RESUMO
High-altitude cerebral edema (HACE) is a severe neurological condition that can occur at high altitudes. It is characterized by the accumulation of fluid in the brain, leading to a range of symptoms, including severe headache, confusion, loss of coordination, and even coma and death. Exosomes play a crucial role in intercellular communication, and their contents have been found to change in various diseases. This study analyzed the metabolomic characteristics of blood exosomes from HACE patients compared to those from healthy controls (HCs) with the aim of identifying specific metabolites or metabolic pathways associated with the development of HACE conditions. A total of 21 HACE patients and 21 healthy controls were recruited for this study. Comprehensive metabolomic profiling of the serum exosome samples was conducted using ultraperformance liquid chromatography-tandem mass spectrometry (UPLCâMS/MS). Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed to identify the metabolic pathways affected in HACE patients. Twenty-six metabolites, including ( +)-camphoric acid, choline, adenosine, adenosine 5'-monophosphate, deoxyguanosine 5'-monophosphate, guanosine, and hypoxanthine-9-ß-D-arabinofuranoside, among others, exhibited significant changes in expression in HACE patients compared to HCs. Additionally, these differentially abundant metabolites were confirmed to be potential biomarkers for HACE. KEGG pathway enrichment analysis revealed several pathways that significantly affect energy metabolism regulation (such as purine metabolism, thermogenesis, and nucleotide metabolism), estrogen-related pathways (the estrogen signaling pathway, GnRH signaling pathway, and GnRH pathway), cyclic nucleotide signaling pathways (the cGMP-PKG signaling pathway and cAMP signaling pathway), and hormone synthesis and secretion pathways (renin secretion, parathyroid hormone synthesis, secretion and action, and aldosterone synthesis and secretion). In patients with HACE, adenosine, guanosine, and hypoxanthine-9-ß-D-arabinofuranoside were negatively correlated with height. Deoxyguanosine 5'-monophosphate is negatively correlated with weight and BMI. Additionally, LPE (18:2/0:0) and pregnanetriol were positively correlated with age. This study identified potential biomarkers for HACE and provided valuable insights into the underlying metabolic mechanisms of this disease. These findings may lead to potential targets for early diagnosis and therapeutic intervention in HACE patients.
Assuntos
Biomarcadores , Edema Encefálico , Exossomos , Metabolômica , Humanos , Masculino , Feminino , Adulto , Metabolômica/métodos , Edema Encefálico/sangue , Edema Encefálico/metabolismo , Edema Encefálico/etiologia , Biomarcadores/sangue , Exossomos/metabolismo , Espectrometria de Massas em Tandem , Doença da Altitude/sangue , Doença da Altitude/metabolismo , Pessoa de Meia-Idade , Redes e Vias Metabólicas , Metaboloma , Estudos de Casos e Controles , AltitudeRESUMO
BACKGROUND AND HYPOTHESIS: This study investigated the role of the medial prefrontal cortex (mPFC)-basolateral amygdala (BLA) pathway in schizophrenia (SCZ)-related cognitive impairments using various techniques. STUDY DESIGN: This study utilized clinical scales, magnetic resonance imaging, single-cell RNA sequencing, and optogenetics to investigate the mPFC-BLA pathway in SCZ patients. In the mouse model, 6-week-old methylazoxymethanol acetate-induced mice demonstrated significant cognitive deficits, which were addressed through stereotaxic injections of an adeno-associated viral vector to unveil the neural connection between the mPFC and BLA. STUDY RESULTS: Significant disparities in brain volume and neural activity, particularly in the dorsolateral prefrontal cortex (DLPFC) and BLA regions, were found between SCZ patients and healthy controls. Additionally, we observed correlations indicating that reduced volumes of the DLPFC and BLA were associated with lower cognitive function scores. Activation of the mPFC-BLA pathway notably improved cognitive performance in the SCZ model mice, with the targeting of excitatory or inhibitory neurons alone failing to replicate this effect. Single-cell transcriptomic profiling revealed gene expression differences in excitatory and inhibitory neurons in the BLA of SCZ model mice. Notably, genes differentially expressed in the BLA of these model mice were also found in the blood exosomes of SCZ patients. CONCLUSIONS: Our research provides a comprehensive understanding of the role of the PFC-BLA pathway in SCZ, underscoring its significance in cognitive impairment and offering novel diagnostic and therapeutic avenues. Additionally, our research highlights the potential of blood exosomal mRNAs as noninvasive biomarkers for SCZ diagnosis, underscoring the clinical feasibility and utility of this method.
