RESUMO
Amyotrophic lateral sclerosis (ALS) is a debilitating and rapidly fatal neurodegenerative disease, which is characterized by the selective loss of the upper and lower motor neurons. The pathogenesis of ALS remains to be elucidated and has been connected to genetic, environmental and immune conditions. Evidence from clinical and experimental studies has suggested that the immune system played an important role in ALS pathophysiology. Autoantibodies are essential components of the immune system. Several autoantibodies directed at antigens associated with ALS pathogenesis have been identified in the serum and/or cerebrospinal fluid of ALS patients. The aim of this review is to summarize the presence and clinical significance of autoantibodies in ALS.
Assuntos
Esclerose Lateral Amiotrófica , Autoanticorpos , Esclerose Lateral Amiotrófica/imunologia , Esclerose Lateral Amiotrófica/sangue , Humanos , Autoanticorpos/imunologia , Autoanticorpos/sangue , Relevância ClínicaRESUMO
Bisabosqual-type meroterpenoids are fungi-derived polyketide-terpenoid hybrids bearing a 2,3,3a,3a1,9,9a-hexahydro-1H-benzofuro[4,3,2-cde]chromene skeleton (6/6/6/5 ring system) or its seco-C-ring structure, and exhibit diverse bioactivities. Their unique structural architecture and impressive biological activities have led to considerable interest in discovering new analogues. However, to date, only nine analogues have been identified. Herein, we reported the isolation and identification of six new bisabosqual-type meroterpenoids stachybisbins C-H (1-6), together with one known compound bisabosqual C (7), from Stachybotrys bisbyi PYH05-7. Intriguingly, we found that 7, which contains the intact tetracyclic skeleton, can be non-enzymatically converted into its seco derivative stachybisbin I (8), unveiling the biosynthetic relationship between bisabosquals and seco-bisabosquals. Moreover, based on CRISPR/Cas9-mediated gene disruption, we revealed that the three-gene cluster responsible for the formation of LL-Z1272ß is associated with the biosynthesis of bisabosqual-type meroterpenoids, and then proposed a plausible route to 1-8.
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Benzopiranos , Policetídeos , Compostos Radiofarmacêuticos , TerpenosRESUMO
Fluid-attenuated inversion recovery vascular hyperintensity (FVH) is frequently observed in patients with acute ischemic stroke (AIS). FVH is associated with functional outcome at 3 months in AIS patients receiving endovascular thrombectomy. In the present study, we assessed whether FVH predicted early neurological deterioration (END) and hemorrhagic transformation (HT) within 72 h in AIS patients receiving endovascular thrombectomy. We retrospectively analyzed 104 patients with acute internal-carotid-artery or proximal middle-cerebral-artery occlusion within 16 h after symptom onset. Before thrombectomy, all patients underwent brain magnetic resonance imaging. END was defined as an increase of 4 points or more from baseline National Institutes of Health Stroke Scale (NIHSS) during 72 h following onset. HT was assessed by brain computed tomography. Statistical analyses were performed to predict END and HT. The proportion of high FVH score, high American Society of Intervention and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grade in non-END group was higher than that in END group (p < 0.001, p < 0.001, respectively). FVH score was positively correlated with ASITN/SIR grade (r = 0.461, p < 0.001). FVH score was a predictor factor for END (adjusted OR, 13.552; 95% CI, 2.408-76.260; p = 0.003), while FVH score was not a predictor factor for HT. Furthermore, NIHSS at admission (adjusted OR, 1.112; 95% CI, 1.006-1.228; p = 0.038) and high-density lipoprotein cholesterol (adjusted OR, 18.865; 95% CI, 2.998-118.683; p = 0.002) were predictor factors for HT. To assess FVH score before thrombectomy might be useful for predicting END in AIS patients receiving endovascular thrombectomy.
Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/cirurgia , Humanos , Infarto da Artéria Cerebral Média/terapia , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/cirurgia , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/cirurgia , Trombectomia/métodos , Resultado do TratamentoRESUMO
BACKGROUND: Reports have proven that shorter door-to-needle time (DTN time) indicates better outcomes in AIS patients received intravenous thrombolysis. Efforts have been made by hospitals and centers to minimize DTN time in many ways including introducing a stroke nurse. However, there are few studies to discuss the specific effect of stroke nurse on patients' prognosis. This study aimed to compare consecutive AIS patients before and after the intervention to analyze the effect of stroke nurse on clinical outcome of AIS patients. METHODS: In this retrospective study, we observed 1003 patients from November 2016 to December 2020 dividing in two groups, collected and analyzed AIS patients' medical history, clinical assessment information, important timelines, 90 mRS score, etc. Comparative analysis and mediation analysis were also used in this study. RESULTS: A total of 418 patients was included in this study, and 199 patients were enrolled in the stroke nurse group and 219 was in the preintervention group. Baseline characteristics of patients showed no significant difference except there seems more patients with previous ischemic stroke history in the group of stroke nurse. (p = 0.008). The median DTN time significantly decreased in the stroke nurse group (25 min versus 36 min, p < 0.001) and multivariate logistic regression analysis showed the 90-day mRS clinical outcome significantly improved in the stroke nurse group (p = 0.001). Mediation analysis indicated the reduction of DTN time plays a partial role on the 90 days mRS score and the stroke nurse has some direct effect on the improvement of clinical outcome (p = 0.006). CONCLUSIONS: The introduction of stroke nurse is beneficial to clinical outcome of AIS patients and can be use of reference in other hospitals or centers.
Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Fibrinolíticos/uso terapêutico , Humanos , Estudos Retrospectivos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica , Tempo para o Tratamento , Ativador de Plasminogênio Tecidual/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND The aim of this study was to investigate whether patients with basal ganglia stroke and patients with pontine stroke have different types of functional connectivity (FC) alterations in the early chronic phase. MATERIAL AND METHODS We included 14 patients with pontine stroke, 17 patients with basal ganglia stroke, and 20 well-matched healthy controls (HCs). All of them underwent resting-state functional magnetic resonance imaging (rs-fMRI) scanning. The independent component analysis (ICA) approach was applied to extract information regarding the default-mode network (DMN), including anterior DMN (aDMN) and posterior DMN (pDMN) components and the sensorimotor network (SMN). RESULTS Compared with HCs, patients with basal ganglia stroke exhibited significantly reduced FC in the left precuneus of the pDMN, right supplementary motor area (SMA), and right superior frontal gyrus (SFG) of the SMN. Additionally, FC in the left medial prefrontal gyrus (MFG) of the aDMN, right precuneus and right posterior cingulate cortex (PCC) of the pDMN, and left middle cingulate gyrus (mid-CC) of the SMN decreased in patients with pontine stroke. CONCLUSIONS The different patterns of FC damage in patients with basal ganglia stroke and patients with pontine stroke in the early chronic phase may provide a new method for investigating lesion-induced network plasticity.
Assuntos
Infartos do Tronco Encefálico/fisiopatologia , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/fisiopatologia , Idoso , Gânglios da Base/diagnóstico por imagem , Gânglios da Base/fisiopatologia , Encéfalo/fisiopatologia , Mapeamento Encefálico/métodos , Infartos do Tronco Encefálico/diagnóstico por imagem , Conectoma/métodos , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Vias Neurais , Descanso , Córtex Sensório-Motor/diagnóstico por imagem , Córtex Sensório-Motor/metabolismoRESUMO
BACKGROUND/AIMS: Recently, we showed that triggering receptor expressed on myeloid cells 1 (TREM1) was involved in the pathogenesis of Alzheimer's disease (AD) since it modulated microglial phagocytic functions and thus affected amyloid-ß clearance in the brain. Interestingly, a soluble form of TREM1 (sTREM1) can be detected in the plasma of human. To date, whether sTREM1 concentrations were altered in the plasma under AD context remained unclear. METHODS: In this study, we compared the plasma concentrations of sTREM1 between 110 AD patients and 128 age- and gender-matched controls. Meanwhile, the relationship of sTREM1 concentrations with total tau levels in the plasma of AD patients was also assessed. RESULTS: We revealed that the concentrations of sTREM1 were significantly increased in AD patients. Meanwhile, the sTREM1 concentrations were gradually increased during disease progression. More importantly, we showed that the sTREM1 concentrations were positively correlated with the levels of total tau in the plasma of AD patients (r = 0.61, P < 0.001). The subsequent subgroup analysis indicated that this correlation was more pronounced in patients with severe dementia (Mini-Mental State Exam score < 10, r = 0.81, P < 0.01). CONCLUSION: These findings indicate a potential association between sTREM1 and tau pathology, and further confirm an involvement of this immune receptor in AD pathogenesis.
