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Caffeine, a nonselective adenosine receptor antagonist, is the major component of coffee and the most consumed psychostimulant at nontoxic doses in the world. It has been identified that caffeine consumption reduces the risk of several neurological diseases. However, the mechanisms by which it impacts the pathophysiology of neurological diseases remain to be elucidated. In this study, we investigated whether caffeine exerts anti-inflammatory effects on lipopolysaccharide (LPS)-induced inflammation and depression in vivo and explored the potential mechanism of caffeine through LPS-induced brain injury. Adult male Sprague-Dawley (SD) rats were intraperitoneal injected with various concentrations of LPS to induce the neuroinflammation and depressive-like behavior. Then SD rats were treated with caffeine in the presence or absence of LPS. Open-filed and closed-field tests were applied to detect the behaviors of SD rats, while western blot was performed to measure the phosphorylation level of protein kinase B (p-AKT) and nuclear factor κB (NF-κB) in the cortex after caffeine was orally administered. Our findings indicated that caffeine markedly improved the neuroinflammation and depressive-like behavior of LPS-treated SD rats. Mechanistic investigations demonstrated that caffeine down-regulated the expression of p-AKT and NF-κB in LPS-induced SD rats cortex. Taken together, these results indicated that caffeine, a potential agent for preventing inflammatory diseases, may suppress LPS-induced inflammatory and depressive responses by regulating AKT phosphorylation and NF-κB.
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Cafeína , Depressão , Lipopolissacarídeos , NF-kappa B , Doenças Neuroinflamatórias , Proteínas Proto-Oncogênicas c-akt , Ratos Sprague-Dawley , Animais , NF-kappa B/metabolismo , Masculino , Cafeína/farmacologia , Cafeína/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Depressão/tratamento farmacológico , Depressão/induzido quimicamente , Depressão/metabolismo , Ratos , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/induzido quimicamente , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Fosforilação/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Inflamação/induzido quimicamenteRESUMO
BACKGROUND: Long noncoding RNA (lncRNA) and mRNA profiles in leukocytes have shown potential as biomarkers for acute ischemic stroke (AIS). This study aimed to identify altered lncRNA and target mRNA profiles in peripheral blood leukocytes as biomarkers and to assess the diagnostic value and association with AIS prognosis. METHODS AND RESULTS: Differentially expressed lncRNAs (DElncRNAs) and differentially expressed target mRNAs (DEmRNAs) were screened by RNA sequencing in the discovery set, which consisted of 10 patients with AIS and 20 controls. Validation sets consisted of a multicenter (311 AIS versus 303 controls) and a nested case-control study (351 AIS versus 352 controls). The discriminative value of DElncRNAs and DEmRNAs added to the traditional risk factors was estimated with the area under the curve. NAMPT-AS, FARP1-AS1, FTH1, and NAMPT were identified in the multicenter case-control study (P<0.05). LncRNA NAMPT-AS was associated with cis-target mRNA NAMPT and trans-target mRNA FTH1 in all validation sets (P<0.001). Similarly, AIS cases exhibited upregulated lncRNA FARP-AS1 and FTH1 expression (P<0.001) in the nested case-control study (P<0.001). Furthermore, lncRNA FARP1-AS1 expression was upregulated in AIS patients at discharge with an unfavorable outcome (P<0.001). Positive correlations were found between NAMPT expression level and NIHSS scores of AIS patients (P<0.05). Adding 2 lncRNAs and 2 target mRNAs to the traditional risk factor model improved area under the curve by 22.8% and 5.2% in the multicenter and the nested case-control studies, respectively. CONCLUSIONS: lncRNA NAMPT-AS and FARP1-AS1 have potential as diagnostic biomarkers for AIS and exhibit good performance when combined with target mRNA NAMPT and FTH1.
