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1.
Cell Rep Med ; 5(4): 101483, 2024 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-38579727

RESUMEN

Immune cell phenotyping frequently detects lineage-unrelated receptors. Here, we report that surface receptors can be transferred from primary macrophages to CD4 T cells and identify the Fcγ receptor CD32 as driver and cargo of this trogocytotic transfer. Filamentous CD32+ nanoprotrusions deposit distinct plasma membrane patches onto target T cells. Transferred receptors confer cell migration and adhesion properties, and macrophage-derived membrane patches render resting CD4 T cells susceptible to infection by serving as hotspots for HIV-1 binding. Antibodies that recognize T cell epitopes enhance CD32-mediated trogocytosis. Such autoreactive anti-HIV-1 envelope antibodies can be found in the blood of HIV-1 patients and, consistently, the percentage of CD32+ CD4 T cells is increased in their blood. This CD32-mediated, antigen-independent cell communication mode transiently expands the receptor repertoire and functionality of immune cells. HIV-1 hijacks this mechanism by triggering the generation of trogocytosis-promoting autoantibodies to gain access to immune cells critical to its persistence.


Asunto(s)
Infecciones por VIH , Seropositividad para VIH , VIH-1 , Humanos , Linfocitos T CD4-Positivos , Receptores de IgG/metabolismo , Autoanticuerpos/metabolismo , Trogocitosis
2.
Mol Neurobiol ; 2023 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-37919601

RESUMEN

Abnormal phosphorylation of the microtubule-binding protein tau in the brain is a key pathological marker for Alzheimer's disease and additional neurodegenerative tauopathies. However, how hyperphosphorylated tau causes cellular dysfunction or death that underlies neurodegeneration remains an unsolved question critical for the understanding of disease mechanism and the design of efficacious drugs. Using a recombinant hyperphosphorylated tau protein (p-tau) synthesized by the PIMAX approach, we examined how cells responded to the cytotoxic tau and explored means to enhance cellular resistance to tau attack. Upon p-tau uptake, the intracellular calcium levels rose promptly. Gene expression analyses revealed that p-tau potently triggered endoplasmic reticulum (ER) stress, unfolded protein response (UPR), ER stress-associated apoptosis, and pro-inflammation in cells. Proteomics studies showed that p-tau diminished heme oxygenase-1 (HO-1), an ER stress-associated anti-inflammation and anti-oxidative stress regulator, while stimulated the accumulation of MIOS and other proteins. p-Tau-induced ER stress-associated apoptosis and pro-inflammation are ameliorated by apomorphine, a brain-permeable prescription drug widely used to treat Parkinson's disease symptoms, and by overexpression of HO-1. Our results reveal probable cellular functions targeted by hyperphosphorylated tau. Some of these dysfunctions and stress responses have been linked to neurodegeneration in Alzheimer's disease. The observations that the ill effects of p-tau can be mitigated by a small compound and by overexpressing HO-1 that is otherwise diminished in the treated cells inform new directions of Alzheimer's disease drug discovery.

3.
bioRxiv ; 2023 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-37292976

RESUMEN

Background: Abnormal phosphorylation of the microtubule-binding protein tau in the brain is a key pathological marker for Alzheimer's disease and additional neurodegenerative tauopathies. However, how hyperphosphorylated tau causes cellular dysfunction or death that underlie neurodegeneration remains an unsolved question critical for the understanding of disease mechanism and the design of efficacious drugs. Methods: Using a recombinant hyperphosphorylated tau protein (p-tau) synthesized by the PIMAX approach, we examined how cells responded to the cytotoxic tau and explored means to enhance cellular resistance to tau attack. Results: Upon p-tau uptake, the intracellular calcium levels rose promptly. Gene expression analyses revealed that p-tau potently triggered endoplasmic reticulum (ER) stress, Unfolded Protein Response (UPR), ER stress-associated apoptosis, and pro-inflammation in cells. Proteomics studies showed that p-tau diminished heme oxygenase-1 (HO-1), an ER stress associated anti-inflammation and anti-oxidative stress regulator, while stimulated the accumulation of MIOS and other proteins. P-tau-induced ER stress-associated apoptosis and pro-inflammation are ameliorated by apomorphine, a brain-permeable prescription drug widely used to treat Parkinson's disease symptoms, and by overexpression of HO-1. Conclusion: Our results reveal probable cellular functions targeted by hyperphosphorylated tau. Some of these dysfunctions and stress responses have been linked to neurodegeneration in Alzheimer's disease. The observations that the ill effects of p-tau can be mitigated by a small compound and by overexpressing HO-1 that is otherwise diminished in the treated cells inform new directions of Alzheimer's disease drug discovery.

