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Fear overgeneralization is widely accepted as a pathogenic marker of post-traumatic stress disorder (PTSD). Recently, GABAergic interneurons have been regarded as key players in the regulation of fear memory. The role of hippocampal GABAergic interneurons in contextual fear generalization of PTSD remains incompletely understood. In the present study, we established a rat model of PTSD with inescapable foot shocks (IFS) and observed the loss of GABAergic interneuron phenotype in the hippocampal cornu ammonis-1 (CA1) subfield. To determine whether the loss of GABAergic interneuron phenotype was associated with fear generalization in PTSD rats, we used adeno-associated virus (AAV) to reduce the expression of GAD67 in CA1 and observed its effect on fear generalization. The results showed that the reduction of GAD67 in CA1 enhanced contextual fear generalization in rats. We investigated whether the PERK pathway was involved in the GABAergic interneuron injury. Increased expression of p-PERK, CHOP, and Caspase12 in GABAergic interneurons of PTSD rats was observed. Then, we used salubrinal, an endoplasmic reticulum stress inhibitor, to modulate the PERK pathway. The salubrinal treatment significantly protected the GABAergic interneurons and relieved fear generalization in PTSD rats. In addition, the results showed that salubrinal down-regulated the expression of CHOP and Caspase12 in GABAergic interneurons of PTSD rats. In conclusion, this study provided evidence that the loss of GABAergic interneuron phenotype in CA1 may contribute to contextual fear generalization in PTSD. The PERK pathway is involved in the GABAergic interneuron injury of PTSD rats and modulating it can protect GABAergic interneurons and constrain contextual fear generalization.
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The excitatory-inhibitory imbalance has been considered an important mechanism underlying stress-related psychiatric disorders. In the present study, rats were exposed to 6 days of inescapable foot shock (IFS) to induce stress. The open field test and elevated plus maze test showed that IFS-exposed rats exhibited increased anxiety-like behavior. Immunofluorescence showed that IFS rats had a decreased density of GAD67-immunoreactive interneurons in the dorsal hippocampal CA1 region, while no significant change in the density of CaMKIIα-immunoreactive glutamatergic neurons was seen. We investigated the expression of different interneuron subtype markers, including parvalbumin (PV), somatostatin (SST), and calretinin (CR), and noted a marked decline in the density of PV-immunoreactive interneurons in the dorsal CA1 region of IFS rats. The perineuronal net (PNN) is a specialized extracellular matrix structure primarily around PV interneurons. We used Wisteria floribunda agglutinin lectin to label the PNNs and observed that IFS rats had an increased proportion of PNN-coated PV-positive interneurons in CA1. The number of PSD95-positive excitatory synaptic puncta on the soma of PNN-free PV-positive interneurons was significantly higher than that of PNN-coated PV-positive interneurons. Our findings suggest that the effect of IFS on the hippocampal GABAergic interneurons could be cell-type-specific. Loss of PV phenotype in the dorsal hippocampal CA1 region may contribute to anxiety in rats. The dysregulated PV-PNN relationship in CA1 after traumatic stress exposure might represent one of the neurobiological correlates of the observed anxiety-like behavior.
Assuntos
Neurônios , Parvalbuminas , Humanos , Ratos , Animais , Parvalbuminas/metabolismo , Matriz Extracelular/metabolismo , Interneurônios/metabolismo , Hipocampo/metabolismo , AnsiedadeRESUMO
Coupling hollow semiconductor with metal-organic frameworks (MOFs) holds great promise for constructing high-efficient CO2 photoreduction systems. However, energy band mismatch between them makes it difficult to exert their advantages to maximize the overall photocatalytic efficiency, since that the blockage of desirable interfacial charge transfer gives rise to the enrichment of photoelectrons and CO2 molecules on the different locations. Herein, an interfacial engineering is presented to overcome this impediment, based on the insertion of plasmonic metal into the heterointerfaces between them, forming a stacked semiconductor/metal@MOF photocatalyst. Experimental observations and theoretical simulations validate the critical roles of embedded Au in maneuvering the charge separation/transfer and surface reaction: (i) bridges the photoelectron transfer from hollow CdS (H-CdS) to ZIF-8; (ii) produces hot electrons and shifts them to ZIF-8; (iii) induces the formation of ZIF-8 defects in promoting the CO2 adsorption/activation and transformation to CO with low energy barriers. Consequently, the as-prepared H-CdS/Au@ZIF-8 with optimal ZIF-8 thickness exhibits distinctly boosted activity and superb selectivity in CO production as compared with H-CdS@ZIF-8 and other counterparts. This work provides protocols to take full advantages of components involved for enhanced solar-to-chemical energy conversion efficiency of hybrid artificial photosynthetic systems through rationally harnessing the charge transfer between them.