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Doença de Alzheimer/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/sangue , Proteínas tau/sangue , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/classificação , Peptídeos beta-Amiloides/metabolismo , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Numerous studies suggested that PM2.5 exposure was associated with increased risk of Alzheimer's disease (AD). But the precise mechanisms by which PM2.5 contributed to AD pathogenesis have not been clarified. METHODS: In the presence or absence of neurons, oligomeric amyloid beta (oAß)-primed microglia were stimulated with PM2.5. Firstly, we determined the effects of PM2.5 exposure on neuronal injury and inflammation in neurons-microglia co-cultures. Then, we examined whether NLRP3 inflammasome activation was involved in PM2.5-induced inflammation. After that, we investigated whether PM2.5 exposure increased ROS level in oAß-stimulated microglia. At last, we examined whether ROS and NLRP3 inflammasome activation was required for PM2.5-induced neuronal injury in neurons-microglia co-cultures. RESULTS: In the present study, we showed that PM2.5 exposure aggravated oAß-induced neuronal injury and inflammation in neurons-microglia co-cultures via increasing IL-1ß production. Further, PM2.5-induced IL-1ß production in oAß-stimulated microglia was possibly dependent on NLRP3 inflammasome activation. Meanwhile, PM2.5 exposure increased ROS level in oAß-stimulated microglia. ROS was required for PM2.5-induced IL-1ß production and NLRP3 inflammasome activation in oAß-stimulated microglia. More importantly, ROS and NLRP3 inflammasome activation was required for PM2.5-induced neuronal injury in neurons-microglia co-cultures. CONCLUSIONS: For the first time, these results suggested that the effects of PM2.5 under AD context were possibly mediated by NLRP3 inflammasome activation, which was triggered by ROS. Taken together, these findings have deepened our understanding on the role of PM2.5 in AD pathogenesis.
Assuntos
Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/toxicidade , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neurônios/metabolismo , Material Particulado/toxicidade , Fragmentos de Peptídeos/toxicidade , Animais , Células Cultivadas , Técnicas de Cocultura , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Tamanho da Partícula , GravidezRESUMO
Inflammatory damage plays an important role in cerebral ischemic pathogenesis and represents a new target for treatment of stroke. Berberine is a natural medicine with multiple beneficial biological activities. In this study, we explored the mechanisms underlying the neuroprotective action of berberine in mice subjected transient middle cerebral artery occlusion (tMCAO). Male mice were administered berberine (25, 50 mg/kg/d, intragastric; i.g.), glycyrrhizin (50 mg/kg/d, intraperitoneal), or berberine (50 mg/kg/d, i.g.) plus glycyrrhizin (50 mg/kg/d, intraperitoneal) for 14 consecutive days before tMCAO. The neurological deficit scores were evaluated at 24 h after tMCAO, and then the mice were killed to obtain the brain samples. We showed that pretreatment with berberine dose-dependently decreased the infarct size, neurological deficits, hispathological changes, brain edema, and inflammatory mediators in serum and ischemic cortical tissue. We revealed that pretreatment with berberine significantly enhanced uptake of 18F-fluorodeoxyglucose of ischemic hemisphere comparing with the vehicle group at 24 h after stroke. Furthermore, pretreatment with berberine dose-dependently suppressed the nuclear-to cytosolic translocation of high-mobility group box1 (HMGB1) protein, the cytosolic-to nuclear translocation of nuclear factor kappa B (NF-κB) and decreased the expression of TLR4 in ischemic cortical tissue. Moreover, co-administration of glycyrrhizin and berberine exerted more potent suppression on the HMGB1/TLR4/NF-κB pathway than berberine or glycyrrhizin administered alone. These results demonstrate that berberine protects the brain from ischemia-reperfusion injury and the mechanism may rely on its anti-inflammatory effects mediated by suppressing the activation of HMGB1/TLR4/NF-κB signaling.
