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1.
Microb Pathog ; 133: 103546, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31112769

RESUMO

With this study, we investigated the effect of synthetic antimicrobial peptides Pep19-2.5 and Pep194LF alone or in combination with antibiotics on S. mutans growth and biofilm formation/disruption. We also examined the cytotoxic effect of each peptide on monocytes. S. mutans was cultured in the presence of different concentrations of each peptide. We showed that Pep19-2.5 and Pep19-4LF were able to significantly (p ≤ 0.01) inhibit the growth of S. mutans. The synthetic peptides also decreased biofilm formation by S. mutans. Furthermore, both peptides reduced the viability of S. mutans in already formed biofilms. The combination of each peptide with antibiotics (penicillin/streptomycin, P/S) produced additive interactions which inhibited S. mutans growth and biofilm formation. Pep19-2.5 and Pep19-4LF were nontoxic, as they did not decrease monocyte viability and did not increase the lactate dehydrogenase activity of the exposed cells. In conclusion, synthetic peptides Pep19-2.5 and Pep19-4LF did inhibit S. mutans growth and its capacity to form biofilm. Both peptides were found to be nontoxic to monocytes. These data provide new insight into the efficacy of synthetic peptides Pep19-2.5 and Pep19-4LF against S. mutans. These peptides may thus be useful in controlling the adverse effects of this cariogenic bacterium in human.


Assuntos
Anti-Infecciosos/farmacologia , Biofilmes/efeitos dos fármacos , Proteínas do Tecido Nervoso/farmacologia , Peptídeos/farmacologia , Streptococcus mutans/efeitos dos fármacos , Peptídeos Catiônicos Antimicrobianos , Biofilmes/crescimento & desenvolvimento , Sobrevivência Celular/efeitos dos fármacos , Combinação de Medicamentos , Sinergismo Farmacológico , Humanos , L-Lactato Desidrogenase/metabolismo , Testes de Sensibilidade Microbiana , Monócitos/efeitos dos fármacos , Proteínas do Tecido Nervoso/síntese química , Penicilinas/farmacologia , Peptídeos/síntese química , Streptococcus mutans/crescimento & desenvolvimento
2.
BMC Neurosci ; 20(1): 11, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30885137

RESUMO

BACKGROUND: Pre-treatment with the corticotropin-releasing factor antagonist α-helical CRF9-41 prevents inhibition of gastric emptying by cocaine-and amphetamine-regulated transcript peptide at a dorsal hindbrain level, but its inhibition of sucrose intake is not affected. This is suggestive of separable underlying mechanisms of action in the caudal brainstem for cocaine-and amphetamine-regulated transcript peptide with regard to food intake and gastrointestinal functions. Here we further examine cocaine-and amphetamine-regulated transcript peptide-corticotropin-releasing factor receptor interactions in caudal brainstem controls of solid food intake. Injections of combinations of vehicle, cocaine-and amphetamine-regulated transcript peptide (0.5 µg or 1 µg) or α-helical CRF9-41 were given into the fourth cerebral ventricle of rats. Nocturnal solid food intake was recorded over 22 h. RESULTS: Pre-treatment with α-helical CRF9-41 into the fourth ventricle significantly increased the responsivity to cocaine-and amphetamine-regulated transcript peptide on hypophagia. In a separate control experiment, α-helical CRF9-41 pre-treatment blocked CRF-induced food intake inhibition indicative of its antagonistic effectiveness. CONCLUSIONS: We conclude that an endogenous Corticotropin-releasing factor agonist may modulate suppression of food intake caused by cocaine-and amphetamine-regulated transcript peptide at a dorsal hindbrain level in the absence of stress. A potential caudal brainstem mechanism whereby cocaine-and amphetamine-regulated transcript peptide effects on food intake is attenuated via corticotropin-releasing factor receptor activity causing tonic inhibition, is suggested.


Assuntos
Fármacos do Sistema Nervoso Central/farmacologia , Hormônio Liberador da Corticotropina/antagonistas & inibidores , Ingestão de Alimentos/efeitos dos fármacos , Proteínas do Tecido Nervoso/farmacologia , Fragmentos de Peptídeos/farmacologia , Rombencéfalo/efeitos dos fármacos , Animais , Hormônio Liberador da Corticotropina/metabolismo , Hormônio Liberador da Corticotropina/farmacologia , Ingestão de Alimentos/fisiologia , Quarto Ventrículo , Injeções Intraventriculares , Masculino , Proteínas do Tecido Nervoso/metabolismo , Fragmentos de Peptídeos/metabolismo , Ratos Sprague-Dawley , Rombencéfalo/metabolismo
3.
Life Sci ; 222: 29-35, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30826495

