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1.
Cell ; 186(7): 1352-1368.e18, 2023 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-37001500

RESUMO

Resilience enables mental elasticity in individuals when rebounding from adversity. In this study, we identified a microcircuit and relevant molecular adaptations that play a role in natural resilience. We found that activation of parvalbumin (PV) interneurons in the primary auditory cortex (A1) by thalamic inputs from the ipsilateral medial geniculate body (MG) is essential for resilience in mice exposed to chronic social defeat stress. Early attacks during chronic social defeat stress induced short-term hyperpolarizations of MG neurons projecting to the A1 (MGA1 neurons) in resilient mice. In addition, this temporal neural plasticity of MGA1 neurons initiated synaptogenesis onto thalamic PV neurons via presynaptic BDNF-TrkB signaling in subsequent stress responses. Moreover, optogenetic mimicking of the short-term hyperpolarization of MGA1 neurons, rather than merely activating MGA1 neurons, elicited innate resilience mechanisms in response to stress and achieved sustained antidepressant-like effects in multiple animal models, representing a new strategy for targeted neuromodulation.


Assuntos
Córtex Auditivo , Camundongos , Animais , Córtex Auditivo/metabolismo , Tálamo/fisiologia , Neurônios/metabolismo , Corpos Geniculados , Interneurônios/fisiologia , Parvalbuminas/metabolismo
2.
Proc Natl Acad Sci U S A ; 120(26): e2301360120, 2023 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-37339206

RESUMO

Traumatic brain injury (TBI) is a pervasive problem worldwide for which no effective treatment is currently available. Although most studies have focused on the pathology of the injured brain, we have noted that the liver plays an important role in TBI. Using two mouse models of TBI, we found that the enzymatic activity of hepatic soluble epoxide hydrolase (sEH) was rapidly decreased and then returned to normal levels following TBI, whereas such changes were not observed in the kidney, heart, spleen, or lung. Interestingly, genetic downregulation of hepatic Ephx2 (which encodes sEH) ameliorates TBI-induced neurological deficits and promotes neurological function recovery, whereas overexpression of hepatic sEH exacerbates TBI-associated neurological impairments. Furthermore, hepatic sEH ablation was found to promote the generation of A2 phenotype astrocytes and facilitate the production of various neuroprotective factors associated with astrocytes following TBI. We also observed an inverted V-shaped alteration in the plasma levels of four EET (epoxyeicosatrienoic acid) isoforms (5,6-, 8,9-,11,12-, and 14,15-EET) following TBI which were negatively correlated with hepatic sEH activity. However, hepatic sEH manipulation bidirectionally regulates the plasma levels of 14,15-EET, which rapidly crosses the blood-brain barrier. Additionally, we found that the application of 14,15-EET mimicked the neuroprotective effect of hepatic sEH ablation, while 14,15-epoxyeicosa-5(Z)-enoic acid blocked this effect, indicating that the increased plasma levels of 14,15-EET mediated the neuroprotective effect observed after hepatic sEH ablation. These results highlight the neuroprotective role of the liver in TBI and suggest that targeting hepatic EET signaling could represent a promising therapeutic strategy for treating TBI.


Assuntos
Lesões Encefálicas Traumáticas , Fármacos Neuroprotetores , Animais , Camundongos , Fármacos Neuroprotetores/farmacologia , Eicosanoides , Astrócitos , Fígado , Epóxido Hidrolases/genética
3.
J Neurosci ; 44(7)2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38124211

RESUMO

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and stereotyped behaviors. Although major advances in basic research on autism have been achieved in the past decade, and behavioral interventions can mitigate the difficulties that individuals with autism experience, little is known about the many fundamental issues of the interventions, and no specific medication has demonstrated efficiency for the core symptoms of ASD. Intermittent hypobaric hypoxia (IHH) is characterized by repeated exposure to lowered atmospheric pressure and oxygen levels, which triggers multiple physiological adaptations in the body. Here, using two mouse models of ASD, male Shank3B -/- and Fmr1 -/y mice, we found that IHH training at an altitude of 5,000 m for 4 h per day, for 14 consecutive days, ameliorated autistic-like behaviors. Moreover, IHH training enhanced hypoxia inducible factor (HIF) 1α in the dorsal raphe nucleus (DRN) and activated the DRN serotonergic neurons. Infusion of cobalt chloride into the DRN, to mimic IHH in increasing HIF1α expression or genetically knockdown PHD2 to upregulate HIF1α expression in the DRN serotonergic neurons, alleviated autistic-like behaviors in Shank3B -/- mice. In contrast, downregulation of HIF1α in DRN serotonergic neurons induced compulsive behaviors. Furthermore, upregulating HIF1α in DRN serotonergic neurons increased the firing rates of these neurons, whereas downregulation of HIF1α in DRN serotonergic neurons decreased their firing rates. These findings suggest that IHH activated DRN serotonergic neurons via upregulation of HIF1α, and thus ameliorated autistic-like phenotypes, providing a novel therapeutic option for ASD.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Camundongos , Masculino , Animais , Transtorno Autístico/genética , Transtorno Autístico/terapia , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/terapia , Núcleo Dorsal da Rafe , Neurônios Serotoninérgicos/fisiologia , Hipóxia , Fenótipo , Proteína do X Frágil da Deficiência Intelectual
4.
J Neurosci ; 43(27): 5092-5113, 2023 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-37308296

