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1.
CNS Neurosci Ther ; 26(4): 416-429, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32154670

RESUMO

INTRODUCTION: Clearance of damaged cells and debris is beneficial for the functional recovery after ischemic brain injury. However, the specific phagocytic receptor that mediates microglial phagocytosis after ischemic stroke is unknown. AIM: To investigate whether P2Y6 receptor-mediated microglial phagocytosis is beneficial for the debris clearance and functional recovery after ischemic stroke. RESULTS: The expression of the P2Y6 receptor in microglia increased within 3 days after transient middle cerebral artery occlusion. Inhibition of microglial phagocytosis by the selective inhibitor MRS2578 enlarged the brain atrophy and edema volume after ischemic stroke, subsequently aggravated neurological function as measured by modified neurological severity scores and Grid walking test. MRS2578 treatment had no effect on the expression of IL-1α, IL-1ß, IL-6, IL-10, TNF-α, TGF-ß, and MPO after ischemic stroke. Finally, we found that the expression of myosin light chain kinase decreased after microglial phagocytosis inhibition in the ischemic mouse brain, which suggested that myosin light chain kinase was involved in P2Y6 receptor-mediated phagocytosis. CONCLUSION: Our results indicate that P2Y6 receptor-mediated microglial phagocytosis plays a beneficial role during the acute stage of ischemic stroke, which can be a therapeutic target for ischemic stroke.

2.
Neurosci Bull ; 36(6): 625-638, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32100248

RESUMO

Aloin is a small-molecule drug well known for its protective actions in various models of damage. Traumatic brain injury (TBI)-induced cerebral edema from secondary damage caused by disruption of the blood-brain barrier (BBB) often leads to an adverse prognosis. Since the role of aloin in maintaining the integrity of the BBB after TBI remains unclear, we explored the protective effects of aloin on the BBB using in vivo and in vitro TBI models. Adult male C57BL/6 mice underwent controlled cortical impact injury, and mouse brain capillary endothelial bEnd.3 cells underwent biaxial stretch injury, then both received aloin treatment. In the animal experiments, we found 20 mg/kg aloin to be the optimum concentration to decrease cerebral edema, decrease disruption of the BBB, and improve neurobehavioral performance after cortical impact injury. In the cellular studies, the optimum concentration of 40 µg/mL aloin reduced apoptosis and reversed the loss of tight junctions by reducing the reactive oxygen species levels and changes in mitochondrial membrane potential after stretch injury. The mechanisms may be that aloin downregulates the phosphorylation of p38 mitogen-activated protein kinase, the activation of p65 nuclear factor-kappa B, and the ratios of B cell lymphoma (Bcl)-2-associated X protein/Bcl-2 and cleaved caspase-3/caspase-3. We conclude that aloin exhibits these protective effects on the BBB after TBI through its anti-oxidative stress and anti-apoptotic properties in mouse brain capillary endothelial cells. Aloin may thus be a promising therapeutic drug for TBI.

3.
Stroke ; 51(2): 619-627, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31822249

RESUMO

Background and Purpose- Blood-brain barrier (BBB) disruption is a critical pathological feature after stroke. MicroRNA-126 (miR-126) maintains BBB integrity by regulating endothelial cell function during development. However, the role of miR-126-3p and -5p in BBB integrity after stroke is unclear. Here, we investigated whether miR-126-3p and -5p overexpression regulates BBB integrity after cerebral ischemia. Methods- A lentivirus carrying genes encoding miR-126-3p or -5p was stereotactically injected into adult male Institute of Cancer Research mouse brains (n=36). Permanent middle cerebral artery occlusion was performed 2 weeks after virus injection. Brain infarct volume, edema volume, and modified neurological severity score were assessed at 1 and 3 days after ischemia. Immunostaining of ZO-1 (zonula occludens-1) and occludin was used to evaluate BBB integrity. IL-1ß (interleukin-1ß), TNF-α (tumor necrosis factor-α), VCAM-1 (vascular cell adhesion molecule-1), and E-selectin expression levels were determined by real-time polymerase chain reaction and Western blot analysis. Results- The expression of miR-126-3p and -5p decreased at 1 and 3 days after ischemia (P<0.05). Injection of lentiviral miR-126-3p or -5p reduced brain infarct volume and edema volume (P<0.05) and attenuated the decrease in ZO-1/occludin protein levels and IgG leakage at 3 days after stroke (P<0.05). Injection of lentiviral miR-126-5p improved behavioral outcomes at 3 days after stroke (P<0.05). miR-126-3p and -5p overexpression downregulated the expression of proinflammatory cytokines IL-1ß and TNF-α and adhesion molecules VCAM-1 and E-selectin, as well as decreased MPO+ (myeloperoxidase positive) cell numbers at 3 days after ischemia (P<0.05). Conclusions- miR-126-3p and -5p overexpression reduced the expression of proinflammatory cytokines and adhesion molecules, and attenuated BBB disruption after ischemic stroke, suggesting that miR-126-3p and -5p are new therapeutic targets in the acute stage of stroke.