Assuntos
Berberina/uso terapêutico , Proteína HMGB1/antagonistas & inibidores , Infarto da Artéria Cerebral Média/tratamento farmacológico , Subunidade p50 de NF-kappa B/antagonistas & inibidores , Fármacos Neuroprotetores/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Encéfalo/patologia , Edema Encefálico/tratamento farmacológico , Regulação para Baixo , Ácido Glicirrízico/uso terapêutico , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Infarto da Artéria Cerebral Média/etiologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Subunidade p50 de NF-kappa B/genética , Subunidade p50 de NF-kappa B/metabolismo , Traumatismo por Reperfusão/complicações , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
PURPOSE: The present study aimed to investigate the corticospinal tract (CST) changes in patients with brainstem ischemic stroke by using the diffusion kurtosis imaging (DKI) approach.. MATERIALS AND METHODS: Twenty-one patients with brainstem stroke and 21 group-matched healthy controls underwent brain DKI with 3.0 T magnetic resonance imaging (MRI). The DKI was obtained by using three b values of 0, 1,000, 2,000 s/mm2 with 15 diffusion directions. Regions of interest (ROIs) were placed at four levels: the pons, posterior limb of the internal capsule (PLIC), corona radiata, and precentral gyrus. The DKI parameters, including fractional anisotropy (FA), mean diffusivity (MD), and mean kurtosis (MK) values, in these regions were measured from the contralateral to the ipsilateral side of patients and both the left and right sides of healthy controls at all the four selected levels. RESULTS: The ipsilateral side of the ischemic lesion showed a decrease in FA and MD and an increase in MK when compared with the contralateral normal region at all the four selected levels with statistically differences (P < 0.05). At these four selected levels, there were no differences between the left and right sides in healthy controls with MD, FA, and MK (P > 0.05). The MD values of the contralateral side of the ischemic lesion in patients at the four selected levels were significantly higher than those in the corresponding side of the healthy controls (P < 0.05). Compared to the healthy controls, there was a decrease at the posterior limb of the internal capsule (PLIC) in FA of the contralateral side of the ischemic lesion in stroke patients (P < 0.05). However, no significant differences were observed for MK values between the groups (P > 0.05). CONCLUSION: The current results suggest that the DKI technique could identify the early microstructural changes along the motor pathway and that these changes were not limited to the ipsilateral side of the ischemic lesion; in fact, the contralateral changes also occurred, especially at the PLIC.
Assuntos
Infartos do Tronco Encefálico/diagnóstico por imagem , Infartos do Tronco Encefálico/patologia , Tratos Piramidais/diagnóstico por imagem , Tratos Piramidais/patologia , Idoso , Idoso de 80 Anos ou mais , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodosRESUMO
Stroke is a disease that mainly affects the elderly. Since the age-related differences in stroke have not been well studied, modeling stroke in aged animals is clinically more relevant. The inflammatory responses to stroke are a fundamental pathological procedure, in which microglial activation plays an important role. Interferon regulatory factor-5 (IRF5) and IRF4 regulate M1 and M2 activation of macrophages, respectively, in peripheral inflammation; but it is unknown whether IRF5/IRF4 are also involved in cerebral inflammatory responses to stroke and whether age-related differences of the IRF5/IRF4 signaling exist in ischemic brain. Here, we investigated the influences of aging on IRF5/IRF4 signaling and post-stroke inflammation in mice. Both young (9-12 weeks) and aged (18 months) male mice were subjected to middle cerebral artery occlusion (MCAO). Morphological and biochemical changes in the ischemic brains and behavior deficits were assessed on 1, 3, and 7 d post-stroke. After MCAO, the aged mice showed smaller infarct sizes but higher neurological deficits and corner test scores than young mice. Young mice had higher levels of IRF4 and CD206 microglia in the ischemic brains, whereas the aged mice expressed more IRF5 and MHCII microglia. After MCAO, serum pro-inflammatory cytokines (TNF-α, iNOS, IL-6) were more prominently up-regulated in aged mice, whereas serum anti-inflammatory cytokines (TGF-ß, IL-4, IL-10) were more prominently up-regulated in young mice. Our results demonstrate that aging has a significant influence on stroke outcomes in mice, which is probably mediated by age-specific inflammatory responses.
Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Fatores Reguladores de Interferon/metabolismo , Microglia/metabolismo , Transdução de Sinais , Fatores Etários , Envelhecimento/patologia , Animais , Comportamento Animal , Encéfalo/patologia , Encéfalo/fisiopatologia , Citocinas/sangue , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/psicologia , Mediadores da Inflamação/sangue , Masculino , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/metabolismo , Fatores de TempoRESUMO
As the most common type of neurodegenerative disease, Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß peptide (Aß) within the brain. Triggering receptor expressed on myeloid cells (TREM) 1 is an immune receptor expressed by mononuclear phagocytes including monocytes and microglia, coupling with TYRO protein tyrosine kinase binding protein to regulate immune reactions. Emerging evidence indicates that rs6910730G, an intronic variant of TREM1, is associated with an increased Aß neuropathology in the brains of elderly subjects, but the underlying mechanisms remain unclear. Here, using two independent cohorts of healthy individuals, we provided evidence that rs6910730G reduced the ability of human monocytes for Aß phagocytosis, and this reduction was likely attributed to a decreased monocytic TREM1 expression. By knockdown and overexpression of Trem1 in mouse primary microglia, we showed that TREM1 facilitated microglial phagocytosis of Aß. In support of this finding, knockdown of Trem1 in the brains of APP/PSEN1 mice increased Aß1-42 levels and total amyloid burden, whereas selective overexpression of Trem1 on microglia or activation of Trem1 signaling by an agonistic antibody ameliorated Aß neuropathology and rescued AD-related spatial cognitive impairments. Altogether, these findings uncover the role of TREM1 in microglial Aß clearance, and establish TREM1 as a potential therapeutic target for AD.
