of 10 nmol each was approximately tenfold higher than that of morphine. The relative anti-nociceptive potencies of enk and morphine were similar to the relative inhibitory potencies obtained previously with the isolated guinea pig ileum pretreated with the three PIs, indicating that the hydrolysis of the i.t.v. administered enk was largely prevented by the three PIs. However, the magnitude of the enk-induced inhibition in rats pretreated s.c. with the three PIs indicated that the hydrolysis of enk injected i.t.v. was not largely prevented by the s.c. administration of three PIs at doses up to 10 micromol each/kg.