4.
Iran J Basic Med Sci ; 26(5): 532-539, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37051108

RESUMEN

Objectives: To examine the effect and potential mechanism of electroacupuncture (EA) pretreatment in spatial learning, memory, gut microbiota, and JNK signaling in D-galactose-induced AD-like rats. Materials and Methods: The AD-like rat model was generated by intraperitoneal injection of D-galactose. Morris water maze was used to determine spatial learning and memory ability, Real-time PCR to determine intestinal flora levels, ELISA to determine tryptophan (Trp) and 5-HT levels in the colon and hippocampal tissues, immunofluorescence to determine 5-HT levels in enterochromaffin cells (ECs), and immunoblotting to determine JNK signaling protein levels in hippocampal tissues. Results: Electroacupuncture pretreatment significantly reduced escape latency and prolonged exploration time in the target quadrant, and significantly increased the relative DNA abundance of Lactobacillus and Bifidobacterium. Meanwhile, electroacupuncture pretreatment also reduced colonic 5-HT levels and increased hippocampal 5-HT levels. Moreover, electroacupuncture pretreatment significantly inhibited hippocampal JNK pathway-related protein expression, including 5-HT6R, JNK, p-JUNK, c-JUN, and p-c-Jun. And the combination of GV20 and ST36 was more effective than single acupoints. Conclusion: Electroacupuncture pretreatment improved the learning and memory ability of D-galactose-induced AD-like model rats, changed the gut microbiota composition, and the mechanism may be related to the gut-brain axis and the JNK signaling pathway. In addition, the combination of GV20 and ST36 could further enhance the efficacy.

5.
Molecules ; 28(2)2023 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-36677579

RESUMEN

It is both important and required to quickly and accurately detect chemical warfare agents, such as the highly toxic nerve agent sarin. Surface-enhanced Raman scattering (SERS) has received considerable attention due to its rapid results, high sensitivity, non-destructive data acquisition, and unique spectroscopic fingerprint. In this work, we successfully prepared SERS cotton swabs (CSs) for the detection of the sarin simulant agent dimethyl methyl phosphonate (DMMP) by anchoring N1-(3-trimethoxysilylpropyl) diethylenetriamine (ATS)/silver nanoparticle (AgNP) nanocomposites on CSs using ATS as the stabilizer and coupling agent. Simultaneously, the binding mode and reaction mechanics between the AgNP, ATS, and CS were confirmed by XPS. The modified CSs exhibited good uniformity, stability, and adsorption capability for SERS measurements, enabling the adsorption and detection of DMMP residue from an irregular surface via a simple swabbing process, with a detection limit of 1 g/L. The relative standard deviations (RSDs) of RSD710 = 5.6% had high reproducibility. In this research, the fabrication method could easily be extended to other cellulose compounds, such as natural fibers and paper. Furthermore, the versatile SERS CSs can be used for the on-site detection of DMMP, particularly in civil and defense applications, to guarantee food security and the health of the population.

6.
7.
Front Psychiatry ; 13: 996996, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36424991

RESUMEN

Purpose: University freshmen are particularly vulnerable as they are undergoing the transition from high school to university with a range of changes. Sleep problems among this group in the Qinghai-Tibet Plateau of China were barely studied. This study aimed to explore sleep disturbance, and its association with quality of life (QoL) and demographic and clinical characteristics among university freshmen in Qinghai-Tibet Plateau, China. Methods: A multistage stratified cluster random sampling method was performed to recruit student participants with a structured questionnaire to collect sociodemographic and clinical characteristics, and lifestyle behaviors. Sleep disturbance including three aspects of sleep disturbance (i.e., difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), and early morning awakening (EMA)) was assessed using standardized measurement. Multiple logistic regression models were applied to analyze the data. Results: Among included 2,769 freshmen, the prevalence of sleep disturbance was 14.8% (95% CI: 14.2-15.5%), and corresponding prevalence of DIS, DMS, and EMA was 8.2% (95% CI: 7.7-8.7%), 8.3% (95% CI: 7.8-8.8%), and 4.2% (95% CI: 3.8-4.6%), respectively. Freshmen with sleeping disturbance had significantly lower QoL in physical [F (1, 2769) = 60.23, p < 0.001], psychological [F (1, 2769) = 46.18, p < 0.001], social [F (1, 2769) = 23.04, p < 0.001], and environment [F (1, 2769) = 6.07, p = 0.01] domains. Multiple logistic regression analyses revealed that having breakfast five times a week or less (less than three times, OR = 1.79, 95% CI: 1.34-2.40; 3-5 times, OR = 1.40, 95% CI: 1.09-1.79), self-perceived severe Internet dependence (OR = 1.71, 95% CI: 1.11-2.65), self-perceived poor health status (OR = 3.44, 95% CI: 2.06-5.74), high academic stress (OR = 1.42, 95% CI: 1.13-1.78), poor relationship with classmates (OR = 3.44, 95% CI: 1.53-7.71), and severe ADHD symptoms (OR = 1.08, 95% CI: 1.05-1.12) were positively associated with sleeping disturbance. Conclusion: Sleep disturbance was common among freshmen and is associated with poorer QoL. Prevention and intervention strategies should be developed and implemented, especially among the vulnerable university freshman groups.