RESUMO

Hereditary spastic paraplegia (HSP) is a severe neurodegenerative movement disorder, the underlying pathophysiology of which remains poorly understood. Mounting evidence has suggested that iron homeostasis dysregulation can lead to motor function impairment. However, whether deficits in iron homeostasis are involved in the pathophysiology of HSP remains unknown. To address this knowledge gap, we focused on parvalbumin-positive (PV+) interneurons, a large category of inhibitory neurons in the central nervous system, which play a critical role in motor regulation. The PV+ interneuron-specific deletion of the gene encoding transferrin receptor 1 (TFR1), a key component of the neuronal iron uptake machinery, induced severe progressive motor deficits in both male and female mice. In addition, we observed skeletal muscle atrophy, axon degeneration in the spinal cord dorsal column, and alterations in the expression of HSP-related proteins in male mice with Tfr1 deletion in the PV+ interneurons. These phenotypes were highly consistent with the core clinical features of HSP cases. Furthermore, the effects on motor function induced by Tfr1 ablation in PV+ interneurons were mostly concentrated in the dorsal spinal cord; however, iron repletion partly rescued the motor defects and axon loss seen in both sexes of conditional Tfr1 mutant mice. Our study describes a new mouse model for mechanistic and therapeutic studies relating to HSP and provides novel insights into iron metabolism in spinal cord PV+ interneurons and its role in the regulation of motor functions.SIGNIFICANCE STATEMENT Iron is crucial for neuronal functioning. Mounting evidence suggests that iron homeostasis dysregulation can induce motor function deficits. Transferrin receptor 1 (TFR1) is thought to be the key component in neuronal iron uptake. We found that deletion of Tfr1 in parvalbumin-positive (PV+) interneurons in mice induced severe progressive motor deficits, skeletal muscle atrophy, axon degeneration in the spinal cord dorsal column, and alterations in the expression of hereditary spastic paraplegia (HSP)-related proteins. These phenotypes were highly consistent with the core clinical features of HSP cases and partly rescued by iron repletion. This study describes a new mouse model for the study of HSP and provides novel insights into iron metabolism in spinal cord PV+ interneurons.


Assuntos
Paraplegia Espástica Hereditária , Masculino , Feminino , Animais , Camundongos , Paraplegia Espástica Hereditária/genética , Parvalbuminas/metabolismo , Proteínas/genética , Fenótipo , Interneurônios/metabolismo , Atrofia
5.
BMC Psychiatry ; 24(1): 135, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38365625

RESUMO

BACKGROUND: Little is known about mobile phone problem use (MPPU) among older adults. This study investigated critical factors affecting MPPU and filled the gap between MPPU and depressive symptoms in older people. METHODS: A cross-sectional study was conducted in community (n = 376) with questionnaires of Multidimensional Scale of Perceived Social Support (MSPSS), Geriatric Depression Scale (GDS-15), Attitudes to Aging Questionnaire (AAQ) and Mobile Phone Problem Use Scale (MPPUS). RESULTS: 80.9% of older people used smartphones and spend less than three hours on mobile phone per day. The average MPPU score of Chinese elderly is greater than the cut off to 41. Female (ß = -0.11, P = 0.037), living with spouse (ß = -0.17, P = 0.03), and late marriage age (ß = -0.16, P = 0.007) are less likely to develop MPPU. The relationship between MPPU and depressive symptoms was partially mediated by social support and attitude to aging. CONCLUSION: Elderly people generally have higher MPPU scores. MPPU was associated with depressive symptoms, through social support and attitude to aging.


Assuntos
Telefone Celular , Depressão , Humanos , Feminino , Idoso , Depressão/diagnóstico , Estudos Transversais , Envelhecimento , Apoio Social , China
6.
Neurol Sci ; 45(6): 2489-2503, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38194198