RESUMO

Recently, several plexins and semaphorins have been associated with osteoclastogenesis, a vital process for bone remodeling. Plexin-A2 is implicated in bone homeostasis, however, whether it plays a role in osteoclastogenesis and the underlying mechanism remain unknown. We show that plexin-A2 expression is upregulated during RANKL-induced osteoclastogenesis. In addition, the soluble Sema6A fused with IgG1 Fc region (Fc-Sema6A) interacts with plexin-A2 from cell lysates of osteoclasts, suggesting that plexin-A2 acts as a receptor of Sema6A in osteoclasts. Moreover, Sema6A treatment stimulates RANKL-induced osteoclastogenesis, and this effect is abolished when plexin-A2 is neutralized, which illustrates an indispensable role of plexin-A2 in mediating Sema6A effect on osteoclastogenesis. Mechanistically, Sema6A-plexin-A2 axis enhances RANKL-induced activation of PLCγ as well as downstream target NFATc1, one master transcriptional factor of osteoclastogenesis. Lastly, inhibition of PLCγ by pharmacological inhibitor U73122 abrogates Sema6A-stimulated NFATc1 activation and RANKL-induced osteoclastogenesis, thus demonstrating that the PLCγ-mediated NFATc1 activation accounts for the promotive role of Sema6A-plexin-A2 axis in RANKL-induced osteoclastogenesis. Taken together, this study uncovers a novel role of Sema6A and plexin-A2 in osteoclastogenesis, and also offers them as possible therapeutic targets in the intervention of osteolytic diseases.


Assuntos
Fatores de Transcrição NFATC/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Osteogênese/fisiologia , Fosfolipase C gama/metabolismo , Ligante RANK/metabolismo , Receptores de Superfície Celular/metabolismo , Semaforinas/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Células Cultivadas , Estrenos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/farmacologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Fosfolipase C gama/antagonistas & inibidores , Pirrolidinonas/farmacologia , Semaforinas/farmacologia
4.
Anticancer Res ; 39(3): 1267-1273, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30842157

RESUMO

BACKGROUND: The members of the slit homolog (SLIT) and roundabout homolog (ROBO) families have emerged as important signaling molecules in tumor metastasis. This study analyzed their role in regulating breast cancer (BC) cell motility and chemotaxis and assessed expression of ROBO1 in brain metastases (BMs) of breast, lung, and colon cancer, and in peritoneal metastases (PMs) of ovarian cancer. MATERIALS AND METHODS: The BC cell line MDA-MB231 was subjected to scratch, motility, and chemotaxis assays using heparin and a purified recombinant N-terminal SLIT2 fragment. Protein expression was assessed in primary tumors and metastases by immunohistochemistry. RESULTS: Exposure to SLIT2 induced MDA-MB231 cell motility, but no significant chemotaxis without the presence of heparin. ROBO1 was expressed in 4/5 primary BC and in 18/21 BC-derived BM samples; 7/9 BM primary lung cancer samples also stained positive. In contrast, BMs from colorectal cancer were negative for ROBO1. Primary ovarian cancer and ovarian PM showed ROBO1 expression in 0/6 and in only 2/6 samples, respectively, whereas SLIT2 was observed in 1/6 primary cancer and in 6/6 PMs samples. CONCLUSION: SLIT2 can induce BC cell motility and chemotaxis, but the latter requires the presence of heparin. BM expression of ROBO1 is a common feature of some, but not all cancer types. SLIT2 expression appears to be a general feature of ovarian cancer-derived PMs.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Receptores Imunológicos/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Heparitina Sulfato/farmacologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas do Tecido Nervoso/farmacologia , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/secundário
5.
J Pept Sci ; 25(4): e3153, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30734396

RESUMO

The aim of the study was to determine the in vitro immunomodulatory, cytotoxic, and insulin-releasing activities of seven phylloseptin-TR peptides and plasticin-TR, first isolated from the frog Phyllomedusa trinitatis. The most cationic peptides, phylloseptin-1.1TR and phylloseptin-3.1TR, showed greatest cytotoxic potency against A549, MDA-MB231, and HT-29 human tumor-derived cells and against mouse erythrocytes. Phylloseptin-4TR was the most hydrophobic and the most effective peptide at inhibiting production of the proinflammatory cytokines TNF-α and IL-1ß by mouse peritoneal cells but was without effect on production of the antiinflammatory cytokine IL-10. Phylloseptin-2.1TR and phylloseptin-3.3TR were the most effective at stimulating the production of IL-10. The noncytotoxic peptide, plasticin-TR, inhibited production of TNF-α and IL-1ß but was without effect on IL-10 production. The results of CD spectroscopy suggest that the different properties of plasticin-TR compared with the immunostimulatory activities of the previously characterized plasticin-L1 from Leptodactylus laticeps may arise from greater ability of plasticin-TR to oligomerize and adopt a stable helical conformation in a membrane-mimetic environment. All peptides stimulated release of insulin from BRIN-BD11 rat clonal ß cells with phylloseptin-3.2TR being the most potent and effective and phylloseptin-2.1TR the least effective suggesting that insulinotropic potency correlates inversely with helicity. The study has provided insight into structure-activity relationships among the phylloseptins. The combination of immunomodulatory and insulinotropic activities together with low cytotoxicity suggests that phylloseptin-3.3TR and plasticin-TR may represent templates for the development of agents for use in antiinflammatory and type 2 diabetes therapies.


