RESUMEN
Glymphatic dysfunction has been correlated with cognitive decline, with a higher choroid plexus volume (CPV) being linked to a slower glymphatic clearance rate. Nevertheless, the interplay between CPV, glymphatic function, and cognitive impairment in white matter hyperintensities (WMHs) has not yet been investigated. In this study, we performed neuropsychological assessment, T1-weighted three-dimensional (3D-T1) images, and diffusion tensor imaging (DTI) in a cohort of 206 WMHs subjects and 43 healthy controls (HCs) to further explore the relationship. The DTI analysis along the perivascular space (DTI-ALPS) index, as a measure of glymphatic function, was calculated based on DTI. Severe WMHs performed significantly worse in information processing speed (IPS) than other three groups, as well as in executive function than HCs and mild WMHs. Additionally, severe WMHs demonstrated lower DTI-ALPS index and higher CPV than HCs and mild WMHs. Moderate WMHs displayed higher CPV than HCs and mild WMHs. Mini-Mental State Examination, IPS, and executive function correlated negatively with CPV but positively with DTI-ALPS index in WMHs patients. Glymphatic function partially mediated the association between CPV and IPS, indicating a potential mechanism for WMHs-related cognitive impairment. CPV may act as a valuable prognostic marker and glymphatic system as a promising therapeutic target for WMHs-related cognitive impairment.
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Plexo Coroideo , Disfunción Cognitiva , Imagen de Difusión Tensora , Sistema Glinfático , Sustancia Blanca , Humanos , Masculino , Femenino , Plexo Coroideo/diagnóstico por imagen , Plexo Coroideo/patología , Plexo Coroideo/fisiopatología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Anciano , Sistema Glinfático/diagnóstico por imagen , Sistema Glinfático/patología , Sistema Glinfático/fisiopatología , Persona de Mediana Edad , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/patología , Pruebas Neuropsicológicas , Imagen por Resonancia Magnética/métodos , Velocidad de ProcesamientoRESUMEN
Growing evidence suggests the involvement of the microbiota-gut-brain axis in cognitive impairment induced by sleep deprivation (SD), however how the microbiota-gut-brain axis work remains elusive. Here, we discovered that chronic SD induced intestinal dysbiosis, activated NLRP3 inflammasome in the colon and brain, destructed intestinal/blood-brain barrier, and impaired cognitive function in mice. Transplantation of "SD microbiota" could almost mimic the pathological and behavioral changes caused by chronic SD. Furthermore, all the behavioral and pathological abnormalities were practically reversed in chronic sleep-deprived NLRP3-/- mice. Regional knockdown NLRP3 expression in the gut and hippocampus, respectively. We observed that down-regulation of NLRP3 in the hippocampus inhibited neuroinflammation, and ameliorated synaptic dysfunction and cognitive impairment induced by chronic SD. More intriguingly, the down-regulation of NLRP3 in the gut protected the intestinal barrier, attenuated the levels of peripheral inflammatory factors, down-regulated the expression of NLRP3 in the brain, and improved cognitive function in chronic SD mice. Our results identified gut microbiota as a driver in chronic SD and highlighted the NLRP3 inflammasome as a key regulator within the microbiota-gut-brain axis.
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Disfunción Cognitiva , Inflamasomas , Ratones , Animales , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Privación de Sueño/complicaciones , Disbiosis/inducido químicamente , Hipocampo/metabolismo , Disfunción Cognitiva/metabolismo , IntestinosRESUMEN
Parkinson's disease (PD) is a progressive neurological disorder that affects millions of people throughout the world. Cuproptosis is a newly discovered form of programmed cell death linked to several neurological disorders. Nevertheless, the precise mechanisms of Cuproptosis-related genes (CRGs) in PD remain unknown. This study investigated immune infiltration and CRG expression profiling in patients with Parkinson's disease and healthy controls. Subsequently, we construct a predictive model based on 5 significant CRGs. The performance of the predictive model was validated by nomograms and external datasets. Additionally, we classified PD patients into two clusters based on CRGs and three gene clusters based on differentially expressed genes (DEG) of CRGs clusters. We further evaluated immunological characterization between the different clusters and created the CRGs scores to quantify CRGs patterns. Finally, we investigate the prediction of CRGs drugs and the ceRNA network, providing new insights into the pathogenesis and management of PD.