RESUMO

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons, and there is currently a lack of reliable diagnostic biomarkers. This meta-analysis aimed to evaluate CHIT1, CHI3L1, and CHI3L2 levels in the cerebrospinal fluid (CSF) or blood and their diagnostic potential in ALS patients. A systematic, comprehensive search was performed of peer-reviewed English-language articles published before April 1, 2023, in PubMed, Scopus, Embase, Cochrane Library, and Web of Science. After a thorough screening, 13 primary articles were included, and their chitinases-related data were extracted for systematic review and meta-analysis. In ALS patients, the CSF CHIT1 levels were significantly elevated compared to controls with healthy control (HC) (SMD, 1.92; 95% CI, 0.78 - 3.06; P < 0.001). CHIT1 levels were elevated in the CSF of ALS patients compared to other neurodegenerative diseases (ONDS) control (SMD, 0.74; 95% CI, 0.22 - 1.27; P < 0.001) and exhibited an even more substantial increase when compared to ALS-mimicking diseases (AMDS) (SMD, 1.15; 95% CI, 0.35 - 1.94, P < 0.001). Similarly, the CSF CHI3L1 levels were significantly higher in ALS patients compared to HC (SMD, 3.16; 95% CI, 1.26 - 5.06, P < 0.001). CHI3L1 levels were elevated in the CSF of ALS patients compared to ONDS (SMD, 0.75; 95% CI, 0.32 - 1.19; P = 0.017) and exhibited a more pronounced increase when compared to AMDS (SMD, 1.92; 95% CI, 0.41 - 3.42; P < 0.001). The levels of CSF chitinases in the ALS patients showed a significant increase, supporting the role of CSF chitinases as diagnostic biomarkers for ALS.


Assuntos
Esclerose Lateral Amiotrófica , Biomarcadores , Quitinases , Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/sangue , Humanos , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Quitinases/líquido cefalorraquidiano , Quitinases/sangue , Prognóstico , Hexosaminidases/líquido cefalorraquidiano , Hexosaminidases/sangue , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Proteína 1 Semelhante à Quitinase-3/sangue
7.
BMC Geriatr ; 24(1): 199, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38413861

RESUMO

BACKGROUND: Physical frailty (PF) and circadian syndrome (CircS) are proposed as novel risks for cardiovascular disease (CVD), but little attention is paid to their combined impact on CVD. This study aimed to investigate the association of PF, CircS and CVD in middle-aged and older adults. METHODS: The sample comprised 8512 participants aged at least 45 years from the China Health and Retirement Longitudinal Study (CHARLS) 2011. PF was examined by the physical frailty phenotype scale. CircS was assessed by the components of the International Diabetes Federation (IDF) MetS plus short sleep duration and depression. The cut-off for CircS was set as ≥ 4. CVD was defined as the presence of physician-diagnosed heart disease and/or stroke. A total of 6176 participants without CVD recruited from CHARLS 2011 and were followed up in 2018. RESULTS: The prevalence of CVD in total populations, neither CircS or PF, PF alone, CircS alone and both CircS and PF were 13.0%, 7.4%, 15.5%, 17.4%, and 30.2%, respectively. CircS was more likely to be PF [OR (95%CI): 2.070 (1.732 ∼ 2.472)] than those without CircS. Both CircS alone [OR (95% CI): 1.954 (1.663 ∼ 2.296)], and coexisting CircS and PF [3.508 (2.739 ∼ 4.494)] were associated with CVD. Longitudinal analysis showed that individuals with both CircS and PF (HR: 1.716, 95%CI: 1.314 ∼ 2.240) and CircS alone [1.520 (1.331 ∼ 1.737)] were more likely to have new onset CVD than neither CircS or PF peers. CONCLUSION: PF and CircS together are associated with higher CVD risk, which provided new evidence for a strong relation that warrants attention to assessing PF and CircS and in community to promote healthy aging.


Assuntos
Doenças Cardiovasculares , Fragilidade , Humanos , Pessoa de Meia-Idade , Idoso , Fragilidade/epidemiologia , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Estudos Longitudinais , Fatores de Risco , Prevalência , Síndrome
8.
BMC Public Health ; 24(1): 597, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38395888

RESUMO

OBJECTIVES: With the world's population increasing in age, there has been a significant rise in the prevalence of cognitive impairment and dementia among individuals. This study aims to investigate the association between grandparenting and cognitive function among middle-aged and older Chinese using data from 2011 to 2018 China Health and Retirement Longitudinal Study (CHARLS). Additionally, the study seeks to explore the potential mediating effect of intergenerational support from children on this relationship, using data from the CHARLS 2011 database. METHODS: 5254 participants were recruited at the baseline survey in CHARLS 2011. Subsequently, a follow-up survey was conducted over 8 years, from CHARLS 2011 to 2018, with 1472 individuals completing the follow-up survey. The CHARLS included surveys on grandparenting and cognitive assessments. Grandparenting was categorized as yes and no. The assessment of cognitive function involved the evaluation of episodic memory and mental intactness. The present study used cross-sectional and longitudinal analyses to examine the relationship between grandparenting and cognitive function. The bootstrap method assessed the mediating effect of children's intergenerational support. RESULTS: The results of both cross-sectional and longitudinal studies indicated a positive association between grandparenting and cognitive function in middle-aged and older Chinese (B = 0.138, p < 0.05; B = 0.218, p < 0.05). Children's emotional and economic support played intermediary roles between grandparenting and cognitive function. CONCLUSION: The results emphasized the significance of policymakers considering the consequences of intergenerational care and family support when formulating and executing social service policies targeted at the middle-aged and older population in China.