Assuntos
Anti-Inflamatórios/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Anuros , Citotoxinas/farmacologia , Proteínas do Olho/farmacologia , Imunomodulação/efeitos dos fármacos , Insulina/metabolismo , Proteínas do Tecido Nervoso/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/isolamento & purificação , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/imunologia , Peptídeos Catiônicos Antimicrobianos/isolamento & purificação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Proteínas do Olho/química , Proteínas do Olho/imunologia , Proteínas do Olho/isolamento & purificação , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/imunologia , Proteínas do Tecido Nervoso/isolamento & purificação , Ratos
6.
PLoS One ; 14(1): e0207190, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30673694

RESUMO

PURPOSE: To analyze the potential neuro-protective and neuro-regenerative effects of Collapsin-response-mediator-protein-5 (CRMP-5) on retinal ganglion cells (RGCs) using in vitro and in vivo animal models of glaucoma. METHODS: Elevated intraocular pressure (IOP) was induced in adult female Sprague-Dawley (SD) rats by cauterization of three episcleral veins. Changes in CRMP-5 expression within the retinal proteome were analyzed via label-free mass spectrometry. In vitro, retinal explants were cultured under elevated pressure (60 mmHg) within a high-pressure incubation chamber with and without addition of different concentrations of CRMP-5 (4 µg/l, 200 µg/l and 400 µg/l). In addition, retinal explants were cultured under regenerative conditions with and without application of 200 µg/l CRMP-5 after performing an optic nerve crush (ONC). Thirdly, an antibody against Protein Kinase B (PKB) was added to examine the possible effects of CRMP-5. RGC count was performed. Number and length of the axons were determined and compared. To undermine a signal-transduction pathway via CRMP-5 and PKB microarray and immunohistochemistry were performed. RESULTS: CRMP-5 was downregulated threefold in animals showing chronically elevated IOP. The addition of CRMP-5 to retinal culture significantly increased RGC numbers under pressure in a dose-dependent manner and increased and elongated outgrowing axons in retinal explants significantly which could be blocked by PKB. Especially the number of neurites longer than 400 µm significantly increased after application of CRMP-5. CRMP-5 as well as PKB were detected higher in the experimental than in the control group. CONCLUSION: CRMP-5 seems to play an important role in an animal model of glaucoma. Addition of CRMP-5 exerts neuro-protective and neuro-regenerative effects in vitro. This effect could be mediated via activation of PKB affecting intra-cellular apoptosis pathways.


Assuntos
Glaucoma/patologia , Glaucoma/fisiopatologia , Modelos Biológicos , Regeneração Nervosa/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Células Ganglionares da Retina/patologia , Animais , Feminino , Glaucoma/metabolismo , Proteínas do Tecido Nervoso/farmacologia , Crescimento Neuronal/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Proteoma/metabolismo , Proteômica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Células Ganglionares da Retina/efeitos dos fármacos
7.
Med Sci Monit ; 24: 4982-4991, 2018 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-30018280

RESUMO

BACKGROUND Collapsin response mediator protein-2 (CRMP-2) is the first member of the CRMP family that has been identified in primary neuronal cells; it was originally found and identified in the regulation of microtubule dimerization into microtubules. MATERIAL AND METHODS In the present study, we aimed to investigate the roles and mechanisms of CRMP-2 in sevoflurane-induced neurocyte injury. Cell viability, proliferation, and apoptosis were measured by Cell Counting Kit-8 (CCK-8) assay and flow cytometry. Colorimetry was performed to measure the activity of caspase-3. Western blot and quantitative real-time reverse transcription assays were used to evaluate the related mRNAs and proteins expression. RESULTS We found that CRMP-2 reversed the inhibitory effect of sevoflurane on the viability of nerve cells. Moreover, CRMP-2 accelerated the proliferation and suppressed the apoptosis of sevoflurane-induced nerve cells. CRMP-2 modulated the expression levels of apoptosis-associated protein in sevoflurane-induced nerve cells. Furthermore, it was demonstrated that CRMP-2 impacted the PI3K-mTOR-S6K pathway. CONCLUSIONS CRMP2 ameliorated sevoflurane-mediated neurocyte injury by targeting the PI3K-mTOR-S6K pathway. Thus, CRMP2 might be an effective target for sevoflurane-induced neurocyte injury therapies.


Assuntos
Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Traumatismos dos Nervos Cranianos/tratamento farmacológico , Feminino , Hipocampo/efeitos dos fármacos , Éteres Metílicos/farmacologia , Proteínas do Tecido Nervoso/farmacologia , Neurônios/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Gravidez , Ratos , Ratos Sprague-Dawley , Proteínas Quinases S6 Ribossômicas/metabolismo , Sevoflurano , Serina-Treonina Quinases TOR/metabolismo
8.
J Mol Neurosci ; 65(3): 377-384, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29956089

