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1.
Biochim Biophys Acta Mol Basis Dis ; 1866(1): 165554, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31513833

RESUMO

Activation of interferon (IFN)-I signaling in B cells contributes to the pathogenesis of systemic lupus erythematosus (SLE). Recent studies have shown that myeloid-derived suppressor cells (MDSCs) significantly expand in SLE patients and lupus-prone MRL/lpr mice and contribute to the pathogenesis of SLE. However, the role of SLE-derived MDSCs in regulating IFN-I signaling activation of B cells remains unknown. Here, we demonstrate that expansions of MDSCs, including granulocyte (G)-MDSCs and monocytic (M)-MDSCs, during the progression of SLE were correlated with the IFN-I signature of B cells. Interestingly, G-MDSCs from MRL/lpr mice, but not M-MDSCs, could significantly promote IFN-I signaling activation of B cells and contribute to the pathogenesis of SLE. Mechanistically, we identified that the long non-coding RNA NEAT1 was over-expressed in G-MDSCs from MRL/lpr mice and could induce the promotion of G-MDSCs on IFN-I signaling activation of B cells through B cell-activating factor (BAFF) secretion. Importantly, NEAT1 deficiency significantly attenuated the lupus symptoms in pristane-induced lupus mice. In addition, there was a positive correlation between NEAT1 and BAFF with the IFN signature in SLE patients. In conclusion, G-MDSCs may contribute to the IFN signature in SLE B cells through the NEAT1-BAFF axis, highlighting G-MDSCs as a potential therapeutic target to treat SLE.

2.
Int J Hyg Environ Health ; 223(1): 116-123, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31588015

RESUMO

Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) are commonly used biomarkers of oxidative stress. However, their associations with air pollutant exposure have not been consistent across studies. We hypothesize that the inconsistency is partly due to confounding of circulating melatonin. We analyzed urinary 6-sulfatoxymelatonin (aMT6s), a surrogate of circulating melatonin, along with 8-OHdG and MDA, in 159 healthy adults who had not taken melatonin supplementation. Within the natural range of endogenously-generated aMT6s (0.3-93.5 ng/mg creatinine) measured in this study, increasing aMT6s levels were significantly associated with increasing concentrations of 8-OHdG and MDA. Measurements of PM2.5, ozone (O3), and nitrogen dioxide (NO2), coupled with time-activity data, were used to calculate time-averaged personal exposures 12 -hour (12h) and 24-hour (24h) prior to urine collection. Without controlling for aMT6s, the relationships between pollutant exposure and 8-OHdG or MDA were not clear. After controlling for aMT6s, an interquartile range (IQR) increase in 12h PM2.5 and 12h NO2 exposure was associated with 6.1% [95%CI: 1.6%-10.8%] and 8.6% [1.3%-16.5%] increase in MDA, respectively. An IQR increase in 12h O3 exposure was associated with a 5.7% [1.9%-9.7%] in 8-OHdG. The findings suggest the need for controlling for aMT6s as a confounder in using urinary 8-OHdG and MDA as biomarkers of oxidative stress related to short-term air pollution exposure.

3.
Cell Mol Biol Lett ; 24: 62, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31798643

RESUMO

Background: Myocardial ischaemia reperfusion injury (MIRI) is a difficult problem in clinical practice, and it may involve various microRNAs. This study investigated the role that endogenous microRNA-146a plays in myocardial ischaemia reperfusion and explored the possible target genes. Methods: MIRI models were established in microRNA-146a deficient (KO) and wild type (WT) mice. MicroRNA-146a expression was evaluated in the myocardium of WT mice after reperfusion. The heart function, area of myocardium infarction and in situ apoptosis were compared between the KO and WT mice. Microarray was used to explore possible target genes of microRNA-146a, while qRT-PCR and dual luciferase reporter assays were used for verification. Western blotting was performed to detect the expression levels of the target gene and related signalling molecules. A rescue study was used for further testing. Results: MicroRNA-146a was upregulated 1 h after reperfusion. MicroRNA-146a deficiency decreased heart function and increased myocardial infarction and apoptosis. Microarray detected 19 apoptosis genes upregulated in the KO mice compared with the WT mice. qRT-PCR and dual luciferase verified that Med1 was one target gene of microRNA-146a. TRAP220, encoded by Med1 in the KO mice, was upregulated, accompanied by an amplified ratio of Bax/Bcl2 and increased cleaved caspase-3. Inhibition of microRNA-146a in H9C2 cells caused increased TRAP220 expression and more apoptosis under the stimulus of hypoxia and re-oxygenation, while knockdown of the increased TRAP220 expression led to decreased cell apoptosis. Conclusions: MicroRNA-146a exerts a protective effect against MIRI, which might be partially mediated by the target gene Med1 and related to the apoptosis signalling pathway.