Assuntos
Cognição , Aposentadoria , Pessoa de Meia-Idade , Criança , Humanos , Idoso , Estudos Longitudinais , Estudos de Coortes , Estudos Transversais , China/epidemiologia
9.
J Gen Intern Med ; 38(6): 1431-1438, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36443629

RESUMO

AIM: This study investigated whether an individual's age at diagnosis of hypertension, which is associated with a decline in cognitive performance in the China Health and Retirement Longitudinal Study (CHARLS) participants. METHODS: Our analysis was based on the CHARLS with baseline data collected between 2011 and 2018. We randomly selected a control participant for each hypertensive participant using propensity score. The cohort comprised 2413 individuals with hypertension and 2411 controls. Participants were divided into three groups as follows: non-hypertension, hypertension diagnose ≥55 years, and hypertension diagnose <55 years. Cognitive performance was measured in both visits and evaluated by the scores of the memory, executive function, and orientation and global cognitive. RESULTS: After multivariable adjustment, individuals with hypertension diagnosed <55 years had a significantly faster cognitive decline in memory test (ß (95% CI, -1.117 [-1.405, -0.83]), orientation test (ß (95% CI, -1.273 [-1.348, -1.198]) and global cognitive (ß (95% CI, -1.611 [-1.744, -1.478]) compared with the corresponding controls. A longer hypertension duration was associated with worse memory test (ß (95% CI, -0.069 [-0.113 to -0.025]). Among treated individuals, blood pressure control at baseline was inversely associated with the decline in orientation test (ß (95% CI, -0.659 [-0.939, -0.380]), orientation test (ß (95% CI, -0.259[-0.365, -0.153])and global cognitive (ß (95% CI, -0.124 [-0.162, -0.086]). CONCLUSIONS: Our findings suggest that hypertension diagnosed in mid-life is associated with worse cognition compared to late life. Besides, longer duration of diagnosis is associated with worse memory test. In addition to hypertension, pressure control might be critical for the preservation of cognitive function.


Assuntos
Disfunção Cognitiva , Hipertensão , Humanos , Estudos Longitudinais , Aposentadoria , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Cognição/fisiologia , Hipertensão/diagnóstico , Hipertensão/epidemiologia
10.
Int J Geriatr Psychiatry ; 38(3): e5894, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36814066

RESUMO

BACKGROUND: Depression affects 10%-20% of older adults worldwide. The course of late-life depression (LLD) is often chronic, with a poor long-term prognosis. Lower treatment adherence, stigma, and suicide risk lead to significant challenges in the continuity of care (COC) for patients with LLD. Elderly patients with chronic diseases can benefit from COC. As a common chronic disease of the elderly, whether depression can also benefit from COC has not been systematically reviewed. METHODS: Systematic literature search in Embase, Cochrane Library, Web of Science, Ovid, PubMed and Medline. Randomized Controlled Trials (RCTs) on the intervention effects of COC and LLD, published on 12 April 2022, were selected. Two independent researchers made research choices based on consensus. An RCT with COC as an intervention measure for the elderly with depression 60 years old was the inclusion criteria. RESULTS: A total of 10 RCTs involving 1557 participants were identified in this study. The findings showed that: (1) COC significantly reduced depressive symptoms compared to usual care (standardized mean difference [SMD] = -0.47, 95% confidence interval: -0.63 to -0.31), with the best improvement at 3- to 6-month follow-up; (2) The reduction in depressive symptoms was more pronounced for patients with comorbid chronic conditions with LLD (SMD = -0.93, 95% CI: -1.18 to -0.68); (3) COC was more effective than other regions for LLD in Europe and the Americas (SMD = -0.84, 95% CI: -1.07 to -0.61); and (4) COC had a positive impact on the quality of life of patients with LLD (SMD = 0.21, 95% CI: 0.02-0.40). LIMITATIONS: The included studies included several multi-component interventions with widely varying methods. Therefore, it was almost impossible to analyze which of these interventions had an impact on the assessed outcomes. CONCLUSIONS: This meta-analysis shows that COC can significantly reduce depressive symptoms and improve quality of life in patients with LLD. However, when treating and caring for patients with LLD, health care providers should also pay attention to timely adjustments of intervention plans according to follow-up, synergistic interventions for multiple co-morbidities, and actively learning from advanced COC programs at home and abroad to improve the quality and effectiveness of services.