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BACKGROUND: As the fifth-largest global mortality risk factor, air pollution has caused nearly one-tenth of the world's deaths, with a death toll of 5 million. 21% of China's disease burden was related to environmental pollution, which is 8% higher than the US. Air pollution will increase the demand and utilisation of Chinese residents' health services, thereby placing a greater economic burden on the government. This study reveals the spatial impact of socioeconomic, health, policy and population factors combined with environmental factors on government health expenditure. METHODS: Spearman's correlation coefficient and GeoDetector were used to identify the determinants of government health expenditure. The GeoDetector consist of four detectors: factor detection, interaction detection, risk detection, and ecological detection. One hundred sixty-nine prefecture-level cities in China are studied. The data sources are the 2017 data from China's Economic and Social Big Data Research Platform and WorldPOP gridded population datasets. RESULTS: It is found that industrial sulfur dioxide attributed to government health expenditure, whose q value (explanatory power of X to Y) is 0.5283. The interaction between air pollution factors and other factors will increase the impact on government health expenditure, the interaction value (explanatory power of × 1â©× 2 to Y) of GDP and industrial sulfur dioxide the largest, whose values is 0.9593. There are 96 simple high-risk areas in these 169 areas, but there are still high-risk areas affected by multiple factors. CONCLUSION: First, multiple factors influence the spatial heterogeneity of government health expenditure. Second, health and socio-economic factors are still the dominant factors leading to increased government health expenditure. Third, air pollution does have an important impact on government health expenditure. As a catalytic factor, combining with other factors, it will strengthen their impact on government health expenditure. Finally, an integrated approach should be adopted to synergisticly governance the high-risk areas with multi-risk factors.
Assuntos
Poluentes Atmosféricos , Poluição do Ar , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , China/epidemiologia , Cidades , Governo , Gastos em Saúde , Humanos , Material Particulado/análise , Dióxido de EnxofreRESUMO
Artemisinin is known for its pharmaceutical effect against malaria and received increased attention for its other potential function. Mounting evidence suggest that artemisinin could also exert cardioprotective effects while the understanding of its regulatory mechanism is still limited. This study is designed to investigate the role of artemisinin in myocardial ischemia/reperfusion (I/R) injury and the involvement of NLRP3 inflammasome. Artemisinin was administrated for 14 consecutive days intragastrically before I/R injury. Cardiac function was assessed by echocardiography. Infarct area was observed through HE and TTC staining. Apoptosis and autophagy were assessed by TUNEL and Western blotting. The artemisinin-treated myocardial I/R rats demonstrated less severe myocardial I/R injury (smaller infarct size and lower CK-MB, LDH), significant inhibition of cardiac autophagy (decreased LC3II/I and increased p62), improved mitochondrial electron transport chain activity, concomitant with decreased activation of NLRP3 inflammasome (decreased NLRP3, ASC, cleaved caspase-1, IL-1ß). In conclusion, our findings further confirmed that activation of the NLRP3 inflammasome pathway is involved in myocardial I/R injury, whereas artemisinin preconditioning could effectively protect against myocardial I/R injury through suppression of NLRP3 inflammasome activation. Therefore, the NLRP3 inflammasome might serve as a promising therapeutic target providing new mechanisms for understanding the effect of artemisinin during the evolution of myocardial infarction.
Assuntos
Artemisininas/farmacologia , Autofagia , Inflamassomos/efeitos dos fármacos , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Antimaláricos/farmacologia , Apoptose , Inflamassomos/metabolismo , Masculino , Isquemia Miocárdica/imunologia , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Ratos , Transdução de SinaisRESUMO
OBJECTIVE: The role of glucose-insulin-potassium (GIK) infusion during cardiac surgery has held interest for so many years without a clear answer. The aim of this meta-analysis was to evaluate the effect of GIK therapy on outcomes in patients undergoing on-pump cardiac surgery. METHODS: A comprehensive online review was performed in The Web of Science, Embase, Medline, PubMed, and The Cochrane Library databases from 2000 to 2019. Eligible studies included randomized controlled trials (RCTs) that compared GIK treatment with placebo or standard care during on-pump cardiac surgery. Risk ratios (RR) were used for binary outcomes and mean difference (MD) was used for continuous variables; both with their 95% confidence intervals (CI). RESULTS: A total of 18 RCTs involving 2,131 patients met the inclusion criteria. Compared with the control group, the GIK treatment significantly reduced in-hospital mortality (RR = 0.56, 95% CI: 0.32-0.97; P = .04), postoperative myocardial infarctions (MI) (RR = 0.71, 95% CI: 0.56-0.91; P = .006), the use of inotropic support (RR = 0.53, 95% CI: 0.45-0.63; P < .00001), and length of stay in the intensive care unit (ICU) (MD = -0.33, 95% CI: -0.52--0.14; P = .0007). Moreover, GIK treatment seemed to be associated with fewer postoperative atrial fibrillation (AF) (RR = 0.81, 95% CI: 0.64-1.03; P = .09). CONCLUSIONS: In patients undergoing on-pump cardiac surgery, GIK infusion has a beneficial role in mortality during hospital stay and demonstrates superior efficacy versus standard care for reduction in postoperative MI, AF, ICU length of stay as well as inotropic agent requirements.