4.
Phys Chem Chem Phys ; 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31802074

RESUMO

Magnetic dimers with very large magnetic anisotropy have great potential in information storage applications. By using density functional theory calculations (DFT), we systematically investigated the magnetic anisotropy energy (MAE) of bi-iridium (Ir2) dimers on four types of graphene-like two-dimensional (2D) material substrates. We considered four possible adsorption sites for Ir2 on each substrate. The Ir2 dimer prefers to remain at the single vacancy site with the largest binding energy for all the 2D materials considered. The spin moment and MAE of Ir2 can be largely affected by the substrate. On the substrate of germanene, the MAE of Ir2 can be enlarged to approximately 100 meV, even with the higher Ir2 areal density of 1.804 nm-2. Moreover, the direction of the easy magnetization axis is determined by the d states in the vicinity of the Fermi level. The present DFT results can be understood with the help of perturbation theory analysis.

6.
Atherosclerosis ; 291: 78-86, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31704554

RESUMO

BACKGROUND AND AIMS: Atherosclerosis is a chronic inflammatory disorder mediated by macrophage activation. MicroRNA-21 (miR-21) is a key regulator in the macrophage inflammatory response. However, the functional role of miR-21 in atherogenesis is far from clear. METHODS AND RESULTS: Here, we report that miR-21 is significantly upregulated in mouse atherosclerotic plaques and peripheral monocytes from patients with coronary artery disease. Compared with miR-21+/+apoE-/- mice (apoE-/- mice), miR-21-/-apoE-/- (double knockout, DKO) mice showed less atherosclerotic lesions, reduced presence of macrophages, decreased smooth muscle cells(SMC) and collagen content in the aorta. We further explored the role of miR-21 in macrophage activation in vitro. Bone marrow-derived macrophages (BMDMs) from DKO mice not only exhibit impaired function of migration induced by chemokine (C-C motif) ligand 2 (CCL2) but also a weakened macrophage-endothelium interaction activated by tumor necrosis factor-α (TNF-α). However, atherogenic inflammatory cytokine secretion was not affected by miR-21 in vitro or in vivo. Additionally, miR-21 knockdown in BMDMs directly derepressed the expression of dual specificity protein phosphatase 8 (Dusp-8), a previously validated miR-21 target in cardiac fibroblasts, which negatively regulates mitogen-activated protein kinase (MAPK) signaling, particularly the p38-and c-Jun N-terminal kinase (JNK)-related signaling pathways. CONCLUSIONS: These data demonstrate that inhibition of miR-21 may restrict the formation of atherosclerotic plaques partly by regulating macrophage migration and adhesion, while, reduced SMCs and collagen content in plaques may lead to a less stable phenotype with the progression of atherosclerosis. Thus, the absence of miR-21 reduces atherosclerotic lesions but may not represent all benefit in atherosclerosis development.

7.
Age Ageing ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31711096

RESUMO

BACKGROUND: post-operative delirium (POD) is a common complication in older patients, though a possible link between metabolic changes and POD development has yet to be investigated. METHODS: older patients with hip fracture who underwent hemi-arthroplasty were recruited, and delirious states were assessed for 3 days after surgery using the confusion assessment method-Chinese revision. Simultaneously, fasting blood samples were collected on the morning of surgery and on the first post-operative day. Ultimately, 244 older patients who met the inclusion and exclusion criteria were assessed. Blood samples from 60 patients with POD and 60 matched controls were analysed using metabolomics platforms. RESULTS: sixty patients (24.6%) developed POD. Principal component analysis scores plot and cross-validated scores plots from orthogonal partial least squares-discriminant analysis were implemented to visualise the differences in metabolites between the two groups before and after surgery (P < 0.05). Our data indicate that levels of ω3 and ω6 fatty acids were lower in the POD group than in the NPOD (non-POD) group both before and after surgery; tricarboxylic cycle intermediate levels were lower in the POD group than in the NPOD group, but glycolysis products were higher in the POD group than in the NPOD group after surgery. Furthermore, the branched-chain amino acid (BCAA)/aromatic amino acid ratio was lower in the POD group than in the NPOD group after surgery. CONCLUSIONS: metabolic abnormalities, including deficiencies in ω3 and ω6 fatty acids, perturbations in tricarboxylic cycle and oxidative stress and metabolic imbalances in BCAA and AAA might contribute to POD development.