4.
Neurosci Lett ; 705: 251-258, 2019 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-30928480

RESUMO

BACKGROUND AND PURPOSE: Studies demonstrated that oxidative damage decreased intracellular ATP level in astrocytes. However, the pathway mediated ATP level decrease is obscure. Our previous study found intracellular ATP could be released via lysosome exocytosis in astrocytes. Here, we explored whether lysosome exocytosis was involved in ATP release during oxidative stress induced by H2O2 in astrocytes. METHODS: Astrocytes were isolated from the cortex of neonatal rats. Intracellular lysosomes and calcium signals were stained in astrocytes before and after H2O2 stimulation. ATP molecules location and ATP level were detected by immunostaining and bioluminescence method, respectively. Extracellular ß-Hexosaminidase and LDH were examined by colorimetric method. RESULTS: We found that ATP located in lysosome of astrocytes. H2O2 stimulation resulted in the decrease of lysosomes staining and the increase of extracellular ATP, compared to the control (p < 0.05). At the same time, intracellular Fluo4 signals and ß-Hexosaminidase level were also increased (p < 0.05). Extracellular LDH level did not show an increase, suggesting that there is no cell membrane damage after H2O2 stimulation. Glycyl-phenylalanine 2-naphthylamide blocked lysosome exocytosis and inhibited ATP release in astrocytes after H2O2-treatment (p < 0.05). CONCLUSION: Our results indicated that H2O2 induced ATP release from intracellular to extracellular via lysosome exocytosis. The increase of intracellular Ca2+ was necessary for lysosome release under oxidative stress induced by H2O2.


Assuntos
Trifosfato de Adenosina/metabolismo , Astrócitos/metabolismo , Exocitose/fisiologia , Peróxido de Hidrogênio/farmacologia , Lisossomos/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Cálcio/metabolismo , Exocitose/efeitos dos fármacos , L-Lactato Desidrogenase/metabolismo , Lisossomos/efeitos dos fármacos , Cultura Primária de Células , Ratos , beta-N-Acetil-Hexosaminidases/metabolismo
5.
CNS Neurosci Ther ; 25(6): 748-758, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30784219

RESUMO

INTRODUCTION: Dl-3-N-butylphthalide (NBP), a small molecule drug used clinically in the acute phase of ischemic stroke, has been shown to improve functional recovery and promote angiogenesis and collateral vessel circulation after experimental cerebral ischemia. However, the underlying molecular mechanism is unknown. AIMS: To explore the potential molecular mechanism of angiogenesis induced by NBP after cerebral ischemia. RESULTS: NBP treatment attenuated body weight loss, reduced brain infarct volume, and improved neurobehavioral outcomes during focal ischemia compared to the control rats (P < 0.05). NBP increased the number of CD31+ microvessels, the number of CD31+ /BrdU+ proliferating endothelial cells, and the functional vascular density (P < 0.05). Further study demonstrated that NBP also promoted the expression of vascular endothelial growth factor and angiopoietin-1 (P < 0.05), which was accompanied by upregulated sonic hedgehog expression in astrocytes in vivo and in vitro. CONCLUSION: NBP treatment promoted the expression of vascular endothelial growth factor and angiopoietin-1, induced angiogenesis, and improved neurobehavioral recovery. These effects were associated with increased sonic hedgehog expression after NBP treatment. Our results broadened the clinical application of NBP to include the later phase of ischemia.

