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1.
J Hazard Mater ; 393: 122457, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32151939

RESUMO

Exposure to fine particulate matter (PM2.5) have been associated with adverse respiratory outcomes, but long-term effect of personal exposure on lung function remains largely unknown. We conducted a panel study of 158 adult residents with 394 measurements of personal PM2.5 concentration and lung function within six years to investigate the long-term association. Linear mixed models were used to identify the associations between lung function changes in relation to different levels of persistent personal PM2.5 exposure in three or six years. We further attempted to validate resident areas (city) and smoking status as potential predictors of the long-term PM2.5 exposure levels (persistently high/ persistently low) by generating ROC curves. Compared with subjects who had persistently low exposure level, those with persistently high levels of personal PM2.5 exposure had an additional 3.63 % decline in FEV1/FVC in three years (-3.63 [-7.25, -0.02]), while 7.15 % decline in six years (-7.15 [-14.27, -0.03]). BMI can modify the association. The AUCs were 0.68 (95 %CI: 0.54, 0.82), 0.75 (0.64, 0.86), and 0.82 (0.71, 0.93) for models including smoking status, resident areas, and smoking status combining resident areas respectively. These findings provide new evidence for the long-term effect of personal PM2.5 exposure on lung function decline.

2.
Emerg Microbes Infect ; 9(1): 558-570, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32172672

RESUMO

World Health Organization has declared the ongoing outbreak of coronavirus disease 2019 (COVID-19) a Public Health Emergency of International Concern. The virus was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses. Human infection with SARS-CoV-2 leads to a wide range of clinical manifestations ranging from asymptomatic, mild, moderate to severe. The severe cases present with pneumonia, which can progress to acute respiratory distress syndrome. The outbreak provides an opportunity for real-time tracking of an animal coronavirus that has just crossed species barrier to infect humans. The outcome of SARS-CoV-2 infection is largely determined by virus-host interaction. Here, we review the discovery, zoonotic origin, animal hosts, transmissibility and pathogenicity of SARS-CoV-2 in relation to its interplay with host antiviral defense. A comparison with SARS-CoV, Middle East respiratory syndrome coronavirus, community-acquired human coronaviruses and other pathogenic viruses including human immunodeficiency viruses is made. We summarize current understanding of the induction of a proinflammatory cytokine storm by other highly pathogenic human coronaviruses, their adaptation to humans and their usurpation of the cell death programmes. Important questions concerning the interaction between SARS-CoV-2 and host antiviral defence, including asymptomatic and presymptomatic virus shedding, are also discussed.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno , Pneumonia Viral/virologia , Animais , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Vetores de Doenças , Humanos , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/transmissão
4.
Insect Biochem Mol Biol ; 120: 103360, 2020 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-32126276

RESUMO

Ammonia is one of the principal kairomones originating from human and other animal emanations and in that context, plays an essential role in the host-seeking behaviors of the malaria vector mosquito Anopheles gambiae. Nevertheless, despite its importance in directing host-seeking, the mechanisms underlying ammonia detection in the mosquito olfactory system remains largely unknown. In addition to ongoing efforts to identify and characterize the molecular receptors that underlie ammonia sensitivity, previous studies have revealed a prominent role for ammonium transporters (Amt) in modulating antennal and behavioral responses in Drosophila melanogaster and An. gambiae. In the former, localization of DmAmt in antennal sensilla to auxiliary cells surrounding the ammonia sensory neurons led to the hypothesis that its role was to clear excess ammonium ions in the sensillar lymph. In the latter, RT-PCR and heterologous expression have been used to examine the expression and functional characteristics of the An. gambiae ammonium transporter, AgAmt. We now employ advanced transgenic tools to comprehensively examine AgAmt spatial localization across the peripheral chemosensory appendages in larvae and adult female An. gambiae. In the larval antennae, AgAmt appears localized in both neuronal and auxiliary cells. In contrast to D. melanogaster, in the adult antennae, AgAmt-derived signals are observed in both non-neuronal auxiliary cells and in sensory neurons in ammonia-responsive basiconic and coeloconic sensilla. In the maxillary palps, labella, and tarsi, AgAmt appears restricted to sensory neurons. We have also characterized the responses to ammonia of adult antennal coeloconic sensilla and maxillary palp capitate pegs revealing a correlation between sensillar AgAmt expression and ammonia sensitivity. Taken together, these data suggest that AgAmt may play heterogeneous roles in the adult and larval chemosensory apparatus and potentially broad utility as a supra-receptor target in mosquito control.