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Procedimentos Cirúrgicos Cardíacos , Ponte Cardiopulmonar , Glucose/uso terapêutico , Insulinas/uso terapêutico , Assistência Perioperatória/métodos , Complicações Pós-Operatórias/prevenção & controle , Potássio/uso terapêutico , Fibrilação Atrial/prevenção & controle , Procedimentos Cirúrgicos Cardíacos/métodos , Cuidados Críticos , Mortalidade Hospitalar , Humanos , Infusões Intravenosas , Tempo de Internação , Infarto do Miocárdio/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Porcine circovirus type 2 (PCV2) is the essential infectious agent causing porcine circovirus-associated disease (PCVD) in pigs and one of the important viruses that severely jeopardize the swine husbandry industry. PCV2 elicits the unfolded protein response (UPR) via activation of the PERK pathway, and its capsid protein (Cap) has also been found to induce UPR with subsequent activation of apoptosis. The open reading frame 5 (ORF5) protein is a recently discovered non-structural protein, and its function in PCV2 pathogenesis remains unknown. The aim of this study was to determine whether the PCV2 ORF5 protein could induce endoplasmic reticulum stress (ERS) and UPR in porcine alveolar macrophages (PAMs). pEGFP-tagged ORF5 protein was transiently overexpressed in PAMs. Transmission electron microscopy (TEM) was employed to examine changes in ER morphology, and quantitative real-time PCR and western blotting analysis were used to measure UPR-related cell signaling alterations. We found that the ORF5 protein triggers swelling and degranulation of the ER and upregulates the expression of ERS markers. Further experiments demonstrated that the PCV2 ORF5 protein induces ERS and UPR via the PERK (RNA-activated protein kinase-like endoplasmic reticulum kinase), ATF6 (activating transcription factor 6) and IRE1 (inositol requiring enzyme 1) signaling pathways. Together with previous studies, we provide new information on the ERS-UPR induced by the PCV2 ORF5 protein.
Assuntos
Circovirus/genética , Estresse do Retículo Endoplasmático/genética , Retículo Endoplasmático/ultraestrutura , Macrófagos Alveolares/patologia , Resposta a Proteínas não Dobradas/genética , Proteínas do Envelope Viral/genética , Proteínas não Estruturais Virais/genética , Fator 6 Ativador da Transcrição/metabolismo , Animais , Linhagem Celular , Infecções por Circoviridae/patologia , Infecções por Circoviridae/veterinária , Retículo Endoplasmático/virologia , Endorribonucleases/metabolismo , Macrófagos Alveolares/virologia , Microscopia Eletrônica de Transmissão , Suínos , Doenças dos Suínos , Proteínas do Envelope Viral/metabolismo , eIF-2 Quinase/metabolismoRESUMO
BACKGROUND/AIMS: Micro RNAs (miRNAs) play a very important role in myocardial ischemia/ reperfusion injury (MIRI), including in inflammation, apoptosis, and angiogenesis. Previous studies have demonstrated up-regulation of miR-327 in renal ischemia/reperfusion injury and MIRI. Via TargetScan, we found RP105 is a possible target gene of miR-327; our previous studies have also confirmed that RP105 acted as a cardioprotective protein in MIRI by reducing inflammation. However, the regulatory effect of miR-327 on RP105 has not previously been proposed. In our study, we aimed to identify the regulatory effect of miR-327 on RP105 protein in MIRI rats. METHODS: Sixty male Sprague-Dawley rats were randomly divided into five groups, which were pre-treated with saline (sham and ischemia/reperfusion group), adenovirus-expressing miR-327-RNAi (Ad-miR-327-i group), control (Ad-NC group), or pri-miR-327 (Ad-miR-327 group) treatments. Three days later, the rat MIRI model was established by ischemia for 30 min, followed by reperfusion for 3 h. Myocardium and plasma were harvested and assessed. RESULTS: miR-327 was increased by nearly 3-fold both in myocardium and plasma, which down-regulated RP105 in a 3'-untranslated region-dependent manner, and down-regulation of miR-327 via adenovirus transfection indirectly suppressed the TLR4/ TLR2-MyD88-NF-κB signaling axis activation via up-regulation of RP105, which subsequently resulted in reduced myocardial infarct size, attenuated cardiomyocyte destruction, and alleviated inflammation. In contrast, up-regulation of miR-327 induced the opposite effect. CONCLUSION: Down-regulation of miR-327 exerts a cardioprotective effect against MIRI by reducing inflammation, which may constitute a promising molecular therapeutic target for treating MIRI.