Assuntos
Complexo Nuclear Basolateral da Amígdala , Disfunção Cognitiva , Modelos Animais de Doenças , Imageamento por Ressonância Magnética , Córtex Pré-Frontal , Esquizofrenia , Animais , Esquizofrenia/fisiopatologia , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/metabolismo , Camundongos , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/diagnóstico por imagem , Córtex Pré-Frontal/fisiopatologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/diagnóstico por imagem , Masculino , Humanos , Complexo Nuclear Basolateral da Amígdala/fisiopatologia , Complexo Nuclear Basolateral da Amígdala/metabolismo , Complexo Nuclear Basolateral da Amígdala/diagnóstico por imagem , Feminino , Adulto , Vias Neurais/fisiopatologia , Pessoa de Meia-Idade , Optogenética , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: A novel compound Cytisine-N-methylene-(5,7,4'-trihydroxy)- isoflavone (LY01) found in the Sophora alopecuroides L is a neuroprotective agent. However, the effect and potential mechanism of LY01 treatment for ischemic stroke (IS) have not been fully elucidated. AIM OF THE STUDY: The aim of this study is to demonstrate whether LY01 can rescue ischemic stroke-induced brain injury and oxygen-glucose deprivation/reperfusion (OGD/R). RESULTS: Our results show that intragastric administration of LY01 improves ischemic stroke behaviors in mice, as demonstrated by neurological score, infarct volume, cerebral water content, rotarod test for activity. Compared with the model group, the ginkgo biloba extract (EGb) and LY01 reversed the neurological score, infarct volume, cerebral water content, rotarod test in model mice. Further analysis showed that the LY01 rescued oxidative stress in the model mice, which was reflected in the increased levels of catalase, superoxide dismutase, total antioxidant capacity and decreased levels of malondialdehyde in the serum of the model mice. Moreover, the expression of the brain-derived neurotrophic factor brain-derived neurotrophic factor (BDNF), phosphorylated protein kinase B (p-Akt), Bax, Bcl-2, (p)-tropomysin related kinase B (p-Trkb) was restored and the expression of Bax, glial fibrillary acidic protein (GFAP) in the brains of the model mice was inhibited through LY01 treatment. In the polymerase chain reaction (PCR) data, after giving LY01, the expression in the brains of model mice was that, IL-10 increased and IL-1ß, Bax, Bcl-2 decreased. Furthermore, the results indicated that LY01 improved cell viability, reactive oxygen species content, and mitochondrial membrane potential dissipation induced by OGD/R in primary culture of rat cortical neurons. Bax and caspase-3 activity was upregulated compared to the before after treatment with LY01. CONCLUSIONS: Our study suggests that LY01 reversed ischemic stroke by reducing oxidative stress and activating the BDNF-TrkB/Akt pathway and exerted a neuroprotective action against OGD/R injury via attenuation, a novel approach was suggested to treat ischemic stroke. Our observations justify the traditional use of LY01 for a treatment of IS in nervous system.