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Biomarcadores , AVC Isquêmico , Leucócitos , RNA Longo não Codificante , RNA Mensageiro , Humanos , RNA Longo não Codificante/sangue , RNA Longo não Codificante/genética , Masculino , Feminino , AVC Isquêmico/genética , AVC Isquêmico/diagnóstico , AVC Isquêmico/sangue , RNA Mensageiro/sangue , RNA Mensageiro/genética , Pessoa de Meia-Idade , Estudos de Casos e Controles , Prognóstico , Leucócitos/metabolismo , Idoso , Biomarcadores/sangue , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/sangue , Citocinas/sangue , Citocinas/genética , Reprodutibilidade dos TestesRESUMO
OBJECTIVE: To delve into the underlying mechanism of Salidroside (Sal) on the improvement of cognitive function in Parkinson's Disease (PD). METHODS: The experimental mice were divided into Control group, Model group [injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)], and Model+Sal (low concentration, high concentration) group. Mouse hippocampal tissues were extracted for RNA sequencing to obtain the core pathway and core gene. Mouse plasma was prepared and analyzed by LC-MS to obtain differential metabolites. In vitro experiments were verified by immunofluorescence and lentiviral transduction. RESULTS: ELISA signaled that Sal facilitated the reduction of neuronal damage and inflammatory reaction in mice. MPTP_Sal_Low and MPTP_Sal_High groups had high levels of glial cell derived neurotrophie factor (GDNF) expression. Differentially expressed genes (DEGs) in control group, MPTP group and MPTP_Sal_High group were identified by transcriptomic, which were classified to the mitogen-activated protein kinase (MAPK) signaling pathway, and the core gene Braf was obtained. Metabolomics manifested that the differential metabolites involved DL-tyrosine, adenosine, phosphoenolpyruvate, and L-tryptophan. In vitro experiments verified that Sal treatment inhibited the up-regulation of p-p38, p-c-Jun N-terminal kinase (JNK), and p-extracellular signal-regulated kinase (ERK) expression, and growth of neuronal protrusions. The OE-Braf group showed a significant up-regulation of the GDNF expression, a decrease in the expression of p-p38, p-JNK, and p-ERK, and a significant growth of neuronal protrusions. CONCLUSION: Sal may exert its effects in PD through the Braf-mediated MAPK signaling pathway, which can increase GDNF expression and promote neuronal protrusion growth for the protection of neurological function and the improvement of cognitive function.
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Cognição , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Glucosídeos , Sistema de Sinalização das MAP Quinases , Fenóis , Proteínas Proto-Oncogênicas B-raf , Animais , Masculino , Camundongos , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Glucosídeos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Fenóis/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Objective.Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder in children. While numerous intelligent methods are applied for its subjective diagnosis, they seldom consider the consistency problem of ADHD biomarkers. In practice, these data-driven approaches lead to varying learned features for ADHD classification across diverse ADHD datasets. This phenomenon significantly undermines the reliability of identified biomarkers and hampers the interpretability of these methods.Approach.In this study, we propose a cross-dataset feature selection (FS) module using a grouped SVM-based recursive feature elimination approach (G-SVM-RFE) to enhance biomarker consistency across multiple datasets. Additionally, we employ connectome gradient data for ADHD classification. In details, we introduce the G-SVM-RFE method to effectively concentrate gradient components within a few brain regions, thereby increasing the likelihood of identifying these regions as ADHD biomarkers. The cross-dataset FS module is integrated into an existing binary hypothesis testing (BHT) framework. This module utilizes external datasets to identify global regions that yield stable biomarkers. Meanwhile, given a dataset which waits for implementing the classification task as local dataset, we learn its own specific regions to further improve the performance of accuracy on this dataset.Main results.By employing this module, our experiments achieve an average accuracy of 96.7% on diverse datasets. Importantly, the discriminative gradient components primarily originate from the global regions, providing evidence for the significance of these regions. We further identify regions with the high appearance frequencies as biomarkers, where all the used global regions and one local region are recognized.Significance.These biomarkers align with existing research on impaired brain regions in children with ADHD. Thus, our method demonstrates its validity by providing enhanced biological explanations derived from ADHD mechanisms.