RESUMO

Nesfatin-1, a recently discovered peptide, is involved in important functions such as food intake regulation and energy homeostasis. Previous studies have demonstrated that it has protective effects following myocardial injury and also protects dopaminergic cells against neurotoxicity with the anti-inflammatory and anti-apoptotic mechanisms. In this study, we aimed to assay the neuroprotective effects of Nesfatin-1 after brain ischemia/reperfusion. Twenty-eight male Wistar rats were randomly selected and allocated in the form of four groups (sham, Nesfatin-1, ischemia, ischemia+Nesfatin-1). Ischemia was created by obstruction couple common carotid arteries in 20-min period. Saline as a vehicle and Nesfatin-1 (20 µg/kg, intraperitoneally) were injected at the time of reperfusion. Spatial memory performances were evaluated by the Morris water maze. The level of protein expression was determined by immunohistochemical and immunofluorescence staining. Nesfatin-1 significantly reduced caspase-3 (P < 0.01) and microglial activation (P < 0.01) and improved spatial memory impairments (P < 0.05) induced by brain ischemia. Nesfatin-1 has significant neuroprotective effects and can be introduced as a therapeutic agent against cerebral ischemia-induced injuries.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Proteínas de Ligação ao Cálcio/uso terapêutico , Proteínas de Ligação a DNA/uso terapêutico , Memória , Microglia/efeitos dos fármacos , Proteínas do Tecido Nervoso/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Proteínas de Ligação ao Cálcio/administração & dosagem , Proteínas de Ligação ao Cálcio/farmacologia , Caspase 3/metabolismo , Proteínas de Ligação a DNA/administração & dosagem , Proteínas de Ligação a DNA/farmacologia , Masculino , Microglia/metabolismo , Proteínas do Tecido Nervoso/administração & dosagem , Proteínas do Tecido Nervoso/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar
9.
Neuropeptides ; 70: 9-15, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29751997

RESUMO

Nesfatin-1, a peptide whose receptor is yet to be identified, has been shown to be involved in the modulation of feeding, stress, and metabolic responses. Recently, increasing evidence has supported a modulatory role of nesfatin-1 in cardiovascular activity. We have previously reported that nesfatin-1 causes an increase in blood pressure in normotensive and hypotensive rats by increasing plasma catecholamine, vasopressin, and renin levels. Recent reports suggest that nesfatin-1 may activate the central cholinergic system. However, there is no evidence showing an interaction between central nesfatin-1 and the cholinergic system. Therefore, this study aimed to determine whether the central cholinergic system may have a functional role in the nesfatin-1-induced cardiovascular effect observed in normotensive rats. Intracerebroventricular injection of nesfatin-1 caused short-term increases in mean arterial pressure and heart rate responses including bradycardic/tachycardic phases in normotensive animals. Central injection of nesfatin-1 increased the acetylcholine and choline levels in the posterior hypothalamus, as shown in microdialysis studies. Central pretreatment with the cholinergic muscarinic receptor antagonist atropine and/or nicotinic receptor antagonist mecamylamine blocked nesfatin-1-induced cardiovascular effects. In conclusion, the results show that centrally administered nesfatin-1 produces a pressor effect on blood pressure and heart rate responses including bradycardic/tachycardic phases in normotensive rats. Moreover, according to our findings, the central cholinergic system can modulate nesfatin-1-evoked cardiovascular activity.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/farmacologia , Proteínas de Ligação a DNA/farmacologia , Hipotensão/etiologia , Proteínas do Tecido Nervoso/farmacologia , Vasoconstritores/farmacologia , Acetilcolina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/administração & dosagem , Catecolaminas/metabolismo , Colinérgicos/farmacologia , Proteínas de Ligação a DNA/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Masculino , Mecamilamina/sangue , Proteínas do Tecido Nervoso/administração & dosagem , Ratos Sprague-Dawley , Vasopressinas/sangue
10.
Biochem Biophys Res Commun ; 501(4): 1016-1022, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29777699

RESUMO

The accumulation of amyloid-beta (Aß) and oxidative stress damage in the brain are recognized as early features of Alzheimer's disease (AD). The cocaine- and amphetamine-regulated transcript (CART) peptide may possibly play an antioxidative role in neurons. The aim of this study was to investigate the potential antioxidant mechanism of CART peptide in a rat model of AD. We microinjected of Aß1-42 (2µl/4µg/hemisphere) into rat hippocampus to set a rat model of AD. A pre-microinjection of CART peptide (1µl/0.02µg/hemisphere) into rat hippocampus was administered for five consecutive days before Aß1-42 treatment. We found that Aß1-42 microinjection led to reduction of endogenous CART level in rat hippocampus. CART pretreatment improved the spatial memory and locomotor ability of AD rats. CART peptide decreased the Aß1-42 and Aß production-associated enzyme BACE1 levels. Moreover, CART peptide attenuated the oxidative stress damage with a concrete manifestation of increased MDA as well as decreased T-SOD, GSH and ATP levels in the hippocampus of Aß1-42-treated rat, which may be causatively implicated the activating of Nrf2/HO-1 signaling pathway. Furthermore, CART peptide attenuated neuronal apoptosis with decreased Bax, caspase-9 and caspase-3 levels and increased Bcl-2 level in rat hippocampus. Our results therefore indicate that CART peptide could serve as an antioxidant in early therapy for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/metabolismo , Heme Oxigenase-1/metabolismo , Hipocampo/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas do Tecido Nervoso/uso terapêutico , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Ácido Aspártico Endopeptidases , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Microinjeções , Atividade Motora/efeitos dos fármacos , Proteínas do Tecido Nervoso/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley
11.
Mol Med Rep ; 17(2): 2757-2763, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29207186