Assuntos
Alcaloides , Fator Neurotrófico Derivado do Encéfalo , AVC Isquêmico , Fármacos Neuroprotetores , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt , Receptor trkB , Transdução de Sinais , Animais , Estresse Oxidativo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos , Masculino , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/metabolismo , AVC Isquêmico/complicações , AVC Isquêmico/patologia , Transdução de Sinais/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Receptor trkB/metabolismo , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Quinolizinas/farmacologia , Quinolizinas/uso terapêutico , Azocinas/farmacologia , Modelos Animais de Doenças , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Alcaloides QuinolizidínicosRESUMO
Foot electrical stimulation (FES) has been considered as a classic stressor that can disturb homeostasis. Acute anemia was observed in the model induced by FES. The aim of this study was to explore the role of inflammatory cytokines underlying the acute anemia and gastrointestinal (GI) mucosal injury in the FES. Twenty-four male Kunming mice (20 ± 2 g) were randomly divided into control group and experimental group. The mice were placed in a footshock chamber that can generate 0.5 mA electrical impulse periodically for 0.5 h. After the process, red blood cell count, hemoglobin concentration and hematocrit, the levels of corticotropin releasing hormone (CRH) in serum and hypothalamus, and adrenocorticotropic hormone (ACTH) in serum and pituitary were detected separately. In addition, we investigated the expressions of inflammatory cytokines (IL-1, IL-6, TNF-α, iNOS, and IL-10) in the hypothalamus and duodenum by Polymerase Chain Reaction (PCR). Results showed that this FES model induced anemia, increased CRH and ACTH activity in the serum after the FES. Moreover, the expressions of IL-1ß, IL-6, TNF-α, and iNOS were significantly increased following the process, while IL-10 was not activated. These findings suggest that anemia, the inflammatory cytokines in the hypothalamus and duodenum of the mice in the model induced by FES is closely related to GI mucosal injury/bleeding. Taken together, these results underscore the importance of anemia, GI mucosal injury/bleeding and stress, future studies would be needed to translate these findings into the benefit of affected patients.
Assuntos
Anemia/genética , Duodeno/imunologia , Estimulação Elétrica/efeitos adversos , Interleucina-6/genética , Óxido Nítrico Sintase Tipo II/genética , Estresse Fisiológico/imunologia , Fator de Necrose Tumoral alfa/genética , Hormônio Adrenocorticotrópico/genética , Hormônio Adrenocorticotrópico/imunologia , Anemia/etiologia , Anemia/imunologia , Anemia/patologia , Animais , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/imunologia , Duodeno/patologia , Contagem de Eritrócitos , Membro Anterior , Regulação da Expressão Gênica , Hematócrito , Hemoglobinas/imunologia , Hemoglobinas/metabolismo , Membro Posterior , Hipotálamo/imunologia , Hipotálamo/patologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-6/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Masculino , Camundongos , Óxido Nítrico Sintase Tipo II/imunologia , Hipófise/imunologia , Hipófise/patologia , Estresse Fisiológico/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Increasing evidence suggests that abnormal regulation of neurotrophic factors is involved in the etiology and pathogenesis of Autism Spectrum Disorder (ASD). However, clinical data on neurotrophic factor levels in children with ASD were inconsistent. Therefore, we performed a systematic review of peripheral blood neurotrophic factors levels in children with ASD, and quantitatively summarized the clinical data of peripheral blood neurotrophic factors in ASD children and healthy controls. A systematic search of PubMed and Web of Science identified 31 studies with 2627 ASD children and 4418 healthy controls to be included in the meta-analysis. The results of random effect meta-analysis showed that the peripheral blood levels of brain-derived neurotrophic factor (Hedges' g = 0.302; 95% CI = 0.014 to 0.591; P = 0.040) , nerve growth factor (Hedges' g = 0.395; 95% CI = 0.104 to 0.686; P = 0.008) and vascular endothelial growth factor (VEGF) (Hedges' g = 0.097; 95% CI = 0.018 to 0.175; P = 0.016) in children with ASD were significantly higher than that of healthy controls, whereas blood neurotrophin-3 (Hedges' g = - 0.795; 95% CI = - 1.723 to 0.134; P = 0.093) and neurotrophin-4 (Hedges' g = 0.182; 95% CI = - 0.285 to 0.650; P = 0.445) levels did not show significant differences between cases and controls. Taken together, these results clarified circulating neurotrophic factor profile in children with ASD, strengthening clinical evidence of neurotrophic factor aberrations in children with ASD.
