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1.
Life Sci ; 241: 117160, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31837331

RESUMO

AIMS: Theanine, as a naturally occurring component in tea, has been shown to deliver benefits against various diseases. However, the exact molecular mechanisms underlying theanine's protective actions against cerebral ischemia/reperfusion (IR) injury still remains largely unknown. MAIN METHODS: In this study, rat cerebral IR injury model was established and were randomly divided into the following five groups: Sham (SH), IR, IR + Theanine (TH), IR + TH+ heme oxygenase-1 (HO-1) inducer cobalt protoporphyrin (Copp), and IR + Copp groups. KEY FINDINGS: We found that theanine significantly inhibited neuron damage and apoptosis in the hippocampus during the 48 h detection period, as detected by hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Meanwhile, reduced levels of malondialdehyde (MDA) and elevated activities of superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH-PX) were observed in the theanine-treated group. Enzyme-linked immunosorbent (ELISA) assay also revealed that theanine markedly decreased the levels of inflammatory cytokines, such as IL-6, IL-1ß, and TNF-α, in IR rats. The anti-apoptotic effect of theanine on IR injury was further verified by flow cytometry assay. Besides, theanine dramatically inhibited HO-1 expression and activity but increased extracellular signal-regulated kinase 1/2 (ERK1/2) activity in hippocampal tissue from rats with cerebral IR injury. However, co-treatment with Copp remarkably abolished the protective effects of theanine on cerebral IR injury. SIGNIFICANCE: These findings demonstrated that the neuroprotective role of theanine was associated with its anti-oxidative, anti-inflammatory, and anti-apoptotic properties, which might be through regulation of HO-1 activation in rats with cerebral IR injury.


Assuntos
Isquemia Encefálica/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Glutamatos/farmacologia , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Hipocampo/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
2.
Acta Neurochir Suppl ; 127: 47-54, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31407062

RESUMO

BACKGROUND: Previously studies have shown that Nox2 and Nox4, as members of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, Nox), participate in brain damage caused by ischemia-reperfusion (I/R). The aim of this study is to investigate the effects of specific chemical inhibitors of Nox2 and Nox4 on cerebral I/R-induced brain injury in rats. METHODS: At 0.5 h before MCAO surgery, the rats were pretreated with vehicle, Nox2 inhibitor (gp91ds-tat), and Nox4 inhibitor (GKT137831), respectively. After reperfusion for 24 h, the infarct sizes of brain tissues in rats in various groups are determined. The penumbra (ischemic) tissues are collected to measure ROS levels, neuronal apoptosis, and degeneration, as well as the integrity of the blood-brain barrier (BBB) in brain tissues of rats. RESULTS: gp91ds-tat and GKT137831 pretreatment significantly reduced the infarct sizes in brain tissues of rats, effectively suppressed I/R-induced increase in ROS levels, neuronal apoptosis and degeneration, and obviously alleviated BBB damage. CONCLUSION: Under cerebral I/R conditions, Nox2 inhibitor (gp91ds-tat) and Nox4 inhibitor (GKT137831) can effectively play a protective role in the brain tissues of rats.


Assuntos
Lesões Encefálicas , Isquemia Encefálica , NADPH Oxidase 2 , NADPH Oxidase 4 , Traumatismo por Reperfusão , Animais , Apoptose/efeitos dos fármacos , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , NADPH Oxidase 2/antagonistas & inibidores , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/antagonistas & inibidores , NADPH Oxidase 4/metabolismo , NADPH Oxidases , Ratos , Espécies Reativas de Oxigênio , Traumatismo por Reperfusão/metabolismo
3.
Biosci Biotechnol Biochem ; 84(1): 134-142, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31490096

RESUMO

Plumbagin (PLB), an alkaloid obtained from the roots of the plants of Plumbago genus, is an inhibitor of NADPH oxidase 4 (NOX4). This study aimed to investigate the beneficial effect of PLB against oxygen-glucose deprivation/reoxygenation (OGDR)-induced neuroinjury in human SH-SY5Y neuronal cultures. Our results showed that OGD/R stimulated NOX4 protein expression and reactive oxygen species (ROS) production in SH-SY5Y cells, whereas increased 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) production, resulting in the activation of the NLRP3 inflammasome. And PLB pretreatment reduced the ROS production by regulating the expression of NOX4 and downregulated NF-κB signaling which was induced by OGDR. Furthermore, PLB inhibited OGDR induced NLRP3 inflammasome activation but not PARP1. Overall, PLB improved OGDR induced neuroinjury by inhibiting NOX4-derived ROS-activated NLRP3 inflammasome.