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Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/genética , Apoptosis , Expresión Génica , ARN Endógeno CompetitivoRESUMEN
BACKGROUND: Abnormal expression of long noncoding RNAs (lncRNAs) has been reported in the acute stage of acute ischemic stroke (AIS). This study aimed to explore differential lncRNA expression in the subpopulations of peripheral blood mononuclear cells (PBMCs) from AIS patients and further evaluate its underlying mechanisms in stroke-induced immunosuppression. METHODS: We reanalyzed lncRNA microarray data and investigated abnormally expressed lncRNAs in the subpopulations of PBMCs by magnetic cell sorting and real-time quantitative PCR. The potential mechanism of small nucleolar RNA host gene 15 (SNHG15) was explored through in vitro and in vivo approaches. RESULTS: The stroke-induced SNHG15 acted as a checkpoint to inhibit peripheral inflammatory responses. Functional studies showed that SNHG15 promoted M2 macrophage polarization. Mechanistically, SNHG15 expression was dysregulated through the Janus kinase (JAK)-signal transducer and activator of transcription 6 (STAT6) signaling pathway. SNHG15, localized in the cytoplasm, interfered with K63-linked ubiquitination of tumor necrosis factor receptor-associated factor 2 and thereby repressed the activation of mitogen-activated protein kinase and nuclear factor kappa-B signaling pathways and prevented the production of proinflammatory cytokines. Administration of an adenovirus targeting SNHG15 improved stroke-induced immunosuppression in mice. CONCLUSIONS: This study identified SNHG15 as a negative regulator of inflammation in stroke-induced immunosuppression, suggesting it as a novel biomarker and therapeutic target in stroke-associated infection. Trial registration ClinicalTrials.gov NCT04175691. Registered November 25, 2019, https://www.clinicaltrials.gov/ct2/show/NCT04175691 .
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Tolerancia Inmunológica , Inflamación/metabolismo , ARN Largo no Codificante/metabolismo , Accidente Cerebrovascular/metabolismo , Factor 2 Asociado a Receptor de TNF/metabolismo , Citocinas/metabolismo , Humanos , Inflamación/inmunología , Interleucina-4/farmacología , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Monocitos/efectos de los fármacos , Monocitos/metabolismo , ARN Largo no Codificante/genética , Accidente Cerebrovascular/inmunología , Factor 2 Asociado a Receptor de TNF/genética , UbiquitinaciónRESUMEN
BACKGROUND: Inflammation is integral to the pathophysiology of ischemic stroke and a prime target for the development of new stroke therapies. The aim of the present study is to seek out the regulatory mechanism of circCDC14A in neuroinflammatory injury in tMCAO mice. METHODS: The expression level of circCDC14A in peri-infarct cortex and plasma of mice were detected by qPCR. The localization of circCDC14A in peripheral blood cells and peri-infarct cortex of tMCAO mice were explored by in situ hybridization and immunofluorescence colocalization staining. Lentivirus were microinjected into lateral ventricular of brain or injected into tail vein to interfere with the expression of circCDC14A, thus their effects on behavior, morphology, and molecular biology of tMCAO mice were analyzed. RESULTS: The expression of circCDC14A in plasma and peri-infarct cortex of tMCAO mice significantly increased, and circCDC14A was mainly localized in neutrophils peripherally while in astrocytes in peri-infarct cortex centrally. Tail vein injection of lentivirus to interfere with the expression of circCDC14A significantly reduced the infarct volume (P < 0.01) at 72 h after reperfusion and density of activated astrocytes in peri-infarct cortex at 3 days, 5 days and 7 days after tMCAO modeling (all P < 0.0001). Moreover, mNSS (P < 0.0001) and survival rate (P < 0.001) were significantly improved within 7 days in si-circCDC14A group compared to circCon group. Additionally, morphology analysis showed the volume and surface area of each activated astrocytes significantly decreased (P < 0.0001). Quantification analysis measured the percentage of N2 phenotype among infiltrated neutrophils in brain sections and found N2 ratio was significantly higher in si-circCDC14A group compared to circCon group (P < 0.001). CONCLUSION: Knocking down the expression of circCDC14A in peripheral blood cells relieved astrocytes activation in peri-infarct cortex, thereby relieved brain damage in the acute phase of ischemic stroke.