8.
Int J Cardiol ; 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31711850

RESUMO

BACKGROUND: Type 2 diabetes mellitus (T2DM) and hypertension are independently related to increasing risk of subsequent incident heart failure with preserved ejection fraction (HFpEF). This study was designed to evaluate the influences of long-term metformin prescription in these patients. METHODS: Using a propensity score matching of 1:2 ratio, this retrospective claims database study compared metformin prescription (n = 130) and non-metformin therapy (n = 260) in patients with T2DM and hypertension and without clinical signs or symptoms of heart failure. RESULTS: With a follow-up of 6 years, the new-onset symptomatic HFpEF occurred in 6 of 130 patients in metformin group and 31 of 260 patients in non-metformin group (P = .020). Metformin also generated more prominent improvement in left ventricular (LV) diastolic function and hypertrophy. And Cox proportional hazards regression model revealed that metformin prescription (HR 0.351, 95% CI: 0.145-0.846, P = .020) was associated with a reduced risk of new onset of symptomatic HFpEF. CONCLUSIONS: Long-term metformin exposure was associated with protective effects in terms of the incidence of new-onset symptomatic HFpEF, LV diastolic dysfunction and hypertrophy in patients with T2DM and hypertension, which might be beneficial for the delay of HFpEF progression.

9.
Sci Total Environ ; : 135523, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31767293

RESUMO

Chronic obstructive pulmonary disease (COPD) and tracheal, bronchus, and lung (TBL) cancers are among the leading causes of mortality worldwide. Many environmental factors have been linked to COPD and TBL cancers. This study examined the associations of cumulative environmental quality indices with COPD mortality and TBL cancers mortality, respectively. Environmental Quality Index (EQI) was constructed to represent cumulative environmental quality for the overall environment and 5 major environmental domains (e.g., air, water, built). Associations of each EQI indices with COPD mortality and TBL cancers mortality, across 3109 counties in the 48 contiguous states of the US, were examined using simultaneous autoregressive (SAR) models. Stratified analyses were conducted in females versus males and according to rural-urban continuum codes (RUCC) to assess the heterogeneity across the overall population. Overall poor environmental quality was associated with a percent difference (PD) of 0.75 [95% confidence intervals (95% CI), 0.46, 1.05] in COPD mortality and an PD of 1.22 (95% CI, 0.97, 1.46) in TBL cancers mortality. PDs were higher in females than in males for both COPD and TBL cancers. The built domain had the largest effect on COPD mortality (PD, 0.85; 95% CI, 0.58, 1.12) while the air domain had the largest effect on TBL cancers mortality (PD, 1.54; 95% CI, 1.31, 1.76). The EQI-mortality associations varied among different RUCCs, but no consistent trend was found. This result suggests that poor environmental quality, particularly poor air quality and built environment quality may increase the mortality risk for COPD and that for TBL cancers. Females appear to be more susceptible to the effect of cumulative environmental quality. Our findings highlight the importance of improving overall and domain-specific cumulative environmental quality in reducing COPD and TBL cancer mortalities in the United States.