6.
J Neurotrauma ; 36(8): 1279-1290, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30351220

RESUMO

Transient receptor potential vanilloid 1 (TRPV1) is expressed widely in the central nervous system and is activated by various stimuli. Inhibiting TRPV1 has neuroprotective effects in cerebral ischemia. The role of inhibiting TRPV1 to maintain blood-brain barrier (BBB) integrity after traumatic brain injury (TBI) remains unclear, however. Therefore, we investigated the effects of capsazepine-mediated TRPV1 inhibition on the BBB in a mouse model of TBI. Adult male C57BL/6 mice underwent controlled cortical impact injury and received capsazepine (1 µmol/kg body weight, twice daily, intraperitoneally) until sacrifice. Further, mouse brain microvascular endothelial (bEnd.3) cells were cultured and underwent biaxial stretch injury to investigate the mechanisms underlying the protective effects of capsazepine. The TRPV1 expression was upregulated in the pericontusional area after TBI, peaking at 24 h post-TBI. Capsazepine-treated mice demonstrated decreased brain edema (p = 0.010), Evans Blue extravasation (p = 0.001), tissue hemoglobin levels (p = 0.002), and loss of tight junction proteins (p = 0.016 ZO-1 expression; p = 0.013 occludin expression) after TBI compared with the vehicle-treated group. Capsazepine significantly alleviated early-stage apoptosis by attenuating activation of JNK, P38, and caspase-3, resulting in a protective effect on the level of ZO-1 in bEnd.3 cells after stretch injury. We conclude that the expression of TRPV1 is upregulated after TBI, and inhibition of TRPV1 attenuated disruption of the BBB in a mouse model of TBI, at least partly, through its antiapoptotic effects on brain endothelial cells. Blocking TRPV1 may be a promising pharmacotherapeutic intervention to protect against BBB disruption after TBI.

7.
World Neurosurg ; 122: 48-52, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30347301

RESUMO

BACKGROUND: Gliomas are usually located in the supratentorial region and are extremely rare at the cerebellopontine angle (CPA). Consequently, gliomas in the CPA are easy to misdiagnose preoperatively. CASE DESCRIPTION: This paper presents a 55-year-old man with an extraaxial CPA glioblastoma arising from the proximal portion of cranial nerve (CN) VIII. Preoperative imaging findings suggested an acoustic neuroma. The tumor was removed subtotally, and it was completely separated from the brainstem and cerebellum. The histopathologic examination showed a glioblastoma. CONCLUSIONS: To our knowledge, this case is the second report of a true primary extraaxial CPA glioblastoma. Therefore glioma should be considered in the differential diagnosis of CPA masses with atypical imaging features, although they are extremely rare.


Assuntos
Neoplasias Cerebelares/diagnóstico , Neoplasias Cerebelares/cirurgia , Ângulo Cerebelopontino , Glioblastoma/diagnóstico , Glioblastoma/cirurgia , Neoplasias Cerebelares/patologia , Diagnóstico Diferencial , Evolução Fatal , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Neuroma Acústico/diagnóstico , Pneumonia Aspirativa
8.
J Neurotrauma ; 35(23): 2850-2860, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29860924