Assuntos
Antígenos CD/metabolismo , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Regiões 3' não Traduzidas , Adenoviridae/genética , Animais , Antagomirs/metabolismo , Antígenos CD/química , Antígenos CD/genética , Modelos Animais de Doenças , Regulação para Baixo , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
BACKGROUND: Molecular hydrogen has been shown to have antioxidant effect and have been used to prevent oxidative stress-related diseases. The goal of this study was to explore if hydrogen-rich saline (HRS) plays a cardioprotective effect on abdominal aortic constriction (AAC) induced cardiac hypertrophy in rats. 60adult Sprague-Dawley rats received surgically the AAC for 6-week. After the surgery, the rats were randomly divided into 4 groups (15 for each):1: sham-operated (sham); 2: AAC-model; 3: AAC + Low HRS (LHRS); and 4: AAC + High HRS (HHRS). The rats in sham and AAC-model groups were treated with normal saline intraperitoneally, while rats in LHRS and HHRS groups were intraperitoneally treated with 3 or 6 mL/kg HRS daily, respectively, for 6-week. RESULTS: The ratios of HW/BW and LVW/BW were shown in an order of Model > LHRS > HHRS > SHAM groups. The cardiac hypertrophy was also manifested with increased expressions of atrial natriuretic peptide (ANP), brain natriuretic peptides (BNP) and fibrosis of cardiac tissues in AAC-model group, which could likewise be restrained in LHRS and HHRS groups. Moreover, the JAK-STAT (Janus Kinase-Signal transducers and activators of transcription) signaling molecule expressions were decreased with HRS treatment. CONCLUSIONS: Our results showed a protective effect of HRS on pressure overload-induced cardiac hypertrophy in rats, which may be associated to a decreasing in JAK-STAT signaling pathway.
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Aorta Abdominal/fisiopatologia , Aorta Abdominal/cirurgia , Pressão Arterial , Cardiomegalia/prevenção & controle , Hidratação/métodos , Hidrogênio/administração & dosagem , Janus Quinases/metabolismo , Miocárdio/enzimologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Cloreto de Sódio/administração & dosagem , Animais , Apoptose , Fator Natriurético Atrial/metabolismo , Cardiomegalia/enzimologia , Cardiomegalia/etiologia , Cardiomegalia/fisiopatologia , Constrição , Modelos Animais de Doenças , Fibrose , Masculino , Miocárdio/patologia , Peptídeo Natriurético Encefálico/metabolismo , Ratos Sprague-DawleyRESUMO
BACKGROUND/AIMS: Oxidative stress is strongly implicated in the pathogenesis of myocardial damage caused by ischemia reperfusion (I/R). Previous studies have confirmed that cardiac CD47 drives left ventricular heart failure. However, the role for CD47 in myocardial I/R injury (MIRI) has not previously been proposed. This study was designed to investigate whether down-regulation of CD47 using RNA interference (RNAi) technology can relieve inhibition of nitric oxide signaling and attenuate myocardial damage in a rat model of I/R. METHODS: Male Sprague-Dawley rats (n = 40) were randomly allocated to four groups and pre-treated either with saline (Sham and I/R groups), or adenovirus expressing either control (Ad-EGFP-N) or CD47-targeting (Ad-EGFP-CD47) RNAi. After four days, the rat MIRI model was established by occluding the left anterior descending coronary artery for 30 min, followed by reperfusion for 3 h. Heart tissue was harvested and assessed by immunohistochemistry, western blot, and quantitative RT-PCR. Outcome measures included infarct size, myocardial enzyme (creatine kinase, creatine kinase-MB, and lactate dehydrogenase) levels in serum, markers of oxidative stress, and morphological changes to the myocardium. RESULTS: Delivery of Ad-EGFP-CD47 RNAi into the myocardium remarkably decreased CD47 expression levels. Down-regulation of CD47 was significantly associated with reduced infarct size and serum levels of myocardial enzymes, increased activity of endothelial nitric oxide synthase, increased levels of nitric oxide, and decreased levels of oxidative stress. CONCLUSION: These data indicate that down-regulation of CD47 exerts a protective effect against MIRI, which may be attributable to attenuation of oxidative stress via activation of the eNOS/NO signaling pathway.