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Encéfalo/metabolismo , Regulación hacia Abajo , Accidente Cerebrovascular Isquémico/genética , ARN Circular/genética , Animales , Astrocitos/metabolismo , Astrocitos/patología , Encéfalo/patología , Modelos Animales de Enfermedad , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Ratones , ARN Circular/metabolismoRESUMEN
Background and Purpose- Circular RNAs (CircRNAs) show promise as stroke biomarkers because of their participation in various pathophysiological processes associated with acute ischemic stroke (AIS) and stability in peripheral blood. Methods- A circRNA microarray was used to identify differentially expressed circulating circRNAs in a discovery cohort (3 versus 3). Validation (36 versus 36) and replication (200 versus 100) were performed in independent cohorts by quantitative polymerase chain reaction. Platelets, lymphocytes, and granulocytes were separated from blood to examine the origins of circRNAs. Results- There were 3 upregulated circRNAs in Chinese population-based AIS patients compared with healthy controls. The combination of 3 circRNAs resulted in an area under the curve of 0.875, corresponding to a specificity of 91% and a sensitivity of 71.5% in AIS diagnosis. Furthermore, the combination of change rate in 3 circRNAs within the first 7 days of treatment showed an area under the curve of 0.960 in predicting stroke outcome. There was significant increase in lymphocytes and granulocytes for circPDS5B (circular RNA PDS5B) and only in granulocytes for circCDC14A (circular RNA CDC14A) in AIS patients compared with healthy controls. Conclusions- Three circRNAs could serve as biomarkers for AIS diagnosis and prediction of stroke outcomes. The elevated levels of circPDS5B and circCDC14A after stroke might be because of increased levels in lymphocytes and granulocytes.
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Isquemia Encefálica , Ácidos Nucleicos Libres de Células/sangre , ARN Circular/sangre , Accidente Cerebrovascular , Regulación hacia Arriba , Enfermedad Aguda , Biomarcadores/sangre , Isquemia Encefálica/sangre , Isquemia Encefálica/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/diagnósticoRESUMEN
Human rho-associated coiled-coil forming kinases (ROCKs) ROCK-I and ROCK-II have been documented as attractive therapeutic targets for cerebrovascular diseases. Although ROCK-I and ROCK-II share a high degree of structural conservation and are both present in classic rho/ROCK signaling pathway, their downstream substrates and pathological functions may be quite different. Selective targeting of the two kinase isoforms with traditional small-molecule inhibitors is a great challenge due to their surprisingly high homology in kinase domain (~90%) and the full identity in kinase active site (100%). Here, instead of developing small-molecule drugs to selectively target the adenosine triphosphate (ATP) site of two isoforms, we attempt to design peptide agents to selectively disrupt the homo-dimerization event of ROCK kinases through their dimerization domains which have a relatively low conservation (~60%). Three helical peptides H1, H2, and H3 are split from the kinase dimerization domain, from which the isolated H2 peptide is found to have the best capability to rebind at the dimerization interface. A simulated annealing (SA) iteration method is used to improve the H2 peptide selectivity between ROCK-I and ROCK-II. The method accepts moderate degradation in peptide affinity in order to maximize the affinity difference between peptide binding to the two isoforms. Consequently, hundreds of parallel SA runs yielded six promising peptide candidates with ROCK-I over ROCK-II (I over II [IoII]) calculated selectivity and four promising peptide candidates with ROCK-II over ROCK-I (II over I [IIoI]) calculated selectivity. Subsequent anisotropy assays confirm that the selectivity values range between 13.2-fold and 83.9-fold for IoII peptides, and between 5.8-fold and 21.2-fold for IIoI peptides, which are considerably increased relative to wild-type H2 peptide (2.6-fold for IoII and 2.0-fold for IIoI). The molecular origin of the designed peptide selectivity is also analyzed at structural level; it is revealed that the peptide residues can be classified into conserved, non-conserved, and others, in which the non-conserved residues play a crucial role in defining peptide selectivity, while conserved residues confer stability to kinase-peptide binding.