Assuntos
Peptídeos beta-Amiloides/farmacologia , Encéfalo/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Fragmentos de Peptídeos/farmacologia , Fagocitose/efeitos dos fármacos , Receptores Imunológicos/metabolismo , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Animais Recém-Nascidos , Anticorpos/farmacologia , Encéfalo/citologia , Células Cultivadas , Regulação da Expressão Gênica/genética , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos Transgênicos , Microglia/metabolismo , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Presenilina-1/genética , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Receptor Gatilho 1 Expresso em Células MieloidesRESUMO
BACKGROUND: The profile and 1-year outcome after acute ischemic stroke (AIS) in Nanjing, China, is uncertain. This study aimed to investigate the profile and outcome after 1-year follow-up of AIS in East China. METHODS: In a prospective cohort study, 2168 patients with AIS were recruited consecutively. The primary outcome was death or dependency defined as a modified Rankin Scale score of 3-6 at 12 months. Plausible risk factors of death or dependency, such as demographics, risk factors of cardiovascular diseases, clinical features, laboratory results, and complications after a stroke, were selected from available variables to perform multivariable logistic regression analyses. RESULTS: Eight hundred thirty-seven (38.6%) patients died or suffered from dependency. Multivariate logistic regression analysis showed that age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.03-1.05), history of diabetes mellitus (OR, 1.50; 95% CI, 1.10-2.04), prior stroke (OR, 2.08; 95% CI, 1.51-2.87), National Institutes of Health Stroke Scale (NIHSS) score (OR, 23.06; 95% CI, 14.24-37.34), estimated glomerular filtration rate (OR, 1.65; 95% CI, 1.02-2.66), pulmonary infection (OR, 2.98; 95% CI, 2.17-4.09), and gastrointestinal bleeding (OR, 7.81; 95% CI, 2.76-22.09) were significantly and independently associated with higher rates of mortality or disability (all P values < .05). Male gender (P values < .001) was the only factor associated with lower mortality or disability. CONCLUSIONS: The main dominating predictors for death or dependency were older age, female gender, diabetes mellitus, prior stroke, NIHSS score, estimated glomerular filtration rate, pulmonary infection, and gastrointestinal bleeding.
Assuntos
Dano Encefálico Crônico/epidemiologia , Isquemia Encefálica/epidemiologia , Idoso , Dano Encefálico Crônico/etiologia , Isquemia Encefálica/complicações , Isquemia Encefálica/terapia , China/epidemiologia , Comorbidade , Diabetes Mellitus/epidemiologia , Feminino , Seguimentos , Hemorragia Gastrointestinal/epidemiologia , Cardiopatias/epidemiologia , Hospitais Públicos/estatística & dados numéricos , Humanos , Hiperlipidemias/epidemiologia , Nefropatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Pneumonia/epidemiologia , Recidiva , Sistema de Registros , Fatores de Risco , Fatores Sexuais , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND AND AIM: The severity of cerebral microbleeds (CMBs) affected the prognosis of patients with acute cerebrovascular disease. Considering the impact of CMBs on clinical decision, it is necessary to assess the risk factors of CMBs. We aimed to evaluate the independent risk factors of CMBs in patients with acute ischemic stroke of large-artery atherosclerosis. MATERIALS AND METHODS: 112 patients were enrolled in the study. The baseline information, the results of laboratory examination and cranial MRI were collected. The independent risk factors of CMBs in patients with acute ischemic stroke due to large-artery atherosclerosis were evaluated. RESULTS: CMBs were found in 56 (50%) patients. Older age and higher homocysteine (Hcy) level were associated with an elevated chance of occurrence of CMBs. Further, there was a positive correlation between CMBs grade and serum Hcy level. CONCLUSIONS: Serum Hcy level is strongly associated with the presence of CMBs in patients with acute ischemic stroke due to large-artery atherosclerosis. Serum Hcy level may be a potential therapeutic target for alleviating adverse clinical outcomes of CMBs.