Assuntos
Hipóxia Celular/efeitos dos fármacos , Glucose/deficiência , Inflamassomos/metabolismo , NADPH Oxidase 4/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Naftoquinonas/farmacologia , Neurônios/metabolismo , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Raízes de Plantas/química , Plumbaginaceae/química
4.
BMC Complement Altern Med ; 19(1): 320, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31747940

RESUMO

BACKGROUND: Cerebral ischemia is the second-leading cause of death and the main cause of permanent adult disabilities worldwide. Qingkailing (QKL) injection, a patented Chinese medicine approved by the China Food and Drug Administration, has been widely used in clinical practice to treat cerebral ischemia in China. The NOD-like receptor pyrin 3 (NLRP3) inflammasome is activated in cerebral ischemia and thus, is an effective therapeutic target. AMP-activated protein kinase (AMPK) is an important regulator inhibiting NLRP3 inflammasome activation. METHODS: We investigated the potential of QKL injection to provide neuroprotection after cerebral ischemia in a rat model of middle cerebral artery occlusion (MCAO). Adult male Sprague-Dawley rats (210-230 g) were randomly divided into three groups which consist of sham, MCAO and 3 ml/kg QKL. Rats in the QKL group received intraperitoneal injections of 3 ml/kg QKL, while rats in other groups were given saline in the same volumes. After 90 min ischemia and 24 h reperfusion, neurological function, laser speckle imaging, brain infarction, brain water content and brain blood barrier permeability were examined and cell apoptosis at prefrontal cortex were evaluated 24 h after MCAO, and western blot and real-time quantitative polymerase chain reaction was also researched, respectively. RESULTS: Intraperitoneal administration of QKL alleviated neurological deficiencies, cerebral infarction, blood-brain barrier permeability, brain oedema and brain cell apoptosis after MCAO induction. QKL decreased pro-inflammatory cytokines, TNF-α, IL-6 and IL-1ß, and increased anti-inflammatory cytokines, IL-4 and IL-10. Furthermore, QKL activated phosphorylated AMPK, decreased oxidative stress and decreased NLRP3 inflammasome activation. CONCLUSIONS: QKL relieved cerebral ischemia reperfusion injury and suppressed the inflammatory response by inhibiting AMPK-mediated activation of the NLRP3 inflammasome. These results suggest that QKL might have potential in treating brain inflammatory response and attenuating the cerebral ischemia-reperfusion injury.


Assuntos
Isquemia Encefálica/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
5.
Adv Neurobiol ; 23: 347-361, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31667815

RESUMO

The astrocyte-neuron lactate transfer shuttle (ANLS) is one of the important metabolic systems that provides a physiological infrastructure for glia-neuronal interactions where specialized architectural organization supports the function. Perivascular astrocyte end-feet take up glucose via glucose transporter 1 to actively regulate glycogen stores, such that high ambient glucose upregulates glycogen and low levels of glucose deplete glycogen stores. A rapid breakdown of glycogen into lactate during increased neuronal activity or low glucose conditions becomes essential for maintaining axon function. However, it fails to benefit axon function during an ischemic episode in white matter (WM). Aging causes a remarkable change in astrocyte architecture characterized by thicker, larger processes oriented parallel to axons, as opposed to vertically-transposing processes. Subsequently, aging axons become more vulnerable to depleted glycogen, although aging axons can use lactate as efficiently as young axons. Lactate equally supports function during aglycemia in corpus callosum (CC), which consists of a mixture of myelinated and unmyelinated axons. Moreover, axon function in CC shows greater resilience to a lack of glucose compared to optic nerve, although both WM tracts show identical recovery after aglycemic injury. Interestingly, emerging evidence implies that a lactate transport system is not exclusive to astrocytes, as oligodendrocytes support the axons they myelinate, suggesting another metabolic coupling pathway in WM. Future studies are expected to unravel the details of oligodendrocyte-axon lactate metabolic coupling to establish that all WM components metabolically cooperate and that lactate may be the universal metabolite to sustain central nervous system function.


Assuntos
Envelhecimento/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Encéfalo/citologia , Encéfalo/metabolismo , Comunicação Celular , Glicogênio/metabolismo , Ácido Láctico/metabolismo , Axônios/metabolismo , Encéfalo/patologia , Glucose/metabolismo , Oligodendroglia/metabolismo
6.
Croat Med J ; 60(5): 439-448, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31686458

RESUMO

AIM: To explore the mechanism underlying the protective effect of adipose-derived mesenchymal stem cells (ADMSCs) against ischemic stroke by focusing on miR-21-3p/MAT2B axis. METHODS: Ischemic brain injury was induced in 126 rats by middle cerebral artery occlusion (MCAO). The effect of ADMSC administration on blood-brain barrier (BBB) condition, apoptosis, inflammation, and the activity of miR-21-3p/MAT2B axis was assessed. The role of miR-21-3p inhibition in the function of ADMSCs was further validated in in vitro neural cells. RESULTS: ADMSCs administration improved BBB condition, inhibited apoptosis, and suppressed inflammation. It also reduced the abnormally high level of miR-21-3p in MCAO rats. Dual luciferase assays showed that miR-21-3p directly inhibited the MAT2B expression in neural cells, and miR-21-3p inhibition by inhibitor or ADMSC-derived exosomes in neurons attenuated hypoxia/reoxygenation-induced impairments similarly to that of ADMSCs in vivo. CONCLUSION: This study confirmed the protective effect of ADMSCs against ischemic brain injury exerted by suppressing miR-21-3p level and up-regulating MAT2B level.