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Transtorno do Deficit de Atenção com Hiperatividade , Biomarcadores , Máquina de Vetores de Suporte , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/classificação , Humanos , Biomarcadores/análise , Criança , Masculino , Feminino , Conectoma/métodos , Encéfalo/metabolismo , Bases de Dados Factuais , Reprodutibilidade dos TestesRESUMO
Obesity has reached pandemic proportions and is a risk factor for neurodegenerative diseases, including Alzheimer's disease. Chronic inflammation is common in obese patients, but the mechanism between inflammation and cognitive impairment in obesity remains unclear. Accumulative evidence shows that protein-tyrosine phosphatase 1B (PTP1B), a neuroinflammatory and negative synaptic regulator, is involved in the pathogenesis of neurodegenerative processes. We investigated the causal role of PTP1B in obesity-induced cognitive impairment and the beneficial effect of PTP1B inhibitors in counteracting impairments of cognition, neural morphology, and signaling. We showed that obese individuals had negative relationship between serum PTP1B levels and cognitive function. Furthermore, the PTP1B level in the forebrain increased in patients with neurodegenerative diseases and obese cognitive impairment mice with the expansion of white matter, neuroinflammation and brain atrophy. PTP1B globally or forebrain-specific knockout mice on an obesogenic high-fat diet showed enhanced cognition and improved synaptic ultrastructure and proteins in the forebrain. Specifically, deleting PTP1B in leptin receptor-expressing cells improved leptin synaptic signaling and increased BDNF expression in the forebrain of obese mice. Importantly, we found that various PTP1B allosteric inhibitors (e.g., MSI-1436, well-tolerated in Phase 1 and 1b clinical trials for obesity and type II diabetes) prevented these alterations, including improving cognition, neurite outgrowth, leptin synaptic signaling and BDNF in both obese cognitive impairment mice and a neural cell model of PTP1B overexpression. These findings suggest that increased forebrain PTP1B is associated with cognitive decline in obesity, whereas inhibition of PTP1B could be a promising strategy for preventing neurodegeneration induced by obesity.
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Doença de Alzheimer , Disfunção Cognitiva , Diabetes Mellitus Tipo 2 , Animais , Humanos , Camundongos , Fator Neurotrófico Derivado do Encéfalo , Inflamação , Leptina , Obesidade/complicaçõesRESUMO
JOURNAL/nrgr/04.03/01300535-202409000-00042/figure1/v/2024-01-16T170235Z/r/image-tiff Parkinson's disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction. Gastrointestinal dysfunction can precede the onset of motor symptoms by several years. Gut microbiota dysbiosis is involved in the pathogenesis of Parkinson's disease, whether it plays a causal role in motor dysfunction, and the mechanism underlying this potential effect, remain unknown. CCAAT/enhancer binding protein ß/asparagine endopeptidase (C/EBPß/AEP) signaling, activated by bacterial endotoxin, can promote α-synuclein transcription, thereby contributing to Parkinson's disease pathology. In this study, we aimed to investigate the role of the gut microbiota in C/EBPß/AEP signaling, α-synuclein-related pathology, and motor symptoms using a rotenone-induced mouse model of Parkinson's disease combined with antibiotic-induced microbiome depletion and fecal microbiota transplantation. We found that rotenone administration resulted in gut microbiota dysbiosis and perturbation of the intestinal barrier, as well as activation of the C/EBP/AEP pathway, α-synuclein aggregation, and tyrosine hydroxylase-positive neuron loss in the substantia nigra in mice with motor deficits. However, treatment with rotenone did not have any of these adverse effects in mice whose gut microbiota was depleted by pretreatment with antibiotics. Importantly, we found that transplanting gut microbiota derived from mice treated with rotenone induced motor deficits, intestinal inflammation, and endotoxemia. Transplantation of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits, intestinal inflammation, endotoxemia, and intestinal barrier impairment. These results highlight the vital role that gut microbiota dysbiosis plays in inducing motor deficits, C/EBPß/AEP signaling activation, and α-synuclein-related pathology in a rotenone-induced mouse model of Parkinson's disease. Additionally, our findings suggest that supplementing with healthy microbiota may be a safe and effective treatment that could help ameliorate the progression of motor deficits in patients with Parkinson's disease.
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Pyroptosis, an inflammatory and programmed cell death process, has been controversial in its role in tumor immunity. However, as the first molecule in the gasdermin family, the mechanism of GSDMA in glioma growth is not well understood. We identified the differentially expressed gene GSDMA from Treg cells-related genes using the TCGA database. The biological functions of GSDMA and the relationship between GSDMA expression and tumor immune cell infiltration and cancer patient survival were investigated using open-source databases and platforms. Additionally, flow cytometry analysis was used to examine the effect of GSDMA on tumor immune cell infiltration. Our study showed that GSDMA expression played an important role in immune evasion in glioma. Patients with high GSDMA expression had a worse prognosis. In vivo studies demonstrated that GSDMA knockdown could enhance the infiltration level of CD8+ T cells. High GSDMA expression was also positively correlated with poor anti-PD-L1 treatment outcomes in GBM patients, suggesting that GSDMA may be a potential biomarker that should be considered in combination with anti-PD-L1 therapy for glioma patients. In conclusion, our study demonstrates that high GSDMA expression in gliomas is associated with immune-infiltrating cells CD8+ T cells and Treg cells, and indicates a worse prognosis in glioma. Therefore, GSDMA may serve as a therapeutic target for glioma progression and should be applied in immunotherapy for glioma patients.