RESUMO

Adjudin, a small molecular compound that is used as a male contraceptive, has been reported to play a neuroprotective role in an ischemic stroke injury model. However, its effect on traumatic brain injury (TBI) has not been assessed. Hence, we investigated the effects of adjudin on cerebral edema using a mouse model of TBI and explored the underlying mechanisms. Adult male C57BL/6 mice received controlled cortical impact (CCI) injury, then an injection of adjudin (50 mg/kg). The mice were euthanized 3 days post-CCI injury, and samples were collected for further analysis. Cultured primary mouse astrocytes were used for in vitro experiments. Adjudin treatment significantly attenuated cerebral edema on Day 3 and improved neurobehavioral outcomes on Days 3, 7, and 14 after CCI injury, compared with the vehicle group. Additionally, the evaluation of Evans blue extravasation and expression of tight junction proteins demonstrated remarkable effects of adjudin on blood-brain barrier protection. Further, adjudin treatment significantly decreased the gene and protein expression of aquaporin 4 in post-injury mice and inhibited progression of neuroinflammation in both mice and cultured astrocytes. The Western blot results of the peritraumatic protein samples demonstrated that adjudin significantly blocked the phosphorylation of IKKα, IκBα/ß, and NF-κB p65, which resulted in a reduction of NF-κB p65 nuclear translocation. In conclusion, adjudin attenuated the development of TBI-induced cerebral edema at least partly via anti-inflammatory effects and inhibition of the NF-κB pathway. These findings suggest that adjudin is a potential therapeutic intervention preventing the development of cerebral edema after TBI.


Assuntos
Edema Encefálico/etiologia , Lesões Encefálicas Traumáticas/complicações , Hidrazinas/farmacologia , Indazóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Edema Encefálico/patologia , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/fisiopatologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL
9.
Acta Pharmacol Sin ; 38(11): 1445-1455, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28770828

RESUMO

Sesamin, a major lignan of sesame oil, was reported to have neuroprotective effects in several brain injury models. However, its protective action in maintaining blood-brain barrier (BBB) integrity has not been studied. In this study we investigated the effects of sesamin on the BBB in a mouse model of traumatic brain injury (TBI) and explored the underlying mechanisms. Adult male C57BL/6 mice were subjected to a controlled cortical impact (CCI) injury and then received sesamin (30 mg·kg-1·d-1, ip). The mice were euthanized on the 1st and 3rd days after CCI injury and samples were collected for analysis. Sesamin treatment significantly attenuated CCI-induced brain edema on the 1st and 3rd days after the injury, evidenced by the decreases in water content, tissue hemoglobin levels, Evans blue extravasation and AQP4 expression levels in the ipsilateral cortical tissue compared with the vehicle-treated group. Furthermore, sesamin treatment significantly alleviated CCI-induced loss of the tight junction proteins ZO-1 and occludin in the brain tissues. The neuroprotective mechanisms of sesamin were further explored in cultured mouse brain microvascular bEnd.3 cells subjected to biaxial stretch injury (SI). Pretreatment with sesamin (50 µmol/L) significantly alleviated SI-induced loss of ZO-1 in bEnd.3 cells. Furthermore, we revealed that pretreatment with sesamin significantly attenuated SI-induced oxidative stress and early-stage apoptosis in bEnd.3 cells by decreasing the activation of ERK, p-38 and caspase-3. In conclusion, sesamin alleviates BBB disruption at least partly through its anti-oxidative and anti-apoptotic effects on endothelial cells in CCI injury. These findings suggest that sesamin may be a promising potential therapeutic intervention for preventing disruption of the BBB after TBI.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Lesões Encefálicas Traumáticas/tratamento farmacológico , Permeabilidade Capilar/efeitos dos fármacos , Dioxóis/farmacologia , Lignanas/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Apoptose/efeitos dos fármacos , Aquaporina 4/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Edema Encefálico/prevenção & controle , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Caspase 3/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Ocludina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fatores de Tempo , Proteína da Zônula de Oclusão-1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno
10.
Metab Brain Dis ; 32(5): 1427-1435, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28391551