8.
Exp Hematol ; 115: 30-43, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36096455

RESUMEN

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of small, mature CD5+ B lymphocytes in the blood, marrow, and lymphoid organs. Cell survival depends on interaction with the leukemic microenvironment. However, the mechanisms controlling CLL cell survival are still incompletely understood. Macrophage migration-inhibitory factor (MIF), a pro-inflammatory and immunoregulatory chemokine-like cytokine, interacts with CXCR4, a major chemokine receptor, as well as with CD74/invariant chain, a single-pass type II receptor. In this study, we analyzed the roles of CXCR4, CD74, and MIF in CLL. Mononuclear cells from patients with hematological malignancies were analyzed for coexpression of CXCR4 and CD74 by flow cytometry. Strong co- and overexpression of CXCR4 and CD74 were observed on B cells of CLL patients (n = 10). Survival and chemotaxis assays indicated that CXCR4 and CD74 work together to enhance the survival and migration of malignant cells in CLL. Blockade of the receptors, either individually or in combination, promoted cell death and led to an abrogation of MIF-driven migration responses in murine and human CLL cells, suggesting that joint activation of both receptors is crucial for CLL cell survival and mobility. These findings indicate that the MIF/CXCR4/CD74 axis represents a novel therapeutic target in CLL.


Asunto(s)
Leucemia Linfocítica Crónica de Células B , Humanos , Ratones , Animales , Leucemia Linfocítica Crónica de Células B/patología , Supervivencia Celular , Antígenos de Diferenciación de Linfocitos B/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Macrófagos/metabolismo , Microambiente Tumoral
9.
Neurobiol Dis ; 171: 105802, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35753626

RESUMEN

ß-thalassemia is associated with multiple hematological and cerebrovascular symptoms linked to a hypercoagulable state that has not been fully replicated in animal models for the development of stroke treatments. Herein we compared the physiological properties and responses to transient cerebral hypoxia-ischemia (tHI) between six-month-old wildtype and heterozygous Th3/+ mice, a model of non-transfusion-dependent ß-thalassemia intermedia (ß-TI). We found that Th3/+ mice developed microcytic anemia, splenomegaly, higher platelet counts, and increased platelet-erythrocyte plus erythrocyte-leukocyte aggregates. Furthermore, Th3/+ mice showed diminished cerebrovascular reactivity (CVR) and cortical oxygen saturation under repetitive hypercapnic challenges. When subjected to a sub-threshold tHI insult, platelets and leukocytes in Th3/+ mice adhered to the cerebrovascular wall or formed aggregates, while their counterparts flew through smoothly in wildtype mice. Subsequently, Th3/+ mice showed increased fibrin deposition around cerebral blood vessels and larger infarction than wildtype mice, especially in female Th3/+ mice. Collectively these results showed that Th3/+ mice mimic key clinical features and a propensity to thromboembolism in ß-TI patients. The hypercoagulable state in Th3/+ mice is likely caused by multiple hematological and CVR anomalies that are similar, but are not identical to those in the mouse model of sickle cell anemia. As such, we suggest that Th3/+ mice are a useful model to study the pathological mechanisms and prophylactic stroke treatments in thalassemia patients.


Asunto(s)
Hipoxia-Isquemia Encefálica , Accidente Cerebrovascular , Talasemia beta , Animales , Modelos Animales de Enfermedad , Femenino , Hipoxia-Isquemia Encefálica/complicaciones , Ratones , Accidente Cerebrovascular/complicaciones , Talasemia beta/complicaciones , Talasemia beta/patología
10.
Org Biomol Chem ; 20(17): 3506-3510, 2022 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-35420611

RESUMEN

A copper-catalyzed cascade reaction of α-diazocarbonyl compounds with ethenesulfonyl fluoride (ESF) is developed, affording a variety of highly functionalized pyrazolyl aliphatic sulfonyl fluorides in good to excellent yields (66-98%). This transformation features broad substrates, exclusive regioselectivity, high atom economy and operational simplicity, thus providing a straightforward method for the direct construction of pyrazole-containing aliphatic sulfonyl fluorides, which will provide great applicable value in medicinal chemistry and other related disciplines.