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Neoplasias Encefálicas , Glioma , Humanos , Linfócitos T CD8-Positivos , Evasão Tumoral , Piroptose , Glioma/patologia , Resultado do Tratamento , Microambiente Tumoral , Neoplasias Encefálicas/patologia , Proteínas Citotóxicas Formadoras de Poros/farmacologiaRESUMO
Alzheimer's disease (AD) is a severe neurodegenerative condition characterized by inflammation, beta-amyloid (Aß) plaques, and neurodegeneration, which currently lack effective treatments. Chiral nanomaterials have emerged as a promising option for treating neurodegenerative disorders due to their high biocompatibility, strong sustained release ability, and specific enantiomer selectivity. The development of a stimulus-responsive chiral nanomaterial, UiO-66-NH2 @l-MoS2 QDs@PA-Ni (MSP-U), for the treatment of AD is reported. MSP-U is found to stimulate neural stem cell (NSCs) differentiation, promote in situ hydrogen (H2 ) production, and clear Aß plaques. l-MoS2 QDs modified with l-Cysteine (l-Cys) effectively enhance the differentiation of NSCs into neurons through circularly polarized near-infrared radiation. Doped-phytic acid nickel (PA-Ni) improves the activity of l-MoS2 QDs in scavenging reactive oxygen species at the lesion site via photocatalytic H2 production. Loading l-MoS2 QDs with UiO-66 type metal oxide suppresses electron-hole recombination effect, thereby achieving rapid charge separation and improving transport of photogenerated electrons, leading to significantly improved H2 production efficiency. The photothermal effect of MSP-U also clears the generated Aß plaques. In vivo evaluations show that MSP-U improves spatial cognition and memory, suggesting a promising potential candidate for the treatment of AD using chiral nanomaterials.
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Doença de Alzheimer , Ácidos Ftálicos , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Molibdênio/farmacologia , Peptídeos beta-Amiloides/metabolismo , CogniçãoRESUMO
The pathological hallmark of Parkinson's disease (PD) is the intraneuronal accumulation of misfolded alpha-synuclein (termed Lewy bodies) in dopaminergic neurons of substantia nigra par compacta (SNc). It is assumed that the α-syn pathology is induced by gastrointestinal inflammation and then transfers to the brain by the gut-brain axis. Therefore, the relationship between gastrointestinal inflammation and α-syn pathology leading to PD remains to be investigated. In our study, rotenone (ROT) oral administration induces gastrointestinal tract (GIT) inflammation in mice. In addition, we used pseudorabies virus (PRV) for tracing studies and performed behavioral testing. We observed that ROT treatments enhance macrophage activation, inflammatory mediator expression, and α-syn pathology in the GIT 6-week post-treatment (P6). Moreover, pathological α-syn was localized with IL-1R1 positive neural cells in GIT. In line with these findings, we also find pS129-α-syn signals in the dorsal motor nucleus of the vagus (DMV) and tyrosine hydroxylase in the nigral-striatum dynamically change from 3-week post-treatment (P3) to P6. Following that, pS129-α-syn was dominant in the enteric neural cell, DMV, and SNc, accompanied by microglial activation, and these phenotypes were absent in IL-1R1r/r mice. These data suggest that IL-1ß/IL-1R1-dependent inflammation of GIT can induce α-syn pathology, which then propagates to the DMV and SNc, resulting in PD.