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Antígeno CD47/metabolismo , Regulação para Baixo , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Óxido Nítrico Sintase Tipo III/metabolismo , Interferência de RNA , Adenoviridae/metabolismo , Animais , Modelos Animais de Doenças , Ativação Enzimática , Proteínas de Fluorescência Verde/metabolismo , Masculino , Miocárdio/enzimologia , Óxido Nítrico/metabolismo , Estresse Oxidativo , Ratos Sprague-Dawley , Transfecção , Regulação para CimaRESUMO
Interactions between doxorubicin (DOX) and iron generate reactive oxygen species and contribute to DOX-induced heart failure. Hydrogen, as a selective antioxidant, is a promising potential therapeutic option for the treatment of a variety of diseases. Therefore, we investigated the preventive effects of hydrogen treatment on DOX-induced heart failure in rats. We found that cardiac function was significantly improved and that the plasma levels of oxidative-stress markers and myocardial autophagic activity were decreased in animals treated with hydrogen-containing saline. Therefore, we conclude that hydrogen-containing saline may have beneficial effects for doxorubicin-induced heart failure.
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Antibióticos Antineoplásicos/antagonistas & inibidores , Antibióticos Antineoplásicos/toxicidade , Cardiotônicos , Doxorrubicina/antagonistas & inibidores , Doxorrubicina/toxicidade , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/prevenção & controle , Hidrogênio/farmacologia , Cloreto de Sódio/química , Animais , Autofagia/efeitos dos fármacos , Western Blotting , Ecocardiografia , Insuficiência Cardíaca/diagnóstico por imagem , Hidrogênio/química , Masculino , Microscopia Eletrônica de Transmissão , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Soluções Farmacêuticas , Ratos , Ratos Wistar , Sobrevida , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
BACKGROUND: With the aging population, the increasing prevalence of chronic non-communicable diseases, and the diversified needs for primary health care (PHC) medicines, it is necessary to rethink the functional role of the supply of PHC medicines. This study aims to evaluate the supply of PHC medicines and the status of meeting PHC medicine needs. METHODS: The mixed-methods study was conducted to evaluate the supply of PHC medicines in Shandong Province. In the quantitative study, survey questionnaires were distributed to county hospitals, township hospitals, and patients, and a prescription review was performed in township hospitals. In the qualitative study, semi-structured interviews were conducted with the pharmacy managers, physicians, and patients in county hospitals, township hospitals, and village clinics. A senior pharmacist from a tertiary hospital who has rich experience on the indications for medicine use, accompanied us on a visit to inspect the PHC pharmacies to survey medicine equipment with a professional perspective. RESULTS: Quantitative analysis revealed that 211 county hospitals and 1,581 township hospitals participated in the survey, revealing the median annual frequency of medicine shortages of 5.0 times for county hospitals and 2.0 times for township hospitals. Of the 6,323 patient medication surveys, after excluding 152 patients not involved in medication use, 945 (15.3%) indicated medicine shortages, with half of these attributable to institutions lacking required medicines (52.8%). On average, the prescription qualified rate of 37 township hospitals was 72.2%. Four final themes emerged during the qualitative data analysis: (1) Supply of PHC medicines; (2) Solutions to the shortage of off-list medicines; (3) Appropriateness of PHC medicines list; (4) Pharmacist workforce development and pharmacy services. CONCLUSIONS: The discrepancy between patients' need for PHC medicine and present medicine supply is noteworthy. It is suggested that governments should optimize the existing lists to adequately meet patient medicine needs and prioritize medicines for chronic diseases, which is also particularly important for developing countries. Integrated health care may be a novel strategy to establish unified medicines list and achieve uniform pharmaceutical services in PHC.
Assuntos
Atenção Primária à Saúde , China , Atenção Primária à Saúde/estatística & dados numéricos , Humanos , Necessidades e Demandas de Serviços de Saúde/estatística & dados numéricos , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Whether the positive associations of blood lipids with psychiatric disorders are causal is uncertain. We conducted this two-sample Mendelian randomization (MR) analysis to comprehensively investigate associations of blood lipids with psychiatric disorders. METHODS: Univariable and multivariable models were established for MR analyses. Inverse variance-weighted (IVW) MR was employed as the main approach; weighted median and MR-Egger were used as sensitivity analysis methods. The possibility of violating MR assumptions was evaluated utilizing several sensitivity analyses, including heterogeneity statistics, horizontal pleiotropy statistics, single SNP analysis, leave-one-out analysis and MR-PRESSO analysis. As instrumental variables, we screened 362 independent single-nucleotide polymorphisms (SNP) related to blood lipids from a recent genome-wide association study involving 76,627 individuals of European ancestry, with a genome-wide significance level of p < 5 × 10- 8. Summary-level information for the six psychiatric disorders was extracted from Psychiatric Genomics Consortium and Alzheimer Disease Genetics Consortium. RESULTS: We observed eight significant associations in univariable MR analysis, four of which were corroborated by multivariable MR (MVMR) analysis modified for the other three lipid traits: high-density lipoprotein cholesterol (HDL-C) level with the risk of PTSD (OR = 0.91, 95% CI = 0.85-0.97, p = 0.002) and AD (OR = 0.79, 95% CI = 0.71-0.88, p < 0.001) and triglycerides (TG) level with the risk of MDD (OR = 1.02, 95% CI = 1.003-1.03, p = 0.01) and panic disorder (OR = 0.83, 95% CI = 0.74-0.92, p < 0.001). In addition, four associations were not significant in MVMR analysis after adjustment for three lipid traits: total cholesterol (TC) level with the risk of PTSD, low-density lipoprotein cholesterol (LDL-C) level with the risk of MDD and AD and TG level with the risk of AD. CONCLUSIONS: Our results show that blood lipids and psychiatric disorders may be related in a causal manner. This shows that abnormal blood lipid levels may act as reliable biomarker of psychiatric disorders and as suitable targets for their prevention and treatment.