RESUMO

Posttraumatic hydrocephalus (PTH) is a disorder of disturbed cerebrospinal fluid (CSF) dynamics after traumatic brain injury (TBI). It can lead to brain metabolic impairment and dysfunction and has a high risk of clinical deterioration and worse outcomes. The incidence and risk factors for the development of PTH after decompressive craniectomy (DC) has been assessed in previous studies, but rare studies identify patients with higher risk for PTH among all TBI patients. This study aimed to develop and validate a risk scoring system to predict PTH after TBI. Demographics, injury severity, duration of coma, radiologic findings, and DC were evaluated to determine the independent predictors of PTH during hospitalization until 6 months following TBI through logistic regression analysis. A risk stratification system was created by assigning a number of points for each predictor and validated in an independent cohort. The model accuracy was assessed by the area under the receiver operating characteristic curve (AUC). Of 526 patients in the derivation cohort, 57 (10.84%) developed PTH during 6 months follow up. Age > 50 yrs (Odd ratio [OR] = 1.91, 95% confidence interval [CI] 1.09-3.75, 4 points), duration of coma ≥1 w (OR = 5.68, 95% CI 2.57-13.47, 9 points), Fisher grade III (OR = 2.19, 95% CI 1.24-4.36, 5 points) or IV (OR = 3.87, 95% CI 1.93-8.43, 7 points), bilateral DC (OR = 6.13, 95% CI 2.82-18.14, 9 points), and extra herniation after DC (OR = 2.36, 95% CI 1.46-4.92, 5 points) were independently associated with PTH. Rates of PTH for the low- (0-12 points), intermediate- (13-22 points) and high-risk (23-34 points) groups were 1.16%, 35.19% and 78.57% (p < 0.0001). The corresponding rates in the validation cohort, where 17/175 (9.71%) developed PTH, were 1.35%, 37.50% and 81.82% (p < 0.0001). The risk score model exhibited good-excellent discrimination in both cohorts, with AUC of 0.839 versus 0.894 (derivation versus validation) and good calibration (Hosmer-Lemshow p = 0.56 versus 0.68). This model will be useful to identify patients at high risk for PTH who may be candidates for preventive interventions, and to improve their outcomes.


Assuntos
Hidrocefalia/epidemiologia , Hidrocefalia/etiologia , Adulto , Fatores Etários , Área Sob a Curva , China/epidemiologia , Estudos de Coortes , Craniectomia Descompressiva , Feminino , Escala de Coma de Glasgow , Hérnia/complicações , Hérnia/etiologia , Humanos , Hidrocefalia/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Modelos Estruturais , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Tomografia Computadorizada por Raios X
11.
J Neurotrauma ; 34(4): 925-933, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-27297934

RESUMO

Glibenclamide is a hypoglycemic drug that is widely used for the treatment of diabetes mellitus type 2 (DM II), but it also plays a protective role following injury to the central nervous system (CNS). However, the precise mechanisms underlying its neuroprotective actions remain to be elucidated. Therefore, the present study evaluated the effects of glibenclamide on the blood-brain barrier (BBB) in a mouse model of traumatic brain injury (TBI). In the present study, 86 adult male C57BL/6 mice were exposed to a controlled cortical impact (CCI) injury and then received glibenclamide (10 µg) for 3 days. Tight junction (TJ) protein levels, BBB permeability, and tissue hemoglobin levels were evaluated following the CCI injury. Additionally, a biaxial stretch injury was applied to cell cultures of bEnd.3 cells using the Cell Injury Controller II system to explore the mechanisms by which glibenclamide inhibits apoptosis-signaling pathways. Compared with the control group, glibenclamide-treated mice exhibited decreases in brain water content (p < 0.05), tissue hemoglobin levels (p < 0.05), and Evans Blue extravasation (p < 0.01) after the CCI injury. Glibenclamide primarily attenuated apoptosis via the JNK/c-jun signaling pathway and resulted in an elevation of stretch injury-induced ZO-1 expression in bEnd.3 cells (p < 0.01).Glibenclamide downregulated the activity of the JNK/c-jun apoptosis-signaling pathway which, in turn, decreased apoptosis in endothelial cells (ECs). This may have prevented the disruption of the BBB in a mouse model of TBI.