Assuntos
Isquemia Encefálica/etiologia , Hemorragia Cerebral/etiologia , Homocisteína/sangue , Hiper-Homocisteinemia/complicações , Arteriosclerose Intracraniana/complicações , Acidente Vascular Cerebral/etiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Isquemia Encefálica/sangue , Isquemia Encefálica/diagnóstico por imagem , Hemorragia Cerebral/sangue , Hemorragia Cerebral/diagnóstico por imagem , China , Feminino , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/diagnóstico , Arteriosclerose Intracraniana/sangue , Arteriosclerose Intracraniana/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Índice de Gravidade de Doença , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico por imagem , Regulação para CimaRESUMO
Numerous studies reveal that Angiotensin II (Ang II), the main effector of renin-angiotensin system, contributes to the pathogenesis of Parkinson's disease (PD) via triggering dopaminergic cell loss. However, the underlying mechanisms remain largely unclear. In the current study, by using CATH.a cell, a dopaminergic neuronal cell line stably expressing Angiotensin II type 1 receptor (AT1R) and Angiotensin II type 2 receptor (AT2R), we showed that Ang II treatment triggered cell apoptosis in a dose-dependent manner, providing the first evidence that apoptotic cell death contributed to the dopaminergic cell loss induced by Ang II. Ang II treatment also led to a significant increment in intracellular reactive oxygen species generation, which could be fully abolished by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors apocynin or diphenylene iodonium, indicating that Ang II enhanced oxidative stress via a NADPH oxidase-dependent manner. More importantly, inhibition of oxidative stress by NADPH oxidase inhibitors partially attenuated cell apoptosis caused by Ang II, implying that the enhancement of NADPH oxidase-dependent oxidative stress contributed to the cell apoptosis triggered by Ang II. Furthermore, the Ang II-induced oxidative stress and subsequent apoptosis could be completely abolished by AT1R blocker losartan rather than AT2R blocker PD1223319, suggesting that the aforementioned detrimental effects of Ang II are mediated by AT1R. In summary, these findings have deepened our understanding on the role of Ang II in PD pathogenesis, and support the use of AT1R blockers in the treatment of this devastating disease.
Assuntos
Angiotensina II/farmacologia , Apoptose/efeitos dos fármacos , Dopamina/metabolismo , NADPH Oxidases/metabolismo , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Linhagem Celular , Neurônios/metabolismoRESUMO
Current predictive models including the CYP2C19 polymorphism and clinical factors still explain only about 12% of variability of clopidogrel responsiveness. Up until recently, the precise mechanism of clopidogrel resistance remains unclear. P-glycoprotein (P-gp) encoded by ABCB1, a transmembrane calcium-dependent efflux pump for clopidogrel, implicated a role in clopidogrel resistance. In this present study, we investigated the methylation status of ABCB1 gene promoter in relation to ABCB1 mRNA expressions and the antiplatelet effects of clopidogrel. This study was a prospective cohort analysis of eligible stroke patients (n = 183, aged 18-75 years) who received clopidogrel (75 mg/day) for at least 5 days before discharge. A final subcohort of 87 patients with CYP2C19*1/*1 genotype were enrolled in the study population. Patients were grouped in quartiles of maximum platelet aggregation (MPA values (Q1, Q2, Q3 and Q4, MPA(Q1) < 14.1%, MPA(Q4) > 35.4%). The methylation status of the ABCB1 promoter was 1.8 times in the Q1 MPA group (10.1 ± 2.4%) than in the Q4 MPA group (5.5 ± 2.1%) (P < 0.001). ABCB1 methylation correlated inversely with MPA (R = - 0.764, P < 0.001) and mRNA expression (R = - 0.839, P < 0.001). Results of a multivariate linear regression model demonstrated that ABCB1 methylation was independently associated with MPA (ß(coef ficient) = - 4.71, P < 0.001). ABCB1 expression was 0.62 times in the Q1 MPA group (5.3 ± 1.4 per thousand) than in the Q4 MPA (8.5 ± 2.5%o), and the expression of ABCB1 correlated positively with ADP-induced MPA (R = 0.791, P < 0.001). ABCB1 promoter methylation status in whole blood appears to be inversely associated with ABCB1 mRNA expressions and MPA. In conclusions, hypomethylation of ABCB1 promoter is associated with a decreased response to clopidogrel in ischemic stroke patients via increased ABCB1 mRNA expression.