Assuntos
Depressão , Qualidade de Vida , Humanos , Idoso , Depressão/terapia , Comorbidade , Doença Crônica , Europa (Continente)
11.
Public Health Nutr ; 26(12): 2780-2789, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37990536

RESUMO

OBJECTIVE: This systematic review aimed to investigate the association between dietary inflammatory potential and liver cancer to provide evidence regarding scientific dietary health education. DESIGN: Systematic review and meta-analysis. SETTING: A comprehensive literature review was conducted to identify case-control or cohort studies that involved dietary inflammation index (DII)/empirical dietary inflammation pattern (EDIP) and liver cancer in PubMed, EMBASE, Cochrane, and Web of Science databases. Using a combination of DII/EDIP and liver cancer as the search terms, the associations between DII/EDIP and liver cancer were then assessed. PARTICIPANTS: Three case-control studies and two cohort studies were brought into the meta-analysis, with 225 713 enrolled participants. RESULTS: Meta-analysis of categorical variables showed that DII/EDIP in the highest category increased the risk of liver cancer compared to DII/EDIP in the lowest category (relative risk (RR) = 2·35; 95 % CI 1·77, 3·13; P = 0·000) and with low heterogeneity across studies (I2 = 40·8 %, P = 0·119). Meta-analysis of continuous variables showed that significant positive association between liver cancer and DII/EDIP scores (RR = 1·24; 95 % CI 1·09, 1·40; P = 0·001), and no heterogeneity (I² = 0·0 %, P = 0·471). Stratified according to the study design, there was a significant positive association between liver cancer and DII/EDIP scores in both cohort studies (RR = 2·16; 95 % CI 1·51, 3·07; P = 0·000) and case-control studies (RR = 2·75; 95 % CI 1·71, 4·41; P = 0·000). CONCLUSION: The higher the DII/EDIP score, the higher the risk of liver cancer. This finding may have prominent implications for the general population.


Assuntos
Dieta , Neoplasias Hepáticas , Humanos , Fatores de Risco , Dieta/efeitos adversos , Inflamação/epidemiologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Padrões Dietéticos
12.
Mol Psychiatry ; 26(8): 4511-4528, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-32015466

RESUMO

Schizophrenia is a complex genetic disorder, the non-Mendelian features of which are likely complicated by epigenetic factors yet to be elucidated. Here, we performed RNA sequencing of peripheral blood RNA from monozygotic twins discordant for schizophrenia, and identified a schizophrenia-associated upregulated long noncoding RNA (lncRNA, AC006129.1) that participates in the inflammatory response by enhancing SOCS3 and CASP1 expression in schizophrenia patients and further validated this finding in AC006129.1-overexpressing mice showing schizophrenia-related abnormal behaviors. We find that AC006129.1 binds to the promoter region of the transcriptional repressor Capicua (CIC), facilitates the interactions of DNA methyltransferases with the CIC promoter, and promotes DNA methylation-mediated CIC downregulation, thereby ameliorating CIC-induced SOCS3 and CASP1 repression. Derepression of SOCS3 enhances the anti-inflammatory response by inhibiting JAK/STAT-signaling activation. Our findings reveal an epigenetic mechanism with etiological and therapeutic implications for schizophrenia.


Assuntos
Metilação de DNA , RNA Longo não Codificante , Esquizofrenia , Proteína 3 Supressora da Sinalização de Citocinas , Animais , Regulação para Baixo , Humanos , Inflamação , Camundongos , RNA Longo não Codificante/genética , Esquizofrenia/genética , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo
13.
Environ Res ; 204(Pt D): 112403, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34800533

RESUMO

Previous studies have indicated maternal exposure to particles with aerodynamic diameter <2.5 µm (PM2.5) is associated with preterm birth (PTB). However, no study has investigated this effect in pre-pregnancy impaired fasting glucose (IFG) women. This study aimed to differentiate the effects of maternal PM2.5 exposure on PTB between pre-pregnancy IFG and normoglycemia women, and to further identify the susceptible window. This cohort study was conducted between January 2014 and December 2017 in 21 Chinese cities. All the recruited women received pre-pregnancy fasting serum glucose (FSG) tests and were followed up for their delivery outcomes. The PM2.5 exposures were estimated by the daily air pollution concentrations of the nearby monitors. Women with FSG below 7.0 mmol/L were included in the analysis. We employed the Cox proportional hazards models to examine whether PM2.5 exposure was associated with PTB. 237957 women were included and 7055 (3.0%) of them were pre-pregnancy IFG. During the entire pregnancy, we found 24.1% (HR = 1.241; 95% CI: 1.069, 1.439), 61.8% (HR = 1.618; 95% CI: 1.311, 1.997) and 18.6% (HR = 1.186; 95% CI: 1.004, 1.402) of increases in risk for all PTB, early PTB (20-33 gestational weeks) and late PTB (34-36 gestational weeks) among the pre-pregnancy IFG women, and 15.9% (HR = 1.159; 95% CI: 1.127, 1.192), 33.9% (HR = 1.339; 95% CI: 1.255, 1.430) and 13.2% (HR = 1.132; 95% CI: 1.098, 1.168) of increases in risk for all PTB, early PTB and late PTB among the normoglycemia women, with each 10 µg/m3 increment of PM2.5 exposure, respectively. Furthermore, PM2.5 exposure had the strongest effect on all PTB during trimester 1 (0-12 gestational weeks) among the pre-pregnancy IFG women, compared with the less strong effect during trimester 1 among the normoglycemia women. In conclusion, pre-pregnancy IFG increases the risk of PTB attributed to PM2.5, especially during trimester 1. Moreover, the effects of PM2.5 are greater on early PTB than late PTB for both pre-pregnancy IFG and normoglycemia women.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Nascimento Prematuro , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , China/epidemiologia , Estudos de Coortes , Jejum , Feminino , Glucose , Humanos , Recém-Nascido , Exposição Materna/efeitos adversos , Material Particulado/análise , Material Particulado/toxicidade , Gravidez , Nascimento Prematuro/induzido quimicamente , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/etiologia
14.
J Neurosci ; 40(42): 8188-8203, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-32973044