RESUMO

Our previous study demonstrated that neuroglobin (Ngb) functions as an independent predictive indicator of the prognosis of patients with glioma and promotes cancer cell growth by suppressing apoptosis. However, the understanding of the mechanisms underlying the survival­enhancing function of Ngb in glioma is limited. In the present study, KEGG PathwayFinder by gene correlation analysis was performed on the R2: Genomics Analysis and Visualization Platform, which revealed a high association between Ngb and the phosphatidylinositol 3­kinase (PI3K)/AKT pathway using glioma data (GSE4290) from the Gene Expression Omnibus database. Furthermore, western blotting experiments were performed in U251 and U87 glioma cells, and Ngb knockdown using short hairpin RNA reduced the protein levels of phosphorylated (p)­AKT, p­mammalian target of rapamycin (mTOR) and antiapoptotic factor Bcl­2, and increased the expression of the proapoptotic protein Bcl­2­associated X, in U251 cells. In addition, Ngb overexpression promoted the activation of the PI3K/AKT pathway in U87 cells. MK2206, a PI3K/AKT signaling inhibitor, reduced the expression of p­AKT and increased the levels of apoptosis­associated proteins, including cleaved poly(ADP­ribose) polymerase 1 and cleaved caspase­3/7/8, in Ngb­overexpressing U87 cells. Furthermore, MK2206 treatment reduced the proliferation and induced the apoptosis of Ngb­overexpressing U87 cells, as indicated by the results of MTT, colony formation and flow cytometry assays. In addition, insulin­like growth factor­1, a PI3K/AKT signaling activator, reversed Ngb knockdown­induced growth arrest and apoptosis in U251 cells. In conclusion, the results of the present study indicate that Ngb may facilitate a malignant phenotype of glioma cells by activating the PI3K/AKT pathway.


Assuntos
Apoptose/efeitos dos fármacos , Globinas/farmacologia , Proteínas do Tecido Nervoso/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Glioma/patologia , Humanos , Neuroglobina , Fenótipo
12.
Gen Comp Endocrinol ; 265: 71-76, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29155267

RESUMO

Recently we discovered a small hypothalamic protein in the chicken, named neurosecretory protein GL (NPGL), which is associated with body growth and energy metabolism in birds and rodents. Genome database analysis suggested that the NPGL gene has a paralogous gene in vertebrates, named neurosecretory protein GM (NPGM). However, the biological action of NPGM remains unclear. In this study, we investigated whether NPGM affects body growth in chicks. We found that subcutaneous infusion of NPGM for six days increased body mass gain in a dose-dependent manner. Despite the observed increase in body mass, infusion of NPGM did not alter food and water intake. Of note, we observed tendency of mass increase of several peripheral tissues, specifically. When we compared several tissue types, NPGM seemed to induce the largest growth increase in white adipose tissue mass. These results suggest that NPGM may accelerate fat accumulation and body growth. In addition, we analyzed whether NPGM increases body growth through the action of pituitary hormones. However, we observed no significant changes in mRNA expression of pituitary hormones or plasma levels of growth hormone in NPGM-treated chicks. This is the first report describing the biological action of NPGM in vertebrates.


Assuntos
Galinhas/crescimento & desenvolvimento , Proteínas do Tecido Nervoso/administração & dosagem , Ganho de Peso , Sequência de Aminoácidos , Animais , Composição Corporal/efeitos dos fármacos , Galinhas/metabolismo , Ingestão de Líquidos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônios/genética , Hormônios/metabolismo , Infusões Subcutâneas , Masculino , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/farmacologia , Hipófise/metabolismo
13.
Gen Comp Endocrinol ; 256: 37-42, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-28554734

RESUMO

Recently, we discovered a novel cDNA encoding the precursor of a small secretory protein, neurosecretory protein GL (NPGL), in the chicken mediobasal hypothalamus. In this study, immunohistochemical analysis revealed that NPGL was produced in the infundibular and medial mammillary nuclei of the mediobasal hypothalamus, with immunoreactive fibers also detected in the hypothalamus and the median eminence. As it is known that these regions are involved in feeding behavior in chicks, we surveyed the effects of chronic intracerebroventricular infusion of NPGL on feeding behavior and body mass for a period of two weeks. NPGL stimulated food and water intake, with a concomitant increase in body mass. However, NPGL did not influence mRNA expression of several hypothalamic ingestion-related neuropeptides. Our data suggest that NPGL may be a novel neuronal regulator involved in growth processes in chicks.


Assuntos
Peso Corporal , Galinhas/metabolismo , Ingestão de Líquidos , Comportamento Alimentar/fisiologia , Infusões Intraventriculares , Proteínas do Tecido Nervoso/administração & dosagem , Proteínas do Tecido Nervoso/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , DNA Complementar/metabolismo , Ingestão de Líquidos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
14.
Clin Exp Hypertens ; 40(5): 414-420, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29027818