Assuntos
Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Lesões Encefálicas Traumáticas/tratamento farmacológico , Glibureto/farmacologia , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Barreira Hematoencefálica/fisiopatologia , Lesões Encefálicas Traumáticas/fisiopatologia , Modelos Animais de Doenças , Glibureto/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/administração & dosagem
12.
Chin J Traumatol ; 19(3): 172-5, 2016 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-27321300

RESUMO

Progressive hemorrhagic injury (PHI) can be divided into coagulopathy-related PHI and normal coagu- lation PHI. Coagulation disorders after traumatic brain injuries can be included in trauma-induced coagulopathy (TIC). Some studies showed that TIC is associated with PHI and increases the rates of disability and mortality. In this review, we discussed some mechanisms in TIC, which is of great importance in the development of PHI, including tissue factor (TF) hypothesis, protein C pathway and thrombocytopenia. The main mechanism in the relation of TIC to PHI is hypocoagulability. We also reviewed some coagulopathy parameters and proposed some possible risk factors, predictors and therapies.


Assuntos
Transtornos da Coagulação Sanguínea/etiologia , Lesões Encefálicas Traumáticas/complicações , Hemorragia Cerebral/etiologia , Transtornos da Coagulação Sanguínea/epidemiologia , Hemorragia Cerebral/epidemiologia , Hemorragia Cerebral/terapia , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Incidência , Proteína C/fisiologia , Fatores de Risco , Tromboplastina/fisiologia
13.
Comput Biol Chem ; 61: 238-44, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26963378

RESUMO

Neuronal polo-like kinase (nPLK) is an essential regular of cell cycle and differentiation in nervous system, and targeting nPLK has been established as a promising therapeutic strategy to treat neurological disorders and to promote neuroregeneration. The protein contains an N-terminal kinase domain (KD) and a C-terminal Polo-box domain (PBD) that are mutually inhibited by each other. Here, the intramolecular KD-PBD complex in nPLK was investigated at structural level via bioinformatics analysis, molecular dynamics (MD) simulation and binding affinity scoring. From the complex interface two regions representing separately two continuous peptide fragments in PBD domain were identified as the hot spots of KD-PBD interaction. Structural and energetic analysis suggested that one (PBD peptide 1) of the two peptides can bind tightly to a pocket nearby the active site of KD domain, which is thus potential as self-inhibitory peptide to target and suppress nPLK kinase activity. The knowledge harvesting from computational studies were then used to guide the structural optimization and mutation of PBD peptide 1. Consequently, two of three peptide mutants separately exhibited moderately and considerably increased affinity as compared to the native peptide. The computationally modeled complex structures of KD domain with these self-inhibitory peptides were also examined in detail to unravel the structural basis and energetic property of nPLK-peptide recognition and interaction.


Assuntos
Peptídeos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Ligantes , Simulação de Dinâmica Molecular , Peptídeos/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo
15.
J Neurochem ; 136(3): 581-93, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26546505

RESUMO

Sirtuin 2 (SIRT2) is a member of the sirtuin family of NAD(+) -dependent protein deacetylases. In recent years, SIRT2 inhibition has emerged as a promising treatment for neurodegenerative diseases. However, to date, there is no evidence of a specific role for SIRT2 in traumatic brain injury (TBI). We investigated the effects of SIRT2 inhibition on experimental TBI using the controlled cortical impact (CCI) injury model. Adult male mice underwent CCI or sham surgery. A selective brain-permeable SIRT2 inhibitor, AK-7, was administrated 30 min before injury. The volume of the brain edema lesion and the water content of the brain were significantly increased in mice treated with AK-7 (20 mg/kg), compared with the vehicle group, following TBI (p < 0.05 at 1 day and p < 0.05 at 3 days, respectively). Concomitantly, AK-7 administration greatly worsened neurobehavioral deficits on days 3 and 7 after CCI. Furthermore, blood-brain barrier disruption and matrix metalloproteinases (MMP)-9 activity increased following SIRT2 inhibition. AK-7 treatment increased TBI-induced microglial activation both in vivo and in vitro, accompanied by a large increase in the expression and release of inflammatory cytokines. Mechanistically, SIRT2 inhibition increased both K310 acetylation and nuclear translocation of NF-κB p65, leading to enhanced NF-κB activation and up-regulation of its target genes, including aquaporin 4 (AQP4), MMP-9, and pro-inflammatory cytokines. Together, these data demonstrate that SIRT2 inhibition exacerbates TBI by increasing NF-κB p65 acetylation and activation. Our findings provide additional evidence of an anti-inflammatory effect of SIRT2. SIRT2 is a member of the sirtuin family of NAD+-dependent protein deacetylases. Our study suggests that the SIRT2 inhibitor AK-7 exacerbates traumatic brain injury (TBI) via a potential mechanism involving increased acetylation and nuclear translocation of NF-κB p65, resulting in up-regulation of NF-κB target genes, including aquaporin 4 (AQP4), matrix metalloproteinase 9 (MMP-9), and pro-inflammatory cytokines. Our findings provide additional evidence of an anti-inflammatory effect of SIRT2.