10.
Front Immunol ; 10: 2518, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31736954

RESUMO

Oxides of nitrogen (NOx) and volatile organic compounds (VOCs) released into the atmosphere can react in the presence of solar irradiation, leading to ozone formation in the troposphere. Historically, before clean air regulations were implemented to control NOx and VOCs, ozone concentrations were high enough to exert acute effects such as eye and nose irritation, respiratory disease emergencies, and lung function impairment. At or above current regulatory standards, day-to-day variations in ozone concentrations have been positively associated with asthma incidence and daily non-accidental mortality rate. Emerging evidence has shown that both short-term and long-term exposures to ozone, at concentrations below the current regulatory standards, were associated with increased mortality due to respiratory and cardiovascular diseases. The pathophysiology to support the epidemiologic associations between mortality and morbidity and ozone centers at the chemical and toxicological property of ozone as a strong oxidant, being able to induce oxidative damages to cells and the lining fluids of the airways, and immune-inflammatory responses within and beyond the lung. These new findings add substantially to the existing challenges in controlling ozone pollution. For example, in the United States in 2016, 90% of non-compliance to the national ambient air quality standards was due to ozone whereas only 10% was due to particulate matter and other regulated pollutants. Climate change, through creating atmospheric conditions favoring ozone formation, has been and will continue to increase ozone concentrations in many parts of world. Worldwide, ozone is responsible for several hundreds of thousands of premature deaths and tens of millions of asthma-related emergency room visits annually. To combat ozone pollution globally, more aggressive reductions in fossil fuel consumption are needed to cut NOx and VOCs as well as greenhouse gas emissions. Meanwhile, preventive and therapeutic strategies are needed to alleviate the detrimental effects of ozone especially in more susceptible individuals. Interventional trials in humans are needed to evaluate the efficacy of antioxidants and ozone-scavenging compounds that have shown promising results in animal studies.

11.
Environ Res ; : 108919, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31753466

RESUMO

The health effects associated with human exposure to airborne fine particulate matter (PM2.5) have been linked to the ability of PM2.5 to facilitate the production of excess cellular reactive oxygen species (oxidative potential). Concern about the adverse human health impacts of PM2.5 has led to the increased use of indoor air cleaners to improve indoor air quality, which can be an important environment for PM2.5 exposure. However, the degree to which the oxidative potential of indoor and personal PM2.5 can be influenced by an indoor air cleaner remains unclear. In this study we enrolled 43 children with physician diagnosed asthma in suburban Shanghai, China and collected two paired-sets of 48-h indoor, outdoor, and personal PM2.5 exposure samples. One set of samples was collected under "real filtration" during which a functioning air cleaner was installed in the child's bedroom, and the other ("false filtration") with an air cleaner without internal filters. The PM2.5 samples were characterized by inductively coupled plasma mass spectroscopy for elements, and by an alveolar macrophage assay for oxidative potential. The sources of metals contributing to our samples were determined by the EPA Positive Matrix Factorization model. The oxidative potential was lower under real filtration compared to sham for indoor (median real/sham ratio: 0.260) and personal exposure (0.813) samples. Additionally, the sources of elements in PM2.5 that were reduced indoors and personal exposure samples by the air cleaner (e.g. regional aerosol and roadway emissions) were found by univariate multiple regression models to be among those contributing to the oxidative potential of the samples. An IQR increase in the regional aerosol and roadway emissions sources was associated with a 107% (95% CI: 80.1-138%) and 38.1% (17.6-62.1%) increase in measured oxidative potential respectively. Our results indicate that indoor air cleaners can reduce the oxidative potential of indoor and personal exposure to PM2.5, which may lead to improved human health.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31714569

RESUMO

High concentrations of ground-level ozone (O3) have been measured outdoors across China but there are limited measurements of O3 in microenvironments, including in homes, and for personal exposure. This highlights the need for cheaper methods to accurately make these measurements and to better capture fine-scale spatial variability in O3 across cities. With this in mind, we conducted a pilot study at six homes in Beijing, China, over 12 days to evaluate the use of portable, low-cost, time-resolved monitors for measuring O3 indoors and outdoors. We also assessed personal exposure for one adult in each home for two 48 hour periods using backpack-mounted monitors. Prior to and following sampling we collocated all monitors with a reference analyzer; we used data from these colocations to generate linear calibrations which we applied to all monitor data. Calibration slopes did not change significantly over the study although some intercepts differed. The average limit of detection (LOD) was 7.0 ppb, average root mean square error was 16.7 ppb, mean absolute error was 13.3 ppb and normalized root mean square error was 33%. Performance varied substantially between sensors, underscoring the importance of monitor-specific calibrations and determinations of measurement error. Outdoor concentrations varied spatially, with home-specific peak hourly averages of 32-165 ppb; indoor concentrations ranged from below the LOD to 15 ppb. Hour-averaged personal exposure was generally higher than O3 indoors, and at times exceeded ambient O3 indicating contributions to personal exposure from ambient sources of O3 away from the home. This work illustrates the feasibility of using these monitors to characterize distributions of O3 spatially and temporally when differences in concentrations are large, and outlines considerations for using these monitors to measure personal exposure.