RESUMO

BACKGROUND: This study aimed to examine the effects of nesfatin-1 on thoracic aorta vasoreactivity and to investigate the inotropic and chronotropic effects of nesfatin-1 on the spontaneous contractions of the isolated rat atria. METHODS: Isolated right atria and thoracic aorta were used in organ baths. The reactivity of the thoracic aorta was evaluated by potassium chloride (KCl), phenylephrine (Phe), acetylcholine (ACh), and sodium nitroprusside (SNP). The effects of nesfatin-1 on the spontaneous contractions of the rat atria were also examined. RESULTS: Nesfatin-1 (0.1-100 ng/ml) produced a concentration-dependent relaxation response in rat thoracic aorta. The relaxant responses to nesfatin-1 were inhibited by the removal of endothelium, NO synthase blocker N-nitro-L-arginine methyl ester (L-NAME, 10-4 M), and soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10-5 M). Nesfatin-1 (10 ng/ml, 30 min) increased the relaxation responses to either ACh or SNP, and the contractile response to both Phe and KCl did not significantly change in the arteries that were incubated with nesfatin-1 compared with the controls. The thoracic aorta contractions induced by the stepwise addition of Ca2+ to a high KCl solution with no Ca2+ were not significantly changed by nesfatin-1. Under calcium-free conditions, the contractions of the thoracic aorta rings incubated with nesfatin-1 in response to Phe were not significantly lower than those of the rings from the control rats. Nesfatin-1 showed positive inotropic and chronotropic effects on rat atria. CONCLUSION: Nesfatin-1 significantly changed the vascular responsiveness in rat thoracic aorta and produced positive inotropic and chronotropic effects on rat atria.


Assuntos
Aorta Torácica/fisiologia , Função Atrial/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/farmacologia , Proteínas de Ligação a DNA/farmacologia , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Proteínas do Tecido Nervoso/farmacologia , Acetilcolina/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Cálcio/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Inibidores Enzimáticos/farmacologia , Guanilato Ciclase/antagonistas & inibidores , Masculino , Músculo Liso Vascular/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Nitroprussiato/farmacologia , Oxidiazóis/farmacologia , Fenilefrina/farmacologia , Cloreto de Potássio/farmacologia , Quinoxalinas/farmacologia , Ratos , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia
15.
Behav Brain Res ; 336: 135-144, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-28864207

RESUMO

The neuropeptide relaxin-3 (RLN3) binds with high affinity to its cognate receptor, relaxin-family peptide receptor 3 (RXFP3), and with lower affinity to RXFP1, the cognate receptor for relaxin. Intracerebroventricular (icv) administration of RLN3 in rats strongly increases food and water intake and alters the activity of the hypothalamic-pituitary-adrenal (HPA) and gonadal (HPG) axes, but the relative involvement of RXFP3 and RXFP1 in these effects is not known. Therefore, the effects of icv administration of equimolar (1.1 nmol) amounts of RLN3 and the RXFP3-selective agonist RXFP3-A2 on food and water intake, plasma levels of corticosterone, testosterone, and oxytocin and c-fos mRNA expression in key hypothalamic regions in male rats were compared. Food intake was increased by both RLN3 and RXFP3-A2, but the orexigenic effects of RXFP3-A2 were significantly stronger than RLN3, 30 and 60min after injection. Water intake and plasma corticosterone and testosterone levels were significantly increased by RLN3, but not by RXFP3-A2. Conversely, RXFP3-A2 but not RLN3 decreased oxytocin plasma levels. RLN3, but not RXFP3-A2, increased c-fos mRNA levels in the parvocellular (PVNp) and magnocellular (PVNm) paraventricular and supraoptic (SON) hypothalamic nuclei, in the ventral medial preoptic area (MPAv), and in the organum vasculosum of the lamina terminalis (OVLT). A significant increase in c-fos mRNA expression was induced in the perifornical lateral hypothalamic area (LHApf) by RLN3 and RXFP3-A2. These results suggest that RXFP1 is involved in the RLN3 stimulation of water intake and activation of the HPA and HPG axes. The reduced food intake stimulation by RLN3 compared to RXFP3-A2 may relate to activation of both orexigenic and anorexigenic circuits by RLN3.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Receptores Acoplados a Proteínas-G/agonistas , Receptores de Peptídeos/agonistas , Relaxina/metabolismo , Animais , Corticosterona/sangue , Ingestão de Líquidos/efeitos dos fármacos , Alimentos , Sistema Hipotálamo-Hipofisário , Hipotálamo , Masculino , Proteínas do Tecido Nervoso/farmacologia , Neurônios/metabolismo , Ocitocina/sangue , Sistema Hipófise-Suprarrenal , Proteínas Proto-Oncogênicas c-fos/sangue , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Peptídeos/metabolismo , Relaxina/farmacologia , Testosterona/sangue
16.
Vet Res Commun ; 42(1): 39-47, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29280084