Assuntos
Barreira Hematoencefálica/patologia , Lesões Encefálicas/complicações , Lesões Encefálicas/patologia , Encefalite/induzido quimicamente , Sirtuína 2/metabolismo , Fator de Transcrição RelA/metabolismo , Acetilação/efeitos dos fármacos , Animais , Edema Encefálico/diagnóstico , Edema Encefálico/etiologia , Citocinas/metabolismo , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Metaloproteinase 8 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Fatores de Tempo , Regulação para Cima/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/metabolismo
16.
Medicine (Baltimore) ; 94(43): e1733, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26512565

RESUMO

This meta-analysis examined whether early decompressive craniectomy (DC) can improve control of intracranial pressure (ICP) and mortality in patients with traumatic brain injury (TBI).Medline, Cochrane, EMBASE, and Google Scholar databases were searched until May 14, 2015, using the following terms: traumatic brain injury, refractory intracranial hypertension, high intracranial pressure, craniectomy, standard care, and medical management. Randomized controlled trials in which patients with TBI received DC and non-DC medical treatments were included.Of the 84 articles identified, 8 studies were selected for review, with 3 randomized controlled trials s having a total of 256 patients (123 DCs, 133 non-DCs) included in the meta-analysis. Patients receiving DC had a significantly greater reduction of ICP and shorter hospital stay. They also seemed to have lower odds of death than patients receiving only medical management, but the P value did not reach significance (pooled odds ratio 0.531, 95% confidence interval 0.209-1.350, Z = 1.95, P = 0.183) with respect to the effect on overall mortality; a separate analysis of 3 retrospective studies yielded a similar result.Whereas DC might effectively reduce ICP and shorten hospital stay in patients with TBI, its effect in decreasing mortality has not reached statistical significance.


Assuntos
Lesões Encefálicas/cirurgia , Craniectomia Descompressiva , Pressão Intracraniana , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/mortalidade , Humanos , Tempo de Internação , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos
17.
Biomarkers ; 20(6-7): 495-501, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26472601

RESUMO

OBJECTIVE: To identify the early changes of serum neuroglobin and Nogo-A concentrations and the relations to traumatic brain injury (TBI) severity and prognosis. METHODS: Serum samples were obtained and analyzed from 34 patients with TBI within the first 96 h after injury. Comparative analysis combined with Glasgow Coma Scale (GCS) scores and the 6-month prognosis of these patients was performed. RESULTS: Significant correlations were found between peak serum neuroglobin and Nogo-A concentrations and a patient's GCS score on admission (p < 0.001). The mean peak serum neuroglobin and Nogo-A concentrations were both significantly higher in patients with an unfavorable outcome at 6 months after injury (p < 0.05). CONCLUSIONS: Serum neuroglobin and Nogo-A levels could be suggested as biomarkers for predicting TBI severity and prognosis.