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Doença de Parkinson , alfa-Sinucleína , Animais , Camundongos , alfa-Sinucleína/metabolismo , Encéfalo/metabolismo , Neurônios Dopaminérgicos/metabolismo , Trato Gastrointestinal/metabolismo , Corpos de Lewy/metabolismo , Doença de Parkinson/metabolismoRESUMO
Importance: Recombinant human prourokinase (rhPro-UK) is a thrombolytic agent that has shown promising findings in a phase 2 clinical trial in patients with acute ischemic stroke (AIS). Objective: To evaluate the efficacy and safety of rhPro-UK thrombolysis within 4.5 hours of symptom onset in patients with AIS. Design, Setting, and Participants: This randomized, alteplase-controlled, open-label, phase 3 clinical trial was conducted from May 2018 to May 2020 at 35 medical centers in China. A total of 684 patients were screened and 674 patients were enrolled. Included patients were aged 18 to 80 years with a diagnosis of AIS and received treatment within 4.5 hours of stroke onset. Data were analyzed from June to October 2020. Interventions: Eligible patients were randomly assigned (1:1) to receive intravenous rhPro-UK or alteplase. Main Outcomes and Measures: The primary objective was to assess whether rhPro-UK was noninferior to alteplase. The noninferiority margin was a between-group difference of less than 10%. The primary outcome was a modified Rankin Scale score of 0 to 1 at 90 days. Results: Among 663 patients in the modified intention-to-treat population (mean [SD] age, 61.00 [10.20] years; 161 females [24.3%]), there were 330 patients in the rhPro-UK group and 333 patients in the alteplase group. The median (IQR) baseline National Institutes of Health Stroke Scale score was 6.00 (5.00-9.00). There were 23 deaths, and 619 patients (93.4%) completed the 3-month follow-up. The primary outcome occurred in 215 patients (65.2%) in the rhPro-UK group and 214 patients (64.3%) in the alteplase group (risk difference, 0.89; 95.4% CI, -6.52 to 8.29). Symptomatic intracerebral hemorrhage occurred in 5 patients (1.5%) in the rhPro-UK group and 6 patients (1.8%) in the alteplase group (P > .99). Systemic bleeding within 90 days occurred more frequently in the alteplase group (141 patients [42.2%]) than the rhPro-UK group (85 patients [25.8%]) (P < .001). By 90 days, 5 thrombolysis-related deaths each had occurred in the rhPro-UK group (1.5%) and alteplase group (1.5%) (P > .99). Conclusions and Relevance: This study found that intravenous rhPro-UK within 4.5 hours of AIS onset was noninferior to alteplase. The rhPro-UK group showed a similar rate of symptomatic ICH but fewer cases of systemic bleeding than the alteplase group. Trial Registration: ClinicalTrials.gov Identifier: NCT03541668.
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AVC Isquêmico , Acidente Vascular Cerebral , Estados Unidos , Feminino , Humanos , Pessoa de Meia-Idade , Ativador de Plasminogênio Tecidual , Fibrinolíticos , Hemorragia CerebralRESUMO
Background: Thrombospondin Type 1 Domain Containing Protein 1 (THSD1) has been suggested to be a new regulator of endothelial barrier function in the angiogenesis process, preserving vascular integrity. We sought to characterize the association of THSD1 genetic variants and mRNA expression with the risk of hemorrhagic stroke (HS) with population-based evidence. Methods: A case-control study was conducted with 843 HS cases and 1,400 healthy controls. A cohort study enrolled 4,080 participants free of stroke at baseline in 2009 and followed up to 2022. A synonymous variant, the main tag SNP rs3803264 of the THSD1 gene, was genotyped in all subjects, and peripheral leukocyte THSD1 mRNA expression was detected using RT-qPCR in 57 HS cases and 119 controls. Results: In the case-control study, rs3803264 AG/GG variations are associated with a decreased risk of HS with odd ratio (OR) and 95% confidence interval (CI) of the dominant model of 0.788 (0.648-0.958), p = 0.017. In addition, rs3803264 and dyslipidemia had a multiplicative interaction [OR (95% CI) = 1.389 (1.032, 1.869), p = 0.030]. In the cohort study, a similar association strength of rs3803264 dominant model and the risk of HS was observed with the incidence rate ratio (IRR) of 0.734 and p-value of 0.383. Furthermore, the risk of HS showed a non-linear as THSD1 mRNA expression increased (p for non-linearity <0.001). For the subjects without hypertension, we observed THSD1 mRNA expression had a negative correlation with systolic blood pressure (SBP; ρ = -0.334, p = 0.022). Conclusion: SNP rs3803264 polymorphisms in THSD1 are associated with the decreased risk of HS and interacted with dyslipidemia, and a non-linear association was observed between THSD1 mRNA expression and the risk of HS.