13.
Am J Emerg Med ; 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31685304

RESUMO

BACKGROUND: To determine the level of inspiratory pressure minimizing the risk of gastric insufflation while providing adequate pulmonary ventilation. METHODS: In this prospective, randomized, double-blind study, patients were allocated to one of the two groups (P10, P15) defined by the inspiratory pressure applied during controlled-pressure ventilation: 10 and 15 cm H2O. Anesthesia was induced using propofol and sufentanil; no neuromuscular-blocking agent was administered. Once loss of eyelash reflex occurred, facemask ventilation was started for a 2-min period. The cross-sectional antral area was measured using ultrasonography before and after facemask ventilation. Respiratory parameters were recorded. RESULTS: Forty patients were analyzed. Mean tidal volume was about 7 ml/kg in group P10, and was >11 ml/kg in group P15 in the same period. As indicated by ultrasonography test, the antral area in P15 group was markedly incresed compared with P10 group. CONCLUSION: Inspiratory pressure of 10 cm H2O allowed for reduced occurrence of gastric insufflation with proper lung ventilation during induction of anesthesia with sufentanil and propofol in nonparalyzed and nonobese patients.

14.
Int J Mol Med ; 44(6): 2091-2102, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31573044

RESUMO

Endothelial­to­mesenchymal transition (EndMT) serves an important role in the vascular remodeling of pulmonary arterial hypertension (PAH). However, little is known about the correlation between hydrogen sulfide (H2S), a protective gaseous mediator in PAH and the process of EndMT. Male Sprague­Dawley rats (10 weeks old) received a single dose of monocrotaline (MCT; i.p., 60 mg/kg) and were randomly treated with NaHS [an H2S donor; intraperitoneal (i.p.) 1 mg/kg/day], DL­propagylglycine (an inhibitor of H2S synthesis; PAG; i.p., 10 mg/kg/day) or saline, 7 days after MCT injection. Rats were sacrificed 21 days after MCT injection. A selection of human pulmonary artery endothelial cells (HPAECs) were pretreated with NaHS or saline and stimulated with transforming growth factor (TGF)­ß1 (10 ng/ml), and the other HPAECs were transfected with a cystathionine γ­lyase (CSE, an H2S synthesizing enzyme) plasmid and subsequently stimulated with TGF­ß1. NaHS was indicated to inhibit EndMT and PAH progression by inhibiting the induction of the nuclear factor (NF)­κB­Snail pathway. In contrast, the depletion of H2S formation by PAG exacerbated EndMT and PAH by activating NF­κB­Snail molecules. In HPAECs, NaHS dose­dependently inhibited TGF­ß1­induced EndMT and the activation of the NF­κB­Snail pathway. Transfection with a CSE plasmid significantly repressed TGF­ß1­induced expression of the mesenchymal marker and upregulated the expression of the endothelial marker, which was accompanied by the suppression of the NF­κB­Snail pathway. The inhibitory effect of CSE overexpression on TGF­ß1­induced EndMT was significantly reversed by pretreatment with PAG. In conclusion, the current study provides novel information elucidating the beneficial effect of H2S on PAH through inhibiting the induction of the NF­κB­Snail pathway and the subsequent process of EndMT in pulmonary arteries.