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Trastornos Cerebrovasculares/metabolismo , Péptidos/química , Péptidos/uso terapéutico , Isoformas de Proteínas/metabolismo , Quinasas Asociadas a rho/metabolismo , Trastornos Cerebrovasculares/genética , Dimerización , Humanos , Simulación de Dinámica Molecular , Unión Proteica , Isoformas de Proteínas/genética , Estructura Secundaria de Proteína , Quinasas Asociadas a rho/genéticaRESUMEN
BACKGROUND: Stroke-induced immunodeficiency syndrome (SIDS) is regarded as a protective mechanism for secondary inflammatory injury as well as a contributor to infection complications. Although stroke-induced hyperactivation of the sympathetic system is proved to facilitate SIDS, the involved endogenous factors and pathways are largely elusive. In this study, we aim to investigate the function of beta-arrestin-2 (ARRB2) in the sympathetic-mediated SIDS. METHODS: Splenic ARRB2 expression and the sympathetic system activity were detected after establishing transient models of middle cerebral artery occlusion (MCAO). In addition, a correlation between ARRB2 expression and the sympathetic system activity was analyzed using a linear correlation analysis. Any SIDS reflected in monocyte dysfunction was investigated by measuring inflammatory cytokine secretion and neurological deficit scores and infarct volume were tested to assess neurological outcome. Further, ARRB2 expression in the monocytes was knocked down in vitro by siRNAs. Following the stimulation of noradrenaline and lipopolysaccharide, cytokine secretion and the nuclear factor-κB (NF-κB) pathway were evaluated to gain insight into the mechanisms related to the contribution of ARRB2 to adrenergic-induced monocyte dysfunction. RESULTS: Splenic ARRB2 expression was significantly increased after stroke and also showed a significant positive correlation with the sympathetic system activity. Stroke-induced monocyte dysfunction resulted in an increase of the interleukin-10 (IL-10) level as well as a decrease of the interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) levels. Also, blockade of adrenergic-activity significantly reversed these cytokine levels, and blockade of adrenergic-activity improved stroke-induced neurological results. However, the improved neurological results had no significant correlation with ARRB2 expression. Furthermore, the in vitro results showed that the deficiency of ARRB2 dramatically repealed adrenergic-induced monocyte dysfunction and the inhibition of NF-κB signaling phosphorylation activity. CONCLUSIONS: ARRB2 is implicated in the sympathetic-triggered SIDS, in particular, monocyte dysfunction after stroke. Accordingly, ARRB2 may be a promising therapeutic target for the immunological management of stroke in a clinic.
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Regulación de la Expresión Génica/fisiología , Síndromes de Inmunodeficiencia/etiología , Síndromes de Inmunodeficiencia/patología , Infarto de la Arteria Cerebral Media/complicaciones , Sistema Nervioso Simpático/fisiopatología , Arrestina beta 2/metabolismo , Animales , Infarto Encefálico/etiología , Línea Celular Transformada , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Macrófagos , Masculino , Monocitos/metabolismo , Examen Neurológico , Propranolol/farmacología , ARN Mensajero/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Ratas , Ratas Sprague-Dawley , Sistema Nervioso Simpático/inmunología , Transfección , Vasodilatadores/farmacología , Arrestina beta 2/genéticaRESUMEN
Long noncoding RNAs (lncRNAs) have been highlighted to be involved in the pathological process of ischemic stroke (IS). The purpose of the present study was to investigate the expression profile of lncRNAs in peripheral blood mononuclear cells (PBMCs) of acute IS patients and to explore their utility as biomarkers of IS. Distinctive expression patterns of PBMC lncRNAs were identified by an lncRNA microarray and individual quantitative real-time PCR (qRT-PCR) in four independent sets for 206 IS, 179 healthy controls (HCs), and 55 patients with transient ischemic attack (TIA). A biomarker panel (lncRNA-based combination index) was established using logistic regression. LncRNA microarray analysis showed 70 up-regulated and 128 down-regulated lncRNAs in IS patients. Individual qRT-PCR validation demonstrated that three lncRNAs (linc-DHFRL1-4, SNHG15, and linc-FAM98A-3) were significantly up-regulated in IS patients compared with HCs and TIA patients. Longitudinal analysis of lncRNA expression up to 90 days after IS showed that linc-FAM98A-3 normalized to control levels by day 7, while SNHG15 remained increased, indicating the ability of lncRNAs to monitor IS dynamics. Receiver-operating characteristic (ROC) curve analysis showed that the lncRNA-based combination index outperformed serum brain-derived neurotrophic factor (BDNF) and neurone-specific enolase (NSE) in distinguishing IS patients from TIA patients and HCs with areas under ROC curve of more than 0.84. Furthermore, the combination index increased significantly after treatment and was correlated with neurological deficit severity of IS. The panel of these altered lncRNAs was associated with acute IS and could serve as a novel diagnostic method.