RESUMO

The present study was designed to determine the effect of central injection of Nesfatin-1 and corticotropin and histaminergic systems on food intake in neonatal meat-type chicks. In this study, 7 experiments were designed, each with 4 treatment groups. In experiment 1, four groups of chicks received the ICV injection of (A) phosphate-buffered saline (PBS), (B) Nesfatin-1 (10 ng), (C) Nesfatin-1 (20 ng) and (D) Nesfatin-1 (40 ng). In experiment 2, (A) PBS, (B) Astressin-B (CRF1/CRF2 receptors antagonist; 30 µg), (C) Nesfatin-1 (40 ng) and (D) Nesfatin-1 + Astressin-B were injected. In experiments 3-6, chicken received ICV injection of the Astressin2-B (CRF2 receptor antagonist; 30 µg), α-FMH (alpha fluoromethyl histidine; as inhibitor of histidine decarboxylase, 250 nmol), Chlorpheniramine (histamine H1 receptors antagonist, 300 nmol), Famotidine (histamine H2 receptors antagonist, 82 nmol) and Thioperamide (histamine H3 receptors antagonist, 300 nmol) instead of the Astressin-B. Then the cumulative food intake measured until 120 min post-injection. According to the results, ICV injection of Nesfatin-1 dose dependently decreased food intake in neonatal chicks (P < 0.05). Co-injection of the Nesfatin-1 and Astressin-B (CRF1/CRF2) inhibited Nesfatin-1 induced hypophagia (P < 0.05). ICV inejction of the Nesfatin-1 + Astressin-B significantly inhibited the effect of Nesfatin-1 on food intake (P < 0.05). In addition, α-FMH and chlorpheniramine attenuated Nesfatin-1-induced hypophagia in chicks (P < 0.05); while thioperamide significantly amplified the effect of Nesfatin-1 on food intake in chicks (P < 0.05). These results suggested Nesfatin-1 has an anorectic effect in 3-hour food deprived neonatal meat-type chicks and this effect was mediated by corticotropin CRF1/CRF2 as well as histamine H1 and H3 receptors.


Assuntos
Proteínas de Ligação ao Cálcio/farmacologia , Galinhas/fisiologia , Proteínas de Ligação a DNA/farmacologia , Proteínas do Tecido Nervoso/farmacologia , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H3/metabolismo , Animais , Animais Recém-Nascidos , Hormônio Liberador da Corticotropina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia
17.
Exp Eye Res ; 164: 129-138, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28823941

RESUMO

Treatment of a mouse model of oxygen-induced retinopathy (OIR) with recombinant human Norrin (Norrie Disease Protein, gene: NDP) accelerates regrowth of the microvasculature into central ischemic regions of the neural retina, which are generated after treatment with 75% oxygen. While this reduces the average duration and severity of ischemia overall, we do not know if this accelerated recovery of the microvasculature results in any significant survival of retinal ganglion cells (RGCs). The purpose of this study was to investigate ganglion cell survival with and without the intravitreal injection of Norrin in the murine model of oxygen induced retinopathy (OIR), using two strains of mice: C57BL/6J and Thy1-YFP mice. Intravitreal injections of Norrin or vehicle were done after five days of exposure to 75% oxygen from ages P7 to P12. The C57BL/J mice were followed by Spectral-Domain Optical Coherence Tomography (SD-OCT), and the average nerve fiber layer (NFL) and inner-plexiform layer (IPL) thicknesses were measured at twenty-four locations per retina at P42. Additionally, some C57BL/J retinas were flat mounted and immunostained for the RGC marker, Brn3a, to compare the population density of surviving retinal ganglion cells. Using homozygous Thy1-YFP mice, single intrinsically fluorescent RGCs were imaged in live animals with a Micron-III imaging system at ages P21, 28 and P42. The relative percentage of YFP-fluorescent RGCs with dendritic arbors were compared. At age P42, the NFL was thicker in Norrin-injected OIR eyes, 14.4 µm, compared to Vehicle-injected OIR eyes, 13.3 µm (p = 0.01). In the superior retina, the average thickness of the IPL was greater in Norrin-injected OIR eyes, 37.7 µm, compared to Vehicle-injected OIR eyes, 34.6 µm (p = 0.04). Retinas from Norrin injected OIR mice had significantly more surviving RGCs (p = 0.03) than vehicle-injected mice. Based upon NFL thickness and counts of RGCs, we conclude that Norrin treatment, early in the ischemic phase, increased the relative population density of surviving RGCs in the central retinas of OIR mice.


Assuntos
Proteínas do Olho/farmacologia , Proteínas do Tecido Nervoso/farmacologia , Retina/patologia , Células Ganglionares da Retina/efeitos dos fármacos , Neovascularização Retiniana/tratamento farmacológico , Animais , Sobrevivência Celular , Modelos Animais de Doenças , Humanos , Isquemia/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Oxigênio/farmacologia , Retina/metabolismo , Células Ganglionares da Retina/patologia , Vasos Retinianos/metabolismo , Fator de Transcrição Brn-3A/metabolismo
18.
Neurol Res ; 39(10): 885-894, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28743230

RESUMO

INTRODUCTION: Cocaine- and amphetamine-regulated transcript (CART) peptide has been demonstrated to exert neuroprotective effects in stroke and some neurodegeneration diseases. In current study, we investigated the protective effects and underlying mechanisms of CART in APP/PS1 mice. METHODS: The protein levels of CART, soluble Aß1-40 and Aß1-42 were measured in the hippocampus of APP/PS1 mice by enzyme-linked immunosorbent assay. We determined the mRNA and protein levels of Aß metabolism-associated enzymes including neprilysin (NEP), insulin-degrading enzyme (IDE), receptor for advanced glycation end products (RAGE), and low-density lipoprotein receptor-related protein 1 (LRP-1) in the hippocampus of APP/PS1 mice using real-time PCR and western blotting. Spatial memory was measured in APP/PS1 mice using the Morris water maze. The phosphorylation of AKT, ERK, p38, and JNK was determined using western blotting. RESULTS: The levels of soluble Aß1-40 and Aß1-42 were significantly decreased in the hippocampus of APP/PS1 mice after CART treatment. CART modulated the levels of NEP, IDE, RAGE, and LRP-1. In addition, CART inhibited the MAPK pathways and activated the AKT pathway, whereas inhibition of the AKT pathway decreased the levels of IDE and LRP-1. Furthermore, CART attenuated spatial memory deficits in the APP/PS1 mice. CONCLUSION: CART decreases the levels of soluble Aß in the hippocampus of APP/PS1 mice by modulating the expression of Aß metabolism-associated enzymes, which may be associated with the MAPK and AKT pathways.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Proteínas do Tecido Nervoso/farmacologia , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Hipocampo/metabolismo , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/metabolismo , Camundongos Transgênicos , Fragmentos de Peptídeos/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Distribuição Aleatória , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologia
19.
Ann Rheum Dis ; 76(8): 1440-1448, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28416516