15.
Int J Nanomedicine ; 14: 7879-7889, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576129

RESUMO

Introduction and objective: Precisely and sensitively diagnosing diseases especially early and accurate tumor diagnosis in clinical magnetic resonance (MR) scanner is a highly demanding but challenging task. Gadolinium (Gd) chelate is the most common T 1 magnetic resonance imaging (MRI) contrast agent at present. However, traditional Gd-chelates are suffering from low relaxivity, which hampers its application in clinical diagnosis. Currently, the development of nano-sized Gd based T 1 contrast agent, such as incorporating gadolinium chelate into nanocarriers, is an attractive and feasible strategy to enhance the T 1 contrast capacity of Gd chelate. The objective of this study is to improve the T 1 contrast ability of Gd-chelate by synthesizing nanoparticles (NPs) for accurate and early diagnosis in clinical diseases. Methods: Reverse microemulsion method was used to coat iron oxide (IO) with tunable silica shell and form cores of NPs IO@SiO2 at step one, then Gd-chelate was loaded on the surface of silica-coated iron oxide NPs. Finally, Gd-based silica coating magnetite NPs IO@SiO2-DTPA-Gd was developed and tested the ability to detect tumor cells on the cellular and in vivo level. Results: The r 1 value of IO@SiO2-DTPA-Gd NPs with the silica shell thickness of 12 nm was about 33.6 mM-1s-1, which was approximately 6 times higher than Gd-DTPA, and based on its high T 1 contrast ability, IO@SiO2-DTPA-Gd NPs could effectively detect tumor cells on the cellular and in vivo level. Conclusion: Our findings revealed the improvement of T 1 relaxation was not only because of the increase of molecular tumbling time caused by the IO@SiO2 nanocarrier but also the generated magnetic field caused by the IO core. This nanostructure with high T 1 contrast ability may open a new approach to construct high-performance T 1 contrast agent.


Assuntos
Quelantes/química , Materiais Revestidos Biocompatíveis/química , Gadolínio/química , Imagem por Ressonância Magnética , Nanopartículas de Magnetita/química , Dióxido de Silício/química , Animais , Morte Celular , Meios de Contraste/química , Feminino , Compostos Férricos/química , Gadolínio DTPA/química , Células HeLa , Humanos , Nanopartículas de Magnetita/ultraestrutura , Camundongos Endogâmicos BALB C , Camundongos Nus , Imagem Molecular
16.
J Immunol Res ; 2019: 8656282, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583260

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating cancer types despite the improvement of modern medicine. In our present study, we found that dickkopf-related protein 2 (DKK2) shares a higher expression in PDAC compared with adjacent pancreas tissue in tissue microarray. In addition, an elevated expression of DKK2 predicts poorer prognosis of patients and positively correlated with poor tumor differentiation. Multivariate Cox regression analysis was also performed and confirmed that the expression of DKK2 is an independent prognostic factor in PDAC. A high expression of DKK2 correlates with cell migration and epithelial mesenchymal transition based on gene set enrichment analysis (GSEA) while knockdown of DKK2 in PDAC cells resulted in impaired cellular migration. Furthermore, GSEA predicts negative correlation between tumor immunity invasion and DKK2 expression. We then confirmed these results and demonstrated that a higher expression of DKK2 imparts the recruitment of CD8+ T cells. Our work suggested that DKK2 imparts tumor immune evasion and is associated with poor prognosis in pancreatic ductal adenocarcinoma.

17.
ACS Nano ; 13(11): 12577-12590, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31657911

RESUMO

In vivo monitoring of cargo protein delivery is critical for understanding the pharmacological efficacies and mechanisms during cancer therapy, but it still remains a formidable challenge because of the difficulty in observing nonfluorescent proteins at high resolution and sensitivity. Here we report an outer-frame-degradable nanovehicle featuring near-infrared (NIR) dual luminescence for real-time tracking of protein delivery in vivo. Upconversion nanoparticles (UCNPs) and fluorophore-doped degradable macroporous silica (DS) with spectral overlap were coupled to form a core-shell nanostructure as a therapeutic protein nanocarrier, which was eventually enveloped with a hyaluronic acid (HA) shell to prevent protein leakage and for recognizing tumor sites. The DS layer served as both a container to accommodate the therapeutic proteins and a filter to attenuate upconversion luminescence (UCL) of the inner UCNPs. After the nanovehicles selectively accumulated at tumor sites and entered cancer cells, intracellular hyaluronidase (HAase) digested the outermost HA protective shell and initiated the outer frame degradation-induced protein release and UCL restoration of UCNPs in the intracellular environment. Significantly, the biodistribution of the nanovehicles can be traced at the 710 nm NIR fluorescence channel of DS, whereas the protein release can be monitored at the 660 nm NIR fluorescence channel of UCNPs. Real-time tracking of protein delivery and release was achieved in vitro and in vivo by NIR fluorescence imaging. Moreover, in vitro and in vivo studies manifest that the protein cytochrome c-loaded nanovehicles exhibited excellent cancer therapeutic efficacy. This nanoplatform assembled by the outer-frame-degradable nanovehicles featuring NIR dual luminescence not only advances our understanding of where, when, and how therapeutic proteins take effect in vivo but also provides a universal route for visualizing the translocation of other bioactive macromolecules in cancer treatment and intervention.