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Isquemia Encefálica/genética , Perfilación de la Expresión Génica , Leucocitos Mononucleares/metabolismo , ARN Largo no Codificante/genética , Accidente Cerebrovascular/genética , Anciano , Anciano de 80 o más Años , Isquemia Encefálica/complicaciones , Isquemia Encefálica/diagnóstico , Estudios de Casos y Controles , Células Cultivadas , Femenino , Humanos , Leucocitos Mononucleares/citología , Modelos Logísticos , Masculino , Persona de Mediana Edad , ARN Largo no Codificante/sangre , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/etiologíaRESUMEN
Stoke results in activation of the sympathetic nervous system (SNS), inducing systemic immunosuppression. However, the potential mechanisms underlying stroke-induced immunosuppression remain unclear. Here, we determined the SNS effects on functional outcome and explored the interactions among SNS, ß-arrestin2 and nuclear factor-κB (NF-κB) after experimental stroke in rats. In the current study, stroke was induced by a transient middle cerebral artery occlusion (MCAO) in rats, and SNS activity was inhibited by intraperitoneal injection of 6-hydroxydopamine HBr (6-OHDA). 7.0 T Micro-MRI and Longa score were employed to assess the functional outcome after stroke. Flow cytometry and ELISA assay were used to measure the expression of MHC class II, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). Western blot was conducted to analyze ß-arrestin2 and NF-κB protein expression levels after experimental stroke. We found significantly increased infarct volumes and functional impairment after MCAO at different post-surgery time points, which were not aggravated by 6-OHDA treatment. SNS blockade partially reversed the expression of MHC class II after stroke over time, as well as TNF-α and IFN-γ levels in lipopolysaccharide-stimulated macrophages in vitro. Treatment of MCAO rats with SNS-inhibitor significantly diminished NF-κB activation and enhanced ß-arrestin2 expression after stroke. This study suggests that pharmacological SNS inhibition dose not aggravate functional outcome after stroke. Stroke-induced immunosuppression may be involved in the SNS-ß-arrestin2-NF-κB pathway.
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Terapia de Inmunosupresión/métodos , Recuperación de la Función/fisiología , Accidente Cerebrovascular/inmunología , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/inmunología , Animales , Masculino , Oxidopamina/farmacología , Oxidopamina/toxicidad , Ratas , Ratas Sprague-Dawley , Recuperación de la Función/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Accidente Cerebrovascular/metabolismo , Sistema Nervioso Simpático/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: The mechanism of stroke-induced immunodepression syndrome (SIDS) remains uncertain. Some studies suggest that hyperactivation of the sympathetic nervous system (SNS) may be the key factor underlying SIDS. Catecholamines impair early lymphocyte response, which can increase the risk of stroke-associated infection (SAI). MATERIAL/METHODS: Our study focused on dynamic changes of metanephrine (MN), normetanephrine (NMN), cytokines, and spleen volume in the rat middle cerebral artery occlusion (MCAO) model. RESULTS: After MCAO, there is hyperactivation of SNS and pro-/anti-inflammatory imbalance, indicating systemic immunodepression. In addition, rat spleen size was reduced. Correlation analysis indicated that MCAO-induced spleen size reduction correlated with the changes in MN, NMN, and cytokines. Blocking SNS with propranolol can partly reverse the immunodepression and the reduction in spleen volume. CONCLUSIONS: Taken together, these findings suggest that acute ischemic stroke induces over-activation of the SNS, which lowers the threshold of infection and increases the risk of infection.
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Terapia de Inmunosupresión , Bazo/inmunología , Bazo/patología , Accidente Cerebrovascular/inmunología , Sistema Nervioso Simpático/inmunología , Sistema Nervioso Simpático/patología , Animales , Infarto Encefálico/complicaciones , Infarto Encefálico/patología , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/patología , Inyecciones Intraperitoneales , Interferón gamma/sangre , Interleucina-10/sangre , Interleucina-1beta/sangre , Angiografía por Resonancia Magnética , Masculino , Metanefrina/sangre , Normetanefrina/sangre , Tamaño de los Órganos , Propranolol/administración & dosificación , Ratas Sprague-Dawley , Coloración y Etiquetado , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/complicacionesRESUMEN
Introduction: Asian citrus psyllid (ACP, Diaphorina citri) is an important transmission vector of "Candidatus Liberibacter asiaticus" (CLas), the causal agent of Huanglongbing (HLB), the most destructive citrus disease in the world. As there are currently no HLB-resistant rootstocks or varieties, the control of ACP is an important way to prevent HLB. Some viruses of insect vectors can be used as genetically engineered materials to control insect vectors. Methods: To gain knowledge on viruses in ACP in China, the prevalence of five RNA and DNA viruses was successfully determined by optimizing reverse transcription polymerase chain reaction (RT-PCR) in individual adult ACPs. The five ACP-associated viruses were identified as follows: diaphorina citri bunyavirus 2, which was newly identified by high-throughput sequencing in our lab, diaphorina citri reovirus (DcRV), diaphorina citri picorna-like virus (DcPLV), diaphorina citri bunyavirus (DcBV), and diaphorina citri densovirus-like virus (DcDV). Results: DcPLV was the most prevalent and widespread ACP-associated virus, followed by DcBV, and it was detected in more than 50% of all samples tested. DcPLV was also demonstrated to propagate vertically and found more in salivary glands among different tissues. Approximately 60% of all adult insect samples were co-infected with more than one insect pathogen, including the five ACP-associated viruses and CLas. Discussion: This is the first time these viruses, including the newly identified ACP-associated virus, have been detected in individual adult ACPs from natural populations in China's five major citrus-producing provinces. These results provide valuable information about the prevalence of ACP-associated viruses in China, some of which have the potential to be used as biocontrol agents. In addition, analysis of the change in prevalence of pathogens in a single insect vector is the basis for understanding the interactions between CLas, ACP, and insect viruses.