5.
Insect Sci ; 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32091165

RESUMO

The southern house mosquito Culex quinquefasciatus relies on its olfactory system to locate the human hosts for blood meals, by which several deadly diseases are transmitted. Olfactory sensory neurons (OSNs) housed in the sensilla on the olfactory appendages send their axons into the antennal lobes (ALs), the primary olfactory center in the brain, where the OSNs expressing the same olfactory receptors converge upon the same spherical structures known as glomeruli in the AL. The structure of the antennal lobe, i.e. the spatial organization of the glomeruli, governs the insect's odor identification and discrimination. Drosophila studies have demonstrated the specific connections between receptors and glomeruli based on the 3D structure of the antennal lobe, deepening our understanding of the relationships between glomerular activities and behaviors, but as yet the structure of the Cx. quinquefasciatus antennal lobe remains unknown. We therefore constructed a 3D model of the Cx. quinquefasciatus antennal lobe using nc82 antibody staining, identifying 62 and 44 glomeruli in the female and male mosquito antennal lobe, respectively, with a significant sexual dimorphism in terms of the antennal lobe volume and glomerulus number. These results demonstrate the structural basis of mosquito odor coding and provide a platform for future studies of the mosquito olfactory signal processing mechanism. This article is protected by copyright. All rights reserved.

6.
Environ Pollut ; 260: 113961, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-32006883

RESUMO

MicroRNAs (miRNAs) are a class of small, non-coding RNAs with a post-transcriptional regulatory function on gene expression and cell processes, including proliferation, apoptosis and differentiation. In recent decades, miRNAs have attracted increasing interest to explore the role of epigenetics in response to air pollution. Air pollution, which always contains kinds of particulate matters, are able to reach respiratory tract and blood circulation and then causing epigenetics changes. In addition, extensive studies have illustrated that miRNAs serve as a bridge between particulate matter exposure and health-related effects, like inflammatory cytokines, blood pressure, vascular condition and lung function. The purpose of this review is to summarize the present knowledge about the expression of miRNAs in response to particulate matter exposure. Epidemiological and experimental studies were reviewed in two parts according to the size and source of particles. In this review, we also discussed various functions of the altered miRNAs and predicted potential biological mechanism participated in particulate matter-induced health effects. More rigorous studies are worth conducting to understand contribution of particulate matter on miRNAs alteration and the etiology between environmental exposure and disease development.

7.
Mol Med Rep ; 21(3): 1071-1076, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31894284

RESUMO

The aim of the present study was to explore the safety and effectiveness of radiofrequency ablation (RFA) of the ciliary body for the treatment of glaucoma. A glaucoma model was established in New Zealand white rabbits, which were then treated with RFA of the ciliary body, utilizing an XL­1­type RF meter developed by the Chinese PLA General Hospital. After treatment, general ocular investigation, including ocular pressure was carried out, the anterior chamber was imaged via ultrasound biomicroscopy, and the pathological changes were observed via hematoxylin and eosin (H&E) staining. It was determined that the glaucoma model was successfully established in the New Zealand white rabbit by inducing high intraocular pressure (IOP). After RFA treatment, ablation spots were observed but no clear anterior chamber reaction was found. The ablation group showed a steady and continuous decrease of IOP, which was significantly lower than the model group at days 3 and 7 (P<0.05). A sclera pathway was observed in the ablation site 1­day post­treatment, which had mostly recovered by day 7. H&E staining demonstrated shedding of the ciliary epithelium, and an unclear boundary between muscle layer and blood vessel at day 1. This had fully recovered by day 14, with clear ciliary layers and well­arranged muscle structures observed. The present study suggested that treatment with RFA could decrease IOP without substantial side effects in the glaucoma model in the rabbit. Therefore, it could be used as a strategy to control IOP and as a treatment for glaucoma in the clinic.