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OBJECTIVE: Few studies correlated n-terminal pro-brain natriuretic peptide (NT-proBNP) with early neurological deterioration (END) and prognosis of acute ischaemic stroke (AIS) patients with rt-PA intravenous thrombolysis. Therefore this study aimed to investigate the relationship between NT-proBNP and END, and prognosis after intravenous thrombolysis in patients with AIS. METHODS: A total of 325 patients with AIS were enrolled. We performed the natural logarithm transformation on the NT-proBNP [ln(NT-proBNP)]. Univariate and multivariate logistic regression analyses were performed to assess the relationship between ln(NT-proBNP) and END, and prognosis and receiver operating characteristic (ROC) curves were used to show the sensitivity and specificity of NT-proBNP. RESULTS: After thrombolysis, among 325 patients with AIS, 43 patients (13.2%) developed END. In addition, three months follow-up showed a poor prognosis in 98 cases (30.2%) and a good prognosis in 227 cases (69.8%). Multivariate logistic regression analysis showed that ln(NT-proBNP) was an independent risk factor for END (OR = 1.450,95%CI:1.072 ~ 1.963, P = 0.016) and poor prognosis at three months follow-up (OR = 1.767, 95%CI: 1.347 ~ 2.317, P < 0.001) respectively. According to ROC curve analysis, ln(NT-proBNP) (AUC 0.735, 95%CI: 0.674 ~0.796, P < 0.001) had a good predictive value for poor prognosis, with a predictive value of 5.12 and sensitivity and specificity of 79.59% and 60.35% respectively. When combined with NIHSS to predict END(AUC 0.718, 95%CI: 0.631 ~ 0.805, P < 0.001) and poor prognosis(AUC 0.780, 95%CI: 0.724 ~ 0.836, P < 0.001), the predictive value of the model is further improved. CONCLUSION: NT-proBNP is independently associated with END and poor prognosis in patients with AIS following intravenous thrombolysis and has a particular predictive value for END and poor prognosis.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Terapia TrombolíticaRESUMO
BACKGROUND: Inflammation plays a prominent role in the pathogenesis and progression of acute ischemic stroke (AIS). The red blood cell distribution width to platelet ratio (RPR) has been demonstrated as a novel biomarker to indicate the severity of inflammatory reaction. This study aimed to explore the association between RPR before intravenous thrombolysis and early neurological deterioration (END) after thrombolysis in AIS patients. METHODS: AIS patients accepting intravenous thrombolysis were recruited continuously. Postthrombolysis END was defined as death or an increase in the National Institute of Health Stroke Scale (NIHSS) score ≥4 points within 24 h after intravenous thrombolysis compared to the NIHSS score before intravenous thrombolysis. We constructed univariate and multivariate logistic regression analyses to investigate the relationship of RPR before intravenous thrombolysis to postthrombolysis END. Moreover, a receiver operating characteristic (ROC) curve was applied to examine the discriminative utility of RPR before intravenous thrombolysis in predicting postthrombolysis END. RESULTS: A total of 235 AIS patients were included, and 31 (13.19%) subjects underwent postthrombolysis END. The univariate logistic regression analysis demonstrated that RPR before intravenous thrombolysis was significantly related to postthrombolysis END (odds ratio [OR], 2.162; 95% confidence interval [CI], 1.605-2.912; P < 0.001). After adjusting for potential confounding variables with P < 0.15 in the univariate logistic regression analysis, the difference remained statistically significant (OR, 2.031; 95% CI, 1.436-2.873; P < 0.001). Furthermore, an optimal cutoff value of 7.66 for RPR before intravenous thrombolysis in predicting postthrombolysis END was observed in the ROC curve analysis, and the sensitivity and specificity were calculated as 61.3% and 81.9%, respectively (area under the curve [AUC], 0.772; 95% CI, 0.684-0.860; P < 0.001). CONCLUSIONS: RPR before intravenous thrombolysis might be an independent risk factor for postthrombolysis END in AIS patients. Elevated levels of RPR before intravenous thrombolysis may predict postthrombolysis END.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/tratamento farmacológico , AVC Isquêmico/complicações , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/tratamento farmacológico , Terapia Trombolítica/efeitos adversos , EritrócitosRESUMO