RESUMO

Alzheimer's disease (AD) is the leading cause of late-onset dementia, and there exists an unmet medical need for effective treatments for AD. The accumulation of neurotoxic amyloid-ß (Aß) plaques contributes to the pathophysiology of AD. EPHX2 encoding soluble epoxide hydrolase (sEH)-a key enzyme for epoxyeicosatrienoic acid (EET) signaling that is mainly expressed in lysosomes of astrocytes in the adult brain-is cosited at a locus associated with AD, but it is unclear whether and how it contributes to the pathophysiology of AD. In this report, we show that the pharmacologic inhibition of sEH with 1-trifluoromethoxyphenyl- 3-(1-propionylpiperidin-4-yl) urea (TPPU) or the genetic deletion of Ephx2 reduces Aß deposition in the brains of both male and female familial Alzheimer's disease (5×FAD) model mice. The inhibition of sEH with TPPU or the genetic deletion of Ephx2 alleviated cognitive deficits and prevented astrocyte reactivation in the brains of 6-month-old male 5×FAD mice. 14,15-EET levels in the brains of these mice were also increased by sEH inhibition. In cultured adult astrocytes treated with TPPU or 14,15-EET, astrocyte Aß clearance was increased through enhanced lysosomal biogenesis. Infusion of 14,15-EET into the hippocampus of 5×FAD mice prevented the aggregation of Aß. Notably, a higher concentration of 14,15-EET (200 ng/ml) infusion into the hippocampus reversed Aß deposition in the brains of 6-month-old male 5×FAD mice. These results indicate that EET signaling, especially 14,15-EET, plays a key role in the pathophysiology of AD, and that targeting this pathway is a potential therapeutic strategy for the treatment of AD.SIGNIFICANCE STATEMENT There are limited treatment options for Alzheimer's disease (AD). EPHX2 encoding soluble epoxide hydrolase (sEH) is located at a locus that is linked to late-onset AD, but its contribution to the pathophysiology of AD is unclear. Here, we demonstrate that sEH inhibition or Ephx2 deletion alleviates pathology in familial Alzheimer's disease (5×FAD) mice. Inhibiting sEH or increasing 14,15-epoxyeicosatrienoic acid (EET) enhanced lysosomal biogenesis and amyloid-ß (Aß) clearance in cultured adult astrocytes. Moreover, the infusion of 14,15-EET into the hippocampus of 5×FAD mice not only prevented the aggregation of Aß, but also reversed the deposition of Aß. Thus, 14,15-EET plays a key role in the pathophysiology of AD and therapeutic strategies that target this pathway may be an effective treatment.


Assuntos
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Doença de Alzheimer/tratamento farmacológico , Ácido 8,11,14-Eicosatrienoico/uso terapêutico , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Química Encefálica/efeitos dos fármacos , Linhagem Celular , Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/genética , Comportamento Exploratório/efeitos dos fármacos , Feminino , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia
15.
J Mol Cell Cardiol ; 154: 80-91, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33378686