18.
Horm Behav ; 117: 104589, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31593697

RESUMO

Studies have shown that the evolutionarily conserved neuropeptide oxytocin (OT) promotes various prosocial behaviors, yet there are few studies of the effect of OT on social judgments, especially on judgments when the actor's intention and the final outcome are incongruent. In a double-blind, placebo-controlled experiment, participants were asked to play the role of the recipient in a dictator game and to make social judgments about the dictator after intranasal OT administration. To isolate the outcome and the intention of the dictator's allocation, we developed a novel social judgment task in which recipients were told that 50% of the dictators' proposals would be reversed. The results showed that the effect of OT on social judgment was modulated by intention: OT increased goodness ratings only towards dictators with hyperfair intention. Our findings support the affiliative-motivation theory which states that OT enhances the affiliative motivation and recognition of positive-valence social stimuli.

19.
Cell Death Dis ; 10(9): 668, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511497

RESUMO

Clinical therapy of doxorubicin (DOX) is limited due to its cardiotoxicity. miR-146a was proved as a protective factor in many cardiovascular diseases, but its role in chronic DOX-induced cardiotoxicity is unclear. The objective of this study was to demonstrate the role of miR-146a in low-dose long-term DOX-induced cardiotoxicity. Experiments have shown that DOX intervention caused a dose-dependent and time-dependent cardiotoxicity involving the increased of apoptosis and dysregulation of autophagy. The cardiotoxicity was inhibited by overexpressed miR-146a and was more severe when miR-146a was downgraded. Further research proved that miR-146a targeted TATA-binding protein (TBP) associated factor 9b (TAF9b), a coactivator and stabilizer of P53, indirectly destroyed the stability of P53, thereby inhibiting apoptosis and improving autophagy in cardiomyocytes. Besides, miR-146a knockout mice were used for in vivo validation. In the DOX-induced model, miR-146a deficiency made it worse whether in cardiac function, cardiomyocyte apoptosis or basal level of autophagy, than wild-type. In conclusion, miR-146a partially reversed the DOX-induced cardiotoxicity by targeting TAF9b/P53 pathway to attenuate apoptosis and adjust autophagy levels.

20.
Anatol J Cardiol ; 22(3): 117-124, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31475951

RESUMO

OBJECTIVE: A higher visit-to-visit variability in low-density lipoprotein cholesterol (LDL-C) is associated with an increased frequency of cardiovascular events. We investigated the association between the visit-to-visit LDL-C variability and all-cause mortality, myocardial infarction (MI), and coronary revascularization in a population with non-obstructive coronary artery disease (CAD). METHODS: From this retrospective cohort of individuals who underwent coronary angiography from 2006 to 2010, a total of 2.012 consecutive patients with non-obstructive CAD, who underwent three or more LDL-C determinations during the first 2 years, were identified and followed up for 5 years. The variability in the visit-to-visit LDL-C was measured by standard deviation (SD) and coefficient of variation (CV). The risk of all-cause mortality and composite endpoints, MI, and coronary revascularization were evaluated by a multivariable Cox regression analysis. RESULTS: During a 5-year follow-up, a total of 99 (4.92%) mortality cases and 154 (7.65%) cases of composite endpoints were observed. The percentage of subjects who experienced mortality or composite endpoints was higher in those with a higher LDL-C-SD or LDL-C-CV level. The association between the LDL-C variability and clinical endpoints was regardless of possible confounding factors. CONCLUSION: Among the patients with non-obstructive CAD, a higher visit-to-visit LDL-C variability is associated with increasing all-cause mortality or composite endpoints during the long-term follow-up.

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