Assuntos
Tecido Adiposo/citologia , Isquemia Encefálica , Transplante de Células-Tronco Mesenquimais , Metionina Adenosiltransferase/metabolismo , MicroRNAs/metabolismo , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/cirurgia , Células-Tronco Mesenquimais/citologia , Metionina Adenosiltransferase/genética , MicroRNAs/genética , Ratos , Transdução de Sinais/fisiologia , Acidente Vascular Cerebral , Regulação para Cima
7.
Zhongguo Zhen Jiu ; 39(11): 1205-10, 2019 Nov 12.
Artigo em Chinês | MEDLINE | ID: mdl-31724358

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) on the expressions of growth arrest-specific protein 7 (Gas7) and nerve growth factor (NGF) in arcuate nucleus (ARC) of rats with focal cerebral ischemia and explore the potential action mechanism of EA in treatment of focal cerebral ischemia. METHODS: A total of 50 SD rats were randomized into 4 groups, named a normal group (n =12), a sham-operation group (n =12), a model group (n =14) and an EA group (n =12). In the model group and the EA group, the thread embolization method was adopted to duplicate the model of the right middle cerebral arterial embolism. In the sham-operation group, the skin of the neck was opened and sutured without any other intervention. In the EA group, EA was applied to "Baihui" (CV 20) and "Zusanli" (ST 36) on the left side, once a day, 30 min each time, consecutively for 21 days, while there was no any intervention in the normal group, the sham-operation group and the model group. Using the immunohistochemistry (IHC) method and Western blot method, the expressions of Gas7 and NFG of ARC on the ischemic side were determined. Using Nissle staining, the morphological changes in ARC neurons were observed. RESULTS: The results of Nissle staining showed that there was no significant change in the morphology of ARC neurons in the normal group and the sham-operation group. In the model group, the volume of neuron cells was atrophied obviously and the cells were arranged irregularly. In the EA group, the morphology of ARC neuron was similar to the normal group. The results of IHC and Western blot indicated that the expressions of immunoreactive neurons and protein of Gas7 and NGF in ARC of the rats in the model group were increased obviously as compared with the normal group and the sham-operation group and the expressions in the EA group were further enhanced as compared with the model group (all P<0.05). CONCLUSION: Gas7 and NGF may be participated in the compensatory process of partial protection of the body in the patients with focal cerebral ischemia. EA up-regulates the expressions of Gas7 and NGF in ARC, which may be one of the neuroprotective mechanisms of EA in treatment of cerebral ischemia.


Assuntos
Isquemia Encefálica , Infarto Cerebral , Eletroacupuntura , Fator de Crescimento Neural/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/terapia , Infarto Cerebral/metabolismo , Infarto Cerebral/terapia , Humanos , Ratos , Ratos Sprague-Dawley
8.
BMC Neurol ; 19(1): 236, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615442

RESUMO

BACKGROUND: Brain ischemia activates the parasympathetic cholinergic pathway in animal models of human disease. However, it remains unknown whether activation of the cholinergic pathway impacts immune defenses and disease outcomes in patients with ischemic stroke. This study investigated a possible association between peripheral cholinergic activity, post-stroke infection, and mortality. METHODS: In this study, we enrolled 458 patients with acute ischemic stroke (< 24 h after onset), 320 patients with ischemic stroke on day 10, and 216 healthy subjects. Peripheral cholinergic activity, reflected by intracellular acetylcholine (ACh) content in human peripheral blood mononuclear cells (PBMCs), was determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Expression of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) was measured by quantitative real-time PCR and western blot. Regression analyses were used to assess associations between peripheral cholinergic function and clinical outcomes. RESULTS: Within 24 h after the onset of acute ischemic stroke, there was a rapid increase in peripheral cholinergic activity that correlated with brain infarction volume (r = 0.67, P < 0.01). Specifically, lymphocyte-derived ACh levels were significantly higher in stroke patients with pneumonia (0.21 ± 0.02 ng/106 PBMC versus 0.15 ± 0.01 ng/106 PBMC, P = 0.03). Of note, lymphocytic AChE catalytic activity was significantly lower in these patients. One-year mortality was significantly greater in patients with higher intracellular ACh levels within the first 24 h after acute stroke. CONCLUSIONS: Lymphocytes produced increased amounts of ACh in patients with acute stroke, and pneumonia was a likely result. The association between this enhanced cholinergic activity and increased risk of pneumonia/mortality suggests that increased cholinergic activity may contribute to fatal post-stroke infection.