8.
Gut Microbes ; : 1-17, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31928124

RESUMO

Background: Vogt-Koyanagi-Harada (VKH) disease is a multisystemic autoimmune disorder characterized by granulomatous panuveitis. Gut microbiome has been considered to play a role in the pathogenesis of this disease but whether the alternation of gut microbiome was involved is unclear. This study was set up to identify abnormalities of gut microbiome composition in VKH disease.Results: Depleted butyrate-producing bacteria, lactate-producing bacteria and methanogens as well as enriched Gram-negative bacteria were identified in the active VKH patients, as well as in VKH patients of Mix enterotype and Bacteroides enterotype. Changes of gut microbiome in the VKH patients were partially restored after an immunosuppressive treatment. The disease susceptibility genotype HLA-DRA was associated with Bacteroides sp.2.1.33B, Paraprevotella clara, Alistipes finegoldii and Eubacterium eligens. A microbial marker profile including 40 disease-associated species was established to differentiate patients from controls. Another microbial marker profile including 37 species was found to be associated with the response to treatment. An animal experiment showed that transfer of gut microbiome from VKH patients could significantly exacerbate disease activity clinically and pathologically in the recipient mice.Conclusion: Our results revealed a distinct gut microbiome signature in VKH patients and showed an exacerbating effect of this gut microbiome on experimental autoimmune uveitis (EAU). We also developed two microbial marker profiles in differentiating VKH patients from healthy controls as well as predicting the effectiveness of treatment.

9.
J Cell Biochem ; 121(2): 1283-1294, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31535400

RESUMO

Cutaneous melanoma (CM) has become a major public health concern. Studies illustrate that minichromosome maintenance protein 7 (MCM7) participate in various diseases including skin disease. Our study aimed to study the effects of MCM7 silencing on CM cell autophagy and apoptosis by modulating the AKT threonine kinase 1 (AKT1)/mechanistic target of rapamycin kinase (mTOR) signaling pathway. Initially, microarray analysis was used to screen the CM-related gene expression data as well as differentially expressed genes. Subsequently, MCM7 expression vector and lentivirus RNA used for MCM7 silencing (LV-shRNA-MCM7) were constructed, and these vectors, dimethyl sulfoxide (DMSO) and AKT activator SC79 were then introduced into CM cell line SK-MEL-2 to validate the role of MCM7 in cell autophagy, viability, apoptosis, cell cycle, migration, and invasion. To further investigate the regulatory mechanisms of MCM7 in CM progress, the expression of MCM7, AKT1, mTOR, cyclin D1, as well as autophagy and apoptosis relative factors, such as LC3B, SOD2, DJ-1, p62, Bcl-2, Bax, and caspase-3 in melanoma cells was determined. MCM7 might mediate the AKT1/mTOR signaling pathway to influence the progress of melanoma. MCM7 silencing contributed to the increased expression of Bax, capase-3, and autophagy-related genes (LC3B, SOD2, and DJ-1), but decreased the expression of Bcl-2, which suggested that MCM7 silencing promoted autophagy and cell apoptosis. At the same time, MCM7 silencing also attenuated cell viability, invasion, and migration, and reduced the cyclin D1 expression and protein levels of p-AKT1 and p-mTOR. Taken together, MCM7 silencing inhibited CM via inactivation of the AKT1/mTOR signaling pathway.