RESUMEN
Emerging evidence indicates that sleep deprivation (SD) can lead to Alzheimer's disease (AD)-related pathological changes and cognitive decline. However, the underlying mechanisms remain obscure. In the present study, we identified the existence of a microbiota-gut-brain axis in cognitive deficits resulting from chronic SD and revealed a potential pathway by which gut microbiota affects cognitive functioning in chronic SD. Our findings demonstrated that chronic SD in mice not only led to cognitive decline but also induced gut microbiota dysbiosis, elevated NLRP3 inflammasome expression, GSK-3ß activation, autophagy dysfunction, and tau hyperphosphorylation in the hippocampus. Colonization with the "SD microbiota" replicated the pathological and behavioral abnormalities observed in chronic sleep-deprived mice. Remarkably, both the deletion of NLRP3 in NLRP3 -/- mice and specific knockdown of NLRP3 in the hippocampus restored autophagic flux, suppressed tau hyperphosphorylation, and ameliorated cognitive deficits induced by chronic SD, while GSK-3ß activity was not regulated by the NLRP3 inflammasome in chronic SD. Notably, deletion of NLRP3 reversed NLRP3 inflammasome activation, autophagy deficits, and tau hyperphosphorylation induced by GSK-3ß activation in primary hippocampal neurons, suggesting that GSK-3ß, as a regulator of NLRP3-mediated autophagy dysfunction, plays a significant role in promoting tau hyperphosphorylation. Thus, gut microbiota dysbiosis was identified as a contributor to chronic SD-induced tau pathology via NLRP3-mediated autophagy dysfunction, ultimately leading to cognitive deficits. Overall, these findings highlight GSK-3ß as a regulator of NLRP3-mediated autophagy dysfunction, playing a critical role in promoting tau hyperphosphorylation.
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Autofagia , Disbiosis , Microbioma Gastrointestinal , Proteína con Dominio Pirina 3 de la Familia NLR , Privación de Sueño , Proteínas tau , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Microbioma Gastrointestinal/fisiología , Privación de Sueño/metabolismo , Privación de Sueño/fisiopatología , Privación de Sueño/complicaciones , Ratones , Autofagia/fisiología , Proteínas tau/metabolismo , Proteínas tau/genética , Masculino , Hipocampo/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Inflamasomas/metabolismoRESUMEN
The progressive loss of dopaminergic neurons in the midbrain is the hallmark of Parkinson's disease (PD). A newly emerging form of lytic cell death, ferroptosis, has been implicated in PD. However, it remains unclear in terms of PD-associated ferroptosis underlying causative genes and effective therapeutic approaches. This research explored the underlying mechanism of ferroptosis-related genes in PD. Here, Firstly, we found NOX1 associated with ferroptosis differently in PD patients by bioinformatics analysis. In vitro and in vivo models of PD were constructed to explore the underlying mechanism. qPCR, Western blot analysis, immunohistochemistry, immunofluorescence, Ferro orange, and BODIPY C11 were utilized to analyze the levels of ferroptosis. Transcriptomics sequencing was to investigate the downstream pathway and the analysis of immunoprecipitation to validate the upstream factor. In conclusion, NOX1 upregulation and activation of ferroptosis-related neurodegeneration, therefore, might be useful as a clinical therapeutic agent.