Assuntos
Acetilcolina/metabolismo , Isquemia Encefálica/imunologia , Isquemia Encefálica/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Acetilcolina/imunologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
9.
Life Sci ; 237: 116915, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610207

RESUMO

AIMS: The objective of the study was to determine whether ß-caryophyllene (BCP) exerts a neuroprotective effect in cerebral ischemia-reperfusion (I/R) injury by inhibiting microglial activation and modulating their polarization via the TLR4 pathway. MAIN METHODS: Wild-type (WT) and TLR4 knockout (KO) C57BL/6J mice were subjected to cerebral I/R injury and neurologic dysfunction, cerebral infarct volume, brain edema, microglia activation and polarization, and TLR4 expression were determined. In vitro, primary microglia were stimulated with LPS and IFN-γ or IL-4 to induce polarization of microglia toward M1 or M2 phenotypes. KEY FINDINGS: BCP reduced cerebral infarct volume, brain edema, and neurologic deficits in WT mice after I/R. The optimal dose of BCP, 72 mg/kg body weight, inhibited microglial activation and reduced the secretion of proinflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and IL-6 by microglia of WT mice. BCP inhibited the level of TLR4 in WT mice, and partially reduced neurologic deficits, infarct volume, and brain edema in TLR4 KO mice. Importantly, BCP reduced the number of activated M1-type microglia and increased the number of M2-type microglia in the ipsilateral cortex of both WT and TLR4 KO mice. In vitro, BCP decreased the secretion of proinflammatory cytokines induced by LPS plus IFN-γ, downregulated the level of TLR4 protein, and polarized microglia towards the M2 phenotype. SIGNIFICANCES: The decrease in TLR4 activity mediated, at least in part, the anti-inflammatory effects of BCP and its ability to shift microglia polarization from the M1 to M2 phenotype.


Assuntos
Isquemia Encefálica/prevenção & controle , Macrófagos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Sesquiterpenos/farmacologia , Acidente Vascular Cerebral/prevenção & controle , Receptor 4 Toll-Like/fisiologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/imunologia , Microglia/metabolismo , Microglia/patologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
10.
Comput Biol Chem ; 83: 107116, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31561071

RESUMO

According to the Trial of Org 10172 in Acute Stroke Treatment, ischemic stroke is classified into five subtypes. However, the predictive biomarkers of ischemic stroke subtypes are still largely unknown. The utmost objective of this study is to map, construct and analyze protein-protein interaction (PPI) networks for all subtypes of ischemic stroke, and to suggest the predominant biological pathways for each subtypes. Through 6285 protein data retrieved from PolySearch2 and STRING database, the first PPI networks for all subtypes of ischemic stroke were constructed. Notably, F2 and PLG were identified as the critical proteins for large artery atherosclerosis (LAA), lacunar, cardioembolic, stroke of other determined etiology (SOE) and stroke of undetermined etiology (SUE). Gene ontology and DAVID analysis revealed that GO:0030193 regulation of blood coagulation and GO:0051917 regulation of fibrinolysis were the important functional clusters for all the subtypes. In addition, inflammatory pathway was the key etiology for LAA and lacunar, while FOS and JAK2/STAT3 signaling pathways might contribute to cardioembolic stroke. Due to many risk factors associated with SOE and SUE, the precise etiology for these two subtypes remained to be concluded.


Assuntos
Isquemia Encefálica/classificação , Mapas de Interação de Proteínas , Proteínas/análise , Acidente Vascular Cerebral/classificação , Biomarcadores/análise , Biomarcadores/metabolismo , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Bases de Dados de Proteínas , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Ligação Proteica , Proteínas/genética , Proteínas/metabolismo , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo
11.
Ann Hematol ; 98(12): 2673-2681, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31478061