Asunto(s)
Fluoruros , Ácidos Sulfínicos , Química Farmacéutica , Fluoruros/química , Pirazoles , Ácidos Sulfínicos/química
11.
Theranostics ; 12(2): 512-529, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34976198

RESUMEN

Rationale: Monocytes belong to the mononuclear phagocyte system and are immune responders to tissue injury and infection. There were also reports of monocytes transforming to microglia-like cells. Here we explore the roles of monocytes in microglia ontogeny and the pathogenesis of neonatal cerebral hypoxic-ischemic (HI) brain injury in mice. Methods: We used three genetic methods to track the development of monocytes, including CX3CR1GFP/+; CCR2RFP/+ reporter mice, adoptive transfer of GFP+ monocytes, and fate-mapping with CCR2-CreER mice, in neonatal mouse brains with or without lipopolysaccharide (LPS, 0.3 mg/kg)-sensitized Vannucci HI. We also used genetic (CCR2RFP/ RFP, CCR2 knockout) and pharmacological methods (RS102895, a CCR2 antagonist) to test the roles of monocytic influx in LPS/HI brain injury. Results: CCR2+ monocytes entered the late-embryonic brains via choroid plexus, but rapidly became CX3CR1+ amoeboid microglial cells (AMCs). The influx of CCR2+ monocytes declined after birth, but recurred after HI or LPS-sensitized HI (LPS/HI) brain injury, particularly in the hippocampus. The CCR2-CreER-based fate-mapping showed that CCR2+ monocytes became CD68+ TNFα+ macrophages within 4 d after LPS/HI, and maintained as TNFα+ MHCII+ macrophages or persisted as Tmem119+ Sall1+ P2RY12+ ramified microglia for at least five months after injury. Genetic deletion of the chemokine receptor CCR2 markedly diminished monocytic influx, the expression of pro- and anti-inflammatory cytokines, and brain damage. Post-LPS/HI application of RS102895 also reduced inflammatory responses and brain damage, leading to better cognitive functions. Conclusion: These results suggest that monocytes promote acute inflammatory responses and may become pathological microglia long after the neonatal LPS/HI insult. Further, blocking the influx of monocytes may be a potential therapy for neonatal brain injury.


Asunto(s)
Lesiones Encefálicas/patología , Hipoxia-Isquemia Encefálica/patología , Microglía/patología , Monocitos/inmunología , Enfermedades Neuroinflamatorias/patología , Traslado Adoptivo , Animales , Animales Recién Nacidos , Movimiento Celular , Células Cultivadas , Plexo Coroideo/citología , Plexo Coroideo/inmunología , Femenino , Inflamación/patología , Masculino , Ratones Endogámicos C57BL , Monocitos/trasplante , Enfermedades Neuroinflamatorias/inmunología , Receptores CCR2/genética , Receptores CCR2/metabolismo
12.
Nat Commun ; 12(1): 5289, 2021 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-34489419

RESUMEN

Microglia are brain-resident immune cells with a repertoire of functions in the brain. However, the extent of their interactions with the vasculature and potential regulation of vascular physiology has been insufficiently explored. Here, we document interactions between ramified CX3CR1 + myeloid cell somata and brain capillaries. We confirm that these cells are bona fide microglia by molecular, morphological and ultrastructural approaches. Then, we give a detailed spatio-temporal characterization of these capillary-associated microglia (CAMs) comparing them with parenchymal microglia (PCMs) in their morphological activities including during microglial depletion and repopulation. Molecularly, we identify P2RY12 receptors as a regulator of CAM interactions under the control of released purines from pannexin 1 (PANX1) channels. Furthermore, microglial elimination triggered capillary dilation, blood flow increase, and impaired vasodilation that were recapitulated in P2RY12-/- and PANX1-/- mice suggesting purines released through PANX1 channels play important roles in activating microglial P2RY12 receptors to regulate neurovascular structure and function.