RESUMO

Obesity-driven cardiac lipid accumulation can progress to lipotoxic cardiomyopathy. Soluble epoxide hydrolase (sEH) is the major enzyme that metabolizes epoxyeicosatrienoic acids (EETs), which have biological activity of regulating lipid metabolism. The current study explores the unknown role of sEH deficiency in lipotoxic cardiomyopathy and its underlying mechanism. Wild-type and Ephx2 knock out (sEH KO) C57BL/6 J mice were fed with high-fat diet (HFD) for 24 weeks to induce lipotoxic cardiomyopathy animal models. Palmitic acid (PA) was utilized to induce lipotoxicity to cardiomyocytes for in vitro study. We found sEH KO, independent of plasma lipid and blood pressures, significantly attenuated HFD-induced myocardial lipid accumulation and cardiac dysfunction in vivo. HFD-induced lipotoxic cardiomyopathy and dysfunction of adenosine 5'-monophosphate-activated protein kinase-mammalian target of rapamycin complex (AMPK-mTORC) signaling mediated lipid autophagy in heart were restored by sEH KO. In primary neonatal mouse cardiomyocytes, both sEH KO and sEH substrate EETs plus sEH inhibitor AUDA treatments attenuated PA-induced lipid accumulation. These effects were blocked by inhibition of AMPK or autophagy. The outcomes were supported by the results that sEH KO and EETs plus AUDA rescued HFD- and PA-induced impairment of autophagy upstream signaling of AMPK-mTORC, respectively. These findings revealed that sEH deficiency played an important role in attenuating myocardial lipid accumulation and provided new insights into treating lipotoxic cardiomyopathy. Regulation of autophagy via AMPK-mTORC signaling pathway is one of the underlying mechanisms.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Epóxido Hidrolases/deficiência , Miocárdio/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Biomarcadores , Cardiomiopatias/fisiopatologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Metabolismo dos Lipídeos , Camundongos , Camundongos Knockout
16.
Nat Chem Biol ; 15(12): 1214-1222, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31591566

RESUMO

Iron is essential for a broad range of biochemical processes in the brain, but the mechanisms of iron metabolism in the brain remain elusive. Here we show that iron functionally translocates among brain regions along specific axonal projections. We identified two pathways for iron transport in the brain: a pathway from ventral hippocampus (vHip) to medial prefrontal cortex (mPFC) to substantia nigra; and a pathway from thalamus (Tha) to amygdala (AMG) to mPFC. While vHip-mPFC transport modulates anxiety-related behaviors, impairment of Tha-AMG-mPFC transport did not. Moreover, vHip-mPFC iron transport is necessary for the behavioral effects of diazepam, a well-known anxiolytic drug. By contrast, genetic or pharmacological promotion of vHip-mPFC transport produced anxiolytic-like effects and restored anxiety-like behaviors induced by repeated restraint stress. Taken together, these findings provide key insights into iron metabolism in the brain and identify the mechanisms underlying iron transport in the brain as a potential target for development of novel anxiety treatments.


Assuntos
Ansiedade/metabolismo , Axônios/metabolismo , Encéfalo/metabolismo , Ferro/metabolismo , Animais , Transporte Biológico , Masculino , Camundongos
17.
Ecotoxicol Environ Saf ; 218: 112308, 2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-33975224

RESUMO

Accumulating studies have revealed the toxicity of antimony (Sb) to soil-dwelling and aquatic organisms at the individual level. However, little is known about the neurotoxic effects of antimony and its underlying mechanisms. To assess this issue, we investigated the neurotoxicity of antimony (0, 200, 400, 600 and 800 mg/L) in zebrafish embryos. After exposure, zebrafish embryos showed abnormal phenotypes such as a shortened body length, morphological malformations, and weakened heart function. Behavioral experiments indicated that antimony caused neurotoxicity in zebrafish embryos, manifested in a decreased spontaneous movement frequency, delayed response to touch, and reduced movement distance. We also showed that antimony caused a decrease in acetylcholinesterase (AChE) levels in zebrafish embryos, along with decreased expression of neurofunctional markers such as gfap, nestin, mbp, and shha. Additionally, antimony significantly increased reactive oxygen species levels and significantly reduced glutathione (GSH) and superoxide dismutase (SOD) activity. In summary, our findings indicated that antimony can induce developmental toxicity and neurotoxicity in zebrafish embryos by affecting neurotransmitter systems and oxidative stress, thus altering behavior. These outcomes will advance our understanding of antimony-induced neurotoxicity, environmental problems, and health hazards.

18.
Arch Psychiatr Nurs ; 35(3): 317-322, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33966799

RESUMO

Tongqi (gays' wives) in China were under tremendous distress and social pressure due to their special identities and were not clearly known. A sample of 179 Chinese Tongqi were recruited through online social media groups in 2017-2018. Their hidden lives, social support, and coping styles were analyzed. The results showed that the majority of Tongqi concealed their identities, had negative responses to cope with their tremendous distress, and did not have sufficient social support. Their social support was mainly from family members. Hidden identities obstructed Tongqi's access to extrafamilial social support that could alleviate their distress. Tongqi need more social support and protection.