RESUMO

Sickle cell anemia (SCA) is an autosomal recessive monogenic disease with significant clinical variability. Cerebrovascular disease, particularly ischemic stroke, is one of the most severe complications of SCA in children. This study aimed to investigate the influence of genetic variants on the levels of fetal hemoglobin (Hb F) and biochemical parameters related with chronic hemolysis, as well as on ischemic stroke risk, in ninety-one unrelated SCA patients, children of sub-Saharan progenitors. Our results show that a higher Hb F level has an inverse relationship with the occurrence of stroke, since the group of patients who suffered stroke presents a significantly lower mean Hb F level (5.34 ± 4.57% versus 9.36 ± 6.48%; p = 0.024). Furthermore, the co-inheritance of alpha-thalassemia improves the chronic hemolytic pattern, evidenced by a decreased reticulocyte count (8.61 ± 3.58% versus 12.85 ± 4.71%; p < 0.001). In addition, our findings have confirmed the importance of HBG2 and BCL11A loci in the regulation of Hb F expression in sub-Saharan African SCA patients, as rs7482144_A, rs11886868_C, and rs4671393_A alleles are significantly associated with a considerable increase in Hb F levels (p = 0.019, p = 0.026, and p = 0.028, respectively). Concerning KLF1, twelve different variants were identified, two of them novel. Seventy-three patients (80.2%) presented at least one variant in this gene. However, no correlation was observed between the presence of these variants and Hb F level, severity of hemolysis, or stroke occurrence, which is consistent with their in silico-predicted minor functional consequences. Thus, we conclude that the prevalence of functional KLF1 variants in a sub-Saharan African background does not seem to be relevant to SCA clinical modulation.


Assuntos
Grupo com Ancestrais do Continente Africano , Anemia Falciforme , Isquemia Encefálica , Hemoglobina Fetal , Regulação da Expressão Gênica , Acidente Vascular Cerebral , Adolescente , Anemia Falciforme/complicações , Anemia Falciforme/etnologia , Anemia Falciforme/genética , Anemia Falciforme/metabolismo , Isquemia Encefálica/etnologia , Isquemia Encefálica/etiologia , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Criança , Pré-Escolar , Feminino , Hemoglobina Fetal/biossíntese , Hemoglobina Fetal/genética , Loci Gênicos , Humanos , Masculino , Acidente Vascular Cerebral/etnologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo
12.
Med Sci Monit ; 25: 5934-5941, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31397429

RESUMO

BACKGROUND The impact of low-density lipoprotein cholesterol (LDL-C) levels on outcomes in patients with non-diabetic acute ischemic stroke remains uncertain. The objective of this study was to explore whether LDL-C could refine outcomes after acute ischemic stroke in patients with non-diabetic acute ischemic stroke. MATERIAL AND METHODS A multi-center, retrospective, clinical-based study was conducted within eight hospitals between January 2015 and August 2016. Adjusted odds ratio (aOR) was used for measurement of unfavorable outcome which was evaluated by the modified Rankin Scale (mRS) score at 6 months after acute ischemic stroke, estimated categorically according to multivariate logistic regression. RESULTS A total of 1614 participants with non-diabetic acute ischemic stroke were enrolled, of which 376 patients (23.3%) had unfavorable neurologic outcomes at 6 months. After multivariate analysis comparing 4 LDL-C levels by quartiles (Q), we found that compared to Q1 (LDL-C level ≤2.41 mmol/L), there was a significant association between the frequency of unfavorable outcomes and levels of LDL-C (Q3: 2.95-3.54 mmol/L) for all participants (adjusted odds ratio [aOR]=0.63; 95% CI: 0.44-0.92, P=0.016) and patients with first ever strokes (aOR=0.52; 95% CI: 0.31-0.87, P=0.013). CONCLUSIONS Compared to lower LDL-C levels, non-diabetic patients with LDL-C levels in Q3 (2.95-3.54 mmol/L), were less likely to have unfavorable functional outcomes at 6 months after acute ischemic stroke. Managing HDL-C is one of the most important steps for the recovery of acute ischemic stroke.


Assuntos
LDL-Colesterol/efeitos adversos , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , China , LDL-Colesterol/metabolismo , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
13.
Int J Immunopathol Pharmacol ; 33: 2058738419869055, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409163

RESUMO

The purpose of the study was to evaluate the effect of Astragalus membranaceus extract and ligustrazine combination on ameliorating inflammation in cerebral ischemic rats that have undergone thrombolysis. Astragalus membranaceus and ligustrazine per se, or a combination of A. membranaceus and ligustrazine was administered by intraperitoneal injection immediately after surgery and sham surgery. After the induction of thrombolysis, the neurological function was measured and cerebral lesion volume was determined. The regulatory T cells in the spleen were measured by flow cytometry. To explore the protective effects of the combination drug on the neurological function and inflammation, the expression of transcription factor Foxp3 and cytokines, including transforming growth factor beta 1, interleukin 10, interleukin 4, interleukin 1 beta, interferon gamma, interleukin 17, in damaged brain was examined using reverse transcription polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay. The cerebral lesion volume was markedly reduced in the combination drug-treated rats compared to the rats treated with either A. membranaceus or ligustrazine alone (P < 0.05). The neurological function, regulatory T cells, transcription factor Foxp3, transforming growth factor beta 1, interleukin 10, and interleukin 4 were markedly elevated in the rats treated with combination drugs (P < 0.05). The expression of interleukin 1 beta, interferon gamma, and interleukin 17 was reduced in the rats treated with combination drug therapy (P < 0.05). Treatment with a combination of A. membranaceus and ligustrazine can ameliorate inflammation after thrombolysis and regulate the related cytokines by elevating the expression of endogenous regulatory T cells.