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Análise da Randomização Mendeliana , Transtornos Mentais , Humanos , Estudo de Associação Genômica Ampla , Transtornos Mentais/genética , LDL-Colesterol , Lipídeos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
We investigated the short-term and medium-term results in patients with pulmonary arterial hypertension (PAH) associated with atrial septal defect (ASD) undergoing transcatheter closure. Fifteen patients with severe PAH associated with ASD who underwent successful occluder implantation from 2007 to 2010 were included. Clinical, echocardiographic, and hemodynamic data were reviewed. Severe PAH was defined as pulmonary arterial systolic pressure measured by catheterization was ≥60 mmHg and pulmonary vascular resistance (PVR) ≥6 Wood Units (WU). Compared with baseline, the 6-minwalking distance significantly increased by 29.7 ± 26.3 m (P < 0.001) at 3 months (short-term) and 65.4 ± 63.6 m (P < 0.001) at 23.4 ± 9.7 months (medium-term), World Health Organization function class considerably improved after postclosure short-term and medium-term. Repeat cardiac catheterization (n = 7) showed that mean pulmonary arterial pressure decreased from 51.6 ± 9.4 mmHg at baseline to 21.0 ± 3.8 mmHg (P < 0.001) at follow-up of 12 months. The PVR decreased by 5.6 ± 1.1 WU (P < 0.001). Through carefully selected patients with severe PAH associated with ASD, transcatheter closure can be safely performed with a promising short-term and medium-term outcome. Trial occlusion is an effective way for deciding the reversibility of severe PAH in ASD patients. The role of aerosolized iloprost for pulmonary vasoreactivity testing in patients with severe PAH secondary to ASD requires further investigation.
Assuntos
Cateterismo Cardíaco/instrumentação , Hipertensão Pulmonar/etiologia , Dispositivo para Oclusão Septal , Administração por Inalação , Adulto , Aerossóis , Idoso , Pressão Arterial , Cateterismo Cardíaco/efeitos adversos , Cateterismo de Swan-Ganz , Distribuição de Qui-Quadrado , Teste de Esforço , Tolerância ao Exercício , Hipertensão Pulmonar Primária Familiar , Feminino , Comunicação Interatrial/complicações , Comunicação Interatrial/diagnóstico por imagem , Comunicação Interatrial/fisiopatologia , Comunicação Interatrial/terapia , Humanos , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/fisiopatologia , Iloprosta/administração & dosagem , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/fisiopatologia , Recuperação de Função Fisiológica , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia , Resistência Vascular , Caminhada , Adulto JovemRESUMO
Adipose-derived mesenchymal stem cells (ADSCs) are ideal sources for the treatment of diabetes, and the differentiation of ADSCs into insulin-producing cells (IPCs) through transfection of exogenous regulatory genes in vitro has been studied in depth. The differentiation of ADSCs is strictly regulated by a variety of transcription factors such as Pdx1, Ngn3, Pax4, Nkx2.2, and Sox9. However, whether these genes can coordinately regulate the differentiation of ADSCs into IPCs is still unknown. In this study, five multigene coexpressing adenovirus vectors (pAdTrack-Pdx1-Ngn3-AdEasy, pAdTrack-Pdx1-Ngn3-Sox9-AdEasy, pAdTrack-Pdx1-Ngn3-Pax4-Sox9-AdEasy, pAdTrack-Pdx1-Ngn3-Nkx2.2-Sox9-AdEasy, and pAdTrack-Pdx1-Ngn3-Nkx2.2-Pax4-AdEasy) were constructed, and then the stocks of the packaged adenoviruses were used to infect the canine ADSCs (cADSCs). Based on results of morphological observation, dithizone staining, sugar-stimulated insulin secretion test, cellular insulin immunofluorescence assays, and the detection of pancreatic ß-cell development-related genes in the induced cells, the best induction combination (pAdTrack-Pdx1-Ngn3-Nkx2.2-Pax4-AdEasy) was identified after comparative screening. This study provides a theoretical reference and an experimental basis for further research on stem cell replacement therapy for diabetes.