Assuntos
Isquemia Encefálica/sangue , Isquemia Encefálica/tratamento farmacológico , Inibidores da Agregação Plaquetária/farmacologia , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/tratamento farmacológico , Ticlopidina/análogos & derivados , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Difosfato de Adenosina/farmacologia , Adolescente , Adulto , Idoso , Povo Asiático , Clopidogrel , Citocromo P-450 CYP2C19/metabolismo , Metilação de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Ticlopidina/farmacologia , Adulto JovemRESUMO
Accumulation of amyloid-ß peptides (Aß) within brain is a major pathogenic hallmark of Alzheimer's disease (AD). Emerging evidence suggests that autophagy, an important intracellular catabolic process, is involved in Aß clearance. Here, we investigated whether temsirolimus, a newly developed compound approved by Food and Drug Administration and European Medicines Agency for renal cell carcinoma treatment, would promote autophagic clearance of Aß and thus provide protective effects in cellular and animal models of AD. HEK293 cells expressing the Swedish mutant of APP695 (HEK293-APP695) were treated with vehicle or 100nM temsirolimus for 24h in the presence or absence of 3-methyladenine (5mM) or Atg5-siRNA, and intracellular Aß levels as well as autophagy biomarkers were measured. Meanwhile, APP/PS1 mice received intraperitoneal injection of temsirolimus (20mg/kg) every 2 days for 60 days, and brain Aß burden, autophagy biomarkers, cellular apoptosis in hippocampus, and spatial cognitive functions were assessed. Our results showed that temsirolimus enhanced Aß clearance in HEK293-APP695 cells and in brain of APP/PS1 mice in an autophagy-dependent manner. Meanwhile, temsirolimus attenuated cellular apoptosis in hippocampus of APP/PS1 mice, which was accompanied by an improvement in spatial learning and memory abilities. In conclusion, our study provides the first evidence that temsirolimus promotes autophagic Aß clearance and exerts protective effects in cellular and animal models of AD, suggesting that temsirolimus administration may represent a new therapeutic strategy for AD treatment. Meanwhile, these findings emphasize the notion that many therapeutic agents possess pleiotropic actions aside from their main applications.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Antineoplásicos/farmacologia , Encéfalo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Sirolimo/análogos & derivados , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/genética , Animais , Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Células HEK293 , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos Transgênicos , Fármacos Neuroprotetores/uso terapêutico , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/metabolismoRESUMO
It is unclear whether previous statin therapy influences the prognosis, hemorrhagic transformation, and plasma matrix metalloproteinases (MMP)-9 levels in Chinese stroke patients receiving intravenous thrombolysis. We conduct a prospective cohort study of 193 patients treated with intravenous thrombolysis. All the enrolled patients were divided into 2 groups (the control group and the statin group), according to the previous history of statin use. The plasma MMP-9 levels were detected before and at 6 hours, 12 hours, 24 hours, and 72 hours after intravenous thrombolysis. The clinical outcome of stroke was measured in terms of the functional outcome and occurrence of symptomatic intracerebral hemorrhage. The MMP-9 levels increased after thrombolysis in statin group and control group. No significant intergroup difference was found in the MMP-9 levels before and at 6 hours after thrombolysis, but the levels were significantly lower in the statin group than in the control group at 12, 24, and 72 hours (P < .001) after thrombolysis. Similarly, no significant intergroup difference was noted in the occurrence of symptomatic intracranial hemorrhage as was the case with the modified Rankin scale (assessed by the Mann-Whitney U test) at 7 days (P = .428) and 90 days (P = .419) after thrombolysis. Our results indicate that pretreatment with statin can inhibit the thrombolysis-induced increase in plasma MMP-9 levels but does not significantly affect the prognosis of acute ischemic stroke patients undergoing intravenous thrombolysis.
Assuntos
Fibrinolíticos/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Metaloproteinase 9 da Matriz/sangue , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica , Administração Intravenosa , Idoso , Povo Asiático , Biomarcadores/sangue , China , Feminino , Fibrinolíticos/efeitos adversos , Humanos , Hemorragias Intracranianas/sangue , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/enzimologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/etnologia , Terapia Trombolítica/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
Multidrug resistance protein 3 (MRP3), encoded by ABCC3, is an ATP-dependent efflux pump mediating the transport of many drugs, implicated in clopidogrel resistance. This study enrolled 87 ischemic stroke patients with CYP2C1 9*1/*1 genotype, who received clopidogrel (75 mg/day) for at least 5 days before discharge. The maximum platelet aggregation (MPA) was measured by light transmittance aggregometry (LTA) to assess platelet function. Whole blood samples were obtained to evaluate the ABCC3 promoter methylation and mRNA expression of ABCC3. Pyrosequencing was carried out to investigate ABCC3 methylation and ABCC3 mRNA expression was evaluated by qPCR. The ABCC3 methylation was neither significantly different among the four MPA quartile groups (P = 0.275) nor independently associated with MPA values (R = 0.100, P = 0.358). However, the ABCC3 promoter methylation status in 87 clinical samples from patients correlated inversely with the expression of ABCC3 (R = - 0.854, P < 0.001). In addition, the ABCC3 expression was neither significantly different among the four quartile groups (P = 0.499) nor independently associated with MPA values (R = 0.060, P = 0.582). ABCC3 promoter methylation does not seem to exhibit any impact on MPA and clopidogrel response at all.