Assuntos
Astragalus propinquus/química , Isquemia Encefálica/tratamento farmacológico , Infarto Cerebral/tratamento farmacológico , Fibrinolíticos/farmacologia , Inflamação/tratamento farmacológico , Extratos Vegetais/farmacologia , Pirazinas/farmacologia , Animais , Isquemia Encefálica/metabolismo , Infarto Cerebral/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada/métodos , Inflamação/metabolismo , Masculino , Ratos , Ratos Wistar , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo
14.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370244

RESUMO

Aneurysmal subarachnoid hemorrhage (aSAH), characterized by the extravasation of blood into the subarachnoid space caused by an intracranial aneurysm rupture, may lead to neurocognitive impairments and permanent disability and usually carries poor outcome. Dental or gingiva-derived stem cells have been shown to contribute to immune modulation and neuroregeneration, but the underlying mechanisms are unclear. In the present study, we sought to investigate whether dental pulp stem cells (DPSCs) secrete certain factor(s) that can ameliorate the neural damage and other manifestations in a rat aSAH model. Twenty-four hours after the induction of aSAH, microthrombosis, cortical vasoconstriction, and the decrease in microcirculation and tissue oxygen pressure were detected. Intrathecal administration of DPSC-derived conditioned media (DPSC-CM) ameliorated aSAH-induced vasoconstriction, neuroinflammation, and improved the oxygenation in the injured brain. Rotarod test revealed that the aSAH-induced cognitive and motor impairments were significantly improved by this DPSC-CM administration. Cytokine array indicated the major constituent of DPSC-CM was predominantly insulin growth factor-1 (IGF-1). Immunohistochemistry staining of injured brain tissue revealed the robust increase in Iba1-positive cells that were also ameliorated by DPSC-CM administration. Antibody-mediated neutralization of IGF-1 moderately deteriorated the rescuing effect of DPSC-CM on microcirculation, Iba1-positive cells in the injured brain area, and the cognitive/motor impairments. Taken together, the DPSC-derived secretory factors showed prominent therapeutic potential for aSAH. This therapeutic efficacy may include improvement of microcirculation, alleviation of neuroinflammation, and microglial activation; partially through IGF-1-dependent mechanisms.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Meios de Cultivo Condicionados/farmacologia , Transtornos Neurocognitivos/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Transtornos Psicomotores/tratamento farmacológico , Hemorragia Subaracnóidea/tratamento farmacológico , Trombose/tratamento farmacológico , Animais , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Meios de Cultivo Condicionados/química , Polpa Dentária/citologia , Polpa Dentária/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Injeções Espinhais , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Microcirculação/efeitos dos fármacos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Transtornos Neurocognitivos/genética , Transtornos Neurocognitivos/metabolismo , Transtornos Neurocognitivos/fisiopatologia , Fármacos Neuroprotetores/química , Consumo de Oxigênio/efeitos dos fármacos , Transtornos Psicomotores/genética , Transtornos Psicomotores/metabolismo , Transtornos Psicomotores/fisiopatologia , Ratos , Ratos Wistar , Teste de Desempenho do Rota-Rod , Células-Tronco/química , Células-Tronco/citologia , Células-Tronco/metabolismo , Hemorragia Subaracnóidea/genética , Hemorragia Subaracnóidea/metabolismo , Hemorragia Subaracnóidea/fisiopatologia , Trombose/genética , Trombose/metabolismo , Trombose/fisiopatologia , Vasoconstrição/efeitos dos fármacos
15.
J Stroke Cerebrovasc Dis ; 28(10): 104299, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31371141

RESUMO

Cognitive dysfunction is the most common nonphysical impairment in the stroke survivors. This impairment has a negative impact on patients' quality of life affects their daily living activities. Both pharmacological and nonpharmacological interventions are employed to improve cognitive impairment. Recently, nonpharmacological interventions have attracted great attention. Cognitive rehabilitation is considered as a therapeutic strategy to improve and maintain cognitive skills in patients with stroke. Enriched environment (EE), as a cognitive rehabilitation strategy, has been shown to facilitate physical, cognitive, as well as social abilities. Moreover, EE has been shown to increase endogenous growth factors. Growth factors have pivotal role in neurogenesis, synaptogenesis, as well as brain remodeling through neuron development, differentiation, and survival. In addition, administration of exogenous growth factors prevents cognitive dysfunction. Here, we review preclinical and clinical evidence of cognitive rehabilitation and role of growth factors in treating poststroke cognitive impairment.