Assuntos
Adaptação Psicológica , Apoio Social , China , Estudos Transversais , Humanos , Masculino , Inquéritos e Questionários
19.
Nurs Ethics ; 28(2): 297-310, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32975494

RESUMO

BACKGROUND: Social media has become an integrated part of nursing profession, requiring nursing students to develop confidentiality and professional fitness to practice. The aim of this study was to investigate nursing students' usage, professionalism and attitudes toward social media. METHODS: A cross-section study was conducted online among undergraduate nursing students (n = 654). Questionnaires of self-directed learning, self-efficacy and usage and views toward social media were administered. ETHICAL CONSIDERATIONS: Ethical approval was obtained from the Hubei University of Chinese Medicine. RESULTS: All participants were social media users. QQ (93.2%) was the most frequently used. 74.5% respondents spent 2-6 h on social media daily. The majority held positive attitudes toward social media. Year group and gender had influence on perceptions and attitudes toward social media. Furthermore, 81.5% students believed that social media positively influenced self-directed learning. Self-directed learning and learning motivation acted as predictors of the attitudes toward social media. Meanwhile, 67.3% students had posted personal photos and videos online, and 82.4% of them did not have privacy setting on social media. In addition,13.8% students attacked others or posted improper photos online. 22.9% participants witnessed improper posts from schoolmates or teachers, such as complaints about schoolmates or teachers (22.2%), foul language (11.1%), violence (3.9%), sexually suggestive photos (2.6%) and patient confidentiality (0.7%). In all, 15.0% respondents accepted "friend request" from patients. A total of 58.2% students were not aware of professional standards of behavior online for health care providers. In addition, 52.3% participants insisted that it is essential to develop social media and professionalism course for nursing students. CONCLUSION: Nursing students use social media extensively. Some students are at risk of carrying out unprofessional behavior which have detrimental effects on students' future opportunities. This suggests that best practices and training in nurse education should be implemented to help students to be informed of professionalism.


Assuntos
Bacharelado em Enfermagem , Mídias Sociais , Estudantes de Enfermagem , Humanos , Privacidade , Profissionalismo
20.
J Neurosci ; 39(23): 4606-4623, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-30902874

RESUMO

Major depressive disorder is the most common mental illness. Mounting evidence indicates that astrocytes play a crucial role in the pathophysiology of depression; however, the underlying molecular mechanisms remain elusive. Compared with other neuronal cell types, astrocytes are enriched for arachidonic acid metabolism. Herein, we observed brain-region-specific alterations of epoxyeicosatrienoic acid (EET) signaling, which is an arachidonic acid metabolic pathway, in both a mouse model of depression and postmortem samples from patients with depression. The enzymatic activity of soluble epoxide hydrolase (sEH), the key enzyme in EET signaling, was selectively increased in the mPFC of susceptible mice after chronic social defeated stress and was negatively correlated with the social interaction ratio, which is an indicator of depressive-like behavior. The specific deletion of Ephx2 (encode sEH) in adult astrocytes induced resilience to stress, whereas the impaired EET signaling in the mPFC evoked depressive-like behaviors in response to stress. sEH was mainly expressed on lysosomes of astrocytes. Using pharmacological and genetic approaches performed on C57BL/6J background adult male mice, we found that EET signaling modulated astrocytic ATP release in vitro and in vivo Moreover, astrocytic ATP release was required for the antidepressant-like effect of Ephx2 deletion in adult astrocytes. In addition, sEH inhibitors produced rapid antidepressant-like effects in multiple animal models of depression, including chronic social defeated stress and chronic mild stress. Together, our results highlight that EET signaling in astrocytes in the mPFC is essential for behavioral adaptation in response to psychiatric stress.SIGNIFICANCE STATEMENT Astrocytes, the most abundant glial cells of the brain, play a vital role in the pathophysiology of depression. Astrocytes secrete adenosine ATP, which modulates depressive-like behaviors. Notably, astrocytes are enriched for arachidonic acid metabolism. In the present study, we explored the hypothesis that epoxyeicosatrienoic acid signaling, an arachidonic acid metabolic pathway, modulates astrocytic ATP release and the expression of depressive-like behaviors. Our work demonstrated that epoxyeicosatrienoic acid signaling in astrocytes in the mPFC is essential for behavioral homeostatic adaptation in response to stress, and the extent of astrocyte functioning is greater than expected based on earlier reports.


Assuntos
Astrócitos/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Eicosanoides/fisiologia , Córtex Pré-Frontal/fisiologia , Adulto , Animais , Ácidos Araquidônicos/metabolismo , Comportamento Animal/efeitos dos fármacos , Química Encefálica , Células Cultivadas , Transtorno Depressivo Maior/genética , Modelos Animais de Doenças , Método Duplo-Cego , Eicosanoides/análise , Epóxido Hidrolases/deficiência , Epóxido Hidrolases/genética , Epóxido Hidrolases/fisiologia , Genes Reporter , Vetores Genéticos/administração & dosagem , Humanos , Lentivirus/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Córtex Pré-Frontal/química , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/fisiologia , Transdução de Sinais , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Suicídio , Adulto Jovem
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