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OBJECTIVE: Microglial polarization plays a critical role in neuroinflammation and may be a potential therapeutic target for ischemic stroke. This study was to explore the role and underlying molecular mechanism of Circular RNA PTP4A2 (circPTP4A2) in microglial polarization after ischemic stroke. METHODS: C57BL/6J mice underwent transient middle cerebral artery occlusion (tMCAO), while primary mouse microglia and BV2 microglial cells experienced oxygen glucose deprivation/reperfusion (OGD/R) to mimic ischemic conditions. CircPTP4A2 shRNA lentivirus and Colivelin were used to knock down circPTP4A2 and upregulate signal transducer and activator of transcription 3 (STAT3) phosphorylation, respectively. Microglial polarization was assessed using immunofluorescence staining and Western blot. RNA pull-down and RNA binding protein immunoprecipitation (RIP) were applied to detect the binding between circPTP4A2 and STAT3. RESULTS: The levels of circPTP4A2 were significantly increased in plasma and peri-infarct cortex in tMCAO mice. CircPTP4A2 knockdown reduced infarct volume, increased cortical cerebral blood flow (CBF), and attenuated neurological deficits. It also decreased pro-inflammatory factors levels in peri-infarct cortex and plasma, and increased anti-inflammatory factors concentrations 24 h post-stroke. In addition, circPTP4A2 knockdown suppressed M1 microglial polarization and promoted M2 microglial polarization in both tMCAO mice and OGD/R-induced BV2 microglial cells. Moreover, circPTP4A2 knockdown inhibited the phosphorylation of STAT3 induced by oxygen-glucose deprivation. In contrast, increased phosphorylation of STAT3 partly counteracted the effects of circPTP4A2 knockdown. RNA pull-down and RIP assays further certified the binding between circPTP4A2 and STAT3. CONCLUSION: These results revealed regulatory mechanisms of circPTP4A2 that stimulated neuroinflammation by driving STAT3-dependent microglial polarization in ischemic brain injury. CircPTP4A2 knockdown reduced cerebral ischemic injury and promoted microglial M2 polarization, which could be a novel therapeutic target for ischemic stroke.
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Lesiones Encefálicas , Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Ratones , Animales , Microglía , Accidente Cerebrovascular Isquémico/metabolismo , Isquemia Encefálica/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , ARN Circular/farmacología , Enfermedades Neuroinflamatorias , Factor de Transcripción STAT3/metabolismo , Ratones Endogámicos C57BL , Infarto de la Arteria Cerebral Media/genética , Infarto de la Arteria Cerebral Media/metabolismo , Lesiones Encefálicas/metabolismo , Oxígeno , Glucosa/metabolismoRESUMEN
OBJECTIVE: To investigate the prevalence of male sexual dysfunction in males with Parkinson's disease and the pathogenesis and related factors of the problem. METHODS: We evaluated the sexual function of 140 men with Parkinson's disease using Mini-mental State Examination (MMSE), Unified Parkinson's Disease Rating Scale (Part III) (UPDRS III), Hoenhn-Yahr Staging (HYS), Hamilton Depression Scale (HAMD) and Sexual Dysfunction Standard of ICD-10. We calculated the Levodopa equivalent doses (LED) for all the patients. RESULTS: Sexual dysfunction was found in 58 (41.43%) of the patients with Parkinson's disease. There were no significant differences in age, education, age of onset, course of disease and scores on UPDRS III, HYS and LED between the sexual dysfunction and normal sexual function groups. The HAMD score was 14.95 +/- 9.12 in the sexual dysfunction group, significantly higher than 10.96 +/- 9.82 in the normal sexual function group (P < 0.05), and it was positively correlated with the inci- dence of male sexual dysfunction (P < 0.05). CONCLUSION: Sexual dysfunction is a common symptom in males with Parkinson's disease, and is correlated with the high HAMD score of Parkinson's disease patients.
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Enfermedad de Parkinson/fisiopatología , Disfunciones Sexuales Fisiológicas/etiología , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Escalas de Valoración PsiquiátricaRESUMEN
Parkinson's disease (PD) is the second most common neurodegenerative disease globally. Levodopa (L-dopa) has been the cornerstone for treating Parkinson's since the 1960s. However, complications such as "wearing-off" and dyskinesia inevitably appear with disease progression. With the further development of microbiomics in recent years, It has been recognized that gut microbiota plays a crucial role in Parkinson's disease pathogenesis. However, Little is known about the impact of gut microbiota in PD treatment, especially in levodopa metabolism. This review examines the possible mechanisms of gut microbiota, such as Helicobacter pylori, Enterobacter faecalis, and Clostridium sporogenes, affecting L-dopa absorption. Furthermore, we review the current status of gut microbiota intervention strategies, providing new insights into the treatment of PD.