Objective: Evidence shows that the impairment of executive function (EF) is mainly attributed to the degeneration of frontal-striatal dopamine pathway. Glial cell line-derived neurotrophic factor (GDNF), as the strongest protective neurotrophic factor for dopaminergic neurons (DANs), may play a role in EF to some extent. This study mainly explored the correlation between serum GDNF concentration and EF performance in Parkinson's disease (PD). Methods: This study recruited 45 healthy volunteers (health control, HC) and 105 PD patients, including 44 with mild cognitive impairment (PD-MCI), 20 with dementia (PD-D), and 20 with normal cognitive function (PD-N). Neuropsychological tests were performed to evaluate EF (working memory, inhibitory control, and cognitive flexibility), attention, language, memory, and visuospatial function. All subjects were tested for serum GDNF and homovanillic acid (HVA) levels by ELISA and LC-ESI-MS/MS, respectively. Results: PD-MCI patients showed impairments in the trail making test (TMT) A (TMT-A), TMT-B, clock drawing test (CDT) and semantic fluency test (SFT), whereas PD-D patients performed worse in most EF tests. With the deterioration of cognitive function, the concentration of serum GDNF and HVA in PD patients decreased. In the PD group, the serum GDNF and HVA levels were negatively correlated with TMT-A (r GDNF = -0.304, P < 0.01; r HVA = -0.334, P < 0.01) and TMT-B (r GDNF = -0.329, P < 0.01; r HVA = -0.323, P < 0.01) scores. Serum GDNF levels were positively correlated with auditory verbal learning test (AVLT-H) (r = 0.252, P < 0.05) and SFT (r = 0.275, P < 0.05) scores. Serum HVA levels showed a positively correlation with digit span test (DST) (r = 0.277, P < 0.01) scores. Stepwise linear regression analysis suggested that serum GDNF and HVA concentrations and UPDRS-III were the influence factors of TMT-A and TMT-B performances in PD patients. Conclusion: The decrease of serum GDNF concentration in PD patients was associated with impaired inhibitory control, cognitive flexibility, and attention performances. The changes of GDNF and HVA might synergistically participate in the occurrence and development of executive dysfunction in PD patients.
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Background and Objectives: Schizophrenia with aggression often has an inflammatory abnormality. The monocyte/high-density lipoprotein ratio (MHR), neutrophil/high-density lipoprotein ratio (NHR), platelet/high-density lipoprotein ratio (PHR) and lymphocyte/high-density lipoprotein ratio (LHR) have lately been examined as novel markers for the inflammatory response. The objective of this study was to assess the relationship between these new inflammatory biomarkers and aggression in schizophrenia patients. Materials and Methods: We enrolled 214 schizophrenia inpatients in our cross-sectional analysis. They were divided into the aggressive group (n = 94) and the non-aggressive group (n = 120) according to the Modified Overt Aggression Scale (MOAS). The severity of schizophrenia was assessed using the Positive and Negative Syndrome Scale (PANSS). The numbers of platelets (PLT), neutrophils (NEU), lymphocytes (LYM), monocytes (MON) and the high-density lipoprotein (HDL) content from subjects were recorded. The NHR, PHR, MHR and LHR were calculated. We analyzed the differences between those indexes in these two groups, and further searched for the correlation between inflammatory markers and aggression. Results: Patients with aggression had higher positive symptom scores (p = 0.002). The values of PLT, MON, MHR and PHR in the aggressive group were considerably higher (p < 0.05). The NHR (r = 0.289, p < 0.01), LHR (r = 0.213, p < 0.05) and MHR (r = 0.238, p < 0.05) values of aggressive schizophrenia patients were positively correlated with the total weighted scores of the MOAS. A higher MHR (ß = 1.529, OR = 4.616, p = 0.026) and positive symptom scores (ß = 0.071, OR = 1.047, p = 0.007) were significant predictors of aggression in schizophrenia patients. Conclusions: The MHR and the positive symptom scores may be predictors of aggressive behavior in schizophrenia patients. The MHR, a cheap and simple test, may be useful as a clinical tool for risk stratification, and it may direct doctors' prevention and treatment plans in the course of ordinary clinical care.