Asunto(s)
Encéfalo/irrigación sanguínea , Conexinas/genética , Microglía/metabolismo , Células Mieloides/metabolismo , Proteínas del Tejido Nervioso/genética , Receptores Purinérgicos P2Y12/genética , Animales , Encéfalo/citología , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Receptor 1 de Quimiocinas CX3C/genética , Receptor 1 de Quimiocinas CX3C/metabolismo , Recuento de Células , Circulación Cerebrovascular/fisiología , Conexinas/deficiencia , Electrodos Implantados , Femenino , Regulación de la Expresión Génica , Genes Reporteros , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Masculino , Ratones , Ratones Noqueados , Microglía/citología , Células Mieloides/citología , Proteínas del Tejido Nervioso/deficiencia , Neuroimagen/instrumentación , Neuroimagen/métodos , Receptores Purinérgicos P2Y12/deficiencia , Receptores Purinérgicos P2Y12/metabolismo , Vasodilatación/fisiología
13.
JCI Insight ; 6(17)2021 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-34324436

RESUMEN

The creatine transporter (CrT) maintains brain creatine (Cr) levels, but the effects of its deficiency on energetics adaptation under stress remain unclear. There are also no effective treatments for CrT deficiency, the second most common cause of X-linked intellectual disabilities. Herein, we examined the consequences of CrT deficiency in brain energetics and stress-adaptation responses plus the effects of intranasal Cr supplementation. We found that CrT-deficient (CrT-/y) mice harbored dendritic spine and synaptic dysgenesis. Nurtured newborn CrT-/y mice maintained baseline brain ATP levels, with a trend toward signaling imbalance between the p-AMPK/autophagy and mTOR pathways. Starvation elevated the signaling imbalance and reduced brain ATP levels in P3 CrT-/y mice. Similarly, CrT-/y neurons and P10 CrT-/y mice showed an imbalance between autophagy and mTOR signaling pathways and greater susceptibility to cerebral hypoxia-ischemia and ischemic insults. Notably, intranasal administration of Cr after cerebral ischemia increased the brain Cr/N-acetylaspartate ratio, partially averted the signaling imbalance, and reduced infarct size more potently than intraperitoneal Cr injection. These findings suggest important functions for CrT and Cr in preserving the homeostasis of brain energetics in stress conditions. Moreover, intranasal Cr supplementation may be an effective treatment for congenital CrT deficiency and acute brain injury.


Asunto(s)
Encefalopatías Metabólicas Innatas/genética , Encéfalo/metabolismo , Creatina/deficiencia , ADN/genética , Proteínas de Transporte de Membrana/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Mutación , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/deficiencia , Animales , Animales Recién Nacidos , Encéfalo/ultraestructura , Encefalopatías Metabólicas Innatas/metabolismo , Encefalopatías Metabólicas Innatas/patología , Creatina/genética , Creatina/metabolismo , Análisis Mutacional de ADN , Modelos Animales de Enfermedad , Homeostasis , Masculino , Proteínas de Transporte de Membrana/deficiencia , Discapacidad Intelectual Ligada al Cromosoma X/metabolismo , Discapacidad Intelectual Ligada al Cromosoma X/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Mutantes , Microscopía Electrónica , Neuronas/metabolismo , Neuronas/ultraestructura , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/genética , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/metabolismo
14.
Neurobiol Dis ; 148: 105200, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33248237