Assuntos
Isquemia Encefálica/reabilitação , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Terapia Cognitivo-Comportamental , Disfunção Cognitiva/reabilitação , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Reabilitação do Acidente Vascular Cerebral/métodos , Acidente Vascular Cerebral/terapia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/psicologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/psicologia , Resultado do Tratamento
16.
Postgrad Med ; 131(7): 423-437, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31382796

RESUMO

Hyperglycemia on hospital admission is a common phenomenon in acute ischemic stroke patients and represents an independent predictor of poor clinical outcome with or without acute recanalization therapies (systemic thrombolysis or mechanical thrombectomy). Effective restoration of normoglycemia is considered to be beneficial, but conclusive evidence from randomized controlled clinical trials and specific recommendations are lacking. In addition, aggressive glucose control can be complicated by hypoglycemia leading to early neurological deterioration. We conducted a systematic literature review with the aim of addressing several questions: timing of glucose control, target range, type of insulin delivery, duration and practicability of glucose-lowering protocols. Special issues regarding mechanical thrombectomy and glycemic variability can then be investigated in future trials which are also being considered.


Assuntos
Isquemia Encefálica/terapia , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Acidente Vascular Cerebral/terapia , Glicemia/metabolismo , Isquemia Encefálica/complicações , Isquemia Encefálica/metabolismo , Hospitalização , Humanos , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Hipoglicemia/induzido quimicamente , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/metabolismo , Trombectomia , Terapia Trombolítica
17.
Biomed Pharmacother ; 117: 109155, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31387178

RESUMO

Stroke is a leading cause of mortality and disability globally. Cerebral ischaemia-reperfusion (I/R) injury is characterized by significant inflammation and extensive cell death. Multiple signaling pathways play essential roles in the process, and identifying the unclear crucial regulators of these pathways may provide promising targets for treatment. CASP8 and FADD-like apoptosis regulator (CFLAR) is expressed in multiple organs to regulate inflammation. Here, we reported that CFLAR expression was markedly reduced in brain samples of mice with middle cerebral artery occlusion (MCAO) stroke. Furthermore, CFLAR knockdown markedly elevated the neurological deficit, brain water content and the infarct volume. In addition, significantly promoted inflammation and endoplasmic reticulum (ER) stress was detected in brain tissues of mice after MCAO, as evidenced by the promoted expression of p-IκBα, p-nuclear factor (NF)-κB (p65), glucose-regulated protein 78 (GRP78), PKR-like ER kinase (PERK), activating transcription factor-6 (ATF-6) and cleaved Caspase-12. Notably, MCAO-induced cerebral I/R injury was markedly alleviated in mice over-expressing CFLAR through suppressing inflammation and ER stress. Furthermore, our in vitro results indicated that oxygen-glucose deprivation (OGD)-induced cell death was evidently ameliorated by CFLAR over-expression. In contrast, the cell death triggered by OGD was accelerated by CFLAR knockdown in vitro through enhancing Caspase-3 cleavage, and this effect was obviously ameliorated by the blockage of ER stress using 4-phenyl butyric acid (4-PBA). Collectively, these results demonstrated that CFLAR could be considered as a novel candidate to develop effective therapeutic treatment against cerebral I/R injury.


Assuntos
Isquemia Encefálica/metabolismo , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Retículo Endoplasmático/metabolismo , Inflamação/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Apoptose/fisiologia , Encéfalo/metabolismo , Linhagem Celular , Células HEK293 , Humanos , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Acidente Vascular Cerebral/metabolismo
18.
World Neurosurg ; 131: e486-e494, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31382062

RESUMO

OBJECTIVE: To assess the effects of miR-199a-5p on cerebral ischemic injury and its underlying mechanisms. METHODS: Infarct volume, neurologic deficit scores, and brain water content were evaluated after 24 hours of reperfusion. The histopathological damage in cortical neurons was assayed by hematoxylin and eosin staining. Neuronal apoptosis was evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. The regulatory effect of miR-199a-5p on discoidin domain receptor 1 (DDR1) was investigated using a dual luciferase reporter gene assay. Expression levels of miR-199a-5p and DDR1 were detected by real-time fluorogenic polymerase chain reaction and Western blot analysis. Expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-ß, and IL-6 were investigated by enzyme-linked immunosorbent assay. RESULTS: Our results suggest that DDR1 is the target gene of miR-199a-5p. The expression levels of miR-199a-5p and DDR1 were significantly down-regulated and up-regulated in the rats with cerebral ischemia compared with the control and sham groups, respectively. Moreover, infarct volume, neurologic score, brain water content, neuronal damage, and neuronal apoptosis were significantly decreased in the mimics group, siRNA DDR1 (siDDR1) group, and especially the mimics + siDDR1 group. The results also confirmed significantly weakened expression levels of proinflammatory cytokines (TNF-α, IL-6, and IL-1ß) in mimics, siDDR1, and especially mimics + siDDR1 rats. In addition, DDR1 silencing attenuated the effects of the miR-199a-5p inhibitor on neurologic function, infarct volume, brain water content, and proinflammatory cytokine expressions after middle cerebral artery occlusion in rats. CONCLUSIONS: miR-199a-5p may protect against cerebral ischemic injury by down-regulating DDR1 in rats.