Assuntos
Células Secretoras de Insulina , Células-Tronco Mesenquimais , Animais , Diferenciação Celular/genética , Cães , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Insulina/metabolismo , Secreção de InsulinaRESUMO
Early life stress (ELS) can cause long-term changes in gene expression, affect cognition, mood, and behavior, and increase susceptibility to post-traumatic stress disorder (PTSD) in adulthood, in which the histone acetylation plays a crucial role. Studies have found that environmental enrichment (EE) mitigated the unfavorable outcomes of ELS. However, the underlying mechanism of the histone acetylation is not yet completely clear. The purpose of this study was to explore the effect of EE on the histone acetylation after ELS. In this study, using single prolonged stress (SPS) paradigm in early adolescent rats explored the long-term effects of ELS on behavior, the activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs), as well as the acetylation levels of the lysine 9 site of histone H3 (H3K9) and lysine 12 site of histone H4 (H4K12) in the hippocampus and amygdala. Meanwhile, the protective effects of EE intervention were examined. We found that adult male rats exposed to ELS showed behavioral changes, including reduced locomotor activity, increased anxiety-like behaviors, impaired spatial learning and memory, enhanced contextual and cued fear memory, and the HATs/HDACs ratio and acetyl H3K9 (Ac-H3K9) and acetyl H4K12 (Ac-H4K12) were increased in the hippocampus and decreased in the amygdala. Furthermore, EE attenuated the behavioral abnormalities from ELS, possibly through down-regulating the activity of HATs in the hippocampus and up-regulating HDACs activities in the amygdala. These finding suggested that EE could ameliorate ELS-induced PTSD-like behaviors by regulating histone acetylation in the hippocampus and amygdala, reducing the susceptibility to PTSD in adulthood.
Assuntos
Tonsila do Cerebelo , Hipocampo , Histonas , Transtornos de Estresse Pós-Traumáticos , Acetilação , Tonsila do Cerebelo/metabolismo , Animais , Hipocampo/metabolismo , Histona Acetiltransferases/metabolismo , Histona Desacetilases/metabolismo , Histonas/metabolismo , Lisina/metabolismo , Masculino , Ratos , Transtornos de Estresse Pós-Traumáticos/metabolismoRESUMO
BACKGROUND: Findings concerning gender differences in the associations between tobacco smoke exposure (TSE) and depression are inconsistent. This study aimed to investigate the gender-specific associations between active and passive TSE with depressive symptoms in a large, nationally representative sample of U.S. adults. METHODS: Data were from 27,175 adults aged ≥20 years in the 2007-2018 National Health and Nutrition Examination Survey (NHANES). Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9). Multivariable logistic regression was used to adjust for possible confounders. Whether the TSE-depression relationships may differ by age, race/ethnicity, socioeconomic status, body mass index (BMI), and self-reported health status was examined. RESULTS: After adjustment for lifestyle- and health-related variables, no significant associations between active (OR, 1.16 [95% CI, 0.87-1.55]) and passive TSE (OR, 0.84 [95% CI, 0.59-1.19]) and depressive symptoms were found among men. Among women, active TSE was associated with depressive symptoms (OR, 1.90 [95% CI, 1.51-2.39]), while the association for passive TSE was nonsignificant (OR, 1.11 [95% CI, 0.91-1.34]) after adjusting for lifestyle- and health-related variables. Interaction and subgroup analyses showed that self-reported health status could modify the relationship between passive TSE and depressive symptoms among women. Furthermore, a dose-response relationship between serum cotinine and depressive symptoms was found in women, but not in men. CONCLUSIONS: This study suggests a stronger TSE-depression association in women than in men. Understanding these gender-specific patterns and identifying the potential moderators of such relationships will enable better targeting of public health interventions.
Assuntos
Poluição por Fumaça de Tabaco , Adulto , Cotinina , Depressão/epidemiologia , Feminino , Humanos , Masculino , Inquéritos Nutricionais , Fatores Sexuais , Poluição por Fumaça de Tabaco/efeitos adversos , Adulto JovemRESUMO
Constructing a step-scheme (S-scheme) heterojunction represents a promising route to overcome the drawbacks of single-component and traditional heterostructured photocatalysts by simultaneously broadening the optical response range and optimizing the redox ability of the photocatalytic system, the efficiency of which greatly lies in the separation behaviors of photogenerated charge carriers with strong redox capabilities. Herein, we demonstrate interfacial facet engineering as an effective strategy to manipulate the charge transfer and separation for substantially improving the photocatalytic activities of S-scheme heterojunctions. The facet engineering is performed with the growth of ZnIn2S4 on (010) and (001) facet-dominated BiOBr nanosheets to fabricate ZIS/BOB-(010) and ZIS/BOB-(001) S-scheme heterojunctions, respectively. It is disclosed that a larger Fermi level difference between BiOBr-(001) and ZnIn2S4 enables the formation of a stronger built-in electric field with more serious band bending in the space charge region around the interface. As a result, the directional migration and recombination of pointless photoexcited electrons in the conduction band (CB) of BiOBr and holes in the valence band (VB) of ZnIn2S4 with weak redox ability are speeded up enormously, thereby contributing to more efficient spatial separation of powerful CB electrons of ZnIn2S4 and VB holes of BiOBr for participating in overall redox reactions. Profiting from these merits, the ZIS/BOB-(001) displays a significant superiority in photocatalytic H2 evolution over ZIS/BOB-(010) and mono-component counterparts. This work provides new deep insights into the rational construction of a S-scheme photocatalyst based on an interfacial facet design from the viewpoint of internal electric field regulation.