RESUMEN

Hypoxia-inducible factor-1α (HIF1α) is a major regulator of cellular adaptation to hypoxia and oxidative stress, and recent advances of prolyl-4-hydroxylase (P4H) inhibitors have produced powerful tools to stabilize HIF1α for clinical applications. However, whether HIF1α provokes or resists neonatal hypoxic-ischemic (HI) brain injury has not been established in previous studies. We hypothesize that systemic and brain-targeted HIF1α stabilization may have divergent effects. To test this notion, herein we compared the effects of GSK360A, a potent P4H inhibitor, in in-vitro oxygen-glucose deprivation (OGD) and in in-vivo neonatal HI via intracerebroventricular (ICV), intraperitoneal (IP), and intranasal (IN) drug-application routes. We found that GSK360A increased the erythropoietin (EPO), heme oxygenase-1 (HO1) and glucose transporter 1 (Glut1) transcripts, all HIF1α target-genes, and promoted the survival of neurons and oligodendrocytes after OGD. Neonatal HI insult stabilized HIF1α in the ipsilateral hemisphere for up to 24 h, and either ICV or IN delivery of GSK360A after HI increased the HIF1α target-gene transcripts and decreased brain damage. In contrast, IP-injection of GSK360A failed to reduce HI brain damage, but elevated the risk of mortality at high doses, which may relate to an increase of the kidney and plasma EPO, leukocytosis, and abundant vascular endothelial growth factor (VEGF) mRNAs in the brain. These results suggest that brain-targeted HIF1α-stabilization is a potential treatment of neonatal HI brain injury, while systemic P4H-inhibition may provoke unwanted adverse effects.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Glicina/análogos & derivados , Subunidad alfa del Factor 1 Inducible por Hipoxia/efectos de los fármacos , Prolina Dioxigenasas del Factor Inducible por Hipoxia/antagonistas & inhibidores , Hipoxia-Isquemia Encefálica/metabolismo , Neuronas/efectos de los fármacos , Oligodendroglía/efectos de los fármacos , Quinolonas/farmacología , Administración Intranasal , Animales , Animales Recién Nacidos , Supervivencia Celular/efectos de los fármacos , Eritropoyetina/genética , Transportador de Glucosa de Tipo 1/efectos de los fármacos , Transportador de Glucosa de Tipo 1/genética , Glicina/farmacología , Hemo Oxigenasa (Desciclizante)/efectos de los fármacos , Hemo Oxigenasa (Desciclizante)/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inyecciones Intraperitoneales , Inyecciones Intraventriculares , Neuronas/metabolismo , Oligodendroglía/metabolismo , Ratas
15.
J Neurosci ; 40(49): 9386-9400, 2020 12 02.
Artículo en Inglés | MEDLINE | ID: mdl-33127853

RESUMEN

Growing evidence suggests that early-life interactions among genetic, immune, and environment factors may modulate neurodevelopment and cause psycho-cognitive deficits. Maternal immune activation (MIA) induces autism-like behaviors in offspring, but how it interplays with perinatal brain injury (especially birth asphyxia or hypoxia ischemia [HI]) is unclear. Herein we compared the effects of MIA (injection of poly[I:C] to dam at gestational day 12.5), HI at postnatal day 10, and the combined MIA/HI insult in murine offspring of both sexes. We found that MIA induced autistic-like behaviors without microglial activation but amplified post-HI NFκB signaling, pro-inflammatory responses, and brain injury in offspring. Conversely, HI neither provoked autistic-like behaviors nor concealed them in the MIA offspring. Instead, the dual MIA/HI insult added autistic-like behaviors with diminished synaptic density and reduction of autism-related PSD-95 and Homer-1 in the hippocampus, which were missing in the singular MIA or HI insult. Further, the dual MIA/HI insult enhanced the brain influx of Otx2-positive monocytes that are associated with an increase of perineuronal net-enwrapped parvalbumin neurons. Using CCR2-CreER mice to distinguish monocytes from the resident microglia, we found that the monocytic infiltrates gradually adopted a ramified morphology and expressed the microglial signature genes (Tmem119, P2RY12, and Sall1) in post-MIA/HI brains, with some continuing to express the proinflammatory cytokine TNFα. Finally, genetic or pharmacological obstruction of monocytic influx significantly reduced perineuronal net-enwrapped parvalbumin neurons and autistic-like behaviors in MIA/HI offspring. Together, these results suggest a pathologic role of monocytes in the two-hit (immune plus neonatal HI) model of neurodevelopmental defects.SIGNIFICANCE STATEMENT In autism spectrum disorders (ASDs), prenatal infection or maternal immune activation (MIA) may act as a primer for multiple genetic and environmental factors to impair neurodevelopment. This study examined whether MIA cooperates with neonatal cerebral hypoxia ischemia to promote ASD-like aberrations in mice using a novel two-hit model. It was shown that the combination of MIA and neonatal hypoxia ischemia produces autistic-like behaviors in the offspring, and has synergistic effects in inducing neuroinflammation, monocytic infiltrates, synaptic defects, and perineuronal nets. Furthermore, genetic or pharmacological intervention of the MCP1-CCR2 chemoattractant pathway markedly reduced monocytic infiltrates, perineuronal nets, and autistic-like behaviors. These results suggest reciprocal escalation of immune and neonatal brain injury in a subset of ASD that may benefit from monocyte-targeted treatments.