Assuntos
Biomarcadores/sangue , Lesões Encefálicas/sangue , Proteínas da Mielina/sangue , Proteínas do Tecido Nervoso/sangue , Adulto , Idoso , Lesões Encefálicas/diagnóstico , Feminino , Escala de Coma de Glasgow , Globinas , Humanos , Masculino , Pessoa de Meia-Idade , Neuroglobina , Proteínas Nogo , Prognóstico , Estudos Prospectivos , Curva ROC , Fatores de Tempo , Adulto Jovem
18.
Neurochem Res ; 40(8): 1671-80, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26253398

RESUMO

Transforming growth factor-ß 1 (TGFß1) has a diverse role in astrogliosis and neuronal survival, but the underlying mechanism remains to be elucidated, especially in traumatic brain injury (TBI). Here, we show that the expression of TGFß1 was increased in the pericontusional region, accompanied with astrogliosis and neuronal loss in TBI rats. Moreover, TGFß1 knockdown not only reduced the number of neurons and inhibited astrogliosis but also resulted in a significant neurological dysfunction in rats with TBI. Subsequently, Smad3, a key downstream signal of TGFß1, was involved in pericontusional region after TBI. These findings therefore indicate that TGFß1 is involved in neuroprotection and astrogliosis, via activation of down stream Smad3 signal in the brain after injury.


Assuntos
Lesões Encefálicas/metabolismo , Recuperação de Função Fisiológica/fisiologia , Transdução de Sinais/fisiologia , Proteína Smad3/biossíntese , Fator de Crescimento Transformador beta1/fisiologia , Animais , Lesões Encefálicas/patologia , Feminino , Ratos , Ratos Sprague-Dawley
19.
Comput Biol Chem ; 54: 57-65, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25625417

RESUMO

Mammalian target of rapamycin (mTOR), a key mediator of PI3K/Akt/mTOR signaling pathway, has recently emerged as a compelling molecular target in glioblastoma. The mTOR is a member of serine/threonine protein kinase family that functions as a central controller of growth, proliferation, metabolism and angiogenesis, but its signaling is dysregulated in various human diseases especially in certain solid tumors including the glioblastoma. Here, considering that there are various kinase inhibitors being approved or under clinical or preclinical development, it is expected that some of them can be re-exploited as new potent agents to target mTOR for glioblastoma therapy. To achieve this, a synthetic pipeline that integrated molecular grafting, consensus scoring, virtual screening, kinase assay and structure analysis was described to systematically profile the binding potency of various small-molecule inhibitors deposited in the protein kinase-inhibitor database against the kinase domain of mTOR. Consequently, a number of structurally diverse compounds were successfully identified to exhibit satisfactory inhibition profile against mTOR with IC50 values at nanomolar level. In particular, few sophisticated kinase-inhibitors as well as a flavonoid myricetin showed high inhibitory activities, which could thus be considered as potential lead compounds to develop new potent, selective mTOR-inhibitors. Structural examination revealed diverse nonbonded interactions such as hydrogen bonds, hydrophobic forces and van der Waals contacts across the complex interface of mTOR with myricetin, conferring both stability and specificity for the mTOR-inhibitor binding.


Assuntos
Antineoplásicos/química , Flavonoides/química , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Bibliotecas de Moléculas Pequenas/química , Serina-Treonina Quinases TOR/antagonistas & inibidores , Bases de Dados Factuais , Descoberta de Drogas , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas de Neoplasias/química , Estrutura Terciária de Proteína , Relação Quantitativa Estrutura-Atividade , Eletricidade Estática , Serina-Treonina Quinases TOR/química , Interface Usuário-Computador
20.
Neural Regen Res ; 10(11): 1865-8, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26807126

RESUMO

In the present study, we investigated the role of endogenous neurotrophin-3 in nerve terminal sprouting 2 months after spinal cord dorsal root rhizotomy. The left L1-5 and L7-S2 dorsal root ganglia in adult cats were exposed and removed, preserving the L6 dorsal root ganglia. Neurotrophin-3 was mainly expressed in large neurons in the dorsal root ganglia and in some neurons in spinal lamina II. Two months after rhizotomy, the number of neurotrophin-3-positive neurons in the spared dorsal root ganglia and the density of neurite sprouts emerging from these ganglia were increased. Intraperitoneal injection of an antibody against neurotrophin-3 decreased the density of neurite sprouts. These findings suggest that endogenous neurotrophin-3 is involved in spinal cord plasticity and regeneration, and that it promotes axonal sprouting from the dorsal root ganglia after spinal cord dorsal root rhizotomy.

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