10.
Ocul Immunol Inflamm ; 28(2): 200-208, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30794473

RESUMO

Purpose: To investigate the role of G-protein-coupled bile acid receptor-1, Gpbar1 (TGR5) in the pathogenesis of Vogt-Koyanagi-Harada (VKH) disease.Methods: The mRNA level of TGR5, iNOS, Arg1, CD16, and CD206 in macrophages was assayed by real-time PCR. ELISA was used to detect the production of cytokines in cell culture supernatants. The frequencies of CD4+IFN-γ+ and CD4+ IL-17+ T cells were tested by flow cytometry.Results: A decreased expression of TGR5 in M1 macrophages was observed in active VKH patients as compared with normal controls. TGR5 stimulation of M1 macrophages with INT-777 caused a shift of the inflammatory M1 toward the anti-inflammatory M2 macrophage subtype. TGR5 activation of macrophages co-cultured with CD4+ T cells inhibited Th1 and Th17 polarization, as well as the release of IFN-γ and IL-17 in the culture supernatant.Conclusion: Our results show that a decreased TGR5 expression might contribute to the pathogenesis of VKH disease.

11.
Lab Chip ; 20(3): 496-504, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31840725

RESUMO

This study presented a flexible liquid metal-based microdroplet capacitive sensor that would simply and accurately measure the speed and length of droplets flowing in microchannels. A pair of coplanar U-shaped electrodes was used to form a capacitance through droplet microchannels. Liquid metal was injected into polydimethylsiloxane (PDMS) channels to form the U-shaped electrodes. The sensor would generate a multi-plateau capacitance waveform as a droplet passes through the sensing area, and each plateau period corresponds to the droplet position in the sensing area. The droplet speed and length would be directly calculated from the multi-plateau capacitance waveform. The errors for the capacitive result relative to the real value were <7.2% for length and <2.8% for speed. Moreover, the sensor still maintained excellent performance for droplet length and speed measurement even though the microfluidic chip was bent to 96°. We have demonstrated that the capacitive sensor would be used for sweat rate monitoring.

12.
Pest Manag Sci ; 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31855313

RESUMO

BACKGROUND: Herbivore-induced plant volatiles (HIPVs) can prime plant defenses and enhance herbivore resistance in neighboring plants. Although a trade-off between constitutive defense and HIPV emission has been documented in many plant species, little is known about the effect of HIPV variation on defense priming, and whether there is a trade-off between defense priming and constitutive defense in neighboring plants. RESULTS: Using three tomato genotypes, including two wild types [Moneymaker (MM) and Castlemart (CM)] and one jasmonic acid (JA) overexpression 35S::prosys genotype, we investigated the effects of exposure to volatiles from plants infested by beet armyworm (Spodoptera exigua) caterpillars on the defenses and resistance of conspecific neighboring plants. We also analyzed the HIPV emissions from the three genotypes and their constitutive defense and resistance. Exposure to volatiles from S. exigua-infested MM plants primed an array of defensive responses (including the accumulation of JA and PI-II protein and the expression of the defense genes PI-I and PI-II), and enhanced plant resistance against the caterpillars. In contrast, exposure to volatiles from S. exigua-infested CM or 35S::prosys did not result in defense priming or an increase in plant resistance. Analyses of HIPVs and gene expression indicated that defense priming in MM was due to enhanced emission of ß-ocimene and linalool. We further demonstrated that levels of constitutive defense and resistance are low in MM and high in CM and 35S::prosys, suggesting a negative correlation between defense priming and constitutive defense. CONCLUSION: Our findings suggest that there is a trade-off between defense priming by HIPVs and constitutive defense in tomato. This suggests that defense priming should be used with caution in agriculture. © 2020 Society of Chemical Industry.