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Lipoproteínas HDL , Esquizofrenia , Humanos , Monócitos , HDL-Colesterol , Estudos Transversais , Esquizofrenia/complicações , Biomarcadores , Estudos RetrospectivosRESUMO
Background: Depression, one of the most frequent complications after stroke, increases the disease's burden and physical disability. Poststroke depression (PSD) is a multifactorial disease with genetic, environmental and biological factors involved in its occurrence. Genetic studies on PSD to date have mainly focused on the monoamine system and brain-derived neurotrophic factors. However, understanding is still limited about the influence of the single nucleotide polymorphism (SNP) of other neurotrophic factors on PSD. Aims: The present study aimed to investigate the relationship between seven vascular endothelial growth factor (VEGF) family gene variants that occur with PSD. Methods: A multicentre candidate gene study from five hospitals in Jiangsu Province from June 2013 to December 2014 involved 121 patients with PSD and 131 patients with non-PSD. Demographic characteristics and neuropsychological assessments were collected. The χ2 test was used to evaluate categorical variables, while the independent t-test was applied to continuous variables. SNPs in seven genes (VEGFA, VEGFB, KDR, FLT-1, IGF-1, IGF-1R and PlGF) were genotyped. Single-marker association for PSD was analysed by χ2 tests and logistic regression using SPSS and PLINK software. Results: Patients with PSD included more women and those with lower education levels, lower body mass indexes, lower Mini-Mental State Examination scores, and higher scores on the 17-item Hamilton Depression Rating Scale than non-PSD patients. Ninety-two SNPs with seven genes were genotyped and passed quality control. The rs7692791 CC genotypes, the C allele of KDR and the rs9282715 T allele of IGF-1R increased the risk for PSD (χ2=7.881, p=0.019; χ2=4.259, p=0.039; χ2=4.222, p=0.040, respectively). In addition, the SNP rs7692791 of KDR was significantly associated with PSD by the logistic regression of an additive model (p=0.015, OR=9.584, 95% CI: 1.549 to 59.31). Conclusions: Patients with rs7692791 C allele carriers or the CC genotype of KDR and the rs9282715 T allele of IGF-1R may have PSD susceptibility. Findings such as these may help clinicians to identify the high-risk population for PSD earlier and, thus, enable them to provide more timely interventions. Trial registration number: ChiCTR-OCH-13003133.
RESUMO
Sleep disturbances are the most prevalent non-motor symptoms in the preclinical stage of Parkinson's disease (PD). Adenosine, glial-derived neurotrophic factor (GDNF), and associated neurotransmitters are crucial in the control of sleep arousal. This study aimed to detect the serum levels of adenosine, GDNF, and associated neurotransmitters and explored their correlations with PD with sleep disorders. Demographic characteristics and clinical information of PD patients and healthy participants were assessed. Serum concentrations of adenosine, GDNF, and related neurotransmitters were detected by ELISA and LC-MS. The correlation between serum levels of adenosine, GDNF, and associated neurotransmitters and sleep disorders was explored using logistic regression. PD patients with sleep disorders had higher scores of HAMA, HAMD, ESS, UPDRS-III, and H-Y stage. Lower levels of adenosine, GDNF, and γ-GABA were observed in PD patients who had sleep problems. Logistic regression analysis showed adenosine and GDNF were protective factors for preventing sleep disorders. Adenosine combined with GDNF had a higher diagnostic efficiency in predicting PD with sleep disorders by ROC analysis. This study revealed low adenosine and GDNF levels may be risk factors for sleep disorders in PD. The decrease of serum adenosine and GDNF levels may contribute to the diagnosis of PD with sleep disturbances.
RESUMO
Obesity is a risk factor for neurodegenerative disease associated with cognitive dysfunction, including Alzheimer's disease. Low-grade inflammation is common in obesity, but the mechanism between inflammation and cognitive impairment in obesity is unclear. Accumulative evidence shows that quinolinic acid (QA), a neuroinflammatory neurotoxin, is involved in the pathogenesis of neurodegenerative processes. We investigated the role of QA in obesity-induced cognitive impairment and the beneficial effect of butyrate in counteracting impairments of cognition, neural morphology, and signaling. We show that in human obesity, there was a negative relationship between serum QA levels and cognitive function and decreased cortical gray matter. Diet-induced obese mice had increased QA levels in the cortex associated with cognitive impairment. At single-cell resolution, we confirmed that QA impaired neurons, altered the dendritic spine's intracellular signal, and reduced brain-derived neurotrophic factor (BDNF) levels. Using Caenorhabditis elegans models, QA induced dopaminergic and glutamatergic neuron lesions. Importantly, the gut microbiota metabolite butyrate was able to counteract those alterations, including cognitive impairment, neuronal spine loss, and BDNF reduction in both in vivo and in vitro studies. Finally, we show that butyrate prevented QA-induced BDNF reductions by epigenetic enhancement of H3K18ac at BDNF promoters. These findings suggest that increased QA is associated with cognitive decline in obesity and that butyrate alleviates neurodegeneration.