Asunto(s)
Trastorno Autístico/inmunología , Trastorno Autístico/psicología , Conducta Animal , Discapacidades del Desarrollo/inmunología , Discapacidades del Desarrollo/psicología , Monocitos/inmunología , Animales , Isquemia Encefálica/genética , Isquemia Encefálica/psicología , Femenino , Activación de Macrófagos , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/inmunología , FN-kappa B , Parvalbúminas/genética , Poli I-C , Densidad Postsináptica , Embarazo , Transducción de Señal , Conducta Social
16.
Sci Adv ; 6(35): eabb2119, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32923636

RESUMEN

Whether monocytes contribute to the brain microglial pool in development or after brain injury remains contentious. To address this issue, we generated CCR2-CreER mice to track monocyte derivatives in a tamoxifen-inducible manner. This method labeled Ly6Chi and Ly6Clo monocytes after tamoxifen dosing and detected a surge of perivascular macrophages before blood-brain barrier breakdown in adult stroke. When dosed by tamoxifen at embryonic day 17 (E17), this method captured fetal hematopoietic cells at E18, subdural Ki67+ ameboid cells at postnatal day 2 (P2), and perivascular microglia, leptomeningeal macrophages, and Iba1+Tmem119+P2RY12+ parenchymal microglia in selective brain regions at P24. Furthermore, this fate mapping strategy revealed an acute influx of monocytes after neonatal stroke, which gradually transformed into a ramified morphology and expressed microglial marker genes (Sall1, Tmem119, and P2RY12) for at least 62 days after injury. These results suggest an underappreciated level of monocyte-to-microglia transition in development and after neonatal stroke.


Asunto(s)
Microglía , Accidente Cerebrovascular , Animales , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Monocitos/metabolismo , Receptores CCR2/genética , Receptores CCR2/metabolismo , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/metabolismo , Tamoxifeno
17.
Blood Adv ; 4(7): 1222-1231, 2020 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-32227212

RESUMEN

The Rose Bengal (RB) dye-based photothrombotic stroke (PTS) model has many methodological advantages including consistent location and size of infarct, low mortality, and relatively simple surgical procedures. However, the standard PTS has the caveat of poor responses to tissue-type plasminogen activator (tPA)-mediated lytic treatment, likely as a result of the platelet-rich, fibrin-poor content of the blood clots. Here we tested whether the admixture of thrombin (80 U/kg) and RB dye (50 mg/kg) in the proximal middle cerebral artery (MCA)-targeted PTS will modify the clot composition and elevate the responsiveness to tPA-lytic treatment (Alteplase, 10 mg/kg). Indeed, intravital imaging, immunostaining, and immunoblot analyses showed less-compacted platelet aggregates with a higher fibrin content in the modified thrombin (T) plus RB photothrombotic stroke (T+RB-PTS) model compared with the standard RB-PTS-induced clots. Both RB-PTS and T+RB-PTS showed steady recovery of cerebral blood flow (CBF) in the ischemic border from 1 day after infarction, but without recanalization of the proximal MCA branch. Intravital imaging showed high potency of restoring the blood flow by tPA after single vessel-targeted T+RB-PTS. Further, although intravenous tPA failed to restore CBF or attenuate infarction in RB-PTS, it conferred 25% recovery of CBF and 55% reduction of the infarct size in T+RB-PTS (P < .05) if tPA was administered within 2 hours postphotoactivation. These results suggest that T+RB-PTS produces mixed platelet:fibrin clots closer to the clinical thrombus composition and enhanced the sensitivity to tPA-lytic treatment. As such, the modified photothrombosis may be a useful tool to develop more effective thrombolytic therapies of cerebral ischemia.


Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular , Animales , Fibrina , Ratones , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/etiología , Terapia Trombolítica , Activador de Tejido Plasminógeno/uso terapéutico
18.
Artículo en Inglés | MEDLINE | ID: mdl-32178394

RESUMEN

BACKGROUND: This study aimed to examine the degrees of job burnout and occupational stressors and their associations among healthcare professionals from county-level health alliances in Qinghai-Tibet Plateau, China. METHODS: A cross-sectional study was conducted in county-level health alliances in Qinghai Province, China, in November 2018. The Maslach Burnout Inventory-General Survey and the 38-item Chinese version of the "Scale for occupational stressors on clinicians" were used. Medical staff in four health alliances from two counties were invited to complete the questionnaire. RESULTS: A total of 1052 (age: 34.06 ± 9.22 years, 79.1% females) healthcare professionals were included, 68.2% (95% CI: 65.2-71.0%) of the participants had job burnout symptoms. Occupational stressors had positive associations with moderate (OR = 1.06, 95% CI: 1.05-1.07) and serious (OR = 1.15, 95% CI: 1.13-1.19) level of job burnout. Stressors from vocational interest produced the greatest magnitude of odds ratio (OR = 1.76, 95% CI: 1.62-1.92) for serious degree of burnout, followed by doctor-patient relationship, interpersonal relationship as well as other domains of occupational stressors. CONCLUSIONS: Job burnout was very common among healthcare professionals working in Chinese county-level health alliances, different occupational stressors had associations with job burnout. Appropriate and effective policies and measures should be developed and implemented.