RESUMO

OBJECTIVES: Inappropriate activation of neutrophils plays a pathological role in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The aim of this study was to investigate the functions of semaphorin 4D (SEMA4D) in regulation of neutrophil activation, and its involvement in AAV pathogenesis. METHODS: Serum levels of soluble SEMA4D were evaluated by ELISA. Blood cell-surface expression of membrane SEMA4D was evaluated by flow cytometry. To determine the functional interactions between neutrophil membrane SEMA4D and endothelial plexin B2, wild-type and SEMA4D-/- mice neutrophils were cultured with an endothelial cell line (MS1) stained with SYTOX green, and subjected to neutrophil extracellular trap (NET) formation assays. The efficacy of treating human neutrophils with recombinant plexin B2 was assessed by measuring the kinetic oxidative burst and NET formation assays. RESULTS: Serum levels of soluble SEMA4D were elevated in patients with AAV and correlated with disease activity scores. Cell-surface expression of SEMA4D was downregulated in neutrophils from patients with AAV, a consequence of proteolytic cleavage of membrane SEMA4D. Soluble SEMA4D exerted pro-inflammatory effects on endothelial cells. Membranous SEMA4D on neutrophils bound to plexin B2 on endothelial cells, and this interaction decreased NET formation. Recombinant plexin B2 suppressed neutrophil Rac1 activation through SEMA4D's intracellular domain, and inhibited pathogen-induced or ANCA-induced oxidative burst and NET formation. CONCLUSIONS: Neutrophil surface SEMA4D functions as a negative regulator of neutrophil activation. Proteolytic cleavage of SEMA4D as observed in patients with AAV may amplify neutrophil-mediated inflammatory responses. SEMA4D is a promising biomarker and potential therapeutic target for AAV.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Antígenos CD/imunologia , Células Endoteliais/imunologia , Armadilhas Extracelulares/imunologia , Proteínas do Tecido Nervoso/imunologia , Neutrófilos/imunologia , Semaforinas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos CD/genética , Ensaio de Imunoadsorção Enzimática , Armadilhas Extracelulares/efeitos dos fármacos , Feminino , Citometria de Fluxo , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/farmacologia , Neutrófilos/efeitos dos fármacos , Espécies Reativas de Oxigênio/imunologia , Explosão Respiratória/efeitos dos fármacos , Semaforinas/genética , Proteínas rac1 de Ligação ao GTP/efeitos dos fármacos , Proteínas rac1 de Ligação ao GTP/imunologia
20.
Sci Rep ; 7(1): 746, 2017 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-28389649

RESUMO

Brain tissue surrounding surgical resection site can be injured inadvertently due to procedures such as incision, retractor stretch, and electrocauterization when performing neurosurgical procedures, which is termed as surgical brain injury (SBI). Blood brain barrier (BBB) disruption due to SBI can exacerbate brain edema in the post-operative period. Previous studies showed that Slit2 exhibited vascular anti-permeability effects outside the brain. However, BBB protective effects of Slit2 following SBI has not been evaluated. The objective of this study was to evaluate whether recombinant Slit2 via its receptor roundabout4 (Robo4) and the adaptor protein, Paxillin were involved in reducing BBB permeability in SBI rat model. Our results showed that endogenous Slit2 increased in the surrounding peri-resection brain tissue post-SBI, Robo4 remained unchanged and Paxillin showed a decreasing trend. Recombinant Slit2 administered 1 h before injury increased BBB junction proteins, reduced BBB permeability, and decreased neurodeficits 24 h post-SBI. Furthermore, recombinant Slit2 administration increased Rac1 activity which was reversed by Robo4 and Paxillin siRNA. Our findings suggest that recombinant Slit2 reduced SBI-induced BBB permeability, possibly by stabilizing BBB tight junction via Robo4 mediated Rac1 activation. Slit2 may be beneficial for BBB protection during elective neurosurgeries.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Lesões Encefálicas/etiologia , Lesões Encefálicas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Complicações Intraoperatórias/metabolismo , Proteínas do Tecido Nervoso/farmacologia , Receptores de Superfície Celular/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Animais , Barreira Hematoencefálica/patologia , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/patologia , Modelos Animais de Doenças , Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Complicações Intraoperatórias/tratamento farmacológico , Complicações Intraoperatórias/patologia , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Especificidade de Órgãos/genética , Paxilina/genética , Paxilina/metabolismo , Permeabilidade , Ratos , Receptores de Superfície Celular/genética , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos
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