Assuntos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Inibidores da Agregação Plaquetária/uso terapêutico , Regiões Promotoras Genéticas , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/genética , Ticlopidina/análogos & derivados , Idoso , Povo Asiático , Clopidogrel , Citocromo P-450 CYP2C19/biossíntese , Citocromo P-450 CYP2C19/metabolismo , Metilação de DNA , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ticlopidina/uso terapêuticoRESUMO
PURPOSE: The motor symptoms (MS) of Parkinson's disease (PD) have been affecting the quality of life in patients. In clinical practice, most patients with PD report that MS are more severe in winter than in summer, and hyperthermic baths (HTB) could temporarily improve MS. The study aimed to evaluate the effects of seasonal variation and aquatic thermal environment of HTB on the MS of PD. PATIENTS AND METHODS: A cross-sectional study of 203 Chinese Han patients was performed. Univariate and multivariate analyses were performed to analyze seasonal variation in MS relative to baseline data (sex, age at onset, duration, season of birth, Hoehn and Yahr stage, family history, levodopa equivalent dose, and the effect of HTB on MS). Ten subjects participated in the HTB study, and one patient dropped out. The paired Wilcoxon rank test was used to assess the differences in the Movement Disorder Society-United Parkinson's disease Rating Scale (MDS-UPDRS) part III motor examination total scores and the modified Webster Symptoms Score between non-HTB and before HTB and between non-HTB and after HTB. RESULTS: The improvement of MS after HTB was an independent risk factor for seasonal variation in MS (OR, 25.203; 95% CI, 10.951-58.006; p = .000). Patients with PD had significant improvements in the MDS-UPDRS part III motor examination total scores, especially in bradykinesia (p = .043), rigidity (p = .008), posture (p = .038), and rest tremor amplitude (p = .047). CONCLUSION: Seasonal variation in temperature and water temperature of HTB may affect MS in some patients with PD. Simple HTB could be recommended as physiotherapy for patients with PD who report temperature-sensitive MS.
Assuntos
Doença de Parkinson , Salicilatos , Humanos , Estudos Transversais , Doença de Parkinson/tratamento farmacológico , Projetos Piloto , Qualidade de Vida , TemperaturaRESUMO
Purpose: Acute ischemic stroke (AIS) has seriously threatened people's health worldwide and there is an urge need for early diagnosis and effective treatment of AIS. This research intended to clarify the regulatory role of circ_0008146/miR-342-5p/ACSL4 axis in AIS. Methods: High-throughput small RNA sequencing analysis was adapted to identify differentially expressed miRNAs between the AIS and control group. The circ_0008146, miR-342-5p, and ACSL4 levels were detected by qRT-PCR. Middle cerebral artery occlusion/reperfusion (MCAO/R) models were constructed in C57BL/6J mice. Assay kits were used to determine Fe2+ levels and a battery of oxidative stress and lipid peroxidation indicators, including ROS, MDA, LPO, SOD and GSH/GSSG ratio. The protein levels of ACSL4 were measured by Western blot. The behavioral function was assessed using neurobehavioral tests. TTC staining was employed to visualize infarction size. Nissl staining was adapted to detect histopathological changes. Receiver operating characteristic curve and correlation analysis were applied to investigate the clinical value and association of miR-342-5p and ACSL4. Results: A total of 44 AIS patients and 49 healthy controls were enrolled in our study. The small RNA sequencing unveiled a significant decrease in miR-342-5p levels in AIS patients. MiR-342-5p inhibited oxidative stress and RSL3-induced ferroptosis after cerebral ischemic/reperfusion injury in vivo by targeting ferroptosis-related gene ACSL4. Circ_0008146 acted as a sponge of miR-342-5p, and overexpression of circ_0008146 increased neurological deficits and brain injury in mice. Circ_0008146 contributed to ferroptosis in cerebral infarction via sponging miR-342-5p to regulate ACSL4. Plasma miR-342-5p and ACSL4 demonstrated significant correlation and good diagnostic value for AIS patients. Conclusion: This study provides the first in vivo evidence to show that circ_0008146 exacerbates neuronal ferroptosis after AIS via the miR-342-5p/ACSL4 axis. Furthermore, miR-342-5p/ACSL4 axis holds promise as a viable therapeutic target and practical biomarkers for AIS patients.