Asunto(s)
Agotamiento Profesional , Personal de Salud , Estrés Laboral , Adulto , Agotamiento Profesional/epidemiología , China/epidemiología , Estudios Transversales , Femenino , Personal de Salud/estadística & datos numéricos , Humanos , Satisfacción en el Trabajo , Masculino , Estrés Laboral/epidemiología , Relaciones Médico-Paciente , Encuestas y Cuestionarios , Adulto Joven
19.
Reprod Toxicol ; 91: 74-91, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31711903

RESUMEN

Pluripotent stem cells recapitulate many aspects of embryogenesis in vitro. Here, we established a novel culture system to differentiate human embryonic stem cell aggregates (HESCA), and evaluated its utility for teratogenicity assessment. Culture of HESCA with modulators of developmental signals induced morphogenetic and molecular changes associated with differentiation of the paraxial mesoderm and neuroectoderm. To examine impact of teratogenic exposures on HESCA differentiation, 18 compounds were tested, for which adequate information on in vivo plasma concentrations is available. HESCA treated with each compound were examined for gross morphology and transcript levels of 15 embryogenesis regulator genes. Significant alterations in the transcript levels were observed for 94% (15/16) of the teratogenic exposures within 5-fold margin, whereas no alteration was observed for 92% (11/12) of the non-teratogenic exposures. Our study demonstrates that transcriptional changes in HESCA serve as predictive indicator of teratogenicity in a manner comparable to in vivo exposure levels.


Asunto(s)
Técnicas de Cultivo de Célula , Células Madre Embrionarias Humanas/efectos de los fármacos , Teratógenos/toxicidad , Agregación Celular , Diferenciación Celular , Células Cultivadas , Desarrollo Embrionario/efectos de los fármacos , Desarrollo Embrionario/genética , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Células Madre Embrionarias Humanas/metabolismo , Humanos , Teratogénesis
20.
Zhongguo Zhen Jiu ; 40(12): 1323-7, 2020 Dec 12.
Artículo en Chino | MEDLINE | ID: mdl-33415876

RESUMEN

OBJECTIVE: To observe the effect of pretreatment of acupuncture on the expression of nucleotide-binding oligomerization domain-like receptor 3(NLRP3), Caspase-1, interleukin1ß(IL-1ß) and the number of activated microglia (MG) in the hippocampus in Alzheimer's disease (AD) like rats, so as to explore the mechanism of pretreatment of acupuncture in preventing and treating AD. METHODS: A total of 36 SD rats were randomly divided into a blank group, a model group and an electroacupuncture (EA) group, 12 rats in each group. The AD like rat model was established by 8-week continuous intraperitoneal injection of D-galactose (120 mg·kg-1·d-1) in the model group and the EA group. The rats in the EA group were intervened with EA at "Baihui" (GV 20) and "Zusanli" (ST 36), continuous wave, 5 Hz in frequency, 1 mA in intensity, 20 min each intervention, once a day, for 8 weeks. After the intervention, the spatial learning-memory ability was evaluated by the Morris water maze test. The expression levels of NLRP3, Caspase-1 and IL-1ß protein in hippocampus were detected by Western blot method. The number of activated MG in hippocampus was detected by immunofluorescence labeling method. RESULTS: Compared with the blank group, the average escape latency was prolonged (P<0.01), the number of platform crossing was reduced (P<0.01), and the exploration time of target quadrant was shortened (P<0.01) in the model group. Compared with the model group, the average escape latency was shortened (P<0.01), the number of platform crossing was increased (P<0.01), and the exploration time of target quadrant was prolonged (P<0.01) in the EA group. Compared with the blank group, the expression levels of NLRP3, Caspase-1, IL-1ß protein in hippocampus were increased (P<0.01), and the number of activated MG was increased (P<0.01) in the model group. Compared with the model group, the expression levels of NLRP3, Caspase-1, IL-1ß protein in hippocampus were decreased (P<0.01), and the number of activated MG was decreased (P<0.05) in the EA group. CONCLUSION: Pretreatment of acupuncture could prevent and treat the learning-memory dysfunction in AD like rats, and its mechanism may be related to the inhibition of NLRP3 inflammatsome related protein and MG activation.


Asunto(s)
Enfermedad de Alzheimer , Electroacupuntura , Enfermedad de Alzheimer/terapia , Animales , Hipocampo , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Ratas , Ratas Sprague-Dawley
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