RESUMEN
Parkinson's disease (PD) is the second most common neurodegenerative disease that affects about 10 million people worldwide. Non-motor and motor symptoms usually accompany PD. Major depressive disorder (MDD) is one of the non-motor manifestations of PD it remains unrecognized and undertreated effectively. MDD in PD has complicated pathophysiologies and remains unclear. The study aimed to explore the candidate genes and molecular mechanisms of PD with MDD. PD (GSE6613) and MDD (GSE98793) gene expression profiles were downloaded from Gene Expression Omnibus (GEO). Above all, the data of the two datasets were standardized separately, and differentially expressed genes (DEGs) were obtained by using the Limma package of R. Take the intersection of the two differential genes and remove the genes with inconsistent expression trends. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were investigated to explore the function of the common DEGs. Additionally, the construction of the protein-protein interaction (PPI) network was to search the hub genes, and then the least absolute shrinkage and selection operator (LASSO) regression was used to further identify the key genes. GSE99039 for PD and GSE201332 for MDD were performed to validate the hub genes by the violin plot and receiver operating characteristic (ROC) curve. Last but not least, immune cell dysregulation in PD was investigated by immune cell infiltration. As a result, a total of 45 common genes with the same trend. Functional analysis revealed that they were enriched in neutrophil degranulation, secretory granule membrane, and leukocyte activation. LASSO was performed on 8 candidate hub genes after CytoHubba filtered 14 node genes. Finally, AQP9, SPI1, and RPH3A were validated by GSE99039 and GSE201332. Additionally, the three genes were also detected by the qPCR in vivo model and all increased compared to the control. The co-occurrence of PD and MDD can be attributed to AQP9, SPI1, and RPH3A genes. Neutrophils and monocyte infiltration play important roles in the development of PD and MDD. Novel insights may be gained from the findings for the study of mechanisms.
Asunto(s)
Trastorno Depresivo Mayor , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Humanos , Trastorno Depresivo Mayor/genética , Enfermedad de Parkinson/genética , Ontología de Genes , MonocitosRESUMEN
Ischemic stroke (IS) produces a powerful inflammatory cascade in the brain, resulting in the occurrence of neuroinflammation. Neuroinflammation is triggered not only by resident immune cells, but also by neutrophils, macrophages, and T lymphocytes infiltrating the peripheral immune system. The disruption of the blood-brain barrier appears to exacerbate inflammatory infiltrates after IS. In turn, IS also has effects on peripheral immunity, manifested as peripheral immunosuppression syndrome, which increases the risk of stroke-associated infections such as pneumonia. Moreover, strokes also damage peripheral organs such as the heart, lungs, spleen, and kidneys. The purpose of this review is to provide an overview of central neuroinflammation and stroke-induced immunosuppression in the context of IS.
Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Enfermedades Neuroinflamatorias , EncéfaloRESUMEN
BACKGROUND: Platelet-neutrophil crosstalk is being increasingly recognized as a driver of inflammation and thrombosis in patients with ischemic stroke. The aim of this study was to investigate the potential of PNR value in predicting the long-term prognosis and evaluate whether or not an available and routine blood cell biomarker could help predict the long-term neurological function and mortality in AIS patients. METHODS: A total of 718 patients with suspected acute ischemic stroke were involved and followed up for 1 year by standard telephone interview or reexamination. Kaplan-Meier curve, Univariate and Multivariate Cox Regression were analyzed using Statistical Packages for Social Sciences. RESULTS: ROC curve for PNR to evaluate 1-year outcomes was analyzed and the area under the curve (AUC) was 0.659 (P < 0.001). The cutoff point was observed at 38.30, with a sensitivity of 53.09 % and a specificity of 71.25 %. Moreover, patients in PNR ≤ 38.30 were more likely to have more serious NIHSS on admission, 1-year mRS and higher 1-year mortality (P < 0.001, respectively). The 1-year mortality in the low PNR group was significantly higher than that of the high PNR group (log-rank tests: P < 0.0001). Age, NIHSS, RBC and PNR were combined into model B which significantly increased the AUC value from 0.736 to 0.888 compared to model A (including Age, NIHSS and RBC). CONCLUSION: PNR may serve as a readily assessable biomarker for early predicting neurological deterioration and the long-term prognosis of AIS. The nomogram that included age, NIHSS, PNR and RBC may be a useful predictive tool for 1-year mortality.