13.
Lipids Health Dis ; 18(1): 229, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31881889

RESUMO

BACKGROUND: Hypertension is a highly prevalent disease and the leading cause of chronic kidney disease (CKD). Metabolic syndrome could also be the risk factor for CKD. We sought to study the association between metabolic syndrome components and the prevalence of CKD in patients with hypertension. METHODS: We carried out a multi-center cross-sectional study from Apr. 2017- Apr. 2018 in 15 cities in China. RESULTS: A total of 2484 patients with hypertension were enrolled. Among them, 56% were male and the average age was 65.12 ± 12.71 years. The systolic BP/diastolic BP was 142 ± 18/83 ± 12 mmHg. Metabolic syndrome components turned out to be highly prevalent in patients with hypertension, ranging from 40 to 58%. The prevalence of chronic kidney disease reached 22.0%. Multi-variate logistic analysis revealed that elevated triglyceride (TG) (OR = 1.81, 95% CI 1.28-2.57, p < 0.01), elevated fasting blood glucose (FBG) (OR = 1.43, 95% CI 1.00-2.07, p = 0.05) and hypertension grades (OR = 1.20, 95% CI 1.00-1.44, p = 0.05) were associated with the prevalence of CKD. In sub-group analysis, elevated TG remained strongly associated with CKD in both diabetes (OR = 2.10, 95%CI 1.22-3.61, p < 0.01) and non-diabetes (OR = 1.53, 95% CI 1.09-2.16, p = 0.01). In sub-group analysis of hypertension grades, there was also a graded trend between elevated TG and CKD from controlled blood pressure (BP) to hypertension grade 2 (OR = 1.81, 95%CI 1.06-3.11, p = 0.03; OR = 1.85, 95%CI 1.00-3.43, p = 0.05; OR = 2.81, 95% CI 1.09-7.28, p = 0.03, respectively). CONCLUSION: Elevated TG, elevated FBG and hypertension grades were significantly associated with the prevalence of CKD in patients with hypertension. Particularly, elevated TG was strongly associated with CKD, independent of diabetes and hypertension grades.

14.
Pharmacology ; : 1-10, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31722363

RESUMO

Depression is a progressive and chronic syndrome and commonly related to several neuropsychiatric comorbidities, of which depression is the most studied. Population-based studies have suggested a positive role of statins in ameliorating depression risk. However, the role of statins in the treatment of diabetes-related depression has not been well examined. Herein, we investigated the effects of lovastatin (LOV) on depressive phenotypes in streptozotocin-induced diabetic mice. The data suggested that the treatment of LOV at 10 or 20 mg/kg for 3 weeks markedly prevented diabetes-associated depressive behaviors reflected by better performance in the sucrose preference test, tail suspension test, and novelty-suppressed feeding test. The study further showed that these treatments improved the hippocampal neurogenesis as evidenced by increased bromodeoxyuridine-positive cells in the dentate gyrus with higher expression of mature brain-derived neurotrophic factor and increased phosphorylation of cAMP-response element-binding protein. As expected, diabetic mice treated with LOV showed significant improvement of hyperlipidemia rather than hyperglycemia. These results suggest that LOV may be employed as a drug for the treatment of diabetes-related depression.

15.
Environ Pollut ; 255(Pt 2): 113341, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31610512

RESUMO

Cadmium (Cd) is a toxic heavy metal that is widely distributed in the environment. However, the mechanisms linking Cd exposure and type 2 diabetes risks are not completely elucidated. In this study, we aim to investigate the roles of C-reactive protein (CRP) on the association between urinary Cd and type 2 diabetes risk. We determined urinary Cd and plasma CRP concentrations among 3,140 adults from Wuhan-Zhuhai cohort. Dose-response relationships between urinary Cd, plasma CRP, and type 2 diabetes were explored using multivariate logistic regression and linear mixed regression models. Mediation analysis was performed to investigate the role of plasma CRP in the associations between urinary Cd and type 2 diabetes risk. With adjustment for potential confounders, the odds ratios (ORs) of type 2 diabetes showed an upward trend when urinary Cd concentration gradually increased (P trend <0.01). Significantly positive dose-response relationships were observed between urinary Cd and plasma CRP, as well as between plasma CRP and type 2 diabetes risk. Compared to those when both Cd and CRP levels were low, the adjusted ORs (95%CI) of type 2 diabetes was the highest [2.053(1.395-3.020)] in individuals with high levels of urinary Cd and plasma CRP. Mediation analysis estimated that plasma CRP mediated 4.01% of the association between urinary Cd and type 2 diabetes risk [mediating effect: OR (95%CI) = 1.019(1.002-1.057)]. Individuals with high levels of urinary Cd and plasma CRP had a much higher risk of type 2 diabetes. Plasma CRP may serve as a mediator in the association between urinary Cd and type 2 diabetes risk, providing clues for further study on the biological pathway for type 2 diabetes related to Cd exposure.