Assuntos
Transtorno do Espectro Autista/sangue , Fatores de Crescimento Neural/sangue , Biomarcadores/sangue , Fator Neurotrófico Derivado do Encéfalo/sangue , Estudos de Casos e Controles , Criança , Feminino , Humanos , Masculino , Fator de Crescimento Neural/sangue , Neurotrofina 3/sangue , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
Restraint water-immersion stress (RWIS) consists of psychological and physical stimulation, and it has been utilized in the research of gastric mucosal damage. It has been shown by previous studies that the nucleus raphe magnus (NRM) is closely involved in the gastrointestinal function, but its functions on the stress-induced gastric mucosal injury (SGMI) have not been thoroughly elucidated to date. Consequently, in this research, we aim to measure the expression of astrocytic glial fibrillary acidic protein (GFAP), neuronal c-Fos, and phosphorylation extracellular signal regulated kinase 1/2 (p-ERK1/2) in the process of RWIS with immunohistochemistry and western blot methods. What is more, we detect the relation between astrocytes and neurons throughout the stress procedure and explore the regulation of the ERK1/2 signaling pathway on the activity of astrocytes and neurons after RWIS. The results indicated that all three proteins expression multiplied following peaked 3 h substantially. The SMGI, astrocyte and neuron activity were affected after the astrocytotoxin L-A-aminohexanedioic acid (L-AA) and c-fos antisense oligonucleotide (ASO) injections. After the injection of PD98059, the gastric mucosal injury, astrocyte and neuron activity significantly fell off. These results suggested that RWIS-induced activity of astrocytes and neurons in the NRM may play a significant part in gastric mucosa damage via the ERK1/2 signaling pathway.
Assuntos
Astrócitos/metabolismo , Mucosa Gástrica/fisiopatologia , Sistema de Sinalização das MAP Quinases/fisiologia , Neurônios/metabolismo , Núcleo Magno da Rafe/metabolismo , Animais , Flavonoides/farmacologia , Mucosa Gástrica/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Restrição Física/efeitos adversos , Estresse Psicológico/fisiopatologiaRESUMO
Restraint water-immersion stress (RWIS) is considered to be a compound stress model that includes psychological and physical stimulation and may cause gastric mucosal damage. Studies have shown that locus coeruleus (LC) is involved in the gastrointestinal function, but whether it is involved in RWIS-induced gastric mucosal damage has not yet been reported. Here, we investigated the expression of glial fibrillary acidic protein (GFAP), c-Fos, and phosphorylation extracellular signal regulated kinase 1/2 (p-ERK1/2) in the LC after RWIS using immunocytochemical staining and western blotting in order to explore whether the ERK1/2 signaling pathway interacts with the neuron-astrocyte network in the LC during RWIS and whether it is involved in causing RWIS-induced gastric mucosal damage. Expression of c-Fos, GFAP, and p-ERK1/2 increased significantly following RWIS and peaked at 3â¯h after RWIS. After intracerebroventricular injection of c-Fos antisense oligodeoxynucleotides (ASO) and astrocytic toxin L-a-aminoadipate (L-AA), the gastric mucosal damage and the activation of neurons and astrocytes in the LC significantly decreased. Intracerebroventricular injection of ERK1/2 signaling pathway inhibitor PD98059 suppressed gastric mucosal damage as well as the RWIS-induced activation of neurons and astrocytes in the LC. Activation of LC neurons and astrocytes induced by RWIS through the ERK1/2 signaling pathway may play a critical role in RWIS-induced gastric mucosa damage.