Assuntos
Encéfalo/metabolismo , Receptor com Domínio Discoidina 1/genética , Infarto da Artéria Cerebral Média/genética , MicroRNAs/genética , Animais , Apoptose/genética , Western Blotting , Encéfalo/patologia , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Receptor com Domínio Discoidina 1/metabolismo , Regulação para Baixo , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Fator de Necrose Tumoral alfa/metabolismo
19.
BMC Neurol ; 19(1): 177, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31345181

RESUMO

BACKGROUND: Insulin resistance (IR) in relation to diabetes is a risk factor for ischemic stroke (IS), whereas less is known about non-diabetic IR and outcome after IS. METHODS: In non-diabetic IS (n = 441) and controls (n = 560) from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), IR was investigated in relation to IS severity and functional outcome. IR was evaluated acutely and after 3 months using the Homeostasis model assessment of IR (HOMA-IR). Stroke severity was assessed by the National Institutes of Health Stroke Scale (NIHSS). Functional outcome was evaluated using the modified Rankin Scale (mRS) after 3 months, 2 and 7 years. Associations were evaluated by logistic regression. RESULTS: Higher acute and 3-month HOMA-IR was observed in IS compared to the controls (both p < 0.001) and in severe compared to mild IS (both p < 0.05). High acute HOMA-IR was associated with poor outcome (mRS 3-6) after 3 months and 7 years [crude Odds ratios (ORs), 95% confidence intervals (CIs) 1.50, 1.07-2.11 and 1.59, 1.11-2.30, respectively], but not after 2 years. These associations lost significance after adjustment for all covariates including initial stroke severity. In the largest IS subtype (cryptogenic stroke), acute HOMA-IR was associated with poor outcome after 2 years also after adjustment for age and stroke severity (OR 2.86, 95% CI 1.01-8.12). CONCLUSIONS: In non-diabetic IS patients, HOMA-IR was elevated and related to stroke severity, but after adjustment for IS severity, the associations between HOMR-IR and poor outcome lost significance. This could suggest that elevated IR mostly is a part of the acute IS morbidity. However, in the subgroup of cryptogenic stroke, the associations with poor outcome withstood correction for stroke severity.


Assuntos
Isquemia Encefálica/metabolismo , Resistência à Insulina , Acidente Vascular Cerebral/metabolismo , Estudos de Casos e Controles , Feminino , Homeostase , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Prospectivos , Fatores de Risco
20.
Food Funct ; 10(8): 4725-4738, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31304955

RESUMO

Antrodia camphorata is a well-known traditional Chinese mushroom used as a functional food and nutraceutical in Taiwan and China. The aim of this study was to explore the protective effects and mechanism(s) of the ethyl acetate crude extract of A. camphorata (EtOAc-AC) and its active constituent ergostatrien-7,9(11),22-trien-3ß-ol (EK100) in an acute ischemic stroke (AIS) murine model. Treating mice with induced AIS injury by using EtOAc-AC (0.3-0.6 g kg-1, p.o.) and EK100 (60 and 120 mg kg-1, p.o.) 2 h after AIS induction significantly increased the tracking distance and reduced brain infarction. Both EtOAc-AC and EK-100 reduced the expression levels of p65NF-κB and caspase 3 near the peri-infarct cortex and promoted the expression of neurogenesis-associated protein doublecortin (DCX) near the hippocampus, accompanied by glycogen synthase kinase 3 (GSK-3) inhibition and ß-catenin upregulation. Signaling pathway analysis revealed that the advantageous effects of EtOAc-AC and EK-100 involved triggering the activation of PI3K/Akt and inhibition of GSK-3. Our findings suggest that EtOAc-AC and its active constituent EK100 display anti-inflammatory and anti-apoptotic activities. Both EtOAc-AC and EK100 reduce ischemic brain injury by decreasing p65NF-κB and caspase 3 expression, and they promote neurogenesis (DCX) and neuroprotection (Bcl2) by activating the PI3k/Akt-associated GSK3 inhibition and ß-catenin activation.


Assuntos
Antrodia/química , Isquemia Encefálica/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Ergosterol/análogos & derivados , Neurogênese/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Apoptose/efeitos dos fármacos , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Caspase 3/genética , Caspase 3/metabolismo , Cateninas/genética , Cateninas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Ergosterol/administração & dosagem , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/fisiopatologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo
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