RESUMO
Exposure to early stressful events increases susceptibility to post-traumatic stress disorder (PTSD) in adulthood, in which the hypothalamic-pituitary-adrenal (HPA) axis plays a crucial role. Studies have found that environmental enrichment (EE) mitigates the detrimental outcomes of early adversity. However, the HPA-related mechanism remains unclear. In this study, we used the single prolonged stress (SPS) paradigm to explore the long-term effects of early adolescent stress on behavior, HPA axis activity, as well as expression levels of the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), corticotropin-releasing hormone receptor 1 (CRF1R) and CRF2R in the hypothalamus and hippocampus. Meanwhile, the protective effects of EE intervention were examined. We found that adult male rats exposed to adolescent stress showed reduced locomotor activity, increased anxiety-like behaviors, enhanced contextual fear memory, elevated basal plasma ACTH levels, and enhanced HPA negative feedback inhibition, as indicated by decreased plasma ACTH levels in the dexamethasone suppression test (DST). Furthermore, EE normalized the behavioral abnormalities and enhanced HPA negative feedback in stressed rats, possibly through down-regulating GR expression in the hippocampus and hypothalamus. These findings suggested that EE could ameliorate adolescent stress-induced PTSD-like behaviors and aberrant reprogramming of the HPA axis, reducing the risk of developing PTSD in adulthood.
Assuntos
Sistema Hipotálamo-Hipofisário , Transtornos de Estresse Pós-Traumáticos , Animais , Corticosterona , Hormônio Liberador da Corticotropina/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Hipotálamo/metabolismo , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Receptores de Glucocorticoides/metabolismo , Estresse PsicológicoRESUMO
INTRODUCTION: Myasthenia gravis (MG) is an autoimmune disease in which antibodies directly target components of the neuromuscular junction, causing neuromuscular conduction damage that leads to muscle weakness. The current pharmaceutical treatment for MG is still not ideal to address the problems of disease progression, high recurrence rate, and drug side effects. Clinical observations suggest that traditional Chinese medicine (TCM) can strengthen immunity and improve symptoms of MG patients, delay the progression of the disease, reduce or even prevent the need for immunosuppressive therapy when used in combination with acetylcholinesterase inhibitors or low-dose prednisone, as well as improve the quality of life of patients. The Qiangji Jianli Capsule (QJC) is a combination of medicinal herbs which is used in traditional Chinese medicine. Since MG is a rare disorder, randomized controlled trials comparing large cohorts are difficult to conduct. Therefore, we proposed to aggregate data from a small series of N-of-1 trials to assess the effect of the Chinese medical prescription QJC, which strengthens the spleen and nourishes Qi, as an add-on treatment for MG with spleen and stomach Qi deficiency syndrome. METHODS AND ANALYSIS: Single-center, randomized, double-blind, multiple crossover N-of-1 studies will compare QJC versus placebo in 5 adult MG patients with spleen and stomach Qi deficiency syndrome. Patients will undergo 3 cycles of two 4-week intervention periods. According to the treatment schedule, patients will continue to be treated with pyridine bromide tablets, prednisone acetate, tablets and/or tacrolimus capsules throughout the entire trial. Each period consisting of 4-week oral add-on treatment with QJC will be compared with 4-week add-on treatment with a placebo. The primary endpoints are quantitative myasthenia gravis (QMG) test; measurement of the amount of Treg cells and cytokines such as interferon-γ (IFN-γ), interleukin-4 (IL-4), interleukin-17A (IL-17A), and transforming growth factor-ß (TGF-ß); and corticosteroid or immunosuppressive agent dosage. Secondary outcome measures: Clinical: Evaluation of the effect of TCM syndromes; MG-activities of daily living (MG-ADL) scales; adverse events. ETHICS AND DISSEMINATION: This study was approved by The First Affiliated Hospital of Guangzhou University of Chinese Medicine (GZUCM), No. ZYYECK[2019]038. The results will be published in a peer-reviewed publication. Regulatory stakeholders will comment on the suitability of the trial for market authorization and reimbursement purposes. Trial registration: Chinese Clinical Trial Register, ID: ChiCTR2000033516. Registered on 3 June 2020, http://www.chictr.org.cn/showprojen.aspx?proj=54618.