Assuntos
Proteína C-Reativa/metabolismo , Cádmio/urina , Diabetes Mellitus Tipo 2/metabolismo , Exposição Ambiental/estatística & dados numéricos , Poluentes Ambientais/metabolismo , Adulto , Cádmio/toxicidade , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances
16.
EuroIntervention ; 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31589145

RESUMO

AIMS: This study was aimed at investigating the prognostic ability of quantitative flow ratio (QFR) guided residual functional SYNTAX score (Q-rFSS) and functional incomplete revascularization (IR) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: A total of consecutive 354 STEMI patients was included. Q-rFSS was defined as residual SYNTAX score (rSS) measured in vessels with QFR ≤0.8. At 2-year follow-up, functional IR (Q-rFSS≥1) showed significantly higher risk for major adverse cardiac events (MACE) than functional complete revascularization (CR) (Q-rFSS=0) (functional IR vs. CR, 22.0% vs. 7.4%; hazard ratio: 3.21; 95% confidence interval (Cl): 1.74 to 5.91; p<0.001). The area under curve (AUC) of Q-rFSS (0.738, 95% CI: 0.659 to 0.817) was significantly greater than that of rSS (0.648, 95% CI: 0.547 to 0.749). C-statistic for MACE increased from 0.656 (0.582 to 0.729) to 0.767 (0.705 to 0.829) after the addition of Q-rFSS to the clinical risk factors. Q-rFSS significantly improved risk classification compared with rSS (net reclassification improvement 0.439, 95% CI: 0.201 to 0.548; p<0.001). CONCLUSIONS: Functional IR is associated with higher risk of MACE during long-term follow-up in STEMI patients undergoing PCI. Q-rFSS has a better prognostic ability for the risk of MACE.

17.
Artigo em Inglês | MEDLINE | ID: mdl-31597487

RESUMO

Introduction: Microwaves (MWs) quickly deliver relatively high temperatures into tumors and cover a large ablation zone. We present a research protocol for using water-cooled double-needle MW ablation arrays for tumor ablation here. Material and methods: Our research program includes computer modeling, tissue-mimicking phantom experiments, and in vitro swine liver experiments. The computer modeling is based on the finite element method (FEM) to evaluate ablation temperature distributions. In tissue-mimicking phantom and in vitro swine liver ablation experiments, the performances of the new device and the single-needle MW device currently used in clinical practice are compared. Results: FEM shows that the maximum transverse ablation diameter (MTAD) is 4.2 cm at 100 W output and 300 s (assessed at the 50 °C isotherm). In the tissue-mimicking phantom, the MTDA is 2.6 cm at 50 W and 300 s in single-needle MW ablation, and 4 cm in double needle MW ablation array. In in vitro swine liver experiments, the MTAD is 2.820 ± 0.127 cm at 100 W and 300 s in single-needle MW ablation, and 3.847 ± 0.103 cm in MW ablation array. Conclusion: A new type of water-cooled MW ablation array is designed and tested, and has potential advantages over currently used devices.

18.
Cell Death Dis ; 10(9): 671, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511494

RESUMO

Compromised learning and memory is a common feature of multiple neurodegenerative disorders. A paradigm spatial memory impairment could be caused by developmental lead (Pb) exposure. Growing evidence implicates epigenetic modifications in the Pb-mediated memory deficits; however, how histone modifications exemplified by H3K27me3 (H3 Lys27 trimethylation) contribute to this pathogenesis remains poorly understood. Here we found that Pb exposure diminished H3K27me3 levels in vivo by suppressing EZH2 (enhancer of zeste homolog 2) expression at an early stage. EZH2 overexpression in Pb-treated rats rescued the H3K27me3 abundance and partially restored the normal spatial memory, as manifested by the rat performance in a Morris water maze test, and structural analysis of hippocampal spine densities. Furthermore, miR-137 and EZH2 constitute mutually inhibitory loop to regulate the H3K27me3 level, and this feedback regulation could be specifically activated by Pb treatment. Considering genes targeted by H3K27me3, ChIP-chip (chromatin immunoprecipitation on chip) studies revealed that Pb could remodel the genome-wide distribution of H3K27me3, represented by pathways like transcriptional regulation, developmental regulation, cell motion, and apoptosis, as well as a novel Wnt9b locus. As a Wnt isoform associated with canonical and noncanonical signaling, Wnt9b was regulated by the opposite modifications of H3K4me3 (H3 Lys4 trimethylation) and H3K27me3 in Pb-exposed neurons. Rescue trials further validated the contribution of Wnt9b to Pb-induced neuronal impairments, wherein canonical or noncanonical Wnt signaling potentially exhibited destructive or protective roles, respectively. In summary, the study reveals an epigenetic-based molecular change underlying Pb-triggered spatial memory deficits, and provides new potential avenues for our understanding of neurodegenerative diseases with environmental etiology.

19.
Mol Ther Nucleic Acids ; 18: 110-122, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31541797

RESUMO

Myocardial infarction (MI) is a life-threatening cardiac event that results in extreme damage to the heart muscle. The Wnt signaling pathway has been implicated in the development of heart diseases. Hence, the current study aimed to investigate the role of microRNA (miRNA) in association with the Wnt signaling pathway to identify potential candidates for MI therapy. Differentially expressed miRNAs associated with MI occurrence were screened, and miR-494 was selected for subsequent experiments. Sprague-Dawley rats were included to establish a MI model via intraperitoneal injection of 0.1 mg/kg atropine sulfate and 40 mg/kg pentobarbital sodium. Then, the interaction between miR-494 and LRG1 was identified. The effect of miR-494 on expression of the Wnt signaling pathway-related genes, proliferation, migration, and invasion ability of fibroblasts and vascular endothelial cells (VECs) was subsequently evaluated through a series of gain- and loss-of-function experiments. The results revealed that miR-494 was poorly expressed and LRG1 was highly expressed in MI rats. miR-494 targets and downregulates LRG1, which resulted in the inactivation of the Wnt signaling pathway and promoted proliferation, migration, and invasion ability of fibroblasts and VECs. In conclusion, this study provided evidence suggesting that overexpressed miR-494 could potentially promote the proliferation, migration, and invasion of fibroblasts and VECs in MI through the inactivation of the Wnt signaling pathway by binding to LRG1.

20.
Biomed Pharmacother ; 118: 109339, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545270

RESUMO

Bevacizumab (BEV) is widely used for the treatment of patients with recurrent glioblastoma (GBM), but recent evidence demonstrated that BEV induced cytoprotective autophagy, which allows tumor cells to survive. Hydroxychloroquine (HCQ) inhibits lysosomal acidification and blocks autophagy via influencing autophagosome fusion and degradation. HCQ is often used to enhance the efficacy of chemoradiotherapy. However, whether HCQ sensitizes GBM cells to BEV and the molecular mechanism of this effect are not clear. We showed that high concentrations of BEV increased the LC3-II/LC3-I ratio and caused the degradation of Beclin1 in the LN18 and LN229 cell lines, indicating that high concentrations of BEV induced the autophagy of the LN18 and LN229 cells. However, BEV (100 µg/ml) did not influence the autophagy of the LN18 and LN229 cells, and HCQ at less than 5 µg/ml significantly accumulated LC3B-II and p62 proteins and blocked the autophagy process. Importantly, we found that HCQ (5 µg/ml) potentiated the anti-cancer effect of BEV (100 µg/ml). Therefore, HCQ is a novel strategy that may augment the efficacy of BEV for GBM via the inhibition of autophagy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Autofagia , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/ultraestrutura , Linhagem Celular Tumoral , Sinergismo Farmacológico , Glioblastoma/patologia , Glioblastoma/ultraestrutura , Humanos , Hidroxicloroquina/farmacologia , Proteínas de Neoplasias/metabolismo
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